Nothing Special   »   [go: up one dir, main page]

WO2005035500A2 - Therapeutic agents useful for treating pain - Google Patents

Therapeutic agents useful for treating pain Download PDF

Info

Publication number
WO2005035500A2
WO2005035500A2 PCT/US2004/033621 US2004033621W WO2005035500A2 WO 2005035500 A2 WO2005035500 A2 WO 2005035500A2 US 2004033621 W US2004033621 W US 2004033621W WO 2005035500 A2 WO2005035500 A2 WO 2005035500A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
animal
another embodiment
effective amount
diaminoalkylene
Prior art date
Application number
PCT/US2004/033621
Other languages
French (fr)
Other versions
WO2005035500A3 (en
Inventor
Parviz Gharagozloo
Original Assignee
Euro-Celtique S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Euro-Celtique S.A. filed Critical Euro-Celtique S.A.
Publication of WO2005035500A2 publication Critical patent/WO2005035500A2/en
Publication of WO2005035500A3 publication Critical patent/WO2005035500A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632—Organic additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to Diaminoalkylene Compounds, compositions comprising an effective amount of a Diaminoalkylene Compound and methods for treating or preventing a condition such as pain, comprising administering to an animal in need thereof an effective amount of a Diaminoalkylene Compound.
  • Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self- limited, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K.M. Foley, Pain, in Cecil Textbook of Medicine 100-107 (J.C. Bennett and F. Plum eds., 20th ed. 1996)). Chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or central nervous system and is maintained by aberrant somatosensory processing.
  • Nociceptive pain has been traditionally managed by administering non- opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id.
  • non- opioid analgesics such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen
  • opioid analgesics including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone.
  • neuropathic pain which can be difficult to treat, has also been treated with anti-epileptics (e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenytoin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline).
  • UI is uncontrollable urination, generally caused by bladder-detrusor- muscle instability. UI affects people of all ages and levels of physical health, both in health care settings and in the community at large.
  • Physiologic bladder contraction results in large part from acetylcholine-induced stimulation of post-ganglionic muscarinic-receptor sites on bladder smooth muscle.
  • Treatments for UI include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity.
  • anticholinergics such as propantheline bromide and glycopyrrolate
  • smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic
  • U.S. Patent No. 5,556,838 to Mayer et al. discloses the use of nontoxic NMDA-blocking agents co-administered with an addictive substance to prevent the development of tolerance or withdrawal symptoms.
  • U.S. Patent No. 5,574,052 to Rose et al. discloses co-administration of an addictive substance with an antagonist to partially block the pharmacological effects of the addictive substance.
  • U.S. Patent No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat addiction.
  • U.S. Patents No. 5,039,680 and 5,198,459 to Imperato et al. disclose using a serotonin antagonist to treat chemical addiction.
  • U.S. Patent No. 5,556,837 to Nestler et. al. discloses infusing BDNF or NT-4 growth factors to inhibit or reverse neurological adaptive changes that correlate with behavioral changes in an addicted individual.
  • U.S. Patent No. 6,204,284 to Beer et al. discloses racemic ( ⁇ )-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in the prevention or relief of a withdrawal syndrome resulting from addiction to drugs and for the treatment of chemical dependencies. Glutamate release is enhanced during opioid withdrawal (K. Jhamandas et al, J. Neurosience 16:2758-2766 (1996)). Recent evidence suggests a role for Group I mGluRs in opioid tolerance and dependence.
  • Drugs commonly used for the treatment of Parkinson's disease include carbidopa/levodopa, pergolide, bromocriptine, selegiline, amantadine, and trihexyphenidyl hydrochloride.
  • drugs useful for the treatment of Parkinson's disease and having an improved therapeutic profile.
  • benzodiazepines are the most commonly used anti-anxiety agents for generalized anxiety disorder. Benzodiazepines, however, carry the risk of producing impairment of cognition and skilled motor functions, particularly in the elderly, which can result in confusion, delerium, and falls with fractures. Sedatives are also commonly prescribed for treating anxiety.
  • the azapirones, such as buspirone are also used to treat moderate anxiety.
  • azapirones are less useful for treating severe anxiety accompanied with panic attacks.
  • Antagonists of the mGluR5 receptor have also been shown to exert anxiolytic and anti-depressant activity in in vivo animal models (E. Tatarczynska et al, Br. J. Pharmacol. 132(7): 1423-1430 (2001) and PJ.M. Will et al, Trends in Pharmacological Sciences 22(7):331-37 (2001)).
  • Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, ⁇ -vinyl GABA, acetazolamide, and felbamate.
  • Anti-seizure drugs can have side effects such as drowsiness; hyperactivity; hallucinations; inability to concentrate; central and peripheral nervous system toxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingival hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, Stevens- Johnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as red-cell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia (see, e.g., The Merck Manual of Medical Information 345-350 (R.
  • Symptoms of strokes vary depending on what part of the brain is affected. Symptoms include loss of or abnormal sensations in an arm or leg or one side of the body, weakness or paralysis of an arm or leg or one side of the body, partial loss of vison or hearing, double vision, dizziness, slurred speech, difficulty in thinking of the appropriate word or saying it, inability to recognize parts of the body, unusual movements, loss of bladder control, imbalance, and falling, and fainting. The symptoms can be permanent and can be associated with coma or stupor.
  • drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids.
  • anticoagulants such as heparin
  • drugs that break up clots such as streptokinase or tissue plasminogen activator
  • drugs that reduce swelling such as mannitol or corticosteroids.
  • Pruritus is an unpleasant sensation that prompts scratching.
  • pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazol, and tricyclic antidepressants.
  • mGluR5 have been shown to exert analgesic activity in in vivo animal models (K. Walker et al, Europharmacology 40:1-9 (2000) and A. Dogrul et al. , Neuroscience Let, 292(2 : 115-118 (2000) .
  • Selective antagonists of the mGluR5 receptor have also been shown to exert anti-Parkinson activity in vivo (K. J. Ossowska et al, Neuropharmacology 41(4):413-20 (2001) and P.J.M. Will et al, Trends in Pharmacological Sciences 22(7):331-37 (2001)).
  • Selective antagonists of the mGluR5 receptor have also been shown to exert anti-dependence activity in vivo (C.
  • R 2 is -H, -(C 1 -C 10 )alkyl, -(C 2 -C 1 o)alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C 1 )bicycloalkyl, -(C 8 -C 1 )tricycloalkyl, -(C 5 -C 10 )cycloalkenyl, -(C 8 -C ⁇ 4 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -2-pyridyl, 4-pyridyl, -furyl, -thiophenyl, -pyrrolyl, -o
  • each R 5 is independently -H, -(C 1 -C 6 )alkyl, -(C -C 6 )alkenyl, -(C 2 - C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5- membered)heterocycle, -C(halo) 3 , or -CH(halo) 2 ;
  • X is C(H) or N;
  • Y is N, C(H), C(NO 2 ), C(CN), C(halo), C(CH 3 ), or C(CF 3 );
  • a "Diaminoalkylene Compound” is useful for treating or preventing pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, a seizure, a stroke, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression (each being a "Condition”) in an animal.
  • the invention also relates to compositions comprising an effective amount of a Diaminoalkylene Compound and a pharmaceutically acceptable carrier or excipient. The compositions are useful for treating or preventing a Condition in an animal.
  • the invention further relates to methods for treating a Condition, comprising administering to an animal in need thereof an effective amount of a Diaminoalkylene Compound.
  • the invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Diaminoalkylene Compound.
  • the invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Diaminoalkylene Compound.
  • the invention still further relates to methods for inhibiting mGluRl function in a cell, comprising contacting a cell capable of expressing mGluRl with an effective amount of a Diaminoalkylene Compound.
  • the invention still further relates to a method for preparing a composition, comprising the step of admixing a Diaminoalkylene Compound and a pharmaceutically acceptable carrier or excipient.
  • the invention still further relates to a kit comprising a container containing an effective amount of a Diaminoalkylene Compound.
  • the kit may further comprise printed instructions for using the Diaminoalkylene Compound to treat any of the aforementioned Conditions.
  • R 1? Ri', R 2 , R , X, Y, Z and n are defined above.
  • n is 1.
  • n is 2.
  • R and Ri' are each -H.
  • R and Ri' are each -(Ci-C 4 )alkyl.
  • R and Ri' are each -methyl,
  • R and Ri' are each -ethyl,
  • R and Ri' are each -n-propyl.
  • R and Ri' are each -wo-propyl.
  • R and Ri' are each -n-butyl.
  • R and Ri' are each -w ⁇ -butyl. In another embodiment, R and Ri' are each -tert-butyl. In another embodiment, R is -H and R is -(C ⁇ -C 4 )alkyl. In another embodiment, R is -H and Ri' is -methyl, In another embodiment, R is -H and Ri' is -ethyl, In another embodiment, R is -H and Ri' is -n-propyl. In another embodiment t, R is -H and Ri' is -zs ⁇ -propyl. In another embodimentt., R is -H and Ri' is -n-butyl.
  • R is -H and Ri' is -iso-butyl. In another embodiment .,, R is -H and Ri' is -tert-butyl. In another embodiment .., R is -(C ⁇ -C 4 )alkyl and Ri' is -H. In another embodiment .,, R is -(C ⁇ -C 4 )alkyl and Ri' is -methyl. In another embodiment ., R is -(Ci-C 4 )alkyl and Ri' is -ethyl. In another embodiment ., R is -( -C ⁇ alkyl and Ri' is -n-propyl.
  • R is -(Ci-C 4 )alkyl and Ri' is -wo-propyl. In another embodiment ., R is -(Ci-C 4 )alkyl and Ri' is -n-butyl. In another embodiment .. R is -(Ci-C 4 )alkyl and Ri' is -iso-butyl. In another embodiment ., R is -(Ci-C 4 )alkyl and Ri' is -tert-butyl. In another embodiment , R is -methyl and Ri' is -H. In another embodiment ., R is -methyl and Ri' is -(Ci-C )alkyl.
  • R is -methyl and Ri' is -ethyl. In another embodiment .,, R is -methyl and Ri' is -n-propyl. In another embodiment .,, R is -methyl and Ri' is -wo-propyl. In another embodiment ., R is -methyl and Ri' is -n-butyl. In another embodiment ., R is -methyl and Ri' is -iso-butyl. In another embodiment .,, R is -methyl and Ri' is -tert-butyl. In another embodiment *, R. is -ethyl and Ri' is -H.
  • R is -ethyl and Ri' is -(Ci-C 4 )alkyl. In another embodiment *, is -ethyl and Ri' is -methyl. In another embodiment ., R is -ethyl and Ri' is -n-propyl. In another embodiment .,, R is -ethyl and Ri' is -/s ⁇ -propyl. In another embodimentt, R is -ethyl and Ri' is -n-butyl. In another embodiment ., R is -ethyl and Ri' is -iso-butyl. In another embodiment .., R is -ethyl and Ri' is -tert-butyl.
  • R -n-propyl and Ri' is -H. In another embodiment .., R -n-propyl and Ri' is -( -C ⁇ alkyl. In another embodiment , . ⁇ n-propyl and Ri' is -methyl. In another embodiment ., R -n-propyl and Ri' is -ethyl. In another embodiment ., R •n-propyl and Ri' is -w ⁇ -propyl. In another embodiment, R is -n-propyl and Ri' is -n-butyl. In another embodiment, R is -n-propyl and Ri' is -wo-butyl.
  • R is -n-propyl and Ri' is -tert-butyl. In another embodiment, R is -z ' so-propyl and Ri is -H. In another embodiment, R is - iso-propyl and R ⁇ is -(Ci-C 4 )alkyl. In another embodiment, R is -z o-propyl and Ri is -methyl, In another embodiment, R is -zso-propyl and Ri is -ethyl, In another embodiment, R is -zso-propyl and Ri is -n-propyl. In another embodiment, R is -zso-propyl and Ri is -n-butyl.
  • R is -zso-propyl and Ri is -iso-butyl. In another embodiment, R is -zso-propyl and Ri is -tert-butyl. In another embodiment, R is -n-butyl and Ri' is -H. In another embodiment, R is -n-butyl and Ri' is -(C ⁇ -C 4 )alkyl. In another embodiment, R is -n-butyl and Ri' is -methyl. In another embodiment, R is -n-butyl and Ri' is -ethyl, In another embodiment, R is -n-butyl and Ri' is -n-propyl.
  • R is -n-butyl and Ri' is -zso-propyl. In another embodiment, R is -n-butyl and Ri' is -z ' s ⁇ -butyl. In another embodiment, R is -n-butyl and Ri' is -tert-butyl. In another embodiment, R -z ' so-butyl and Ri' is -H. In another embodiment, R -zso-butyl and Ri' is -(d-C ⁇ alkyl. In another embodiment, R -z ' so-butyl and Ri' is -methyl, In another embodiment, R -zso-butyl and Ri' is -ethyl.
  • R -z'so-butyl and Ri' is -n-propyl. In another embodiment, R -zso-butyl and Ri' is -zso-propyl. In another embodiment, R -iso-butyl and Ri' is -n-butyl. In another embodiment, R -iso-butyl and Ri' is -tert-butyl. In another embodiment, R -tert-butyl and Ri' is -H. In another embodiment, R -tert-butyl and Ri' is -(C ⁇ -C 4 )alkyl. In another embodiment, R -tert-butyl and Ri' is -methyl.
  • R -tert-butyl and Ri' is -ethyl. In another embodiment, R -tert-butyl and Ri' is -n-propyl. In another embodiment, R -tert-butyl and Ri' is -zso-propyl. In another embodiment, R ⁇ is -tert-butyl and Ri' is -n-butyl. In another embodiment, Rl is -tert-butyl and Rl' is -z ' so-butyl.
  • n is 1 or 2; and R is -H, -(C ⁇ -Cio)alkyl, -(C 2 -C 10 )alkenyl, -(Ca- c alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C ⁇ )tricycloalkyl, -(C 5 -Cio)cycloalkenyl, -(C 8 -C 14 )bicycloalkenyl, -(C 8 - C 14 )tricycloalkenyl, -(3- to 7-membered)heteroaryl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, -phenyl, -naphthyl -(C 1 )aryl, or -
  • n is 3; and R 2 is -H, -(Ci-C ⁇ o)alkyl, -(C -Cio)alkenyl, -(C 2 -Cio)alkynyl, -(C3-Cio)cycloalkyl, -(C 8 -C 1 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 -Cio)cycloalkenyl, -(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -2-pyridyl, 4-pyridyl, -furyl, -thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl
  • R 2 is -phenyl, -naphthyl -(C 14 )aryl, -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 4 groups.
  • R 2 is unsubstituted phenyl.
  • R 2 is -phenyl which is substituted with an R group ortho to the point of attachment to the triple bond.
  • R 2 is -phenyl which is substituted with -(Ci-C 6 )alkyl, -C(halo) 3 , -halo or -NO 2 ortho to the point of attachment to the triple bond.
  • R is -phenyl which is substituted with an R group meta to the point of attachment to the triple bond.
  • R 2 is -phenyl which is substituted with -(Ci-C 6 )alkyl, -C(halo) 3 , -halo or -NO 2 meta to the point of attachment to the triple bond.
  • R 2 is -phenyl which is substituted with an R 4 group para to the point of attachment to the triple bond.
  • R 2 is -phenyl which is substituted with
  • n is 1 or 2; and R 2 is a -(5- to 10- membered)heteroaryl, which is unsubstituted or substituted with one or more R 4 groups.
  • R 2 is a -2-pyridyl or -4-pyridyl, each of which is unsubstituted or substituted with one or more R 4 groups.
  • R 2 is -2-pyridyl, which is unsubstituted or substituted with one or more R 4 groups.
  • R 2 is -2-pyridyl, which is substituted with an R group at the 6-positon of the pyridyl ring.
  • R 2 is -2-pyridyl, which is substituted with
  • R 2 is -4-pyridyl, which is unsubstituted or substituted with one or more R 4 groups.
  • R 2 is -4-pyridyl, which is substituted with -(Ci-C 6 )alkyl, -C(halo) 3 , -halo or -NO 2 at the 2- ⁇ osition of the pyridyl ring.
  • R 2 is -4-pyridyl, which is substituted with -(Ci-C 6 )alkyl, -C(halo) 3 , -halo or -NO 2 at the 2 and 6 positions of the pyridyl ring.
  • n is 1 or 2; and R is substituted or unsubstituted -3-pyridyl.
  • each R 3 is -H.
  • each R 3 is -(Ci-C 6 )alkyl.
  • the R 3 group attached to ring atom 4 is -(Ci-C 6 )alkyl and the R 3 group attached to ring atom 5 is -H.
  • the R 3 group attached to ring atom 4 is -H and the R 3 group attached to ring atom 5 is -(Ci-C 6 )alkyl.
  • X is C(H).
  • X is N.
  • Z is C(H). In another embodiment, Z is N.
  • X is C(H) and Z is C(H).
  • X is C(H) and Z is N.
  • X is N and Z is C(H). In another embodiment, X is N and Z is N.
  • Y is N, C(H) or C(NO 2 ).
  • Y is N.
  • Y is C(H).
  • Y is C(NO 2 ).
  • X is C(H)
  • Y is C(H)
  • Z is C(H).
  • X is C(H)
  • Y is C(NO 2 )
  • Z is C(H).
  • X is C(H)
  • Y is C(halo)
  • Z is C(H).
  • X is C(H)
  • Y is C(CH3)
  • Z is C(H).
  • X is C(H), Y is C(CF3) and Z is C(H).
  • X is C(H), Y is C(H) and Z is N.
  • X is C(H)
  • Y is C(NO 2 )
  • Z is N.
  • X is C(H)
  • Y is C(halo)
  • Z is N.
  • X is C(H)
  • Y is C(CH3)
  • Z is N.
  • X is C(H), Y is C(CF3) and Z is N. In another embodiment, X is C(H), Y is N and Z is N.
  • Diaminoalkylene Compounds are listed below in Tables 1-7.
  • the designations (a)-(z) and (aa)-(ae) in connection with each of the Compounds 101-340 have the following meaning: (a) the compound's phenyl ring that is attached to the triple bond has a -CH 3 at the 4' position; (b) the compound's phenyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 4' position; (c) the compound's phenyl ring that is attached to the triple bond has a -CF 3 at the 4' position; (d) the compound's phenyl ring that is attached to the triple bond has a -F at the 4' position; (e) the compound's phenyl ring that is attached to the triple bond has a -CI at the 4' position; (f) the compound's phenyl ring that is attached to the triple bond has a -NO 2 at the 4' position; (g) the compound's phenyl ring that is attached
  • the compound's phenyl ring that is attached to the triple bond has a -OC(O)CH 3 at the 4' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CH 3 at the 3' position; (1) the compound's phenyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 3' position; (m) the compound's phenyl ring that is attached to the triple bond has a -CF 3 at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -F at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CI at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -NO 2 at the 3 ' position;
  • the compound's phenyl ring that is attached to the triple bond has a -OC(O)CH 3 at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CH 3 at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CF 3 at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a -F at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a
  • the compound's phenyl ring that is attached to the triple bond has a -NO 2 at the 2' position; (aa) the compound's phenyl ring that is attached to the triple bond has a -C(O)CH 3 at the 2' position; (ab) the compound's phenyl ring that is attached to the triple bond has a -C(CH 3 ) 3 at the 2' position; (aa) the compound's phenyl ring that is attached to the triple bond has a -CH(CH 3 ) 2 at the 2' position; (ad) the compound's phenyl ring that is attached to the triple bond has a
  • the designations (a)-(u) in connection with each of the Compounds 341- 580 have the following meaning: (a) the compound's pyridyl ring that is attached to the triple bond has a -CH 3 at the 5' position; (b) the compound's pyridyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 5' position; (c) the compound's pyridyl ring that is attached to the triple bond has a -CF 3 at the 5' position; (d) the compound's pyridyl ring that is attached to the triple bond has a -F at the 5' position; (e) the compound's pyridyl ring that is attached to the triple bond has a -CI at the 5' position; (f) the compound's pyridyl ring that is attached to the triple bond has a -NO 2 at the 5' position; (g) the compound's pyridy
  • the compound's pyridyl ring that is attached to the friple bond has a -CH 3 at the 6' position; (1) the compound's pyridyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 6' position; (m) the compound's pyridyl ring that is attached to the triple bond has a -CF 3 at the 6' position; (n) the compound's pyridyl ring that is attached to the triple bond has a -F at the 6' position; (o) the compound's pyridyl ring that is attached to the triple bond has a
  • the compound's pyridyl ring that is attached to the triple bond has a -NO at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH 3 at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -C(CH 3 ) 3 at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -CH(CH 3 ) 2 at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a
  • the designations (a)-(u) in connection with each of the Compounds 581- 740 have the following meaning: (a) the compound's pyridyl ring that is attached to the triple bond has a -CH 3 at the 2' position; (b) the compound's pyridyl ring that is attached to the triple bond has a " CH 2 (CH 3 ) at the 2' position; (c) the compound's pyridyl ring that is attached to the triple bond has a -CF 3 at the 2' position; (d) the compound's pyridyl ring that is attached to the triple bond has a
  • the compound's pyridyl ring that is attached to the triple bond has a -CI at the 2' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -NO 2 at the 2' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH 3 at the 2' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -C(CH 3 ) 3 at the 2' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -C(CH 3 ) 3 at the 2' position;
  • the compound's pyridyl ring that is attached to the triple bond has a
  • the compound's pyridyl ring that is attached to the triple bond has a -OC(O)CH 3 at the 2' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -CH 3 at the 6' position; (1) the compound's pyridyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 6' position; (m) the compound's pyridyl ring that is attached to the triple bond has a -CF 3 at the 6' position; (n) the compound's pyridyl ring that is attached to the triple bond has a
  • the compound's pyridyl ring that is attached to the triple bond has a -CI at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -NO 2 at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH 3 at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -C(CH 3 ) 3 at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -CH(CH 3 ) 2 at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -CH(CH 3 ) 2 at the 6' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -CH(CH 3 ) 2 at
  • the designations (a)-(u) in connection with each of the Compounds 741- 980 have the following meaning: (a) the compound's pyridyl ring that is attached to the triple bond has a -CH 3 at the 2' position; (b) the compound's pyridyl ring that is attached to the triple bond has a " CH 2 (CH 3 ) at the 2' position; (c) the compound's pyridyl ring that is attached to the triple bond has a -CF 3 at the 2' position; (d) the compound's pyridyl ring that is attached to the triple bond has a -F at the 2' position; (e) the compound's pyridyl ring that is attached to the triple bond has a -CI at the 2' position; (f) the compound's pyridyl ring that is attached to the triple bond has a -NO 2 at the 2' position; (g) the compound's pyridyl
  • the compound's pyridyl ring that is attached to the triple bond has a -CH 3 at the 3' position; (1) the compound's pyridyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 3' position; (m) the compound's pyridyl ring that is attached to the triple bond has a -CF 3 at the 3' position; (n) the compound's pyridyl ring that is attached to the triple bond has a -F at the 3' position; (o) the compound's pyridyl ring that is attached to the triple bond has a
  • the compound's pyridyl ring that is attached to the triple bond has a -NO 2 at the 3' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH 3 at the 3' position;
  • the compound's pyridyl ring that is attached to the friple bond has a -C(CH 3 ) 3 at the 3' position;
  • the compound's pyridyl ring that is attached to the triple bond has a -CH(CH 3 ) 2 at the 3' position;
  • the compound's pyridyl ring that is attached to the triple bond has a
  • the designations (a)-(d) in connection with each of the Compounds 981- 1340 have the following meaning: (a) the compound's 6-membered aromatic ring has a -CH 3 at the 5 position; (b) the compound's 6-membered aromatic ring has a -CH 2 (CH ) at the 5 position; (c) the compound's 6-membered aromatic ring has a -CF 3 at the 5 position; and (d) the compound's 6-membered aromatic ring has no other substitution.
  • the designations (a)-(d) in connection with each of the Compounds 1341- 1700 have the following meaning: (a) the compound's 6-membered aromatic ring has a -CH 3 at the 5 position; (b) the compound's 6-membered aromatic ring has a -CH 2 (CH 3 ) at the 5 position; (c) the compound's 6-membered aromatic ring has a -CF 3 at the 5 position; and (d) the compound's 6-membered aromatic ring has no other substitution.
  • the compound's phenyl ring that is attached to the triple bond has a -CF 3 at the 4' position; (d) the compound's phenyl ring that is attached to the triple bond has a -F at the 4' position; (e) the compound's phenyl ring that is attached to the triple bond has a -CI at the 4' position; (f) the compound's phenyl ring that is attached to the friple bond has a -NO 2 at the 4' position; (g) the compound's phenyl ring that is attached to the triple bond has a
  • the compound's phenyl ring that is attached to the friple bond has a -C(CH 3 ) 3 at the 4' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CH(CH 3 ) 2 at the 4' position;
  • the compound's phenyl ring that is attached to the triple bond has a -OC(O)CH 3 at the 4' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CH 3 at the 3' position; (1) the compound's phenyl ring that is attached to the triple bond has a
  • the compound's phenyl ring that is attached to the triple bond has a -CF 3 at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -F at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CI at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -NO 2 at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -C(O)CH 3 at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a
  • the compound's phenyl ring that is attached to the triple bond has a -CH(CH 3 ) 2 at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -OC(O)CH 3 at the 3' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CH 3 at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 2' position;
  • the compound' s phenyl ring that is attached to the triple bond has a -CH 2 (CH 3 ) at the 2' position;
  • the compound' s phenyl ring that is attached to the triple bond has a
  • the compound's phenyl ring that is attached to the triple bond has a -F at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a -CI at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a -NO 2 at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a -C(O)CH 3 at the 2' position;
  • the compound's phenyl ring that is attached to the triple bond has a
  • Representative saturated straight chain -(Ci-C ⁇ o)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl.
  • Representative saturated branched -(Ci-Cio)alkyls include -zso-propyl, -sec-butyl, -z ' so-butyl, -tert-butyl, -z ' so-pentyl, -2-methylbutyl, -3-methylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2-methylhexyl, -3-methylhexyl, -4-methylhexyl, -5-methylhexyl, -2,3-dimethylbutyl, -2,3-dimethylpentyl, -2,4-dimethylpentyl,
  • -(Ci-C 6 )alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative saturated straight chain -(Ci-C 6 )alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl.
  • Representative saturated branched -(Ci-C6)alkyls include -zso-propyl, -sec-butyl,
  • -(Ci-C 4 )alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms.
  • Representative saturated straight chain -(Ci-C 4 )alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.
  • Representative saturated branched -(Ci-C 4 )alkyls include -zso-propyl, -sec-butyl, -z ' so-butyl, and -tert-butyl.
  • "-(Ci-C 3 )alkyl” means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 3 carbon atoms.
  • Representative saturated straight chain -(C 1 -C 3 )alkyls include -methyl, -ethyl, and -n-propyl.
  • a representative saturated branched -(Ci-C 3 )alkyl is -zso-propyl.
  • -(C 2 -C 1 o)alkenyl means a straight chain or branched non-cyclic hydrocarbon containing from 2 to 10 carbon atoms and including at least one carbon- carbon double bond.
  • Representative straight chain and branched (C 2 -C 1 o)alkyls include 1-pentenyl, -2-pentenyl, -3-methyl-l-butenyl, -2-methyl-2-butenyl, - 2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl,
  • -(C 2 -C 6 )alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond.
  • Representative straight chain and branched -(C 2 -C 6 )alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -z ' so-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-l-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl and the like.
  • -(C -C 1 o)alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at lease one carbon-carbon triple bond.
  • Representative straight chain and branched -(C 2 -Cio)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl- 1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-non
  • -(C 2 -C 6 )alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at lease one carbon-carbon triple bond.
  • Representative straight chain and branched (C 2 -C 6 )alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl- 1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl and the like.
  • -(C -Cio)cycloalkyl means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms.
  • Representative (C 3 -Cio)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, and -cyclodecyl.
  • “-(C 3 -C 8 )cycloalkyl” means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms.
  • Representative (C 3 -C 8 )cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl.
  • "-(Cs-C ⁇ 4 )bicycloalkyl” means a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.
  • Representative -(C 8 -C 14 )bicycloalkyls include -indanyl, -1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphfhyl, -perhydronaphthyl and the like.
  • "-(C 8 -C ⁇ 4 )fricycloalkyl” means a tri-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.
  • Representative -(C 8 -C ⁇ )fricycloalkyls include -pyrenyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl, -aceanthreneyl, -1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl and the like.
  • "-(C 5 -C ⁇ o)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms.
  • Representative (C 5 -C ⁇ o)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.
  • -(C 5 -C 8 )cycloalkeny ⁇ means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms.
  • Representative (C 5 -C 8 )cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.
  • -(C 8 -C ⁇ 4 )bicycloalkenyl means a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms.
  • Representative -(C 8 -C ⁇ )bicycloalkenyls include -indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl and the like.
  • -(C 8 -C 14 )tricycloalkenyl means a tri-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms.
  • Representative -(C 8 -C ⁇ 4 )tricycloalkenyls include -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl, - ⁇ s-indacenyl, -s-indacenyl and the like.
  • "-(5- to 10-membered)heteroary ⁇ " means an aromatic heterocycle ring of
  • 5 to 10 members including both mono- and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • one of the -(5- to 10- membered)heteroaryl's rings contains at least one carbon atom.
  • both of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.
  • Representative -(5- to 10-membered)heteroaryls include -pyridyl, -furyl, -benzofuranyl, -thiophenyl, -benzothiophenyl, -quinolinyl, -pyrrolyl, -indolyl, -oxazolyl, -benzoxazolyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -benzothiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -pyridazinyl, -pyrimidyl, -pyrazinyl, -triazinyl, -cinnolinyl, -phthalazinyl, -quinazolinyl and the like.
  • R 2 is not -3 -pyridyl.
  • "-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo” means a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated, non-aromatic or aromatic.
  • a 3- or a 4-membered heterocycle can contain up to 3 heteroatoms, a 5-membered heterocycle can contain up to 4 heteroatoms, a 6-membered heterocycle can contain up to 6 heteroatoms, and a 7-membered heterocycle can contain up to 7 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(3- to 7-membered)heterocycle can be attached via any heteroatom or carbon atom.
  • Representative -(3- to 7-membered)heterocycles include -pyridyl, -furyl, -thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -pyridazinyl, -pyrimidinyl, -pyrazinyl, -triazinyl, -morpholinyl, -pyrrolidinonyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -hydantoinyl, -valerolactamyl, -oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydropyranyl, -tefrahydropyrindinyl, -tetrahydropyrimi
  • “-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo” means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated, non-aromatic or aromatic.
  • a 3- or 4-membered heterocycle can contain up to 3 heteroatoms and a 5-membered heterocycle can contain up to 4 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(3- to 5-membered)heterocycle can be attached via any heteroatom or carbon atom.
  • Representative -(3- to 5- membered)heterocycles include -furyl, -thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -triazinyl, -pyrrolidinonyl, -pyrrolidinyl, -hydantoinyl, -oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydrothiophenyl and the like.
  • -(7- to 10-membered)bicycloheterocycle or "-(7- to 10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic, heterocyclic ring having a saturated, unsaturated, non-aromatic or aromatic group.
  • a -(7- to 10-membered)bicycloheterocycle contains from 1 to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the (7- to 10-membered)bicycloheterocycle can be attached via any heteroatom or carbon atom.
  • Representative -(7- to 10-membered)bicyclo- heterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl, -purinyl, -4H- quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, -carbazolyl, - ⁇ - carbolinyl, 1,3-benzodioxole and the like.
  • -(C 1 )aryl means a 14-membered aromatic carbocyclic moiety such as anthryl and phenanthryl.
  • -CH 2 (halo) means a methyl group where one of the hydrogens of the methyl group has been replaced with a halogen.
  • Representative -CH 2 (halo) groups include -CH 2 F, -CH 2 C1, -CH 2 Br and -CH 2 I.
  • -CH(halo) 2 means a methyl group where two of the hydrogens of the methyl group have been replaced with a halogen.
  • Representative -CH(halo) 2 groups include -CHF 2 , -CHC1 2 , -CHBr 2 , CHBrCl, CHC1I and -CHI 2 .
  • "-C(halo) 3 " means a methyl group where each of the hydrogens of the methyl group has been replaced with a halogen.
  • Representative -C(halo) 3 groups include -CF 3 , -CF 2 C1, -CC1 3 , -CBr 3 , -CFBr 2 and -CI 3 .
  • "-Halogen” or "-halo" means -F, -CI, -Br or -I.
  • the term "animal,” includes, but is not limited to, a cow, monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human.
  • pharmaceutically acceptable salt is any pharmaceutically acceptable salt that can be prepared from a Diaminoalkylene Compound, including a salt formed from an acid and a basic functional group, such as a nitrogen, of one of the Diaminoalkylene Compounds.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,r-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • sulfate citrate, acetate, oxalate, chloride
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl-N-ethylamine; diethylamine; friethylamine; mono-, bis- or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine
  • the phrase "effective amount" when used in connection with a Diaminoalkylene Compound means an amount effective for: (a) treating or preventing a Condition; or (b) inhibiting n GluR5 or mGluRl function in a cell.
  • the phrase "effective amount” when used in connection with another therapeutic agent means an amount for providing the therapeutic effect of the other therapeutic agent.
  • the term “adjunctive” is used interchangeably with “in combination” or “combination.” Such terms are also used where a Diaminoalkylene Compound and at last one therapeutic agent affects the treatment or prevention of a Condition, the same Condition in one embodiment, different Conditions in another embodiment.
  • the term "adjunctively administered” refers to the administration of at last one therapeutic agent in addition to a Diaminoalkylene Compound, either simultaneously with the same or at intervals prior to, during, or following administration of the a Diaminoalkylene Compound to achieve the desired therapeutic or prophylactic effect.
  • a first group is "substituted with one or more" second groups, each of one or more of the first group's hydrogen atoms is replaced with a second group.
  • a first group is substituted with up to three second groups.
  • a first group is substituted with one or two second groups.
  • a first group is substituted with only one second group.
  • UI means urinary incontinence.
  • ALS means amyotrophic lateral sclerosis.
  • treatment of includes the amelioration or cessation of a Condition or a symptom thereof.
  • treating includes inhibiting, for example, decreasing the overall frequency of episodes of a Condition or a symptom thereof.
  • prevention of includes the avoidance of the onset of a Condition or a symptom thereof.
  • Diaminoalkylene Compounds can be made using conventional organic syntheses and/or by the following illustrative methods.
  • Diaminoalkylene Compounds can be obtained by reacting a diaminoalkyl compound of formula A with a (C ⁇ -C ⁇ o)alkyliodide, a (C 2 -Cio)alkenyliodide, or (C 2 - C ⁇ o)alkynyliodide in which the iodide atom is bonded to an sp carbon atom, at low temperature, e.g., about 0°C to about -78°C, in the presence of a strong base, e.g., lithium di-z ' so-propylamide (“LDA”), optionally in hexamethylphosphoramide (“HMPA”) as shown below in Scheme 1, e.g. for a (Ci-Cio)alkyl iod
  • LDA lithium di-z ' so-propy
  • -(Ci-Cio)alkyl, R 3 , X, Y, Z and n are defined above for the Diaminoalkylene Compounds of formula (I); and Ri and Rt' are each independently a -(Ci-C 4 )alkyl or a protecting group such that when the Rt and/or Ri' protecting group is removed, that R t and/or Ri' is -H.
  • a representative procedure for reacting a terminal acetylene with an alkyl iodide is provided in G.M. Strunz et al, Can. J. Chem., 419-432 (1996). Methods for using a protecting group are described below.
  • Diaminoalkylene Compounds where R 2 contains an sp or sp carbon atom bonded to the acetylene group can be obtained by reacting a Diaminoalkylene Compound of formula A with an aryl iodide, or with a (C 2 -Cio)alkenyliodide or (C 2 - C ⁇ o)alkynyl iodide in which the iodide atom is bonded to an sp or sp carbon atom, at room temperature, e.g., about 25°C, in ethyl acetate (“EtOAc”) in the presence of Pd(PH 3 P) 2 (OAc) 2 , Cul and friethylamine (“TEA”), as shown below in Scheme 2, e.g., for an aryl iodide reagent.
  • Suitable protecting groups for hydroxyl group include, but are not limited to, methyl ether, methoxymethyl ether, methoxythiomethyl ether, 2-methoxyethoxymethyl ether, bis(2-chloroethoxy)ethyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether, methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, 1 -ethoxyethyl ether, 1 -methyl- 1 -methoxyethyl ether, 2-(phenylselenyl ether), tert-butyl ether, allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethyl ether, o-napthyldiphenylmethyl ether, -meth
  • Suitable protecting groups for an amino group include, but are not limited to, l,l-dimethyl-2,2,2-trichloroethyl carbamate, l-methyl-l-(4-biphenylyl)ethyl carbamate, 2-trimethylsilylethyl carbamate, 9-fluorenylmethyl carbamate, and tert-butyl carbamate (T.W. Greene et al, Protective Groups in Organic Synthesis, 494-653 (3d ed. 1999)).
  • Diaminoalkylene Compounds can also be obtained by reacting a compound of formula B with a propynoic acid of formula C at, e.g., from about 0°C to about 100°C for about 1 to about 10 hours, in dimethylformamide (“DMF”) followed by additon of 1-hydroxybenzotriazole (“HOBt”) and di- zso-propyl carbodiimide (“DIC”) as shown below in Scheme 3:
  • DMF dimethylformamide
  • HOBt 1-hydroxybenzotriazole
  • DIC di- zso-propyl carbodiimide
  • Diaminoalkylene Compounds of formula (I) A representative procedure for reacting a terminal amine with a carboxylic acid is provided in F.M. Martin et al, Bioorg. Med. Chem. Lett. 9:2887-2892 (1999). Diaminoalkylene Compounds can also be obtained by reacting a compound of formula D with an aryl halide or heteroaryl halide of formula E at a temperature of about 45°C in DMF, in the presence of di-z ' so-propylethylamine ("DIEA"). This process is shown below in Scheme 4:
  • R ls Ri', R , X, Y, Z, halo and n are defined above for the Diaminoalkylene Compounds of formula (I).
  • a representative procedure for reacting an aryl halide or heteroaryl halide with a diamine comprising a Boc-protected amine group is provided in M.J. Genin et al, J. Med. Chem. 42:4140-4149 (1999).
  • the compounds of formula B can be prepared by reacting an aryl halide or heteroaryl halide of formula E with a protected diamine of formula F, where the protecting group is, e.g., t-butoxycarbonyl (Boc) in of a catalyst, e.g., palladium, and base, e.g., sodium ter-butoxide, in 1,4-dioxane at a temperature of about 25°C to about 45°Cs (see Hartwig et al, Org. Let. 2:1423-24 (2002) for a representative procudure using a palladium catalyst).
  • a representative procedure for deprotecting a Boc-protected amine is provided in J.P. Sanchez et al, J.
  • the compound of formula D can be prepared by reacting the acid chloride of propynoic acid of formula G with a Boc-protected diamine of formula H in the presence of one equivalent of a tertiary amine such as DIEA at about 0°C to about 45°C in dichloromethane (“DCM”) to form the compound of formula J.
  • DCM dichloromethane
  • the protecting group is then removed from the compound of formula J by reaction with TFA as shown below in Scheme 6:
  • R l5 Ri', R 2 and n are defined above for the Diaminoalkylene Compounds of formula (I).
  • the Boc-deprotection procedure is similar to that described above in Scheme 5.
  • Compounds of formulae F and H which contain a Boc-protecting group, can be prepared by methods known in the art (see Protective Groups in Organic Synthesis 518-520 (Greene and Wuts eds., 3rd ed. 1999)).
  • Compounds of formulae C, E and G are commercially available or can be prepared by methods known in the art.
  • Compounds of formula A can be prepared by a procedure that is analogous to that described above in Scheme 3, except that the compound of formula C is propiolic acid (i.e., Ri is -H).
  • Diaminoalkylene Compounds can have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
  • a Diaminoalkylene Compound can be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses Diaminoalkylene Compound and their uses as described herein in the form of their optical isomers, diasteriomers and mixtures thereof, including a racemic mixture.
  • Optical isomers of the Diaminoalkylene Compounds can be obtained by known techniques such as chiral chromatography or formation of diasteromeric salts from an optically active acid or base.
  • one or more hydrogen, carbon or other atoms of a Diaminoalkylene Compound can be replaced by an isotope of the hydrogen, carbon or other atoms.
  • Such compounds which are encompassed by the present invention, are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
  • Therapeutic Uses of the Diaminoalkylene Compounds are administered to an animal in need of treatment or prevention of a Condition.
  • an effective amount of a Diaminoalkylene Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluR5.
  • Examples of conditions that are treatable or preventable by inhibiting mGluR5 include, but are not limited to, pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, and psychosis.
  • an effective amount of a Diaminoalkylene Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluRl.
  • Examples of conditions that are treatable or preventable by inhibiting mGluRl include, but are not limited to, pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, a seizure, stroke, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia and depression.
  • the Diaminoalkylene Compounds can be used to treat or prevent acute or chronic pain.
  • Examples of pain treatable or preventable using the Diaminoalkylene Compounds include, but are not limited to, cancer pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache pain, muscle pain, arthritic pain, neuropathic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis.
  • the Diaminoalkylene Compounds can also be used for treating or preventing pain associated with inflammation or with an inflammatory disease in an animal. Such pain can arise where there is an inflammation of the body tissue, which can be a local inflammatory response and/or a systemic inflammation.
  • the Diaminoalkylene Compounds can be used to treat or prevent pain associated with inflammatory diseases including, but not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grapp et al, J. Mol. Cell Cardiol 3 297-303 (1999)) including, but not limited to, transplantation of the heart, lung, liver, or kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and n
  • the Diaminoalkylene Compounds can also be used for treating or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • inflammatory disease can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
  • the Diaminoalkylene Compounds can be used to treat or prevent UI.
  • Diaminoalkylene Compounds examples include, but are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence.
  • the Diaminoalkylene Compounds can be used to treat or prevent an addictive disorder, including but not limited to, an eating disorder, an impulse-control disorder, an alcohol-related disorder, a nicotine-related disorder, an amphetamine-related disorder, a cannabis-related disorder, a cocaine-related disorder, an hallucinogen-related disorder, an inhalant-related disorders, and an opioid-related disorder, all of which are further sub-classified as listed below.
  • Eating disorders include, but are not limited to, Bulimia Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and Eating Disorder not otherwise specified (NOS).
  • Impulse control disorders include, but are not limited to, Intermittent
  • Alcohol-related disorders include, but are not limited to, Alcohol- Induced Psychotic Disorder with delusions, Alcohol Abuse, Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium,
  • Alcohol-Induced Persisting Dementia Alcohol- Induced Persisting Amnestic Disorder, Alcohol Dependence, Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder not otherwise specified (NOS).
  • Nicotine-related disorders include, but are not limited to, Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related Disorder not otherwise specified (NOS).
  • Amphetamine-related disorders include, but are not limited to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Amphetamine-Induced Psychotic Disorder with delusions, Amphetamine-Induced Psychotic Disorders with hallucinations, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced sexual Dysfunction, Amphetamine-Induced Sleep Disorder, and Amphetamine Related Disorder not otherwise specified (NOS).
  • Cannabis-related disorders include, but are not limited to, Cannabis Dependence, Cannabis Abuse, Cannabis Intoxication, Cannabis Intoxication Delirium, Cannabis-Induced Psychotic Disorder with delusions, Cannabis-Induced Psychotic
  • Cocaine-related disorders include, but are not limited to, Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal, Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder with delusions,
  • Hallucinogen-related disorders include, but are not limited to,
  • Hallucinogen-Induced Sleep Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication, Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder with delusions, Hallucinogen- Induced Psychotic Disorders with hallucinations, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-Induced Sleep
  • Inhalant-related disorders include, but are not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-Induced Psychotic Disorder with delusions, Inhalant-Induced Psychotic
  • Opioid-related disorders include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Intoxication, Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder with delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid-Induced Anxiety Disorder, Opioid Withdrawal, and Opioid Related Disorder not otherwise specified (NOS).
  • the Diaminoalkylene Compounds can be used to treat or prevent Parkinson's disease and parkinsonism and the symptoms associated with Parkinson's disease and parkinsonism, including but not limited to, bradykinesia, muscular rigidity, resting tremor, and impairment of postural balance.
  • the Diaminoalkylene Compounds can be used to treat or prevent generalized anxiety or severe anxiety and the symptoms associated with anxiety, including but not limited to, restlessness, tension, tachycardia, dyspnea, depression including chronic "neurotic" depression, panic disorder, agoraphobia and other specific phobias, eating disorders, and personality disorders.
  • the Diaminoalkylene Compounds can be used to treat or prevent epilepsy, including but not limited to, partial epilepsy, generalized epilepsy, and the symptoms associated with epilepsy, including but not limited to, simple partial seizures, jacksonian seizures, complex partial (psychomotor) seizures, convulsive seizures (grand mal or tonic-clonic seizures), petit mal (absence) seizures, and status epilepticus.
  • the Diaminoalkylene Compounds can be used to treat or prevent a seizure, including but not limited to, infantile spasms, febrile seizures, and epileptic seizures.
  • the Diaminoalkylene Compounds can be used to treat or prevent strokes, including but not limited to, ischemic strokes and hemorrhagic strokes.
  • the Diaminoalkylene Compounds can be used to treat or prevent a pruritic condition, including but not limited to, pruritus caused by dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et ani, malaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, and fiberglass dermatitis.
  • a pruritic condition including but not limited to, pruritus caused by dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et ani, malaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial eruption
  • the Diaminoalkylene Compounds can be used to treat or prevent psychosis, including but not limited to, schizophrenia, including paranoid schizophrenia, hebephrenic or disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, negative or deficit subtype schizophrenia, and non-deficit schizophrenia; a delusional disorder, including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, ashamed subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delusional disorder; and brief psychosis.
  • schizophrenia including paranoid schizophrenia, hebephrenic or disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, negative or deficit subtype schizophrenia, and non-deficit schizophrenia
  • a delusional disorder including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, ashamed subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delusional disorder
  • the Diaminoalkylene Compounds can be used to treat or prevent a cognitive disorder, including but not limited to, delirium and dementia such as multi- infarct dementia, dementia pugilistica, dementia caused by AIDS, and dementia caused by Alzheimer's disease.
  • the Diaminoalkylene Compounds can be used to treat or prevent a memory deficiency, including but not limited to, dissociative amnesia and dissociative fugue.
  • the Diaminoalkylene Compounds can be used to treat or prevent restricted brain function, including but not limited to, that caused by surgery or an organ transplant, restricted blood supply to the brain, a spinal cord injury, a head injury, hypoxia, cardiac arrest, and hypoglycemia.
  • the Diaminoalkylene Compounds can be used to treat or prevent Huntington's chorea.
  • the Diaminoalkylene Compounds can be used to treat or prevent ALS.
  • the Diaminoalkylene Compounds can be used to treat or prevent retinopathy, including but not limited to, arteriosclerotic retinopathy, diabetic arteriosclerotic retinopathy, hypertensive retinopathy, non-proliferative retinopathy, and proliferative retinopathy.
  • the Diaminoalkylene Compounds can be used to treat or prevent a muscle spasm.
  • the Diaminoalkylene Compounds can be used to treat or prevent a migraine.
  • the Diaminoalkylene Compounds can be used to treat (for example, inhibit) or prevent vomiting, including but not limited to, nausea vomiting, dry vomiting (retching), and regurgitation.
  • the Diaminoalkylene Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia.
  • the Diaminoalkylene Compounds can be used to treat or prevent depression, including but not limited to, major depression and bipolar disorder. Without wishing to be bound by theory, Applicants believe that the Diaminoalkylene Compounds are antagonists for mGluR5.
  • the invention relates to methods for inhibiting mGluR5 function in a cell comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Diaminoalkylene Compound.
  • This method can be used in vitro, for example, as an assay to select cells that express mGluR5 and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, psychosis or schizophrenia.
  • the method is also useful for inhibiting mGluR5 function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell in an animal with an effective amount of a Diaminoalkylene Compound.
  • the method is useful for treating or preventing pain in an animal in need thereof. In another embodiment, the method is useful for treating or preventing an addictive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Parkinson's disease in an animal in need thereof. In another embodiment, the method is useful for treating or preventing parkinsonism in an animal in need thereof. In another embodiment, the method is useful for treating or preventing anxiety in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof.
  • the method is useful for treating or preventing schizophrenia in an animal in need thereof.
  • cells capable of expressing mGluR5 are neuronal and glial cells of the central nervous system, particularly the brain, especially in the nucleus accumbens. Methods for assaying cells that express mGluR5 are known in the art. Without wishing to be bound by theory, Applicants believe that the Diaminoalkylene Compounds are antagonists for mGluRl.
  • the invention relates to methods for inhibiting mGluRl function in a cell comprising contacting a cell capable of expressing mGluRl with an effective amount of a Diaminoalkylene Compound.
  • This method can be used in vitro, for example, as an assay to select cells that express mGluRl and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing a Condition.
  • the method is also useful for inhibiting mGluRl function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an effective amount of a Diaminoalkylene Compound.
  • the method is useful for treating or preventing pain in an animal in need thereof.
  • the method is useful for treating or preventing UI in an animal in need thereof.
  • the method is useful for treating or preventing an addictive disorder in an animal in need thereof.
  • the method is useful for treating or preventing Parkinson's disease in an animal in need thereof. In another embodiment, the method is useful for treating or preventing parkinsonism in an animal in need thereof. In another embodiment, the method is useful for treating or preventing anxiety in an animal in need thereof. In another embodiment, the method is useful for treating or preventing epilepsy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a seizure in an animal in need thereof. In another embodiment, the method is useful for treating or preventing stroke in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof.
  • the method is useful for treating or preventing a cognitive disorder in an animal in need thereof.
  • the method is useful for treating or preventing a memory deficit in an animal in need thereof.
  • the method is useful for treating or preventing restricted brain function in an animal in need thereof.
  • the method is useful for treating or preventing Huntington's chorea in an animal in need thereof.
  • the method is useful for treating or preventing ALS in an animal in need thereof.
  • the method is useful for treating or preventing dementia in an animal in need thereof.
  • the method is useful for treating or preventing retinopathy in an animal in need thereof.
  • the method is useful for treating or preventing a muscle spasm in an animal in need thereof.
  • the method is useful for treating or preventing a migraine in an animal in need thereof. In another embodiment, the method is useful for treating or preventing vomiting in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dyskinesia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing depression in an animal in need thereof.
  • Examples of cells capable of expressing mGluRl include, but are not limited to, cerebellar Purkinje neuron cells, Purkinje cell bodies (punctate), cells of spine(s) of the cerebellum; neurons and neurophil cells of olfactory-bulb glomeruli; cells of the superficial layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and spinal trigeminal nucleus cells.
  • cerebellar Purkinje neuron cells Purkinje cell bodies (punctate), cells of spine(s) of the cerebellum; neurons and neurophil cells of olfactory-bulb glomeruli; cells of the superficial layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and spinal trigeminal nucleus cells.
  • Methods for assaying cells that express mGluRl are known in the art.
  • the Diaminoalkylene Compounds are advantageously useful in veterinary and human medicine. As described above, the Diaminoalkylene Compounds are useful for treating or preventing a Condition in an animal in need thereof. When administered to an animal, the Diaminoalkylene Compounds are administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient.
  • the present compositions, which comprise a Diaminoalkylene Compound can be administered orally.
  • Diaminoalkylene Compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.) and can be administered together with another therapeutically active agent. Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the Diaminoalkylene Compound.
  • Methods of administration include, but are not limited to, inttadermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of the Diaminoalkylene Compounds into the bloodstream. In specific embodiments, it can be desirable to administer the Diaminoalkylene Compounds locally.
  • Diaminoalkylene Compounds into the central nervous system or gastrointestinal tract by any suitable route including intraventricular, intrathecal, and epidural injection, and enema.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g. , by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the Diaminoalkylene Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • the Diaminoalkylene Compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al, Liposomes in the Therapy of Infectious Disease and Cancer 317- 327 and 353-365 (1989).
  • the Diaminoalkylene Compounds can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled- or sustained-release systems discussed in the review by Langer, Science 249: 1527-1533 (1990) can be used.
  • a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al. , Surgery 88:507 (1980); and Saudek et al. , N. Engl. J. Med. 321:574 (1989)).
  • polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol Chem.
  • a controlled- or sustained- release system can be placed in proximity of a target of the Diaminoalkylene Compounds, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
  • the present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal.
  • Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipient can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to an animal. Water, and in one embodiment physiological saline, is a particularly useful excipient when the Diaminoalkylene Compound is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule (see e.g., U.S. Patent No. 5,698,155).
  • suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.
  • compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.
  • the excipients are of pharmaceutical grade.
  • the Diaminoalkylene Compounds can be formulated for intravenous administration.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer.
  • the compositions can also include a solubilizing agent.
  • Compositions for intravenous administration can optionally include a local anesthetic such as lidocaine to lessen pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the Diaminoalkylene Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • the Diaminoalkylene Compounds can be administered by controlled- release or sustained-release means or by delivery devices that are known to those skilled in the art.
  • Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference.
  • Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.
  • Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained-release counterparts.
  • a controlled- or sustained- release composition comprises a minimal amount of a Diaminoalkylene Compound to cure or control the condition in a minimum amount of time.
  • Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled- or sustained- release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Diaminoalkylene Compound, and can thus reduce the occurrence of adverse side effects.
  • Controlled- or sustained-release compositions can initially release an amount of a Diaminoalkylene Compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Diaminoalkylene Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the Diaminoalkylene Compound can be released from the dosage form at a rate that will replace the amount of Diaminoalkylene Compound being metabolized and excreted from the body.
  • Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
  • the amount of the Diaminoalkylene Compound that is effective for the treatment or prevention of a condition can be determined using standard clinical techniques.
  • in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed will also depend on the route of administration, and the seriousness of the Condition and can be decided according to the judgment of a practitioner and/or each animal's circumstances. Suitable effective dosage amounts, however, range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although they are typically about 100 mg/kg of body weight or less.
  • the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Diaminoalkylene Compound, in another embodiment, from about 0.02 mg/kg of body weight to about 50 mg/kg of body weight, and in another embodiment, from about 0.025 mg/kg of body weight to about 20 mg/kg of body weight.
  • an effective dosage amount is administred about every 24 h until the Condition is abated.
  • an effective dosage amount is admininstered about every 12 h until the Condition is abated.
  • an effective dosage amount is admininstered about every 8 h until the Condition is abated.
  • an effective dosage amount is admininstered about every 6 h until the Condition is abated. In another embodiment, an effective dosage amount is admininstered about every 4 h until the Condition is abated.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one Diaminoalkylene Compound is administered, the effective dosage amounts correspond to the total amount administered.
  • the amount effective for inhibiting the mGluR5 or mGluRl receptor function in a cell will typically range from about 0.01 ⁇ g/L to about 5 mg/L, in one embodiment, from about 0.01 ⁇ g/L to about 2.5 mg/L, in another embodiment, from about 0.01 ⁇ g/L to about 0.5 mg/L, and in another embodiment, from about 0.01 ⁇ g/L to about 0.25 mg/L of a solution or suspension of a pharmaceutically acceptable carrier or excipient.
  • the volume of solution or suspension comprising the Diaminoalkylene Compound is from about 0.01 ⁇ L to about 1 mL. In another embodiment, the volume of solution or suspension is about 200 ⁇ L.
  • the amount effective for inhibiting the receptor function in a cell will typically range from about 0.01 mg kg of body weight to about 2500 mg/kg of body weight, although it typically ranges from about 100 mg/kg of body weight or less.
  • the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Diaminoalkylene Compound, in another emodiment, from about 0.02 mg/kg of body wieght to about 50 mg/kg of body weight, and in another embodiment, from about 0.025 mg/kg of body weight to about 20 mg/kg of body weight.
  • an effective dosage amount is administered about every 24 h.
  • an effective dosage amount is administered about every 12 h.
  • an effective dosage amount is administered about every 8 h.
  • an effective dosage amount is administered about every 6 h.
  • an effective dosage amount is administered about every 4 h.
  • the Diaminoalkylene Compounds can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • Animal model systems can be used to demonstrate safety and efficacy.
  • the present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering another therapeutic agent to the animal being administered a Diaminoalkylene Compound.
  • the other therapeutic agent is administered in an effective amount.
  • the present methods for inhibiting mGluR5 function in a cell capable of expressing mGluR5 can further comprise contacting the cell with an effective amount of another therapeutic agent.
  • the present methods for inhibiting mGluRl function in a cell capable of expressing mGluRl can further comprise contacting the cell with an effective amount of another therapeutic agent
  • Effective amounts of the other therapeutic agents are known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range, h one embodiment of the invention, where another therapeutic agent is administered to an animal, the effective amount of the Diaminoalkylene Compound is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the Diaminoalkylene Compounds and the other therapeutic agent act synergistically to treat or prevent a Condition.
  • the other therapeutic agent can be, but is not limited to, an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraine agent, a Cox-II inhibitor, an antiemetic, a ⁇ -adrenergic blocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing one or more Conditions, and mixtures thereof.
  • Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmo han, lofent
  • the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • non-steroidal anti-inflammatory agents such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, frioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic
  • non-steroidal anti-inflammatory agents such aspirin,
  • non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, non-steroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; ⁇ r ⁇ -aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenyl
  • useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof.
  • the other therapeutic agent can alternatively be an agent useful for reducing any potential side effects of a Diaminoalkylene Compounds.
  • the other therapeutic agent can be an antiemetic agent.
  • useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, ttimethobenzamide, odansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetton, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulphide, tetrahydrocannabinol, thiethy
  • ⁇ -adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprol
  • useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,
  • Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline
  • Ca2+-channel blockers examples include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.
  • useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil,
  • anti-cancer drugs include, but are not limited to, 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
  • useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, and dicyclomine.
  • useful therapeutic agents for treating or preventing an addictive disorder include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotonin antagonists.
  • Examples of useful therapeutic agents for treating or preventing Parkinson's disease and parkinsonism include, but are not limited to, carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole, entacapone, tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.
  • useful therapeutic agents for treating or preventing anxiety include, but are not limited to, benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non- benzodiazepine agents, such as buspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital, me
  • useful therapeutic agents for treating or preventing epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, ⁇ -vinyl GAB A, acetazolamide, and felbamate.
  • useful therapeutic agents for treating or preventing a seizure include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, ⁇ -vinyl GABA, acetazolamide, and felbamate.
  • useful therapeutic agents for treating or preventing stroke include, but are not limited to, anticoagulants such as heparin, agents that break up clots such as streptokinase or tissue plasminogen activator, agents that reduce swelling such as mannitol or corticosteroids, and acetylsalicylic acid.
  • useful therapeutic agents for treating or preventing a pruritic condition include, but are not limited to, naltrexone; nalmefene; danazol; tricyclics such as amitriptyline, imipramine, and doxepin; antidepressants such as those given below; menthol; camphor; phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.
  • useful therapeutic agents for treating or preventing psychosis include, but are not limited to, phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloroprothixene and thiothixene hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide; and ziprasidone.
  • phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride
  • thioxanthenes such as chloroprothixene and thiothixene hydrochloride
  • clozapine
  • Examples of useful therapeutic agents for treating or preventing Huntington's chorea include, but are not limited to, haloperidol and pimozide.
  • Examples of useful therapeutic agents for treating or preventing ALS include, but are not limited to, baclofen, neurotrophic factors, riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.
  • Examples of useful therapeutic agents for treating or preventing cognitive disorders include, but are not limited to, agents for treating or preventing dementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazine and haloperidol; and antidepressant drugs such as those provided herein.
  • useful therapeutic agents for treating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta-blockers such as propranolol, verapamil, and divalproex.
  • useful therapeutic agents for treating, inhibiting or preventing vomiting include, but are not limited to, 5-HT 3 receptor antagonists such as odansetron, dolasetron, granisetron, and ttopisetron; dopamine receptor antagonists such as prochlorperazine, thiethylperazine, chlorpromazine, metoclopramide, and domperidone; glucocorticoids such as dexamefhasone; and benzodiazepines such as lorazepam and alprazolam.
  • useful therapeutic agents for treating or preventing dyskinesia include, but are not limited to, reserpine and tetrabenazine.
  • useful therapeutic agents for treating or preventing depression include, but are not limited to, tricyclic antidepressants such as amittyptyline, amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine, maprotiline, nefazadone, nortriptyline, protriptyline, trazodone, trimipramine, and venlafaxine; selective serotonin reuptake inhibitors such as fluoxetine, fluvoxamine, paroxetine, citalopram, (S)-citalopram, and setraline; monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine, and tranylcypromine; and psychostimulants such as dextroamphetamine and methylphenidate.
  • a Diaminoalkylene Compound and the other therapeutic agent can act additively or, in one embodiment, synergistically.
  • Diaminoalkylene Compound is administered concurrently with another therapeutic agent, for example, a composition comprising an effective amount of a Diaminoalkylene Compound and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a Diaminoalkylene Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered. In another embodiment, an effective amount of a Diaminoalkylene Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent. In this embodiment, the Diaminoalkylene Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the
  • a composition of the invention is prepared by a method comprising admixing a Diaminoalkylene Compound and pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods known for admixing a compound (or salt) and a pharmaceutically acceptable carrier or excipient. In one embodiment the composition is prepared such that the Diaminoalkylene Compound is present in the composition in an effective amount.
  • kits that can simplify the administration of a Diaminoalkylene Compound to an animal.
  • a typical kit of the invention comprises a unit dosage form of a Diaminoalkylene Compound.
  • the unit dosage form is a container, which can be sterile, containing an effective amount of a Diaminoalkylene Compound and a pharmaceutically acceptable carrier or excipient.
  • the kit can further comprise a label or printed instructions instructing the use of the Diaminoalkylene Compound to treat a Condition.
  • the kit can also further comprise a unit dosage form of another therapeutic agent, for example, a second container containing an effective amount of the other therapeutic agent and a pharmaceutically acceptable carrier or excipient.
  • the kit comprises a container containing an effective amount of a Diaminoalkylene Compound, an effective amount of another therapeutic agent, and a pharmaceutically acceptable carrier or excipient.
  • other therapeutic agents include, but are not limited to, those listed above.
  • Kits of the invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device include but are not limited to a syringe, a drip bag, a patch, an inhaler, and an enema bag.
  • Examples 1-13 relate to the synthesis of non-limiting illustrative Diaminoalkylene Compounds.
  • Example 1 Synthesis of Compound 186(ae)
  • Compound 186(ae) was confirmed by 1H NMR and mass spectrometry.
  • Compound 15 was obtained by a method that is analogous to that used to obtain Compound 4 as described in Example 1 (Step A), except that 2- chloronitrobenzene (Compound 13) (Aldrich Chemical Co.) was used in place of 2- choro-3-nitropyridine (Compound 1).
  • Compound 17 was obtained by a metliod analogous to that used to obtain Compound 186(ae) described in Example 1 (Step B) except that propiolic acid (Compound 16) (Aldrich Chemical Co.) was used in place of phenylpropiolic acid (Compound 5), and Compound 15 was used in place of Compound 4.
  • propiolic acid Compound 16
  • phenylpropiolic acid Compound 5
  • Compound 425(u) was then prepared by reacting Compound 17 (100 mg, 0.4 mmol) and 2-iodopyridine (18) (80 mg, 0.4 mmol) at 25°C EtOAc in the presence of Pd(Ph3P) 2 OAc 2 (15 mg, 0.03 mml), Cul (15 mg, 0.08 mmol), and Et 3 N (0.1 ml). Yield: 100 mg, 83%.
  • the structure of Compound 425(u) was confirmed by 1H NMR and mass spectrometry.
  • Compound 425(u): 1H NMR (400 MHz, CDC1 3 ): 8.60 (ddd, IH, J 0.8,
  • Example 5 Synthesis of Compound 665(u) Compound 665(u) was obtained by a method that is analogous to that used to obtain Compound 425(u) as described in Example 4 except that 3-iodopyridine was used in place of 2-iodopyridine (Step C). The structure of Compound 665(u) was confirmed by 1H NMR and mass spectrometry.
  • Example 7 Synthesis of Compound 185(ae)
  • Compound 185(ae) was obtained by a method that is analogous to that used to obtain Compound 186(ae) as described in Example 1 except that 2-chloronitrobenzene (Aldrich Chemical Co.) was used in place of 2-chloro-3- nitropyridine (Compound 1) (Step A), and Compound 15 was used in place of Compound 4 (Step B).
  • the structure of Compound 185(ae) was confirmed by 1H NMR and mass spectrometry.
  • Example 8 Synthesis of Compound 1465(d)
  • Compound 1465(d) was obtained by a method that is analogous to that used to obtain Compound 186(ae) as described in Example 1 except that 2-chloronitrobenzene was used in place of 2-chloro-3-nitropyridine (Compound 1) (Step A), and 2-heptynoic acid (Aldrich Chemical Co.) was used in place of phenylpropiolic acid (Compound 5) and Compound 15 was used in place of Compound 4 (Step B).
  • the structure of Compound 1465(d)) was confirmed by 1H NMR and mass spectrometry.
  • Example 9 Synthesis of Compound 226(ae)
  • Compound 226(ae) was obtained by a method that is analogous to that used to obtain Compound 186(ae) as described in Example 1 except that N-Boc-N- methylethylenediamine (see Example 6)) was used in place of Compound 2 (Step A of Example 1)
  • the structure of Compound 226(ae) was confirmed by 1H NMR and mass spectrometry.
  • Compound 226(ae): 1H NMR (CDC1 3 ): 8.45 (dd, IH, J 1.7, 3.7 Hz),
  • Example 10 Synthesis of Compound 1112(a) Compound 1112(a) was obtained by a method that is analogous to that used to obtain Compound 186(ae) as described in Example 1 that except 2-bromo-4,6- dimethylpyridine (prepared according to the procedure of G.J. Bridger et al, J. Med.
  • Compound 1112(a) was confirmed by 1H NMR and mass spectrometry.
  • Example 11 Synthesis of Compound 1472(a) Compound 1472(a) was obtained by a method that is analogous to that used to obtain Compound 1112(a) as described in Example 10 except that 2-heptynoic acid (Aldrich) was used in place of 2-hexynoic acid. The structure of Compound 1472(a) was confirmed by 1H NMR and mass spectrometry. Compound 1472(a): 1H NMR (CDC1 3 ): 8.18 (br, IH), 6.34 (s, IH), 6.08
  • Example 12 Synthesis of Compound 1114(a) Compound 1114(a) was obtained by a method that is analogous to that used to obtain Compound 1112(a) as described in Example 10 except that 2-chloro- dimethylpyrimidine (Apollo Chemical, Burlington, NC) was used in place of 2-bromo-
  • Compound 1114(a) 4,6-dimethylpyridine.
  • the structure of Compound 1114(a) was confirmed by 1H NMR and mass spectrometry.
  • Example 13 Synthesis of Compound 1744(d)
  • Compound 1744(d) was obtained by a method that is analogous to that used to obtain Compound 425(u) as described in Example 4 except that 2-chloro- dimethylpyrimidine (Apollo Chemical) was used in place of Compound 13 (Step A) and l-fluoro-4-iodobenzene was used in place of Compound 18 (Step C).
  • the structure of Compound 1744(d) was confirmed by 1H NMR and mass spectrometry.
  • Compound 1744(d) 1H NMR (CDCI 3 ): 8.15 (s, IH), 7.49 (m, 2H), 7.06
  • Example 14 Binding of an Illustrative Diaminoalkylene Compound to mGIuR5 The following assay demonstrates that Compound 1465(d) (see Example
  • oligodendrocytes and microglia were removed by strongly tapping the sides of the flasks.
  • secondary astrocytes cultures were established by subplating onto 96 poly-D-lysine precoated T175 flasks (BIOCOAT) at a density of 65,000 cells/well in DMEM and 10% FCS.
  • the astrocytes were washed with serum free medium and then cultured in DMEM, without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mL epidermal growth factor ("EGF"), 1 mM sodium pyruvate, and IX penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37°C and 5% CO 2 .
  • DMEM serum free medium
  • HEPES 10 ng/mL epidermal growth factor
  • IX penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37°C and 5% CO 2 .
  • the procedure allowed the expression of the mGluR5 receptor by astrocytes, as demonstrated by S. Miller et al, J. Neuroscience 15(9):6103- 6109 (1995).
  • Assay Protocol After 3-5 days incubation with EGF, the astrocytes were washed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 700 mM NaH 2 PO 4 , 2 mM CaCl 2 , 5 mM NaHCO 3 , 8 mM HEPES, 10 mM Glucose at pH 7.4 ("Assay Buffer") and loaded with the dye FLUO-4 (commercially available from Molecular Probes Inc. of Eugene, OR) using 0.1 mL of Assay Buffer containing FLUO-4 (3 mM final).
  • the cells were then washed twice with 0.2 mL Assay Buffer and resuspended in 0.1 mL of Assay Buffer.
  • the plates containing the astrocytes were then transfened to a Fluorometric Imaging Plate reader ("FLIPR") (commercially available from Molecular Devices Corporation of Sunnyvale, CA) for the assessment of calcium mobilization flux in the presence of glutamate and in the presence or absence of antagonist.
  • FLIPR Fluorometric Imaging Plate reader
  • DMSO solutions containing various concentrations of the Diaminoalkylene Compounds diluted in Assay Buffer 0.05 mL of 4X dilutions for competition curves was added to the cell plate and fluorescence were monitored for 2 minutes.
  • Example 15 Binding of a Diaminoalkylene Compound to mGluR5 Alternatively, the following assay can be used to demonstrate that
  • Diaminoalkylene Compounds bind to and modulate the activity of mGluR5.
  • 40,000 CHO-rat mGluR5 cells/well are plated into 96 well plate (Costar 3409, Black, clear bottom, 96 well, tissue culture treated) for an about 16 hour incubation in Dulbecco's Modified Eagle's Medium (DMEM, pH 7.4) and supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500 ⁇ g/mL Geneticin.
  • DMEM Dulbecco's Modified Eagle's Medium
  • CHO-rat mGluR5 cells are washed and treated with Optimem medium and incubated for 1-4 hours prior to loading cells.
  • Cell plates are then washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 700 ⁇ M Na H 2 PO 4 , 2 mM CaCl 2 , 5 mM NaHCO 3 , 8 mM Hepes, and 10 mM glucose, pH 7.4) and then incubated with 3 ⁇ M Fluo 4 (commercially available from Molecular probes Inc. of Eugene, OR) in 0.1 mL of loading buffer. After 90 minutes of dye loading, the cells are then washed twice with 0.2 mL loading buffer and resuspended in 0.1 mL loading buffer.
  • loading buffer 127 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 700 ⁇ M Na H 2 PO 4 , 2 mM CaCl 2 , 5 mM NaHCO 3 , 8 mM Hepes, and 10 mM glucose, pH 7.4
  • 3 ⁇ M Fluo 4
  • the plates containing the CHO-rat mGluR5 cells are then transfened to a FLIPR for the assessment of calcium mobilization flux in the presence of glutamate and in the presence or absence of test compounds.
  • DMSO solutions containing various concentrations of the test compound diluted in loading buffer 0.05 mL of 4X dilutions for the competition curves
  • fluorescence is monitored for 2 minutes.
  • 0.05 mL of 4X glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 ⁇ M. Plate fluorescence is then monitored for an additional 60 seconds after agonist addition.
  • the final DMSO concentration in the assay is 1.0%.
  • Example 16 In Vivo Assays for Treatment or Prevention of Pain The following assays can be used to demonstrate that Diaminoalkylene Compounds are useful for treating or preventing pain.
  • Test Animals Each experiment uses rats weighing between 200-260 g at the start of the experiment. The rats are group-housed and have free access to food and water at all times, except prior to oral administration of a Diaminoalkylene Compound when food is removed for 16 hours before dosing.
  • a control group acts as a comparison to rats treated with a Diaminoalkylene Compound.
  • the control group is administered the carrier for the Diaminoalkylene Compound.
  • the volume of carrier administered to the control group is the same as the volume of earner and Diaminoalkylene Compound administered to the test group.
  • Acute Pain To assess the actions of the Diaminoalkylene Compounds for the treatment or prevention of acute pain the rat tail flick test can be used. Rats are gently restrained by hand and the tail exposed to a focused beam of radiant heat at a point 5 cm from the tip using a tail flick unit (Model 7360, commercially available from Ugo Basile of Italy). Tail flick latencies are defined as the interval between the onset of the thermal stimulus and the flick of the tail.
  • Tail flick latencies are measured immediately before (pre-treatment) and 1, 3, and 5 hours following administration of a Diaminoalkylene Compound. Data are expressed as tail flick latency(s) and the percentage of the maximal possible effect (% MPE), i.e., 20 seconds, is calculated as follows: [ (post administration latency) - (pre-administration latency) ]
  • % MPE X 100 (20 s pre-administration latency)
  • FCA Freund's complete adjuvant
  • Rats are then administered a single injection of 1, 3, 10 or 30 mg/kg of either a Diaminoalkylene Compound; 30 mg/kg of a control selected from Celebrex, indomethacin or naproxen; or canier. Responses to noxious mechanical stimuli are then determined 1, 3, 5 and 24 hours post administration. Percentage reversal of hyperalgesia for each animal is defined as:
  • % Reversal X 100 [ (baseline PWT) - (pre-administration PWT) ] Neuropathic Pain: To assess the actions of the Diaminoalkylene Compounds for the treatment or prevention of neuropathic pain either the Seltzer model or the Chung model can be used.
  • the Seltzer model the partial sciatic nerve ligation model of neuropathic pain is used to produce neuropathic hyperalgesia in rats (Z. Seltzer et al. , "A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury," Pain 43:205-218 (1990)). Partial ligation of the left sciatic nerve is performed under isoflurane/O 2 inhalation anaesthesia.
  • the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps semitendinosus nerve branches off of the common sciatic nerve.
  • a 7-0 silk suture is inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle and tightly ligated so that the dorsal 1/3 to l ⁇ of the nerve thickness is held within the ligature.
  • the wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue.
  • the spinal nerve ligation model of neuropathic pain is used to produce mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats.
  • Surgery is performed under isoflurane/ ⁇ 2 inhalation anaesthesia. Following induction of anaesthesia a 3 cm incision is made and the left paraspinal muscles are separated from the spinous process at the L - S 2 levels. The L 6 transverse process is carefully removed with a pair of small rongeurs to identify visually the L 4 - L 6 spinal nerves.
  • the left L 5 (or L 5 and L 6 ) spinal nerve(s) is isolated and tightly ligated with silk thread.
  • a complete hemostasis is confirmed and the wound is sutured using non- absorbable sutures, such as nylon sutures or stainless steel staples.
  • Sham-treated rats undergo an identical surgical procedure except that the spinal nerve(s) is not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they recover from the anesthesia. Animals are then returned to their home cages until behavioral testing begins. The animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3 and 5 hours after being administered a Diaminoalkylene Compound for the left rear paw of the animal.
  • the animal can also be assessed for response to noxious thermal stimuli or for tactile allodynia, as described below.
  • the Chung model for neuropathic pain is described in S.H. Kim, "An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat," Pain 50(3):355-363 (1992).
  • Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalgesia The paw pressure assay can be used to assess mechanical hyperalgesia.
  • hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in C.
  • hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available from Ugo Basile of Italy) following the technique described by K. Hargreaves et al, "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain 32(l):77-88 (1988).
  • the maximum exposure time is set at 32 seconds to avoid tissue damage and any directed paw withdrawal from the heat source is taken as the end point.
  • Three latencies are determined at each time point and averaged. Only the affected (ipsilateral) paw is tested.
  • Tactile Allodynia To assess tactile allodynia, rats are placed in clear, plexiglass compartments with a wire mesh floor and allowed to habituate for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to the plantar surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive behavioral responses.
  • Example 17 In Vivo Assays for Treatment or Prevention of Anxiety
  • the elevated plus maze test or the shock-probe burying test can be used to assess the anxiolytic activity of Diaminoalkylene Compounds in rats or mice.
  • the Elevated Plus Maze Test The elevated plus maze consists of a platform with 4 arms, two open and two closed (50 x 10 x 50 cm enclosed with an open roof). Rats (or mice) are placed in the center of the platform, at the crossroad of the 4 arms, facing one of the closed arms. Time spent in the open arms vs. the closed arms and number of open arm entries during the testing period are recorded. This test is conducted prior to drug administration and again after drag administration.
  • Test results are expressed as the mean time spent in open arms and the mean number of entries into open arms. Known anxiolytic drags increase both the time spent in open arms and number of open arm entries.
  • the elevated plus maze test is described in D. Treit, "Animal Models for the Study of Anti-anxiety Agents: A Review,” Neuroscience & Biobehavioral Reviews 9(2):203-222 (1985).
  • the Shock-Probe Burying Test For the shock-probe burying test the testing apparatus consists of a plexiglass box measuring 40 x 30 x 40 cm, evenly covered with approximately 5 cm of bedding material (odor absorbent kitty litter) with a small hole in one end through which a shock probe (6.5 cm long and 0.5 cm in diameter) is inserted.
  • the plexiglass shock probe is helically wrapped with two copper wires through which an electric current is administered. The cunent is set at 2 mA. Rats are habituated to the testing apparatus for 30 min on 4 consecutive days without the shock probe in the box. On test day, rats are placed in one corner of the test chamber following drag administration. The probe is not electrified until the rat touches it with its snout or fore paws, at which point the rat receives a brief 2 mA shock. The 15 min testing period begins once the rat receives its first shock and the probe remains electrified for the remainder of the testing period. The shock elicits burying behavior by the rat.
  • the duration of time the rat spends spraying bedding material toward or over the probe with its snout or fore paws is measured as well as the number of contact-induced shocks the rat receives from the probe.
  • Known anxiolytic drugs reduce the amount of burying behavior.
  • an index of the rat's reactivity to each shock is scored on a 4 point scale. The total time spent immobile during the 15 min testing period is used as an index of general activity. The shock-probe burying test is described in D. Treit, 1985, supra.
  • Example 18 In Vivo Assays for Treatment or Prevention of an Addictive Disorder
  • the conditioned place preference test or drag self-administration test can be used to assess the ability of Diaminoalkylene Compounds to attenuate the rewarding properties of known drugs of abuse.
  • the Conditioned Place Preference Test The apparatus for the conditioned place preference test consists of two large compartments (45 x 45 x 30 cm) made of wood with a plexiglass front wall. These two large compartments are distinctly different. Doors at the back of each large compartment lead to a smaller box (36 x 18 x 20 cm) box made of wood, painted grey, with a ceiling of wire mesh. The two large compartments differ in terms of shading (white vs.
  • Rats are given 6 conditioning sessions. Rats are divided into 4 groups: carrier pre-treatment + canier (control group), Diaminoalkylene Compound pre-treatment + carrier, carrier pre-treatment + morphine, Diaminoalkylene Compound pre-treatment + morphine.
  • carrier pre-treatment + canier control group
  • Diaminoalkylene Compound pre-treatment + carrier carrier pre-treatment + morphine
  • Diaminoalkylene Compound pre-treatment + morphine Diaminoalkylene Compound pre-treatment + morphine.
  • the rat is injected with one of the drag combinations and confined to one compartment for 30 min.
  • the rat receives a carrier + carrier treatment and is confined to the other large compartment.
  • Each rat receives three conditioning sessions consisting of 3 drag combination-compartment and 3 carrier- compartment pairings. The order of injections and the drag/compartment pairings are counterbalanced within groups.
  • the Drag Self- Administration Test is a standard commercially available operant conditioning chamber. Before drag trials begin rats are trained to press a lever for a food reward. After stable lever pressing behavior is acquired, rats are tested for acquisition of lever pressing for drug reward. Rats are implanted with chronically indwelling jugular catheters for i.v. administration of compounds and are allowed to recover for 7 days before training begins. Experimental sessions are conducted daily for 5 days in 3 hour sessions. Rats are trained to self-administer a known drug of abuse, such as morphine.
  • a known drug of abuse such as morphine.
  • Rats are then presented with two levers, an "active" lever and an “inactive” lever. Pressing of the active lever results in drag infusion on a fixed ratio 1 (FR1) schedule (i.e., one lever press gives an infusion) followed by a 20 second time out period (signaled by illumination of a light above the levers). Pressing of the inactive lever results in infusion of excipient. Training continues until the total number of morphine infusions stabilizes to within ⁇ 10% per session. Trained rats are then used to evaluate the effect of FR1 (FR1) schedule (i.e., one lever press gives an infusion) followed by a 20 second time out period (signaled by illumination of a light above the levers). Pressing of the inactive lever results in infusion of excipient. Training continues until the total number of morphine infusions stabilizes to within ⁇ 10% per session. Trained rats are then used to evaluate the effect of FR1 (FR1) schedule (i.e., one lever press gives an infusion) followed by a 20 second
  • Diaminoalkylene Compounds pre-treatment on drug self-administration On test day, rats are pre-treated with a Diaminoalkylene Compound or excipient and then are allowed to self-administer drag as usual. If the Diaminoalkylene Compound blocks or reduces the rewarding effects of morphine, rats pre-treated with the Diaminoalkylene Compound will show a lower rate of responding compared to their previous rate of responding and compared to excipient pre-treated rats. Data is analyzed as the change in number of drag infusions per testing session (number of infusions during test session - number of infusions during training session).
  • Example 19 Functional Assay for Characterizing mGluRl Antagonistic Properties
  • Functional assays for the characterization of mGluRl antagonistic properties are known in the art. For example, the following procedure can be used. A CHO-rat mGluRl cell line is generated using cDNA encoding rat mGluRl receptor (M. Masu et al, Nature 349:760-765 (1991)). The cDNA encoding rat mGluRla receptor can be obtained from, e.g., Prof. S. Nakanishi (Kyoto, Japan).
  • CHO-rat mGluRl cells/well are plated into a COSTAR 3409, black, clear bottom, 96 well, tissue culture treated plate (commercially available from Fisher Scientific of Chicago, IL) and are incubated in Dulbecco's Modified Eagle's Medium (DMEM, pH 7.4) supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500 ⁇ g/mL Geneticin for about 12 h.
  • DMEM Dulbecco's Modified Eagle's Medium
  • the CHO-rat mGluRl cells are then washed and treated with OPTIMEM medium (commercially available from Invitrogen, Carlsbad, CA) and incubated for a time period ranging from 1 to 4 hours prior to loading the cells with the dye FLUO-4.
  • OPTIMEM medium commercially available from Invitrogen, Carlsbad, CA
  • the cell plates are washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 700 ⁇ M, NaH 2 PO 4 , 2 mM CaCl 2 , 5 mMNaHCO 3 , 8 mM HEPES, and 10 mM glucose, pH 7.4) and incubated with 3 ⁇ M FLUO-4 in 0.1 mL loading buffer for 90 min.
  • loading buffer 127 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 700 ⁇ M, NaH 2 PO 4 , 2 mM CaCl 2 , 5 mMNaHCO 3 , 8 mM HEPES, and 10 mM glucose, pH 7.4
  • the cells are then washed twice with 0.2 mL loading buffer, resuspended in 0.1 mL of loading buffer, and ttansfened to a FLIPR for measurement of calcium mobilization flux in the presence of glutamate and in the presence or absence of a Diaminoalkylene Compound.
  • fluoresence is monitored for about

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Manufacturing & Machinery (AREA)
  • Ceramic Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Structural Engineering (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The invention provides a compound of formula (I) (where R1, R1’, R2, R3, X, Y, Z and n are disclosed herein) or a pharmaceutically acceptable salt thereof (s “Diaminoalkylene Compound”); pharmaceutical compositions comprising an effective amount of a Diaminoalkylene Compound; and methods for treating pain, as well as other conditions, comprising administering to an animal in need thereof an effective amount of a Diaminoalkylene Compound.

Description

THERAPEUTIC AGENTS USEFUL FOR TREATING PAIN
This application claims the benefit of U.S. provisional application no.
60/510,810, filed October 9, 2003, the disclosure of the provisional application being incorporated by reference herein in its entirety.
1. Field of the Invention The present invention relates to Diaminoalkylene Compounds, compositions comprising an effective amount of a Diaminoalkylene Compound and methods for treating or preventing a condition such as pain, comprising administering to an animal in need thereof an effective amount of a Diaminoalkylene Compound.
2. Background of the Invention Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self- limited, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K.M. Foley, Pain, in Cecil Textbook of Medicine 100-107 (J.C. Bennett and F. Plum eds., 20th ed. 1996)). Chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at both Group I metabotropic glutamate receptors, i.e., metabotropic glutamate receptor 1 ("mGluRl") and metabotropic glutamate receptor 5 ("mGluR5") (M.E. Fundytus, CNS Drugs 15:29-58 (2001)), and vanilloid receptors ("VR1") (V. Di Marzo et al., Current Opinion in Neurobiology 12:372-379 (2002)) to pain processing. Inhibiting mGluRl or mGluR5 reduces pain, as shown by in vivo treatment with antibodies selective for either mGluRl or mGluR5, where neuropathic pain in rats was attenuated (M.E. Fundytus et al, NeuroReport 9:731-735 (1998)). It has also been shown that antisense oligonucleotide knockdown of mGluRl alleviates both neuropathic and inflammatory pain (M.E. Fundytus et al, Brit. J. Pharmacol 132:354-367 (2001); M.E. Fundytus et al, Pharmacol, Biochem. & Behavior 73:401-410 (2002)). Small molecule antagonists for mGluR5-attenuated pain in in vivo animal models are disclosed in, e.g., K. Walker et al, Neuropharmacology 40:1-9 (2000) and A. Dogrul et al, Neuroscience Let. 292:115-118 (2000)). Nociceptive pain has been traditionally managed by administering non- opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the above-listed treatments, neuropathic pain, which can be difficult to treat, has also been treated with anti-epileptics (e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenytoin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline). UI is uncontrollable urination, generally caused by bladder-detrusor- muscle instability. UI affects people of all ages and levels of physical health, both in health care settings and in the community at large. Physiologic bladder contraction results in large part from acetylcholine-induced stimulation of post-ganglionic muscarinic-receptor sites on bladder smooth muscle. Treatments for UI include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity. For example, anticholinergics such as propantheline bromide and glycopyrrolate, and combinations of smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic, have been used to treat UI (see, e.g., A.J. Wein, Urol Clin. N. Am. 22:557-577 (1995); Levin et al, J. Urol. 128:396-398 (1982); Cooke et al, S. Afr. Med. J. 63:3 (1983); R.K. Mirakhur et al. , Anaesthesia 38: 1195-1204 (1983)). These drugs are not effective, however, in all patients having uninhibited bladder contractions. None of the existing commercial drug treatments for UI, however, has achieved complete success in all classes of UI patients, nor has treatment occurred without significant adverse side effects. For example, drowsiness, dry mouth, constipation, blurred vision, headaches, tachycardia, and cardiac arrhythmia, which are related to the anticholinergic activity of traditional anti-UI drugs, can occur frequently and adversely affect patient compliance. Yet despite the prevalence of unwanted anticholinergic effects in many patients, anticholinergic drugs are currently prescribed for patients having UI (see The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997). Certain pharmaceutical agents have been administered for treating addiction. U.S. Patent No. 5,556,838 to Mayer et al. discloses the use of nontoxic NMDA-blocking agents co-administered with an addictive substance to prevent the development of tolerance or withdrawal symptoms. U.S. Patent No. 5,574,052 to Rose et al. discloses co-administration of an addictive substance with an antagonist to partially block the pharmacological effects of the addictive substance. U.S. Patent No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiate agonist/antagonist to treat cocaine and opiate addiction. U.S. Patent No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat addiction. U.S. Patents No. 5,039,680 and 5,198,459 to Imperato et al. disclose using a serotonin antagonist to treat chemical addiction. U.S. Patent No. 5,556,837 to Nestler et. al. discloses infusing BDNF or NT-4 growth factors to inhibit or reverse neurological adaptive changes that correlate with behavioral changes in an addicted individual. U.S. Patent. No. 5,762,925 to Sagan discloses implanting encapsulated adrenal medullary cells into an animal's central nervous system to inhibit the development of opioid tolerance. U.S. Patent No. 6,204,284 to Beer et al. discloses racemic (±)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in the prevention or relief of a withdrawal syndrome resulting from addiction to drugs and for the treatment of chemical dependencies. Glutamate release is enhanced during opioid withdrawal (K. Jhamandas et al, J. Neurosience 16:2758-2766 (1996)). Recent evidence suggests a role for Group I mGluRs in opioid tolerance and dependence. An interaction between opioids and mGhiRs was demonstrated when it was shown that an antagonist at Group I mGluRs significantly attenuated withdrawal symptoms in opioid-dependent rats (M.E. Fundytus et al, Brit. J. Phartnacol. 113:1215-1220 (1994)). More recent results show that antisense oligonucleotide knockdown of mGluRl reduces protein kinase C activity (M.E. Fundytus et al, Brit. J. Pharmacol. 132:354-367 (2001)), which may be associated in the development of opioid tolerance and dependence (see also M.E. Fundytus, CNS Drugs 15:29-58, (2001)). Very recently, it has been shown that antisense oligonucleotide knockdown of mGluRl attenuates the development of opioid tolerance (R.N. Sharif et al, Brit. J. Pharmacol. 136:865-872 (2002)). Selective antagonists of the mGluR5 receptor have also been shown to exert anti-dependence activity in vivo (C. Chiamulera et al, Nature Neuroscience 4:873-874 (2001)). Without treatment, Parkinson's disease progresses to a rigid akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. Drugs commonly used for the treatment of Parkinson's disease include carbidopa/levodopa, pergolide, bromocriptine, selegiline, amantadine, and trihexyphenidyl hydrochloride. There remains, however, a need for drugs useful for the treatment of Parkinson's disease and having an improved therapeutic profile. Currently, benzodiazepines are the most commonly used anti-anxiety agents for generalized anxiety disorder. Benzodiazepines, however, carry the risk of producing impairment of cognition and skilled motor functions, particularly in the elderly, which can result in confusion, delerium, and falls with fractures. Sedatives are also commonly prescribed for treating anxiety. The azapirones, such as buspirone, are also used to treat moderate anxiety. The azapirones, however, are less useful for treating severe anxiety accompanied with panic attacks. Antagonists of the mGluR5 receptor have also been shown to exert anxiolytic and anti-depressant activity in in vivo animal models (E. Tatarczynska et al, Br. J. Pharmacol. 132(7): 1423-1430 (2001) and PJ.M. Will et al, Trends in Pharmacological Sciences 22(7):331-37 (2001)). Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however, can have side effects such as drowsiness; hyperactivity; hallucinations; inability to concentrate; central and peripheral nervous system toxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingival hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, Stevens- Johnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as red-cell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia (see, e.g., The Merck Manual of Medical Information 345-350 (R. Berkow ed., 1997). Symptoms of strokes vary depending on what part of the brain is affected. Symptoms include loss of or abnormal sensations in an arm or leg or one side of the body, weakness or paralysis of an arm or leg or one side of the body, partial loss of vison or hearing, double vision, dizziness, slurred speech, difficulty in thinking of the appropriate word or saying it, inability to recognize parts of the body, unusual movements, loss of bladder control, imbalance, and falling, and fainting. The symptoms can be permanent and can be associated with coma or stupor. Examples of drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids. The Merck Manual of Medical Information 352-355 (R. Berkow ed., 1997). Pruritus is an unpleasant sensation that prompts scratching. Conventionally, pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazol, and tricyclic antidepressants. Selective antagonists of the metabotropic glutamate receptor 5
("mGluR5") have been shown to exert analgesic activity in in vivo animal models (K. Walker et al, Europharmacology 40:1-9 (2000) and A. Dogrul et al. , Neuroscience Let, 292(2 : 115-118 (2000) . Selective antagonists of the mGluR5 receptor have also been shown to exert anti-Parkinson activity in vivo (K. J. Ossowska et al, Neuropharmacology 41(4):413-20 (2001) and P.J.M. Will et al, Trends in Pharmacological Sciences 22(7):331-37 (2001)). Selective antagonists of the mGluR5 receptor have also been shown to exert anti-dependence activity in vivo (C. Chiamulera et al, Nature Neuroscience 4(9):873-74 (2001)). International Publication No. WO 99/37304 by Rohne-Poulenc Rorer Pharmaceuticals, Inc. discloses oxoazaheterocyclic compounds useful for inhibiting factor Xa. International Publication No. WO 99/31064 by Klinge Pharma GMBH discloses aryl-substituted 3-pyridlylalkine carboxamides useful as cystostatic and immunosuppressive agents. There remains, however, a clear need in the art for new drugs useful for treating or preventing pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, a seizure, a stroke, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression in an animal. Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.
3. Summary of the Invention The present invention encompasses compounds of formula (I):
Figure imgf000007_0001
(I)
and pharmaceutically acceptable salts thereof, where: n is 1, 2 or 3; Ri and R^ are each independently -H or -( -C^alkyl; (a) when n is 1 or 2, then R2 is -H, -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C1o)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heteroaryl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, -phenyl, -naphthyl -(C^aryl, or -(5- to
10-membered)heteroaryl, each of which, other than -H, is unsubstituted or substituted with one or more R4; or (b) when n is 3, then R2 is -H, -(C1-C10)alkyl, -(C2-C1o)alkenyl, -(C2-C10)alkynyl, -(C3-Cιo)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C8-C1 )tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-Cι4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -2-pyridyl, 4-pyridyl, -furyl, -thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -pyridazinyl, -pyrimidinyl, -pyrazinyl, -triazinyl, -morpholinyl, -pyπolidinonyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -hydantoinyl, -valerolactamyl, -oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydropyranyl, -tefrahydropyrindinyl, -tetrahydropyrimidinyl, -tetrahydrothiophenyl, -tetrahydrothiopyranyl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, -phenyl, -naphthyl -(C1 )aryl, or -(5- to 10-membered)heteroaryl, each of which, other than -H, is unsubstituted or substituted with one or more R4 groups; each R3 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-
C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5- membered)heterocycle, -C(halo)3, -CH(halo)2, -OCH(halo)2, -CN, -OH, -halo, -N3, -NO2, -NH2, -N(H)(R4), -N(R4)2, -CH=NR4, -CH=NH, -NHOH, -NP^OH, -OR5, -COR5, -C(O)OR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5 or -S(O)2R5; each R4 is independently -( -C^alkyl, -C(halo)3, -CH(halo) ,
-OCH(halo)2, -CN, -OH, -halo, -NO2, -OR5, -COR5, -C(O)OR5, -OC(O)R5, or -OC(O)OR5; each R5 is independently -H, -(C1-C6)alkyl, -(C -C6)alkenyl, -(C2- C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5- membered)heterocycle, -C(halo)3, or -CH(halo)2; X is C(H) or N; Y is N, C(H), C(NO2), C(CN), C(halo), C(CH3), or C(CF3); Z is C(H) or N; and each halo is independently -F, -CI, -Br or -I. A compound of formula (I) or a pharmaceutically acceptable salt thereof
(a "Diaminoalkylene Compound") is useful for treating or preventing pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, a seizure, a stroke, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression (each being a "Condition") in an animal. The invention also relates to compositions comprising an effective amount of a Diaminoalkylene Compound and a pharmaceutically acceptable carrier or excipient. The compositions are useful for treating or preventing a Condition in an animal. The invention further relates to methods for treating a Condition, comprising administering to an animal in need thereof an effective amount of a Diaminoalkylene Compound. The invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Diaminoalkylene Compound. The invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Diaminoalkylene Compound. The invention still further relates to methods for inhibiting mGluRl function in a cell, comprising contacting a cell capable of expressing mGluRl with an effective amount of a Diaminoalkylene Compound. The invention still further relates to a method for preparing a composition, comprising the step of admixing a Diaminoalkylene Compound and a pharmaceutically acceptable carrier or excipient. The invention still further relates to a kit comprising a container containing an effective amount of a Diaminoalkylene Compound. The kit may further comprise printed instructions for using the Diaminoalkylene Compound to treat any of the aforementioned Conditions. The present invention may be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.
4. Detailed Description of the Invention
4.1 Compounds of Formula (I) The present invention encompasses Diaminoalkylene Compounds of formula (I):
Figure imgf000010_0001
(I)
and pharmaceutically acceptable salts thereof, where R1? Ri', R2, R , X, Y, Z and n are defined above. In one embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n LS 3. In another embodiment, R and Ri' are each -H. In another embodiment, R and Ri' are each -(Ci-C4)alkyl. In another embodiment, R and Ri' are each -methyl, In another embodiment, R and Ri' are each -ethyl, In another embodiment, R and Ri' are each -n-propyl. In another embodiment, R and Ri' are each -wo-propyl. In another embodiment, R and Ri' are each -n-butyl. In another embodiment, R and Ri' are each -wø-butyl. In another embodiment, R and Ri' are each -tert-butyl. In another embodiment, R is -H and R is -(Cι-C4)alkyl. In another embodiment, R is -H and Ri' is -methyl, In another embodiment, R is -H and Ri' is -ethyl, In another embodiment, R is -H and Ri' is -n-propyl. In another embodiment t, R is -H and Ri' is -zsø-propyl. In another embodimentt., R is -H and Ri' is -n-butyl. In another embodiment ., R is -H and Ri' is -iso-butyl. In another embodiment .,, R is -H and Ri' is -tert-butyl. In another embodiment .., R is -(Cι-C4)alkyl and Ri' is -H. In another embodiment .,, R is -(Cι-C4)alkyl and Ri' is -methyl. In another embodiment .,, R is -(Ci-C4)alkyl and Ri' is -ethyl. In another embodiment .,, R is -( -C^alkyl and Ri' is -n-propyl. In another embodiment ., R is -(Ci-C4)alkyl and Ri' is -wo-propyl. In another embodiment ., R is -(Ci-C4)alkyl and Ri' is -n-butyl. In another embodiment .. R is -(Ci-C4)alkyl and Ri' is -iso-butyl. In another embodiment ., R is -(Ci-C4)alkyl and Ri' is -tert-butyl. In another embodiment , R is -methyl and Ri' is -H. In another embodiment ., R is -methyl and Ri' is -(Ci-C )alkyl. In another embodiment ., R is -methyl and Ri' is -ethyl. In another embodiment .,, R is -methyl and Ri' is -n-propyl. In another embodiment .,, R is -methyl and Ri' is -wo-propyl. In another embodiment .,, R is -methyl and Ri' is -n-butyl. In another embodiment ., R is -methyl and Ri' is -iso-butyl. In another embodiment .,, R is -methyl and Ri' is -tert-butyl. In another embodiment *, R. is -ethyl and Ri' is -H. In another embodimentt, R is -ethyl and Ri' is -(Ci-C4)alkyl. In another embodiment *, is -ethyl and Ri' is -methyl. In another embodiment ., R is -ethyl and Ri' is -n-propyl. In another embodiment .,, R is -ethyl and Ri' is -/sσ-propyl. In another embodimentt, R is -ethyl and Ri' is -n-butyl. In another embodiment ., R is -ethyl and Ri' is -iso-butyl. In another embodiment .., R is -ethyl and Ri' is -tert-butyl. In another embodiment .,, R -n-propyl and Ri' is -H. In another embodiment .., R -n-propyl and Ri' is -( -C^alkyl. In another embodiment , . ■n-propyl and Ri' is -methyl. In another embodiment ., R -n-propyl and Ri' is -ethyl. In another embodiment ., R •n-propyl and Ri' is -wø-propyl. In another embodiment, R is -n-propyl and Ri' is -n-butyl. In another embodiment, R is -n-propyl and Ri' is -wo-butyl. In another embodiment, R is -n-propyl and Ri' is -tert-butyl. In another embodiment, R is -z'so-propyl and Ri is -H. In another embodiment, R is - iso-propyl and R\ is -(Ci-C4)alkyl. In another embodiment, R is -z o-propyl and Ri is -methyl, In another embodiment, R is -zso-propyl and Ri is -ethyl, In another embodiment, R is -zso-propyl and Ri is -n-propyl. In another embodiment, R is -zso-propyl and Ri is -n-butyl. In another embodiment, R is -zso-propyl and Ri is -iso-butyl. In another embodiment, R is -zso-propyl and Ri is -tert-butyl. In another embodiment, R is -n-butyl and Ri' is -H. In another embodiment, R is -n-butyl and Ri' is -(Cι-C4)alkyl. In another embodiment, R is -n-butyl and Ri' is -methyl. In another embodiment, R is -n-butyl and Ri' is -ethyl, In another embodiment, R is -n-butyl and Ri' is -n-propyl. In another embodiment, R is -n-butyl and Ri' is -zso-propyl. In another embodiment, R is -n-butyl and Ri' is -z'sø-butyl. In another embodiment, R is -n-butyl and Ri' is -tert-butyl. In another embodiment, R -z'so-butyl and Ri' is -H. In another embodiment, R -zso-butyl and Ri' is -(d-C^alkyl. In another embodiment, R -z'so-butyl and Ri' is -methyl, In another embodiment, R -zso-butyl and Ri' is -ethyl. In another embodiment, R -z'so-butyl and Ri' is -n-propyl. In another embodiment, R -zso-butyl and Ri' is -zso-propyl. In another embodiment, R -iso-butyl and Ri' is -n-butyl. In another embodiment, R -iso-butyl and Ri' is -tert-butyl. In another embodiment, R -tert-butyl and Ri' is -H. In another embodiment, R -tert-butyl and Ri' is -(Cι-C4)alkyl. In another embodiment, R -tert-butyl and Ri' is -methyl. In another embodiment, R -tert-butyl and Ri' is -ethyl. In another embodiment, R -tert-butyl and Ri' is -n-propyl. In another embodiment, R -tert-butyl and Ri' is -zso-propyl. In another embodiment, R\ is -tert-butyl and Ri' is -n-butyl. In another embodiment, Rl is -tert-butyl and Rl' is -z'so-butyl.
In another embodiment, n is 1 or 2; and R is -H, -(Cι-Cio)alkyl, -(C2-C10)alkenyl, -(Ca- c alkynyl, -(C3-Cι0)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cι )tricycloalkyl, -(C5-Cio)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8- C14)tricycloalkenyl, -(3- to 7-membered)heteroaryl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, -phenyl, -naphthyl -(C1 )aryl, or -(5- to 10-membered)heteroaryl, each of which, other than -H, is unsubstituted or substituted with one or more R4 groups. In another embodiment, n is 3; and R2 is -H, -(Ci-Cιo)alkyl, -(C -Cio)alkenyl, -(C2-Cio)alkynyl, -(C3-Cio)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-Cio)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -2-pyridyl, 4-pyridyl, -furyl, -thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -pyridazinyl, -pyrimidinyl, -pyrazinyl, -triazinyl, -morpholinyl, -pyrrolidinonyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -hydantoinyl, -valerolactamyl, -oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydropyranyl, -tefrahydropyrindinyl, -tetrahydropyrimidinyl, -tetrahydrothiophenyl, or -tetrahydrothiopyranyl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, -phenyl, -naphthyl, -(C1 )aryl, or -(5- to
10-membered)heteroaryl, each of which, other than -H, is unsubstituted or substituted with one or more R4 groups. In another embodiment, R2 is -phenyl, -naphthyl -(C14)aryl, -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R4 groups. In another embodiment, R2 is unsubstituted phenyl. In another embodiment, R2 is -phenyl which is substituted with an R group ortho to the point of attachment to the triple bond. In another embodiment, R2 is -phenyl which is substituted with -(Ci-C6)alkyl, -C(halo)3, -halo or -NO2 ortho to the point of attachment to the triple bond. In another embodiment, R is -phenyl which is substituted with an R group meta to the point of attachment to the triple bond. In another embodiment, R2 is -phenyl which is substituted with -(Ci-C6)alkyl, -C(halo)3, -halo or -NO2 meta to the point of attachment to the triple bond. In another embodiment, R2 is -phenyl which is substituted with an R4 group para to the point of attachment to the triple bond. In another embodiment, R2 is -phenyl which is substituted with
-(Ci-C6)alkyl, -C(halo)3, -halo or -NO2 para to the point of attachment to the triple bond. In another embodiment, n is 1 or 2; and R2 is a -(5- to 10- membered)heteroaryl, which is unsubstituted or substituted with one or more R4 groups. In another embodiment, R2 is a -2-pyridyl or -4-pyridyl, each of which is unsubstituted or substituted with one or more R4 groups. In another embodiment, R2 is -2-pyridyl, which is unsubstituted or substituted with one or more R4 groups. In another embodiment, R2 is -2-pyridyl, which is substituted with an R group at the 6-positon of the pyridyl ring. In another embodiment, R2 is -2-pyridyl, which is substituted with
-(Cι-C6)alkyl, -C(halo)3, -halo or -NO2 at the 6-positon of the pyridyl ring. In another embodiment, R2 is -4-pyridyl, which is unsubstituted or substituted with one or more R4 groups. In another embodiment, R2 is -4-pyridyl, which is substituted with -(Ci-C6)alkyl, -C(halo)3, -halo or -NO2 at the 2-ρosition of the pyridyl ring. In another embodiment, R2 is -4-pyridyl, which is substituted with -(Ci-C6)alkyl, -C(halo)3, -halo or -NO2 at the 2 and 6 positions of the pyridyl ring. In another embodiment, n is 1 or 2; and R is substituted or unsubstituted -3-pyridyl. In another embodiment each R3 is -H. In another embodiment, each R3 is -(Ci-C6)alkyl. In another embodiment, the R3 group attached to ring atom 4 is -(Ci-C6)alkyl and the R3 group attached to ring atom 5 is -H. In another embodiment, the R3 group attached to ring atom 4 is -H and the R3 group attached to ring atom 5 is -(Ci-C6)alkyl. In another embodiment, X is C(H). In another embodiment, X is N. In another embodiment, Z is C(H). In another embodiment, Z is N.
In another embodiment, X is C(H) and Z is C(H).
In another embodiment, X is C(H) and Z is N.
In another embodiment, X is N and Z is C(H). In another embodiment, X is N and Z is N.
In another embodiment, Y is N, C(H) or C(NO2).
In another embodiment, Y is N.
In another embodiment, Y is C(H).
In another embodiment, Y is C(NO2). In another embodiment, X is C(H), Y is C(H) and Z is C(H).
In another embodiment, X is C(H), Y is C(NO2) and Z is C(H).
In another embodiment, X is C(H), Y is C(halo) and Z is C(H).
In another embodiment, X is C(H), Y is C(CH3) and Z is C(H).
In another embodiment, X is C(H), Y is C(CF3) and Z is C(H). hi another embodiment, X is C(H), Y is C(H) and Z is N.
In another embodiment, X is C(H), Y is C(NO2) and Z is N.
In another embodiment, X is C(H), Y is C(halo) and Z is N.
In another embodiment, X is C(H), Y is C(CH3) and Z is N.
In another embodiment, X is C(H), Y is C(CF3) and Z is N. In another embodiment, X is C(H), Y is N and Z is N.
Illustrative Diaminoalkylene Compounds are listed below in Tables 1-7.
Table 1
Figure imgf000016_0001
(IA)
Figure imgf000016_0002
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
The designations (a)-(z) and (aa)-(ae) in connection with each of the Compounds 101-340 have the following meaning: (a) the compound's phenyl ring that is attached to the triple bond has a -CH3 at the 4' position; (b) the compound's phenyl ring that is attached to the triple bond has a -CH2(CH3) at the 4' position; (c) the compound's phenyl ring that is attached to the triple bond has a -CF3 at the 4' position; (d) the compound's phenyl ring that is attached to the triple bond has a -F at the 4' position; (e) the compound's phenyl ring that is attached to the triple bond has a -CI at the 4' position; (f) the compound's phenyl ring that is attached to the triple bond has a -NO2 at the 4' position; (g) the compound's phenyl ring that is attached to the triple bond has a -C(O)CH3 at the 4' position; (h) the compound's phenyl ring that is attached to the triple bond has a -C(CH3)3 at the 4' position; (i) the compound's phenyl ring that is attached to the triple bond has a
-CH(CH3)2 at the 4' position; (j) the compound's phenyl ring that is attached to the triple bond has a -OC(O)CH3 at the 4' position; (k) the compound's phenyl ring that is attached to the triple bond has a -CH3 at the 3' position; (1) the compound's phenyl ring that is attached to the triple bond has a -CH2(CH3) at the 3' position; (m) the compound's phenyl ring that is attached to the triple bond has a -CF3 at the 3' position; (n) the compound's phenyl ring that is attached to the triple bond has a -F at the 3' position; (o) the compound's phenyl ring that is attached to the triple bond has a -CI at the 3' position; (p) the compound's phenyl ring that is attached to the triple bond has a -NO2 at the 3 ' position; (q) the compound's phenyl ring that is attached to the triple bond has a -C(O)CH3 at the 3' position; (r) the compound's phenyl ring that is attached to the triple bond has a -C(CH3)3 at the 3' position; (s) the compound's phenyl ring that is attached to the triple bond has a
-CH(CH3)2 at the 3' position; (t) the compound's phenyl ring that is attached to the triple bond has a -OC(O)CH3 at the 3' position; (u) the compound's phenyl ring that is attached to the triple bond has a -CH3 at the 2' position; (v) the compound's phenyl ring that is attached to the triple bond has a -CH2(CH3) at the 2' position; (w) the compound's phenyl ring that is attached to the triple bond has a -CF3 at the 2' position; (x) the compound's phenyl ring that is attached to the triple bond has a -F at the 2' position; (y) the compound's phenyl ring that is attached to the triple bond has a
-CI at the 2' position; (z) the compound's phenyl ring that is attached to the triple bond has a -NO2 at the 2' position; (aa) the compound's phenyl ring that is attached to the triple bond has a -C(O)CH3 at the 2' position; (ab) the compound's phenyl ring that is attached to the triple bond has a -C(CH3)3 at the 2' position; (aa) the compound's phenyl ring that is attached to the triple bond has a -CH(CH3)2 at the 2' position; (ad) the compound's phenyl ring that is attached to the triple bond has a
-OC(O)CH3 at the 2' position; and (ae) the compound's phenyl ring that is attached to the triple bond has no other substitution.
Table 2
Figure imgf000024_0001
(IB)
Figure imgf000024_0002
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
The designations (a)-(u) in connection with each of the Compounds 341- 580 have the following meaning: (a) the compound's pyridyl ring that is attached to the triple bond has a -CH3 at the 5' position; (b) the compound's pyridyl ring that is attached to the triple bond has a -CH2(CH3) at the 5' position; (c) the compound's pyridyl ring that is attached to the triple bond has a -CF3 at the 5' position; (d) the compound's pyridyl ring that is attached to the triple bond has a -F at the 5' position; (e) the compound's pyridyl ring that is attached to the triple bond has a -CI at the 5' position; (f) the compound's pyridyl ring that is attached to the triple bond has a -NO2 at the 5' position; (g) the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH3 at the 5' position; (h) the compound's pyridyl ring that is attached to the triple bond has a -C(CH3)3 at the 5' position; (i) the compound's pyridyl ring that is attached to the triple bond has a -CH(CH3)2 at the 5' position; (j) the compound's pyridyl ring that is attached to the triple bond has a
-OC(O)CH3 at the 5' position; (k) the compound's pyridyl ring that is attached to the friple bond has a -CH3 at the 6' position; (1) the compound's pyridyl ring that is attached to the triple bond has a -CH2(CH3) at the 6' position; (m) the compound's pyridyl ring that is attached to the triple bond has a -CF3 at the 6' position; (n) the compound's pyridyl ring that is attached to the triple bond has a -F at the 6' position; (o) the compound's pyridyl ring that is attached to the triple bond has a
-CI at the 6' position; (p) the compound's pyridyl ring that is attached to the triple bond has a -NO at the 6' position; (q) the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH3 at the 6' position; (r) the compound's pyridyl ring that is attached to the triple bond has a -C(CH3)3 at the 6' position; (s) the compound's pyridyl ring that is attached to the triple bond has a -CH(CH3)2 at the 6' position; (t) the compound's pyridyl ring that is attached to the triple bond has a
-OC(O)CH3 at the 6' position; and (u) the compound's pyridyl ring that is attached to the triple bond has no other substitution. Table 3
Figure imgf000031_0001
(IC)
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
The designations (a)-(u) in connection with each of the Compounds 581- 740 have the following meaning: (a) the compound's pyridyl ring that is attached to the triple bond has a -CH3 at the 2' position; (b) the compound's pyridyl ring that is attached to the triple bond has a "CH2(CH3) at the 2' position; (c) the compound's pyridyl ring that is attached to the triple bond has a -CF3 at the 2' position; (d) the compound's pyridyl ring that is attached to the triple bond has a
-F at the 2' position; (e) the compound's pyridyl ring that is attached to the triple bond has a -CI at the 2' position; (f) the compound's pyridyl ring that is attached to the triple bond has a -NO2 at the 2' position; (g) the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH3 at the 2' position; (h) the compound's pyridyl ring that is attached to the triple bond has a -C(CH3)3 at the 2' position; (i) the compound's pyridyl ring that is attached to the triple bond has a
-CH(CH3)2 at the 2' position; (j) the compound's pyridyl ring that is attached to the triple bond has a -OC(O)CH3 at the 2' position; (k) the compound's pyridyl ring that is attached to the triple bond has a -CH3 at the 6' position; (1) the compound's pyridyl ring that is attached to the triple bond has a -CH2(CH3) at the 6' position; (m) the compound's pyridyl ring that is attached to the triple bond has a -CF3 at the 6' position; (n) the compound's pyridyl ring that is attached to the triple bond has a
-F at the 6' position; (o) the compound's pyridyl ring that is attached to the triple bond has a -CI at the 6' position; (p) the compound's pyridyl ring that is attached to the triple bond has a -NO2 at the 6' position; (q) the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH3 at the 6' position; (r) the compound's pyridyl ring that is attached to the triple bond has a -C(CH3)3 at the 6' position; (s) the compound's pyridyl ring that is attached to the triple bond has a -CH(CH3)2 at the 6' position; (t) the compound's pyridyl ring that is attached to the triple bond has a
-OC(O)CH3 at the 6' position; and (u) the compound's pyridyl ring that is attached to the triple bond has no other substitution.
Table 4
Figure imgf000037_0001
(ID)
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
The designations (a)-(u) in connection with each of the Compounds 741- 980 have the following meaning: (a) the compound's pyridyl ring that is attached to the triple bond has a -CH3 at the 2' position; (b) the compound's pyridyl ring that is attached to the triple bond has a "CH2(CH3) at the 2' position; (c) the compound's pyridyl ring that is attached to the triple bond has a -CF3 at the 2' position; (d) the compound's pyridyl ring that is attached to the triple bond has a -F at the 2' position; (e) the compound's pyridyl ring that is attached to the triple bond has a -CI at the 2' position; (f) the compound's pyridyl ring that is attached to the triple bond has a -NO2 at the 2' position; (g) the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH3 at the 2' position; (h) the compound's pyridyl ring that is attached to the triple bond has a -C(CH3)3 at the 2' position; (i) the compound's pyridyl ring that is attached to the triple bond has a -CH(CH3)2 at the 2' position; (j) the compound's pyridyl ring that is attached to the triple bond has a
-OC(O)CH3 at the 2' position; (k) the compound's pyridyl ring that is attached to the triple bond has a -CH3 at the 3' position; (1) the compound's pyridyl ring that is attached to the triple bond has a -CH2(CH3) at the 3' position; (m) the compound's pyridyl ring that is attached to the triple bond has a -CF3 at the 3' position; (n) the compound's pyridyl ring that is attached to the triple bond has a -F at the 3' position; (o) the compound's pyridyl ring that is attached to the triple bond has a
-CI at the 3' position; (p) the compound's pyridyl ring that is attached to the triple bond has a -NO2 at the 3' position; (q) the compound's pyridyl ring that is attached to the triple bond has a -C(O)CH3 at the 3' position; (r) the compound's pyridyl ring that is attached to the friple bond has a -C(CH3)3 at the 3' position; (s) the compound's pyridyl ring that is attached to the triple bond has a -CH(CH3)2 at the 3' position; (t) the compound's pyridyl ring that is attached to the triple bond has a
-OC(O)CH3 at the 3' position; and (u) the compound's pyridyl ring that is attached to the triple bond has no other substitution. Table 5
Figure imgf000044_0001
(IE)
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
The designations (a)-(d) in connection with each of the Compounds 981- 1340 have the following meaning: (a) the compound's 6-membered aromatic ring has a -CH3 at the 5 position; (b) the compound's 6-membered aromatic ring has a -CH2(CH ) at the 5 position; (c) the compound's 6-membered aromatic ring has a -CF3 at the 5 position; and (d) the compound's 6-membered aromatic ring has no other substitution.
Table 6
Figure imgf000053_0001
(IF)
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
The designations (a)-(d) in connection with each of the Compounds 1341- 1700 have the following meaning: (a) the compound's 6-membered aromatic ring has a -CH3 at the 5 position; (b) the compound's 6-membered aromatic ring has a -CH2(CH3) at the 5 position; (c) the compound's 6-membered aromatic ring has a -CF3 at the 5 position; and (d) the compound's 6-membered aromatic ring has no other substitution.
Table 7
Figure imgf000062_0001
(IG)
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000064_0001
The designations (a)-(z) and (aa)-(ae) in connection with each of the Compounds 1701-1820 have the following meaning: (a) the compound's phenyl ring that is attached to the triple bond has a -CH3 at the 4' position; (b) the compound's phenyl ring that is attached to the triple bond has a
-CH2(CH3) at the 4' position; (c) the compound's phenyl ring that is attached to the triple bond has a -CF3 at the 4' position; (d) the compound's phenyl ring that is attached to the triple bond has a -F at the 4' position; (e) the compound's phenyl ring that is attached to the triple bond has a -CI at the 4' position; (f) the compound's phenyl ring that is attached to the friple bond has a -NO2 at the 4' position; (g) the compound's phenyl ring that is attached to the triple bond has a
-C(O)CH3 at the 4' position; (h) the compound's phenyl ring that is attached to the friple bond has a -C(CH3)3 at the 4' position; (i) the compound's phenyl ring that is attached to the triple bond has a -CH(CH3)2 at the 4' position; (j) the compound's phenyl ring that is attached to the triple bond has a -OC(O)CH3 at the 4' position; (k) the compound's phenyl ring that is attached to the triple bond has a -CH3 at the 3' position; (1) the compound's phenyl ring that is attached to the triple bond has a
-CH2(CH3) at the 3' position; (m) the compound's phenyl ring that is attached to the triple bond has a -CF3 at the 3' position; (n) the compound's phenyl ring that is attached to the triple bond has a -F at the 3' position; (o) the compound's phenyl ring that is attached to the triple bond has a -CI at the 3' position; (p) the compound's phenyl ring that is attached to the triple bond has a -NO2 at the 3' position; (q) the compound's phenyl ring that is attached to the triple bond has a -C(O)CH3 at the 3' position; (r) the compound's phenyl ring that is attached to the triple bond has a
-C(CH3)3 at the 3' position; (s) the compound's phenyl ring that is attached to the triple bond has a -CH(CH3)2 at the 3' position; (t) the compound's phenyl ring that is attached to the triple bond has a -OC(O)CH3 at the 3' position; (u) the compound's phenyl ring that is attached to the triple bond has a -CH3 at the 2' position; (v) the compound's phenyl ring that is attached to the triple bond has a -CH2(CH3) at the 2' position; (w) the compound' s phenyl ring that is attached to the triple bond has a
-CF3 at the 2' position; (x) the compound's phenyl ring that is attached to the triple bond has a -F at the 2' position; (y) the compound's phenyl ring that is attached to the triple bond has a -CI at the 2' position; (z) the compound's phenyl ring that is attached to the triple bond has a -NO2 at the 2' position; (aa) the compound's phenyl ring that is attached to the triple bond has a -C(O)CH3 at the 2' position; (ab) the compound's phenyl ring that is attached to the triple bond has a
-C(CH3)3 at the 2' position; (aa) the compound's phenyl ring that is attached to the triple bond has a -CH(CH3)2 at the 2' position; (ad) the compound's phenyl ring that is attached to the friple bond has a -OC(O)CH3 at the 2' position; and (ae) the compound's phenyl ring that is attached to the triple bound has no other substitution. 4.2 Definitions As used herein, the terms used above having following meaning: "-(C1-C1o)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain -(Ci-Cιo)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Representative saturated branched -(Ci-Cio)alkyls include -zso-propyl, -sec-butyl, -z'so-butyl, -tert-butyl, -z'so-pentyl, -2-methylbutyl, -3-methylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2-methylhexyl, -3-methylhexyl, -4-methylhexyl, -5-methylhexyl, -2,3-dimethylbutyl, -2,3-dimethylpentyl, -2,4-dimethylpentyl,
-2,3-dimethylhexyl, -2,4-dimethylhexyl, -2,5-dimethylhexyl, -2,2-dimethylpentyl, -2,2-dimethylhexyl, -3,3-dimethylpentyl, -3,3-dimethylhexyl, -4,4-dimethylhexyl, -2-ethylpentyl, -3-ethylpentyl, -2-ethylhexyl, -3-ethylhexyl, -4-ethylhexyl, -2-methyl- 2-ethylpentyl, -2-methyl-3-ethylpentyl, -2-methyl-4-ethylpentyl, -2-methyl-2-ethylhexyl, -2-methyl-3-ethylhexyl, -2-methyl-4-ethylhexyl, -2,2-diethylpentyl, -3,3-diethylhexyl, -2,2-diethylhexyl, -3,3-diethylhexyl and the like. "-(Ci-C6)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative saturated straight chain -(Ci-C6)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative saturated branched -(Ci-C6)alkyls include -zso-propyl, -sec-butyl,
-z'so-butyl, -tert-butyl, -z'so-pentyl, -2-methylbutyl, -3-methylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl and the like. "-(Ci-C4)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms. Representative saturated straight chain -(Ci-C4)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl. Representative saturated branched -(Ci-C4)alkyls include -zso-propyl, -sec-butyl, -z'so-butyl, and -tert-butyl. "-(Ci-C3)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 3 carbon atoms. Representative saturated straight chain -(C1-C3)alkyls include -methyl, -ethyl, and -n-propyl. A representative saturated branched -(Ci-C3)alkyl is -zso-propyl. "-(C2-C1o)alkenyl" means a straight chain or branched non-cyclic hydrocarbon containing from 2 to 10 carbon atoms and including at least one carbon- carbon double bond. Representative straight chain and branched (C2-C1o)alkyls include 1-pentenyl, -2-pentenyl, -3-methyl-l-butenyl, -2-methyl-2-butenyl, - 2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like. "-(C2-C6)alkenyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched -(C2-C6)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -z'so-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-l-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl and the like. "-(C -C1o)alkynyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at lease one carbon-carbon triple bond. Representative straight chain and branched -(C2-Cio)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl- 1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like. "-(C2-C6)alkynyl" means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at lease one carbon-carbon triple bond. Representative straight chain and branched (C2-C6)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl- 1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl and the like. "-(C -Cio)cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms. Representative (C3-Cio)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, and -cyclodecyl. "-(C3-C8)cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Representative (C3-C8)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl. "-(Cs-Cι4)bicycloalkyl" means a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative -(C8-C14)bicycloalkyls include -indanyl, -1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphfhyl, -perhydronaphthyl and the like. "-(C8-Cι4)fricycloalkyl" means a tri-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative -(C8-Cι )fricycloalkyls include -pyrenyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl, -aceanthreneyl, -1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl and the like. "-(C5-Cιo)cycloalkenyl" means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms. Representative (C5-Cιo)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like. "-(C5-C8)cycloalkenyι" means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms. Representative (C5-C8)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like. "-(C8-Cι4)bicycloalkenyl" means a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. Representative -(C8-Cι )bicycloalkenyls include -indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl and the like. "-(C8-C14)tricycloalkenyl" means a tri-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. Representative -(C8-Cι4)tricycloalkenyls include -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl, -αs-indacenyl, -s-indacenyl and the like. "-(5- to 10-membered)heteroaryι" means an aromatic heterocycle ring of
5 to 10 members, including both mono- and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- to 10- membered)heteroaryl's rings contains at least one carbon atom. In another embodiment, both of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom. Representative -(5- to 10-membered)heteroaryls include -pyridyl, -furyl, -benzofuranyl, -thiophenyl, -benzothiophenyl, -quinolinyl, -pyrrolyl, -indolyl, -oxazolyl, -benzoxazolyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -benzothiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -pyridazinyl, -pyrimidyl, -pyrazinyl, -triazinyl, -cinnolinyl, -phthalazinyl, -quinazolinyl and the like. In embodiments where n is 3, i.e., the amino groups of the compounds of formula (I) are separated by a propylene fragment, then R2 is not -3 -pyridyl. "-(3- to 7-membered)heterocycle" or "-(3- to 7-membered)heterocyclo" means a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated, non-aromatic or aromatic. A 3- or a 4-membered heterocycle can contain up to 3 heteroatoms, a 5-membered heterocycle can contain up to 4 heteroatoms, a 6-membered heterocycle can contain up to 6 heteroatoms, and a 7-membered heterocycle can contain up to 7 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 7-membered)heterocycle can be attached via any heteroatom or carbon atom. Representative -(3- to 7-membered)heterocycles include -pyridyl, -furyl, -thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -pyridazinyl, -pyrimidinyl, -pyrazinyl, -triazinyl, -morpholinyl, -pyrrolidinonyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -hydantoinyl, -valerolactamyl, -oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydropyranyl, -tefrahydropyrindinyl, -tetrahydropyrimidinyl, -tetrahydrothiophenyl, -tetrahydrothiopyranyl and the like. "-(3- to 5-membered)heterocycle" or "-(3- to 5-membered)heterocyclo" means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated, non-aromatic or aromatic. A 3- or 4-membered heterocycle can contain up to 3 heteroatoms and a 5-membered heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 5-membered)heterocycle can be attached via any heteroatom or carbon atom. Representative -(3- to 5- membered)heterocycles include -furyl, -thiophenyl, -pyrrolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -triazinyl, -pyrrolidinonyl, -pyrrolidinyl, -hydantoinyl, -oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydrothiophenyl and the like. "-(7- to 10-membered)bicycloheterocycle" or "-(7- to 10-membered)bicycloheterocyclo" means a 7- to 10-membered bicyclic, heterocyclic ring having a saturated, unsaturated, non-aromatic or aromatic group. A -(7- to 10-membered)bicycloheterocycle contains from 1 to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The (7- to 10-membered)bicycloheterocycle can be attached via any heteroatom or carbon atom. Representative -(7- to 10-membered)bicyclo- heterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl, -purinyl, -4H- quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, -carbazolyl, -β- carbolinyl, 1,3-benzodioxole and the like. "-(C1 )aryl" means a 14-membered aromatic carbocyclic moiety such as anthryl and phenanthryl. "-CH2(halo)" means a methyl group where one of the hydrogens of the methyl group has been replaced with a halogen. Representative -CH2(halo) groups include -CH2F, -CH2C1, -CH2Br and -CH2I. "-CH(halo)2" means a methyl group where two of the hydrogens of the methyl group have been replaced with a halogen. Representative -CH(halo)2 groups include -CHF2, -CHC12, -CHBr2, CHBrCl, CHC1I and -CHI2. "-C(halo)3" means a methyl group where each of the hydrogens of the methyl group has been replaced with a halogen. Representative -C(halo)3 groups include -CF3, -CF2C1, -CC13, -CBr3, -CFBr2 and -CI3. "-Halogen" or "-halo" means -F, -CI, -Br or -I. The term "animal," includes, but is not limited to, a cow, monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human. The phrase "pharmaceutically acceptable salt," as used herein, is any pharmaceutically acceptable salt that can be prepared from a Diaminoalkylene Compound, including a salt formed from an acid and a basic functional group, such as a nitrogen, of one of the Diaminoalkylene Compounds. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,r-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a Diaminoalkylene Compound having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl-N-ethylamine; diethylamine; friethylamine; mono-, bis- or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine and the like. The phrase "effective amount" when used in connection with a Diaminoalkylene Compound means an amount effective for: (a) treating or preventing a Condition; or (b) inhibiting n GluR5 or mGluRl function in a cell. The phrase "effective amount" when used in connection with another therapeutic agent means an amount for providing the therapeutic effect of the other therapeutic agent. As used herein, the term "adjunctive" is used interchangeably with "in combination" or "combination." Such terms are also used where a Diaminoalkylene Compound and at last one therapeutic agent affects the treatment or prevention of a Condition, the same Condition in one embodiment, different Conditions in another embodiment. As used herein, the term "adjunctively administered" refers to the administration of at last one therapeutic agent in addition to a Diaminoalkylene Compound, either simultaneously with the same or at intervals prior to, during, or following administration of the a Diaminoalkylene Compound to achieve the desired therapeutic or prophylactic effect. When a first group is "substituted with one or more" second groups, each of one or more of the first group's hydrogen atoms is replaced with a second group. In one embodiment, a first group is substituted with up to three second groups. In another embodiment, a first group is substituted with one or two second groups. In another embodiment, a first group is substituted with only one second group. The term "UI" means urinary incontinence. The term "ALS" means amyotrophic lateral sclerosis. The phrases "treatment of," "treating" and the like include the amelioration or cessation of a Condition or a symptom thereof. In one embodiment, treating includes inhibiting, for example, decreasing the overall frequency of episodes of a Condition or a symptom thereof. The phrases "prevention of," "preventing" and the like include the avoidance of the onset of a Condition or a symptom thereof.
4.3 Methods for Making the Diaminoalkylene Compounds The Diaminoalkylene Compounds can be made using conventional organic syntheses and/or by the following illustrative methods. Diaminoalkylene Compounds can be obtained by reacting a diaminoalkyl compound of formula A with a (Cι-Cιo)alkyliodide, a (C2-Cio)alkenyliodide, or (C2- Cιo)alkynyliodide in which the iodide atom is bonded to an sp carbon atom, at low temperature, e.g., about 0°C to about -78°C, in the presence of a strong base, e.g., lithium di-z'so-propylamide ("LDA"), optionally in hexamethylphosphoramide ("HMPA") as shown below in Scheme 1, e.g. for a (Ci-Cio)alkyl iodide reactant:
Scheme 1
Figure imgf000074_0001
A Diaminoalkylene Compounds
where -(Ci-Cio)alkyl, R3, X, Y, Z and n are defined above for the Diaminoalkylene Compounds of formula (I); and Ri and Rt' are each independently a -(Ci-C4)alkyl or a protecting group such that when the Rt and/or Ri' protecting group is removed, that Rt and/or Ri' is -H. A representative procedure for reacting a terminal acetylene with an alkyl iodide is provided in G.M. Strunz et al, Can. J. Chem., 419-432 (1996). Methods for using a protecting group are described below. Diaminoalkylene Compounds where R2 contains an sp or sp carbon atom bonded to the acetylene group can be obtained by reacting a Diaminoalkylene Compound of formula A with an aryl iodide, or with a (C2-Cio)alkenyliodide or (C2- Cιo)alkynyl iodide in which the iodide atom is bonded to an sp or sp carbon atom, at room temperature, e.g., about 25°C, in ethyl acetate ("EtOAc") in the presence of Pd(PH3P)2(OAc)2, Cul and friethylamine ("TEA"), as shown below in Scheme 2, e.g., for an aryl iodide reagent. Scheme 2
Figure imgf000075_0001
Diaminoalkylene Compounds
where Ri, Ri', R3, R4, X, Y, Z and n are defined above for the Diaminoalkylene
Compounds of formula (I). A representative procedure for coupling a terminal acetylene with an aryl iodide is provided in L.A. Hay et al. J. Org. Chem. 5050-5058 (1998). If an R3 group of the compound of formula A in Scheme 1 or 2 contains a hydroxyl or amino group, or if an Ri or/and Ri' group in Scheme 1 is -H, that -hydroxyl, -amino or -H group can be protected using a suitable protecting group, using methods known to those skilled in the art, before the compound of formula A is reacted. Suitable protecting groups for hydroxyl group include, but are not limited to, methyl ether, methoxymethyl ether, methoxythiomethyl ether, 2-methoxyethoxymethyl ether, bis(2-chloroethoxy)ethyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether, methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, 1 -ethoxyethyl ether, 1 -methyl- 1 -methoxyethyl ether, 2-(phenylselenyl ether), tert-butyl ether, allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethyl ether, o-napthyldiphenylmethyl ether, -methoxydiphenylmethyl ether, 9-(9-phenyl-10-oxo)anthryl ether (tritylone), ttimethylsilyl ether, z'so-propyldimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, tribenzylsilyl ether, tri-z'so-propylsilyl ether, formate ester, acetate ester, frichloroacetate ester, phenoxyacetate ester, z'so-butyrate ester, pivaloate ester, adamantoate ester, benzoate ester, 2,4,6-trimethyl (mesitoate) ester, methyl carbonate, 2,2,2-trichlorocarbonate, allyl carbonate, p-nitrophenyl carbonate, benzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, N-phenylcarbamate, nitrate ester, and 2,4-dinitrophenylsulfenate ester (see, e.g., T.W. Greene et al., Protective Groups in Organic Synthesis, 17-200 (3d ed. 1999)). Suitable protecting groups for an amino group include, but are not limited to, l,l-dimethyl-2,2,2-trichloroethyl carbamate, l-methyl-l-(4-biphenylyl)ethyl carbamate, 2-trimethylsilylethyl carbamate, 9-fluorenylmethyl carbamate, and tert-butyl carbamate (T.W. Greene et al, Protective Groups in Organic Synthesis, 494-653 (3d ed. 1999)). Diaminoalkylene Compounds can also be obtained by reacting a compound of formula B with a propynoic acid of formula C at, e.g., from about 0°C to about 100°C for about 1 to about 10 hours, in dimethylformamide ("DMF") followed by additon of 1-hydroxybenzotriazole ("HOBt") and di- zso-propyl carbodiimide ("DIC") as shown below in Scheme 3:
Scheme 3
Figure imgf000076_0001
Compounds
where Rl5 Ri', R2, R3, X, Y, Z, and n are defined above for the Diaminoalkylene Compounds of formula (I). A representative procedure for reacting a terminal amine with a carboxylic acid is provided in F.M. Martin et al, Bioorg. Med. Chem. Lett. 9:2887-2892 (1999). Diaminoalkylene Compounds can also be obtained by reacting a compound of formula D with an aryl halide or heteroaryl halide of formula E at a temperature of about 45°C in DMF, in the presence of di-z'so-propylethylamine ("DIEA"). This process is shown below in Scheme 4:
Scheme 4
Compounds
Figure imgf000077_0001
where Ri, Ri', R2, R3, X, Y, Z, halo and n are defined above for the Diaminoalkylene
Compounds of formula (I). A representative procedure for coupling a terminal amine with an aryl halide or heteroaryl halide is provided in Miyamoto et al, Chem. Pharm. Bull. 38:3359- 65 (1990). The compounds of formula B can be prepared by reacting an aryl halide or heteroaryl halide of formula E with a protected diamine of formula F, where the protecting group is, e.g., t-butoxycarbonyl (Boc). The reaction is generally performed in the presence of one equivalent of a tertiary amine such as DIEA at a temperature of about 100°C in organic solvent. The Boc-protecting group is then removed by reaction with, e.g., trifluoroacetic acid ("TFA") as shown below in Scheme 5: Scheme 5
Figure imgf000078_0001
B
where Rls Ri', R , X, Y, Z, halo and n are defined above for the Diaminoalkylene Compounds of formula (I). A representative procedure for reacting an aryl halide or heteroaryl halide with a diamine comprising a Boc-protected amine group is provided in M.J. Genin et al, J. Med. Chem. 42:4140-4149 (1999). Alternatively, the compounds of formula B can be prepared by reacting an aryl halide or heteroaryl halide of formula E with a protected diamine of formula F, where the protecting group is, e.g., t-butoxycarbonyl (Boc) in of a catalyst, e.g., palladium, and base, e.g., sodium ter-butoxide, in 1,4-dioxane at a temperature of about 25°C to about 45°Cs (see Hartwig et al, Org. Let. 2:1423-24 (2002) for a representative procudure using a palladium catalyst). A representative procedure for deprotecting a Boc-protected amine is provided in J.P. Sanchez et al, J. Med. Chem. 31:983-991 (1988). The compound of formula D can be prepared by reacting the acid chloride of propynoic acid of formula G with a Boc-protected diamine of formula H in the presence of one equivalent of a tertiary amine such as DIEA at about 0°C to about 45°C in dichloromethane ("DCM") to form the compound of formula J. The protecting group is then removed from the compound of formula J by reaction with TFA as shown below in Scheme 6:
Scheme 6
Figure imgf000079_0001
where Rl5 Ri', R2 and n are defined above for the Diaminoalkylene Compounds of formula (I). The Boc-deprotection procedure is similar to that described above in Scheme 5. Compounds of formulae F and H, which contain a Boc-protecting group, can be prepared by methods known in the art (see Protective Groups in Organic Synthesis 518-520 (Greene and Wuts eds., 3rd ed. 1999)). Compounds of formulae C, E and G are commercially available or can be prepared by methods known in the art. Compounds of formula A can be prepared by a procedure that is analogous to that described above in Scheme 3, except that the compound of formula C is propiolic acid (i.e., Ri is -H). Certain Diaminoalkylene Compounds can have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A Diaminoalkylene Compound can be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses Diaminoalkylene Compound and their uses as described herein in the form of their optical isomers, diasteriomers and mixtures thereof, including a racemic mixture. Optical isomers of the Diaminoalkylene Compounds can be obtained by known techniques such as chiral chromatography or formation of diasteromeric salts from an optically active acid or base. In addition, one or more hydrogen, carbon or other atoms of a Diaminoalkylene Compound can be replaced by an isotope of the hydrogen, carbon or other atoms. Such compounds, which are encompassed by the present invention, are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. 4.4 Therapeutic Uses of the Diaminoalkylene Compounds In accordance with the invention, the Diaminoalkylene Compounds are administered to an animal in need of treatment or prevention of a Condition. In one embodiment, an effective amount of a Diaminoalkylene Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluR5. Examples of conditions that are treatable or preventable by inhibiting mGluR5 include, but are not limited to, pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, and psychosis. In another embodiment, an effective amount of a Diaminoalkylene Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluRl. Examples of conditions that are treatable or preventable by inhibiting mGluRl include, but are not limited to, pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, a seizure, stroke, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia and depression. The Diaminoalkylene Compounds can be used to treat or prevent acute or chronic pain. Examples of pain treatable or preventable using the Diaminoalkylene Compounds include, but are not limited to, cancer pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache pain, muscle pain, arthritic pain, neuropathic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis. The Diaminoalkylene Compounds can also be used for treating or preventing pain associated with inflammation or with an inflammatory disease in an animal. Such pain can arise where there is an inflammation of the body tissue, which can be a local inflammatory response and/or a systemic inflammation. For example, the Diaminoalkylene Compounds can be used to treat or prevent pain associated with inflammatory diseases including, but not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grapp et al, J. Mol. Cell Cardiol 3 297-303 (1999)) including, but not limited to, transplantation of the heart, lung, liver, or kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer s disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyottophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including Type I and Type II diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, and a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorum); immune-complex vasculitis, and systemic lupus erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The Diaminoalkylene Compounds can also be used for treating or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer. The Diaminoalkylene Compounds can be used to treat or prevent UI. Examples of UI treatable or preventable using the Diaminoalkylene Compounds include, but are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence. The Diaminoalkylene Compounds can be used to treat or prevent an addictive disorder, including but not limited to, an eating disorder, an impulse-control disorder, an alcohol-related disorder, a nicotine-related disorder, an amphetamine-related disorder, a cannabis-related disorder, a cocaine-related disorder, an hallucinogen-related disorder, an inhalant-related disorders, and an opioid-related disorder, all of which are further sub-classified as listed below. Eating disorders include, but are not limited to, Bulimia Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and Eating Disorder not otherwise specified (NOS). Impulse control disorders include, but are not limited to, Intermittent
Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, and Impulse Control Disorder not otherwise specified (NOS). Alcohol-related disorders include, but are not limited to, Alcohol- Induced Psychotic Disorder with delusions, Alcohol Abuse, Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium,
Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol Dependence, Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder not otherwise specified (NOS). Nicotine-related disorders include, but are not limited to, Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related Disorder not otherwise specified (NOS). Amphetamine-related disorders include, but are not limited to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Amphetamine-Induced Psychotic Disorder with delusions, Amphetamine-Induced Psychotic Disorders with hallucinations, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder, and Amphetamine Related Disorder not otherwise specified (NOS). Cannabis-related disorders include, but are not limited to, Cannabis Dependence, Cannabis Abuse, Cannabis Intoxication, Cannabis Intoxication Delirium, Cannabis-Induced Psychotic Disorder with delusions, Cannabis-Induced Psychotic
Disorder with hallucinations, Cannabis-Induced Anxiety Disorder, and Cannabis Related Disorder not otherwise specified (NOS). Cocaine-related disorders include, but are not limited to, Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal, Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder with delusions,
Cocaine-Induced Psychotic Disorders with hallucinations, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine- Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder, and Cocaine Related Disorder not otherwise specified (NOS). Hallucinogen-related disorders include, but are not limited to,
Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication, Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder with delusions, Hallucinogen- Induced Psychotic Disorders with hallucinations, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-Induced Sleep
Disorder, Hallucinogen Persisting Perception Disorder (Flashbacks), and Hallucinogen Related Disorder not otherwise specified (NOS). Inhalant-related disorders include, but are not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-Induced Psychotic Disorder with delusions, Inhalant-Induced Psychotic
Disorder with hallucinations, Inhalant-Induced Anxiety Disorder, and Inhalant Related Disorder not otherwise specified (NOS). Opioid-related disorders include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Intoxication, Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder with delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid-Induced Anxiety Disorder, Opioid Withdrawal, and Opioid Related Disorder not otherwise specified (NOS). The Diaminoalkylene Compounds can be used to treat or prevent Parkinson's disease and parkinsonism and the symptoms associated with Parkinson's disease and parkinsonism, including but not limited to, bradykinesia, muscular rigidity, resting tremor, and impairment of postural balance. The Diaminoalkylene Compounds can be used to treat or prevent generalized anxiety or severe anxiety and the symptoms associated with anxiety, including but not limited to, restlessness, tension, tachycardia, dyspnea, depression including chronic "neurotic" depression, panic disorder, agoraphobia and other specific phobias, eating disorders, and personality disorders. The Diaminoalkylene Compounds can be used to treat or prevent epilepsy, including but not limited to, partial epilepsy, generalized epilepsy, and the symptoms associated with epilepsy, including but not limited to, simple partial seizures, jacksonian seizures, complex partial (psychomotor) seizures, convulsive seizures (grand mal or tonic-clonic seizures), petit mal (absence) seizures, and status epilepticus. The Diaminoalkylene Compounds can be used to treat or prevent a seizure, including but not limited to, infantile spasms, febrile seizures, and epileptic seizures. The Diaminoalkylene Compounds can be used to treat or prevent strokes, including but not limited to, ischemic strokes and hemorrhagic strokes. The Diaminoalkylene Compounds can be used to treat or prevent a pruritic condition, including but not limited to, pruritus caused by dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et ani, malaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, and fiberglass dermatitis. The Diaminoalkylene Compounds can be used to treat or prevent psychosis, including but not limited to, schizophrenia, including paranoid schizophrenia, hebephrenic or disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, negative or deficit subtype schizophrenia, and non-deficit schizophrenia; a delusional disorder, including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, jealous subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delusional disorder; and brief psychosis. The Diaminoalkylene Compounds can be used to treat or prevent a cognitive disorder, including but not limited to, delirium and dementia such as multi- infarct dementia, dementia pugilistica, dementia caused by AIDS, and dementia caused by Alzheimer's disease. The Diaminoalkylene Compounds can be used to treat or prevent a memory deficiency, including but not limited to, dissociative amnesia and dissociative fugue. The Diaminoalkylene Compounds can be used to treat or prevent restricted brain function, including but not limited to, that caused by surgery or an organ transplant, restricted blood supply to the brain, a spinal cord injury, a head injury, hypoxia, cardiac arrest, and hypoglycemia. The Diaminoalkylene Compounds can be used to treat or prevent Huntington's chorea. The Diaminoalkylene Compounds can be used to treat or prevent ALS. The Diaminoalkylene Compounds can be used to treat or prevent retinopathy, including but not limited to, arteriosclerotic retinopathy, diabetic arteriosclerotic retinopathy, hypertensive retinopathy, non-proliferative retinopathy, and proliferative retinopathy. The Diaminoalkylene Compounds can be used to treat or prevent a muscle spasm. The Diaminoalkylene Compounds can be used to treat or prevent a migraine. The Diaminoalkylene Compounds can be used to treat (for example, inhibit) or prevent vomiting, including but not limited to, nausea vomiting, dry vomiting (retching), and regurgitation. The Diaminoalkylene Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia. The Diaminoalkylene Compounds can be used to treat or prevent depression, including but not limited to, major depression and bipolar disorder. Without wishing to be bound by theory, Applicants believe that the Diaminoalkylene Compounds are antagonists for mGluR5. The invention relates to methods for inhibiting mGluR5 function in a cell comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Diaminoalkylene Compound. This method can be used in vitro, for example, as an assay to select cells that express mGluR5 and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, psychosis or schizophrenia. The method is also useful for inhibiting mGluR5 function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell in an animal with an effective amount of a Diaminoalkylene Compound. In one embodiment, the method is useful for treating or preventing pain in an animal in need thereof. In another embodiment, the method is useful for treating or preventing an addictive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Parkinson's disease in an animal in need thereof. In another embodiment, the method is useful for treating or preventing parkinsonism in an animal in need thereof. In another embodiment, the method is useful for treating or preventing anxiety in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing schizophrenia in an animal in need thereof. Examples of cells capable of expressing mGluR5 are neuronal and glial cells of the central nervous system, particularly the brain, especially in the nucleus accumbens. Methods for assaying cells that express mGluR5 are known in the art. Without wishing to be bound by theory, Applicants believe that the Diaminoalkylene Compounds are antagonists for mGluRl. The invention relates to methods for inhibiting mGluRl function in a cell comprising contacting a cell capable of expressing mGluRl with an effective amount of a Diaminoalkylene Compound. This method can be used in vitro, for example, as an assay to select cells that express mGluRl and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing a Condition. The method is also useful for inhibiting mGluRl function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an effective amount of a Diaminoalkylene Compound. In one embodiment, the method is useful for treating or preventing pain in an animal in need thereof. In another embodiment, the method is useful for treating or preventing UI in an animal in need thereof. In another embodiment, the method is useful for treating or preventing an addictive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Parkinson's disease in an animal in need thereof. In another embodiment, the method is useful for treating or preventing parkinsonism in an animal in need thereof. In another embodiment, the method is useful for treating or preventing anxiety in an animal in need thereof. In another embodiment, the method is useful for treating or preventing epilepsy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a seizure in an animal in need thereof. In another embodiment, the method is useful for treating or preventing stroke in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a cognitive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a memory deficit in an animal in need thereof. In another embodiment, the method is useful for treating or preventing restricted brain function in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Huntington's chorea in an animal in need thereof. In another embodiment, the method is useful for treating or preventing ALS in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dementia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing retinopathy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a muscle spasm in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a migraine in an animal in need thereof. In another embodiment, the method is useful for treating or preventing vomiting in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dyskinesia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing depression in an animal in need thereof. Examples of cells capable of expressing mGluRl include, but are not limited to, cerebellar Purkinje neuron cells, Purkinje cell bodies (punctate), cells of spine(s) of the cerebellum; neurons and neurophil cells of olfactory-bulb glomeruli; cells of the superficial layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and spinal trigeminal nucleus cells. Methods for assaying cells that express mGluRl are known in the art.
4.5 Therapeutic/Prophylactic Administration and Compositions of the Invention Due to their activity, the Diaminoalkylene Compounds are advantageously useful in veterinary and human medicine. As described above, the Diaminoalkylene Compounds are useful for treating or preventing a Condition in an animal in need thereof. When administered to an animal, the Diaminoalkylene Compounds are administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient. The present compositions, which comprise a Diaminoalkylene Compound, can be administered orally. The Diaminoalkylene Compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.) and can be administered together with another therapeutically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the Diaminoalkylene Compound. Methods of administration include, but are not limited to, inttadermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of the Diaminoalkylene Compounds into the bloodstream. In specific embodiments, it can be desirable to administer the Diaminoalkylene Compounds locally. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In certain embodiments, it can be desirable to introduce the
Diaminoalkylene Compounds into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g. , by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the Diaminoalkylene Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides. In another embodiment, the Diaminoalkylene Compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al, Liposomes in the Therapy of Infectious Disease and Cancer 317- 327 and 353-365 (1989). In yet another embodiment, the Diaminoalkylene Compounds can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled- or sustained-release systems discussed in the review by Langer, Science 249: 1527-1533 (1990) can be used. In one embodiment, a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al. , Surgery 88:507 (1980); and Saudek et al. , N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol Chem. 23:61 (1983); Levy et al, Science 228:190 (1985); During et al, Ann. Neurol. 25:351 (1989); and Howard et al, J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled- or sustained- release system can be placed in proximity of a target of the Diaminoalkylene Compounds, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose. The present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal. Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipient can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to an animal. Water, and in one embodiment physiological saline, is a particularly useful excipient when the Diaminoalkylene Compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The present compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference. In one embodiment, the Diaminoalkylene Compounds are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade. In another embodiment, the Diaminoalkylene Compounds can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lidocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the Diaminoalkylene Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the Diaminoalkylene Compounds are administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. The Diaminoalkylene Compounds can be administered by controlled- release or sustained-release means or by delivery devices that are known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release. Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained-release counterparts. In one embodiment, a controlled- or sustained- release composition comprises a minimal amount of a Diaminoalkylene Compound to cure or control the condition in a minimum amount of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled- or sustained- release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Diaminoalkylene Compound, and can thus reduce the occurrence of adverse side effects. Controlled- or sustained-release compositions can initially release an amount of a Diaminoalkylene Compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Diaminoalkylene Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the Diaminoalkylene Compound in the body, the Diaminoalkylene Compound can be released from the dosage form at a rate that will replace the amount of Diaminoalkylene Compound being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds. The amount of the Diaminoalkylene Compound that is effective for the treatment or prevention of a condition can be determined using standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed will also depend on the route of administration, and the seriousness of the Condition and can be decided according to the judgment of a practitioner and/or each animal's circumstances. Suitable effective dosage amounts, however, range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although they are typically about 100 mg/kg of body weight or less. In one embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Diaminoalkylene Compound, in another embodiment, from about 0.02 mg/kg of body weight to about 50 mg/kg of body weight, and in another embodiment, from about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. In one emobiment, an effective dosage amount is administred about every 24 h until the Condition is abated. In another embodiment, an effective dosage amount is admininstered about every 12 h until the Condition is abated. In another embodiment, an effective dosage amount is admininstered about every 8 h until the Condition is abated. In another embodiment, an effective dosage amount is admininstered about every 6 h until the Condition is abated. In another embodiment, an effective dosage amount is admininstered about every 4 h until the Condition is abated. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Diaminoalkylene Compound is administered, the effective dosage amounts correspond to the total amount administered. Where a cell capable of expressing mGluR5 or mGluRl is contacted with a Diaminoalkylene Compound in vitro, the amount effective for inhibiting the mGluR5 or mGluRl receptor function in a cell will typically range from about 0.01 μg/L to about 5 mg/L, in one embodiment, from about 0.01 μg/L to about 2.5 mg/L, in another embodiment, from about 0.01 μg/L to about 0.5 mg/L, and in another embodiment, from about 0.01 μg/L to about 0.25 mg/L of a solution or suspension of a pharmaceutically acceptable carrier or excipient. In one embodiment, the volume of solution or suspension comprising the Diaminoalkylene Compound is from about 0.01 μL to about 1 mL. In another embodiment, the volume of solution or suspension is about 200 μL. Where a cell capable of expressing mGluR5 or mGluRl is contacted with a Diaminoalkylene Compound in vivo, the amount effective for inhibiting the receptor function in a cell will typically range from about 0.01 mg kg of body weight to about 2500 mg/kg of body weight, although it typically ranges from about 100 mg/kg of body weight or less. In one embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Diaminoalkylene Compound, in another emodiment, from about 0.02 mg/kg of body wieght to about 50 mg/kg of body weight, and in another embodiment, from about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. In one embodiment, an effective dosage amount is administered about every 24 h. In another embodiment, an effective dosage amount is administered about every 12 h. In another embodiment, an effective dosage amount is administered about every 8 h. In another embodiment, an effective dosage amount is administered about every 6 h. In another embodiment, an effective dosage amount is administered about every 4 h. The Diaminoalkylene Compounds can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy. The present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering another therapeutic agent to the animal being administered a Diaminoalkylene Compound. In one embodiment, the other therapeutic agent is administered in an effective amount. The present methods for inhibiting mGluR5 function in a cell capable of expressing mGluR5 can further comprise contacting the cell with an effective amount of another therapeutic agent. The present methods for inhibiting mGluRl function in a cell capable of expressing mGluRl can further comprise contacting the cell with an effective amount of another therapeutic agent Effective amounts of the other therapeutic agents are known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range, h one embodiment of the invention, where another therapeutic agent is administered to an animal, the effective amount of the Diaminoalkylene Compound is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed that the Diaminoalkylene Compounds and the other therapeutic agent act synergistically to treat or prevent a Condition. The other therapeutic agent can be, but is not limited to, an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraine agent, a Cox-II inhibitor, an antiemetic, a β-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing one or more Conditions, and mixtures thereof. Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmo han, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.
In certain embodiments, the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof. Examples of useful non-opioid analgesics include non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, frioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, non-steroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; αrα-aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more detailed description of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Anti- inflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221 (A.R. Gennaro ed., 19th ed. 1995) which are hereby incorporated by reference in their entireties. Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in U.S. Patent No. 6,136,839, which is hereby incorporated by reference in its entirety. Examples of useful Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib. Examples of useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof. The other therapeutic agent can alternatively be an agent useful for reducing any potential side effects of a Diaminoalkylene Compounds. For example, the other therapeutic agent can be an antiemetic agent. Examples of useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, ttimethobenzamide, odansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetton, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulphide, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof. Examples of useful β-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol. Examples of useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,
5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide. Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulphide, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimelidine. Examples of useful Ca2+-channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiline. Examples of useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin II (including recombinant interleukin II or rBL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-nl, interferon alpha-n3, interferon beta-I a, interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotide acetate, lettozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxanttone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, sfreptozotocin, sulofenur, talisomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, ttiptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride. Examples of other anti-cancer drugs include, but are not limited to, 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox EL-2; capecitabine; carboxamide-amino-ttiazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors
(ICOS); castanospermine; cecropin B; cetrorelix; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosf amide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin
B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drag resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;
O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; odansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosf amide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transf erase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone
Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; sttomelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tefrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; ttopisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Examples of useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, and dicyclomine. Examples of useful therapeutic agents for treating or preventing an addictive disorder include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotonin antagonists. Examples of useful therapeutic agents for treating or preventing Parkinson's disease and parkinsonism include, but are not limited to, carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole, entacapone, tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride. Examples of useful therapeutic agents for treating or preventing anxiety include, but are not limited to, benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non- benzodiazepine agents, such as buspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, and thiopental; and propanediol carbamates, such as meprobamate and tybamate. Examples of useful therapeutic agents for treating or preventing epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, γ-vinyl GAB A, acetazolamide, and felbamate. Examples of useful therapeutic agents for treating or preventing a seizure include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, and felbamate. Examples of useful therapeutic agents for treating or preventing stroke include, but are not limited to, anticoagulants such as heparin, agents that break up clots such as streptokinase or tissue plasminogen activator, agents that reduce swelling such as mannitol or corticosteroids, and acetylsalicylic acid. Examples of useful therapeutic agents for treating or preventing a pruritic condition include, but are not limited to, naltrexone; nalmefene; danazol; tricyclics such as amitriptyline, imipramine, and doxepin; antidepressants such as those given below; menthol; camphor; phenol; pramoxine; capsaicin; tar; steroids; and antihistamines. Examples of useful therapeutic agents for treating or preventing psychosis include, but are not limited to, phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloroprothixene and thiothixene hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide; and ziprasidone. Examples of useful therapeutic agents for treating or preventing Huntington's chorea include, but are not limited to, haloperidol and pimozide. Examples of useful therapeutic agents for treating or preventing ALS include, but are not limited to, baclofen, neurotrophic factors, riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene. Examples of useful therapeutic agents for treating or preventing cognitive disorders include, but are not limited to, agents for treating or preventing dementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazine and haloperidol; and antidepressant drugs such as those provided herein. Examples of useful therapeutic agents for treating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta-blockers such as propranolol, verapamil, and divalproex. Examples of useful therapeutic agents for treating, inhibiting or preventing vomiting include, but are not limited to, 5-HT3 receptor antagonists such as odansetron, dolasetron, granisetron, and ttopisetron; dopamine receptor antagonists such as prochlorperazine, thiethylperazine, chlorpromazine, metoclopramide, and domperidone; glucocorticoids such as dexamefhasone; and benzodiazepines such as lorazepam and alprazolam. Examples of useful therapeutic agents for treating or preventing dyskinesia include, but are not limited to, reserpine and tetrabenazine. Examples of useful therapeutic agents for treating or preventing depression include, but are not limited to, tricyclic antidepressants such as amittyptyline, amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine, maprotiline, nefazadone, nortriptyline, protriptyline, trazodone, trimipramine, and venlafaxine; selective serotonin reuptake inhibitors such as fluoxetine, fluvoxamine, paroxetine, citalopram, (S)-citalopram, and setraline; monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine, and tranylcypromine; and psychostimulants such as dextroamphetamine and methylphenidate. A Diaminoalkylene Compound and the other therapeutic agent can act additively or, in one embodiment, synergistically. In one embodiment, a
Diaminoalkylene Compound is administered concurrently with another therapeutic agent, for example, a composition comprising an effective amount of a Diaminoalkylene Compound and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a Diaminoalkylene Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered. In another embodiment, an effective amount of a Diaminoalkylene Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent. In this embodiment, the Diaminoalkylene Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the
Diaminoalkylene Compound exerts its therapeutic effect for treating or preventing a Condition. A composition of the invention is prepared by a method comprising admixing a Diaminoalkylene Compound and pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods known for admixing a compound (or salt) and a pharmaceutically acceptable carrier or excipient. In one embodiment the composition is prepared such that the Diaminoalkylene Compound is present in the composition in an effective amount.
4.6 Kits The invention encompasses kits that can simplify the administration of a Diaminoalkylene Compound to an animal. A typical kit of the invention comprises a unit dosage form of a Diaminoalkylene Compound. In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a Diaminoalkylene Compound and a pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed instructions instructing the use of the Diaminoalkylene Compound to treat a Condition. The kit can also further comprise a unit dosage form of another therapeutic agent, for example, a second container containing an effective amount of the other therapeutic agent and a pharmaceutically acceptable carrier or excipient. In another embodiment, the kit comprises a container containing an effective amount of a Diaminoalkylene Compound, an effective amount of another therapeutic agent, and a pharmaceutically acceptable carrier or excipient. Examples of other therapeutic agents include, but are not limited to, those listed above. Kits of the invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device include but are not limited to a syringe, a drip bag, a patch, an inhaler, and an enema bag. The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
5. Examples Examples 1-13 relate to the synthesis of non-limiting illustrative Diaminoalkylene Compounds. 5.1 Example 1: Synthesis of Compound 186(ae)
Step A
Figure imgf000106_0001
A solution of 2-choro-3-nitropyridine (Compound 1) (1.0 g, 6.30 mmol) (available from Aldrich Chemical Co., Milwaukee, WI) and N-Boc-ethylenediamine (Compound 2) (1.0 g, 6.30 mmol) (Aldrich Chemical Co.) in DMSO (40 ml) containing Et3N (0.87 ml, 6.3 mmol) was stirred at 100°C for 15 hours. The resultant reaction mixture was cooled to 25°C, and 150 mol of a 2:1 (vohvol) mixture of ethyl acetate
(EtOAc) and brine was added. The organic phase was collected, washed with brine (150 ml), dried with sodium sulfate and concentrated to provide compound 3. Compound 3 was dissolved in DCM (50 ml) at 0°C, and a 50% aqueous solution of TFA (50 ml) was slowly added over 15 minutes. The resultant mixture was allowed to warm to 25°C and stirred for 24 hours at 25°C. The solvent was removed under reduced pressure, and the resultant residue purified using chromatography on a silica gel column (20% EtOAc in hexane as the initial eluent and then increasing to 50% EtOAc) to provide Compound 4 as a yellow powder (1.0 g, 87% yield). Step B
Figure imgf000107_0001
Figure imgf000107_0002
A solution of Compound 4 (200 mg, 1.09 mmol) in DMF (5 ml) was treated with phenylpropiolic acid (Compound 5) (159 mg, 1.09 mmol) (available from Aldrich Chemical Co.). To the resultant mixture was added a mixture of HOBt (334 mg, 2.18 mmol) and DIC (275 mg, 2.18 mmol) in one portion. The reaction mixture was stirred for 12 hours at 25 °C. The solvent was removed under reduced pressure, and the resultant residue was purified using flash chromatography (50% ethanol in n-hexane as the eluent) to provide Compound 186(ae) (245 mg, yield 72%). The structure of Compound 186(ae) was confirmed by 1H NMR and mass spectrometry. Compound 186(ae): 1H NMR (400 MHz, CD3OD): δ 3.61 (m, 2H), 3.82 (m, 2H), 6.71 (m, IH), 7.01 (s, IH), 7.31-7.52 (bm, 5H), 8.44 (m, 3H); MS (El): 310 (M+l).
5.2 Example 2; Synthesis of Compound 184(ae)
Step A
Figure imgf000108_0001
8
A solution of phenylpropiolyl chloride (Compound 6) (1.3 g, 7.9 mmol), N-Boc-ethylenediamine (1.3 g, 7.9 mmol) (Compound 2) and DIEA (1.3 ml, 7.9 mmol) in DCM (30 ml) was stirred at 25°C for 15 hours. The solvent was removed under reduced pressure, and the resultant residue was redissolved in DCM (5 ml) and treated with 50% TFA (50 ml). The solvent was removed under reduced pressure, and the resultant residue was purified using chromatography on a silica gel column (20% EtOAc in hexane as the initial eluent and then increasing to 50% EtOAc) to provide Compound 8 (1.39 g, yield 94%).
Step B
Figure imgf000109_0001
Figure imgf000109_0002
To a solution of Compound 8 (140 mg, 0.743 mmol) in DMF (10 ml) was added 2-chloropyrimidine (Compound 9) (85 mg, 0.743 mmol) in one portion followed by DIEA (95 mg, 0.743 mmol). The reaction mixture was stirred for 15 hours at 80°C. The solvent was removed under reduced pressure, and the resultant residue was purified using flash chromatography (50% ethyl acetate in n-hexane as the eluent) to provide Compound 184(ae) (150 mg, yield 76%). The structure of Compound 184(ae) was confirmed by 1H NMR and mass spectrometry. Compound 184(ae): 1H NMR (400 MHz, CD3OD): δ 5.11-5.45 (bm, 4H), 5.92 (s, IH), 6.56 (q, IH), 7.10 (s, IH), 7.22 (m, 2H), 7.45 (m, IH), 7.54 (m, 2H), 8.45 (t, 2H); MS (El): 267 (M+l).
5.3 Example 3: Synthesis of Compound 266(ae
Step A
Figure imgf000110_0001
A solution of Compound 1 (1.0 g, 6.30 mmol), N-Boc-1,3- diaminopropane (Compound 10) (1.1 g, 6.30 mmol) (Aldrich Chemical Co.) and Et3N (1.0 ml, 6.30 mmol) in DMSO (40 ml) was stirred at 100°C for 15 hours. The resultant mixture was cooled to about 25°C, and 150 ml of a 2:1 (vohvol:) mixture of EtOAc and brine was added. The organic phase was collected, washed with brine, dried with sodium sulfate and concentrated under reduced pressure to provide Compound 11.
Compound 11 was redissolved in DCM (5 ml), treated with 100 ml of 50% TFA at 25°C, and the resultant mixture was stirred for 2 hours at 25°C. The solvent was removed under reduced pressure, and the resultant residue was purified using chromatography on a silica gel column (20% EtOAc in hexane as the initial eluent and then increasing to 50% EtOAc) to provide Compound 12 as a yellow powder (1.1 g, yield 89%). Part B
Figure imgf000111_0001
266(ae)
To a solution of Compound 12 (300 mg, 1.53 mmol) and phenylpropiolic acid (Compound 5) (205 mg, 1.43 mmol) in DMF (4 ml) was added a mixture of HOBt (195 mg, 1.27 mmol) and DIC (193 mg, 1.53 mmol) in one portion. The reaction mixture was stirred for 15 hours at 25°C. The solvent was removed under reduced pressure, and the resultant residue was purified using flash chromatography (50% EtOAc in hexane as the eluent) to provide Compound 266(ae) (350 mg, yield 75%). The structure of Compound 266(ae) was confirmed by 1H NMR and mass spectrometry. Compound 266(ae): 1H NMR (400 MHz, CD3OD): δ 1.99 (bm, 2H), 3.41 (bm, 2H), 3.75 (bm, 2H), 6.61 (m, IH), 6.81 (s, IH), 7.35 (m, 3H), 7.51 (m, 2H), 8.52 (t, 3H); MS (El): 281 (M+l). 5.4 Example 4: Synthesis of Compound 425(u)
Step A
Figure imgf000112_0001
14
Figure imgf000112_0002
Compound 15 was obtained by a method that is analogous to that used to obtain Compound 4 as described in Example 1 (Step A), except that 2- chloronitrobenzene (Compound 13) (Aldrich Chemical Co.) was used in place of 2- choro-3-nitropyridine (Compound 1).
Ste B
Figure imgf000112_0003
Compound 17 was obtained by a metliod analogous to that used to obtain Compound 186(ae) described in Example 1 (Step B) except that propiolic acid (Compound 16) (Aldrich Chemical Co.) was used in place of phenylpropiolic acid (Compound 5), and Compound 15 was used in place of Compound 4.
Step C
Pd(Ph3P)2OAc2/CuI/Et3N EtOAC
Figure imgf000113_0001
Figure imgf000113_0002
Compound 425(u) was then prepared by reacting Compound 17 (100 mg, 0.4 mmol) and 2-iodopyridine (18) (80 mg, 0.4 mmol) at 25°C EtOAc in the presence of Pd(Ph3P)2OAc2 (15 mg, 0.03 mml), Cul (15 mg, 0.08 mmol), and Et3N (0.1 ml). Yield: 100 mg, 83%. The structure of Compound 425(u) was confirmed by 1H NMR and mass spectrometry. Compound 425(u): 1H NMR (400 MHz, CDC13): 8.60 (ddd, IH, J = 0.8,
1.5 and 4.8 Hz), 8.25 (br, IH), 8.16 (dd, IH, J = 1.5 and 8.6 Hz), 7.91 (ddd, IH, J = 1.5,
7.6 and 7.9 Hz), 7.71 (ddd, IH, J = 1.0, 7.8 and 7.9 Hz), 7.54-7.60 (m, 3H), 7.13 (dd, IH, J = 1.1 and 8.8 Hz), 6.71 (ddd, IH, J = 1.0, 7.0 and 8.7 Hz), 3.58-3.62 (m, 4H); MS (El): 311 (M+l)
5.5 Example 5: Synthesis of Compound 665(u) Compound 665(u) was obtained by a method that is analogous to that used to obtain Compound 425(u) as described in Example 4 except that 3-iodopyridine was used in place of 2-iodopyridine (Step C). The structure of Compound 665(u) was confirmed by 1H NMR and mass spectrometry. Compound 665(u): 1H NMR (400 MHz, CDC13): 8.75(s, IH), 8.65 (dd, IH, J = 1.3 and 4.8Hz), 8.19 (dd, IH, J = 1.3 and 8.7Hz), 7.83 (ddd, IH, J = 1.7, 1.9 and 7.8Hz), 7.49 (ddd, IH, J = 1.7, 7.0 and 7.8Hz), 7.3-7.34 (m, IH), 6.99 (dd, IH, J = 1.0 and 8.7Hz), 6.72 (ddd, IH, J = 1.5, 7.2 and 8.0Hz), 3.64-3.72 (m, 4H); MS (El): 311 (M+l). 5.6 Example 6: Synthesis of Compound 206(ae) Compound 206(ae) was obtained by a method that is analogous to that used to obtain Compound 184(ae) as described in Example 2 except that N-Boc-N- methylethylenediamine (prepared according to the procedure of Saari et al, J. Med. Chem. 33:97-101 (1990)) was used in place of N-Boc-ethylenediamine (Compound 2) (Step A), and 2-chloro-3-nitropyridine (Compound 1) was used in place of 2- chloropyrimidine (Compound 9) (Step B). The structure of Compound 206(ae) was confirmed by 1H NMR and mass spectrometry. Compound 206(ae): 1H NMR (400 MHz, CDC13): 8.35 (dd, 0.9H, J = 1.7 and 4.6 Hz) [rotamer 8.31 (dd, 0.1H, J = 1.7 and 4.6Hz)], 8.14 (dd, 0.9H, J = 1.7 and 7.9Hz) [rotamer 8.10 (dd, 0.1H, J = 1.7 and 7.9 Hz)], 7.51-7.54 (m, 2H), 7.36-7.44 (m, 3H), 7.20 (br, IH - NH), 6.77 (dd, 0.9H, J = 4.4 and 7.7 Hz) [rotamer 6.73 (dd, 0.1H, J = 4.6 and 7.9 Hz), 3.92-3.95 (m, 2H), 3.68-3.72 (m, 2H), 2.90 (s, 2.7H) [rotamer 2.91 (s, 0.3H)]; MS (El): 325 (M+l). 5.7 Example 7: Synthesis of Compound 185(ae) Compound 185(ae) was obtained by a method that is analogous to that used to obtain Compound 186(ae) as described in Example 1 except that 2-chloronitrobenzene (Aldrich Chemical Co.) was used in place of 2-chloro-3- nitropyridine (Compound 1) (Step A), and Compound 15 was used in place of Compound 4 (Step B). The structure of Compound 185(ae) was confirmed by 1H NMR and mass spectrometry. Compound 185(ae): 1H NMR (CDC13): 8.20 (br, IH), 8.14 (dd, 0.9H, J = 1.5 and 8.7 Hz) [rotamer 8.07 (dd, 0.1H, J = 1.5 and 8.7 Hz)], 7.33-7.53 (m, 7H), 7.00 (dd, IH, J = 1.1 and 8.7 Hz), 6.67 (ddd, IH, J = 1.1, 7.2 and 8.7 Hz), 3.31-3.34 (m, 4H); MS (El): 310 (M+l). 5.8 Example 8: Synthesis of Compound 1465(d) Compound 1465(d) was obtained by a method that is analogous to that used to obtain Compound 186(ae) as described in Example 1 except that 2-chloronitrobenzene was used in place of 2-chloro-3-nitropyridine (Compound 1) (Step A), and 2-heptynoic acid (Aldrich Chemical Co.) was used in place of phenylpropiolic acid (Compound 5) and Compound 15 was used in place of Compound 4 (Step B). The structure of Compound 1465(d)) was confirmed by 1H NMR and mass spectrometry. Compound 1465(d): 1H NMR (CDC13): 8.20 (dd, IH, J =1.5 and 8.6 Hz), 8.16 (br, IH), 7.46-7.51 (m, IH), 6.98 (dd, IH, J = 1.0 and 8.8 Hz), 6.71 (ddd, IH, J = 1.3, 7.0 and 8.5 Hz), 6.08 (br, IH), 3.56-3.62 (m, 3.8H) [rotamer 3.72-3.76 (m, 0.2H)], 2.25 (t, 2H, J = 7.1Hz), 1.52-1.6 (m, 2H), 1.40-1.47 (m, 2H), 0.93 (t, 3H, J = 7.2 Hz); MS (El): 290 (M+l).
5.9 Example 9: Synthesis of Compound 226(ae) Compound 226(ae) was obtained by a method that is analogous to that used to obtain Compound 186(ae) as described in Example 1 except that N-Boc-N- methylethylenediamine (see Example 6)) was used in place of Compound 2 (Step A of Example 1) The structure of Compound 226(ae) was confirmed by 1H NMR and mass spectrometry. Compound 226(ae): 1H NMR (CDC13): 8.45 (dd, IH, J = 1.7, 3.7 Hz),
8.38 (br, IH, NH), 8.31 (dd, IH, J = 1.9, 5.1 Hz), 7.35-7.55 (m, 5H), 6.54 (dd, 0.7H, J = 4.8, 7.8 Hz) [rotamer 6.69-6.72 (m, 0.3H)], 3.8-3.95 (m, 4H), 3.12 (s, 2.1H) [rotamer 3.36 (s, 0.9H)]; MS (El): 347 (M+23).
5.10 Example 10: Synthesis of Compound 1112(a) Compound 1112(a) was obtained by a method that is analogous to that used to obtain Compound 186(ae) as described in Example 1 that except 2-bromo-4,6- dimethylpyridine (prepared according to the procedure of G.J. Bridger et al, J. Med.
Chem. 1996, 39:109 (1996)) was used in place of Compound 1 (Step A) and 2-hexynoic acid (Lancaster Synthesis, Windham, NH) was used in place of Compound 5 (Step B).
The structure of Compound 1112(a) was confirmed by 1H NMR and mass spectrometry. Compound 1112(a): 1H NMR (CDC13): 8.20 (br, IH), 6.33 (s, IH), 6.07 (s, IH), 4.62 (br, IH), 3.44-3.56 (m, 4H), 2.38 (s, 2.8H) [2.35 (s, 0.2H)], 2.25 (t, 2H, J = 7.2 Hz), 2.18 (s, 3H), 1.53-1.61 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz); MS (El): 260 (M+l). 5.11 Example 11: Synthesis of Compound 1472(a) Compound 1472(a) was obtained by a method that is analogous to that used to obtain Compound 1112(a) as described in Example 10 except that 2-heptynoic acid (Aldrich) was used in place of 2-hexynoic acid. The structure of Compound 1472(a) was confirmed by 1H NMR and mass spectrometry. Compound 1472(a): 1H NMR (CDC13): 8.18 (br, IH), 6.34 (s, IH), 6.08
(s, 0.9H) [rotamer 6.03 (s, 0.1H)], 4.63 (br, IH), 3.42-3.52 (m, 4H), 2.38 (s, 2.7H) [2.35 (s, 0.3H)], 2.28 (t, 2H, J = 7.0 Hz), 2.19 (s, 3H), 1.48-1-54 (m, 2H), 1.37-1.43 (m,2H), 0.91 (t, 3H, J = 7.1 Hz); MS (El): 274 (M+l). 5.12 Example 12: Synthesis of Compound 1114(a) Compound 1114(a) was obtained by a method that is analogous to that used to obtain Compound 1112(a) as described in Example 10 except that 2-chloro- dimethylpyrimidine (Apollo Chemical, Burlington, NC) was used in place of 2-bromo-
4,6-dimethylpyridine. The structure of Compound 1114(a) was confirmed by 1H NMR and mass spectrometry. Compound 1114(a): 1H NMR (CDCI3): 7.83 (s, IH), 6.37 (s, IH), 5.59 (t, IH), 3.57 (m, 2H), 3.46 (m, 2H), 2.32 (s, 6H), 2.22 (t, 2H), 1.51 (m, 2H), 0.94 (t, 3H); MS (El): 261 (M+l). 5.13 Example 13: Synthesis of Compound 1744(d) Compound 1744(d) was obtained by a method that is analogous to that used to obtain Compound 425(u) as described in Example 4 except that 2-chloro- dimethylpyrimidine (Apollo Chemical) was used in place of Compound 13 (Step A) and l-fluoro-4-iodobenzene was used in place of Compound 18 (Step C). The structure of Compound 1744(d) was confirmed by 1H NMR and mass spectrometry. Compound 1744(d): 1H NMR (CDCI3): 8.15 (s, IH), 7.49 (m, 2H), 7.06
(m, 2H), 6.38 (s, IH), 5.32 (s, IH), 3.63 (m, 2H), 3.56 (m, 2H), 2.31 (s, 6H); MS (El): 313 (M+l)
5.14 Example 14: Binding of an Illustrative Diaminoalkylene Compound to mGIuR5 The following assay demonstrates that Compound 1465(d) (see Example
8), an illustrative Diaminoalkylene Compound binds to mGluR5. Cell Cultures: Primary glial cultures were prepared from cortices of
Sprague-Dawley 18 days old embryos. The cortices were dissected and then dissociated by trituration. The resulting cell homogenate was plated onto poly-D-lysine precoated T175 flasks (BIOCOAT, commercially available from Becton Dickinson and Company Inc. of Franklin Lakes, NJ) in Dulbecco's Modified Eagle's Medium ("DMEM," pH 7.4), buffered with 25 mM HEPES, and supplemented with 15% fetal calf serum ("FCS," commercially available from Hyclone Laboratories Inc. of Omaha, NE ), and incubated at 37°C and 5% CO2. After 24 hours, FCS supplementation was reduced to 10%. On day six, oligodendrocytes and microglia were removed by strongly tapping the sides of the flasks. One day following this purification step, secondary astrocytes cultures were established by subplating onto 96 poly-D-lysine precoated T175 flasks (BIOCOAT) at a density of 65,000 cells/well in DMEM and 10% FCS. After 24 hours, the astrocytes were washed with serum free medium and then cultured in DMEM, without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mL epidermal growth factor ("EGF"), 1 mM sodium pyruvate, and IX penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37°C and 5% CO2. The procedure allowed the expression of the mGluR5 receptor by astrocytes, as demonstrated by S. Miller et al, J. Neuroscience 15(9):6103- 6109 (1995). Assay Protocol: After 3-5 days incubation with EGF, the astrocytes were washed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl2, 700 mM NaH2PO4, 2 mM CaCl2, 5 mM NaHCO3, 8 mM HEPES, 10 mM Glucose at pH 7.4 ("Assay Buffer") and loaded with the dye FLUO-4 (commercially available from Molecular Probes Inc. of Eugene, OR) using 0.1 mL of Assay Buffer containing FLUO-4 (3 mM final). After 90 minutes of dye loading, the cells were then washed twice with 0.2 mL Assay Buffer and resuspended in 0.1 mL of Assay Buffer. The plates containing the astrocytes were then transfened to a Fluorometric Imaging Plate reader ("FLIPR") (commercially available from Molecular Devices Corporation of Sunnyvale, CA) for the assessment of calcium mobilization flux in the presence of glutamate and in the presence or absence of antagonist. After monitoring fluorescence for 15 seconds to establish a baseline, DMSO solutions containing various concentrations of the Diaminoalkylene Compounds diluted in Assay Buffer (0.05 mL of 4X dilutions for competition curves) was added to the cell plate and fluorescence were monitored for 2 minutes. 0.05 mL of a 4X glutamate solution (agonist) were then added to each well to provide a final glutamate concentration in each well of 10 mM. Plate fluorescence was then monitored for an additional 60 seconds after agonist addition. The final DMSO concentration in the assay was 1.0%. In each experiment, fluorescence was monitored as a function of time and the data analyzed using Microsoft Excel and GraphPad Prism. Dose-response curves were fit using a non-linear regression to determine the IC50 value. Compound 1465(d) showed an IC50 value of 17 ± 7.70 nM (mean of 4 experiments).
5.15 Example 15: Binding of a Diaminoalkylene Compound to mGluR5 Alternatively, the following assay can be used to demonstrate that
Diaminoalkylene Compounds bind to and modulate the activity of mGluR5. 40,000 CHO-rat mGluR5 cells/well are plated into 96 well plate (Costar 3409, Black, clear bottom, 96 well, tissue culture treated) for an about 16 hour incubation in Dulbecco's Modified Eagle's Medium (DMEM, pH 7.4) and supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500μg/mL Geneticin. CHO-rat mGluR5 cells are washed and treated with Optimem medium and incubated for 1-4 hours prior to loading cells. Cell plates are then washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl2, 700 μM Na H2PO4, 2 mM CaCl2, 5 mM NaHCO3, 8 mM Hepes, and 10 mM glucose, pH 7.4) and then incubated with 3μM Fluo 4 (commercially available from Molecular probes Inc. of Eugene, OR) in 0.1 mL of loading buffer. After 90 minutes of dye loading, the cells are then washed twice with 0.2 mL loading buffer and resuspended in 0.1 mL loading buffer. The plates containing the CHO-rat mGluR5 cells are then transfened to a FLIPR for the assessment of calcium mobilization flux in the presence of glutamate and in the presence or absence of test compounds. After monitoring fluorescence for 15 seconds to establish a baseline, DMSO solutions containing various concentrations of the test compound diluted in loading buffer (0.05 mL of 4X dilutions for the competition curves) are added to the cell plate and fluorescence is monitored for 2 minutes. 0.05 mL of 4X glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 μM. Plate fluorescence is then monitored for an additional 60 seconds after agonist addition. The final DMSO concentration in the assay is 1.0%. In each experiment, fluorescence is monitored as a function of time and the data analyzed using Microsoft Excel and GraphPad Prism. Dose-response curves are fit using a non-linear regression to determine the IC50 value. In each experiment, each data point is determined two times. 5.16 Example 16: In Vivo Assays for Treatment or Prevention of Pain The following assays can be used to demonstrate that Diaminoalkylene Compounds are useful for treating or preventing pain. Test Animals: Each experiment uses rats weighing between 200-260 g at the start of the experiment. The rats are group-housed and have free access to food and water at all times, except prior to oral administration of a Diaminoalkylene Compound when food is removed for 16 hours before dosing. A control group acts as a comparison to rats treated with a Diaminoalkylene Compound. The control group is administered the carrier for the Diaminoalkylene Compound. The volume of carrier administered to the control group is the same as the volume of earner and Diaminoalkylene Compound administered to the test group. Acute Pain: To assess the actions of the Diaminoalkylene Compounds for the treatment or prevention of acute pain the rat tail flick test can be used. Rats are gently restrained by hand and the tail exposed to a focused beam of radiant heat at a point 5 cm from the tip using a tail flick unit (Model 7360, commercially available from Ugo Basile of Italy). Tail flick latencies are defined as the interval between the onset of the thermal stimulus and the flick of the tail. Animals not responding within 20 seconds are removed from the tail flick unit and assigned a withdrawal latency of 20 seconds. Tail flick latencies are measured immediately before (pre-treatment) and 1, 3, and 5 hours following administration of a Diaminoalkylene Compound. Data are expressed as tail flick latency(s) and the percentage of the maximal possible effect (% MPE), i.e., 20 seconds, is calculated as follows: [ (post administration latency) - (pre-administration latency) ]
% MPE = X 100 (20 s pre-administration latency)
The rat tail flick test is described in F.E. D' Amour et al. , "A Method for Determining Loss of Pain Sensation," J. Pharmacol. Exp. Ther. 72:74-79 (1941). Acute pain can also be assessed by measuring the animal's response to noxious mechanical stimuli by determining the paw withdrawal threshold ("PWT"), as described below. Inflammatorv Pain: To assess the actions of the Diaminoalkylene
Compounds for the treatment or prevention of inflammatory pain the Freund's complete adjuvant ("FCA") model of inflammatory pain is used. FCA-induced inflammation of the rat hind paw is associated with the development of persistent inflammatory mechanical hyperalgesia and provides reliable prediction of the anti-hyperalgesic action of clinically useful analgesic drags (L. Bartho et al , "Involvement of Capsaicin-sensitive Neurones in Hyperalgesia and Enhanced Opioid Antinociception in Inflammation," Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)). The left hind paw of each animal is administered a 50 μL intraplantar injection of 50% FCA. 24 hour post injection, the animal is assessed for response to noxious mechanical stimuli by determining the PWT, as described below. Rats are then administered a single injection of 1, 3, 10 or 30 mg/kg of either a Diaminoalkylene Compound; 30 mg/kg of a control selected from Celebrex, indomethacin or naproxen; or canier. Responses to noxious mechanical stimuli are then determined 1, 3, 5 and 24 hours post administration. Percentage reversal of hyperalgesia for each animal is defined as:
[ (post administration PWT) - (pre-administration PWT) ]
% Reversal = X 100 [ (baseline PWT) - (pre-administration PWT) ] Neuropathic Pain: To assess the actions of the Diaminoalkylene Compounds for the treatment or prevention of neuropathic pain either the Seltzer model or the Chung model can be used. In the Seltzer model, the partial sciatic nerve ligation model of neuropathic pain is used to produce neuropathic hyperalgesia in rats (Z. Seltzer et al. , "A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury," Pain 43:205-218 (1990)). Partial ligation of the left sciatic nerve is performed under isoflurane/O2 inhalation anaesthesia. Following induction of anesthesia, the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps semitendinosus nerve branches off of the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle and tightly ligated so that the dorsal 1/3 to lΛ of the nerve thickness is held within the ligature. The wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue.
Following surgery, the wound area is dusted with antibiotic powder. Sham-treated rats undergo an identical surgical procedure except that the sciatic nerve is not manipulated. Following surgery, animals are weighed and placed on a warm pad until they recover from anesthesia. Animals are then returned to their home cages until behavioral testing begins. The animal is assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3 and 5 hours after drug administration for the left rear paw of the animal. Percentage reversal of neuropathic hyperalgesia is defined as: [ (post administration PWT) - (pre-administration PWT) ]
% Reversal = X 100 [ (baseline PWT) - (pre-administration PWT) ]
In the Chung model, the spinal nerve ligation model of neuropathic pain is used to produce mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats. Surgery is performed under isoflurane/θ2 inhalation anaesthesia. Following induction of anaesthesia a 3 cm incision is made and the left paraspinal muscles are separated from the spinous process at the L - S2 levels. The L6 transverse process is carefully removed with a pair of small rongeurs to identify visually the L4 - L6 spinal nerves. The left L5 (or L5 and L6) spinal nerve(s) is isolated and tightly ligated with silk thread. A complete hemostasis is confirmed and the wound is sutured using non- absorbable sutures, such as nylon sutures or stainless steel staples. Sham-treated rats undergo an identical surgical procedure except that the spinal nerve(s) is not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they recover from the anesthesia. Animals are then returned to their home cages until behavioral testing begins. The animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3 and 5 hours after being administered a Diaminoalkylene Compound for the left rear paw of the animal. The animal can also be assessed for response to noxious thermal stimuli or for tactile allodynia, as described below. The Chung model for neuropathic pain is described in S.H. Kim, "An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat," Pain 50(3):355-363 (1992). Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalgesia: The paw pressure assay can be used to assess mechanical hyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in C. Stein, "Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds," Pharmacol. Biochem. and Behavior 31 :451-455 (1988). The maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw. PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested. Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia: The plantar test can be used to assess thermal hyperalgesia. For this test, hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available from Ugo Basile of Italy) following the technique described by K. Hargreaves et al, "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain 32(l):77-88 (1988). The maximum exposure time is set at 32 seconds to avoid tissue damage and any directed paw withdrawal from the heat source is taken as the end point. Three latencies are determined at each time point and averaged. Only the affected (ipsilateral) paw is tested. Assessment of Tactile Allodynia: To assess tactile allodynia, rats are placed in clear, plexiglass compartments with a wire mesh floor and allowed to habituate for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to the plantar surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive behavioral responses.
5.17 Example 17: In Vivo Assays for Treatment or Prevention of Anxiety The elevated plus maze test or the shock-probe burying test can be used to assess the anxiolytic activity of Diaminoalkylene Compounds in rats or mice. The Elevated Plus Maze Test: The elevated plus maze consists of a platform with 4 arms, two open and two closed (50 x 10 x 50 cm enclosed with an open roof). Rats (or mice) are placed in the center of the platform, at the crossroad of the 4 arms, facing one of the closed arms. Time spent in the open arms vs. the closed arms and number of open arm entries during the testing period are recorded. This test is conducted prior to drug administration and again after drag administration. Test results are expressed as the mean time spent in open arms and the mean number of entries into open arms. Known anxiolytic drags increase both the time spent in open arms and number of open arm entries. The elevated plus maze test is described in D. Treit, "Animal Models for the Study of Anti-anxiety Agents: A Review," Neuroscience & Biobehavioral Reviews 9(2):203-222 (1985). The Shock-Probe Burying Test: For the shock-probe burying test the testing apparatus consists of a plexiglass box measuring 40 x 30 x 40 cm, evenly covered with approximately 5 cm of bedding material (odor absorbent kitty litter) with a small hole in one end through which a shock probe (6.5 cm long and 0.5 cm in diameter) is inserted. The plexiglass shock probe is helically wrapped with two copper wires through which an electric current is administered. The cunent is set at 2 mA. Rats are habituated to the testing apparatus for 30 min on 4 consecutive days without the shock probe in the box. On test day, rats are placed in one corner of the test chamber following drag administration. The probe is not electrified until the rat touches it with its snout or fore paws, at which point the rat receives a brief 2 mA shock. The 15 min testing period begins once the rat receives its first shock and the probe remains electrified for the remainder of the testing period. The shock elicits burying behavior by the rat. Following the first shock, the duration of time the rat spends spraying bedding material toward or over the probe with its snout or fore paws (burying behavior) is measured as well as the number of contact-induced shocks the rat receives from the probe. Known anxiolytic drugs reduce the amount of burying behavior. In addition, an index of the rat's reactivity to each shock is scored on a 4 point scale. The total time spent immobile during the 15 min testing period is used as an index of general activity. The shock-probe burying test is described in D. Treit, 1985, supra.
5.18 Example 18: In Vivo Assays for Treatment or Prevention of an Addictive Disorder The conditioned place preference test or drag self-administration test can be used to assess the ability of Diaminoalkylene Compounds to attenuate the rewarding properties of known drugs of abuse. The Conditioned Place Preference Test: The apparatus for the conditioned place preference test consists of two large compartments (45 x 45 x 30 cm) made of wood with a plexiglass front wall. These two large compartments are distinctly different. Doors at the back of each large compartment lead to a smaller box (36 x 18 x 20 cm) box made of wood, painted grey, with a ceiling of wire mesh. The two large compartments differ in terms of shading (white vs. black), level of illumination (the plexiglass door of the white compartment is covered with aluminum foil except for a window of 7 x 7 cm), texture (the white compartment has a 3 cm thick floor board (40 x 40 cm) with nine equally spaced 5 cm diameter holes and the black has a wire mesh floor), and olfactory cues (saline in the white compartment and 1 mL of 10% acetic acid in the black compartment). On habituation and testing days, the doors to the small box remain open, giving the rat free access to both large compartments. The first session that a rat is placed in the apparatus is a habituation session and entrances to the smaller grey compartment remain open giving the rat free access to both large compartments. During habituation, rats generally show no preference for either compartment. Following habituation, rats are given 6 conditioning sessions. Rats are divided into 4 groups: carrier pre-treatment + canier (control group), Diaminoalkylene Compound pre-treatment + carrier, carrier pre-treatment + morphine, Diaminoalkylene Compound pre-treatment + morphine. During each conditioning session the rat is injected with one of the drag combinations and confined to one compartment for 30 min. On the following day, the rat receives a carrier + carrier treatment and is confined to the other large compartment. Each rat receives three conditioning sessions consisting of 3 drag combination-compartment and 3 carrier- compartment pairings. The order of injections and the drag/compartment pairings are counterbalanced within groups. On the test day, rats are injected prior to testing (30 min to 1 hour) with either morphine or carrier and the rat is placed in the apparatus, the doors to the grey compartment remain open and the rat is allowed to explore the entire apparatus for 20 min. The time spent in each compartment is recorded. Known drags of abuse increase the time spent in the drug-paired compartment during the testing session. If the Diaminoalkylene Compound blocks or reduces the acquisition of morphine conditioned place preference (reward), there will be no difference in time spent in each side in rats pre-freated with a Diaminoalkylene Compound and the group will not be different from the group of rats that was given carrier + canier in both compartments. Data will be analyzed as time spent in each compartment (drag combination-paired vs. carrier-paired). Generally, the experiment is repeated with a minimum of 3 doses of a Diaminoalkylene Compound. The Drag Self- Administration Test: The apparatus for the drug self- administration test is a standard commercially available operant conditioning chamber. Before drag trials begin rats are trained to press a lever for a food reward. After stable lever pressing behavior is acquired, rats are tested for acquisition of lever pressing for drug reward. Rats are implanted with chronically indwelling jugular catheters for i.v. administration of compounds and are allowed to recover for 7 days before training begins. Experimental sessions are conducted daily for 5 days in 3 hour sessions. Rats are trained to self-administer a known drug of abuse, such as morphine. Rats are then presented with two levers, an "active" lever and an "inactive" lever. Pressing of the active lever results in drag infusion on a fixed ratio 1 (FR1) schedule (i.e., one lever press gives an infusion) followed by a 20 second time out period (signaled by illumination of a light above the levers). Pressing of the inactive lever results in infusion of excipient. Training continues until the total number of morphine infusions stabilizes to within ± 10% per session. Trained rats are then used to evaluate the effect of
Diaminoalkylene Compounds pre-treatment on drug self-administration. On test day, rats are pre-treated with a Diaminoalkylene Compound or excipient and then are allowed to self-administer drag as usual. If the Diaminoalkylene Compound blocks or reduces the rewarding effects of morphine, rats pre-treated with the Diaminoalkylene Compound will show a lower rate of responding compared to their previous rate of responding and compared to excipient pre-treated rats. Data is analyzed as the change in number of drag infusions per testing session (number of infusions during test session - number of infusions during training session). 5.19 Example 19: Functional Assay for Characterizing mGluRl Antagonistic Properties Functional assays for the characterization of mGluRl antagonistic properties are known in the art. For example, the following procedure can be used. A CHO-rat mGluRl cell line is generated using cDNA encoding rat mGluRl receptor (M. Masu et al, Nature 349:760-765 (1991)). The cDNA encoding rat mGluRla receptor can be obtained from, e.g., Prof. S. Nakanishi (Kyoto, Japan). 40,000 CHO-rat mGluRl cells/well are plated into a COSTAR 3409, black, clear bottom, 96 well, tissue culture treated plate (commercially available from Fisher Scientific of Chicago, IL) and are incubated in Dulbecco's Modified Eagle's Medium (DMEM, pH 7.4) supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500 μg/mL Geneticin for about 12 h. The CHO-rat mGluRl cells are then washed and treated with OPTIMEM medium (commercially available from Invitrogen, Carlsbad, CA) and incubated for a time period ranging from 1 to 4 hours prior to loading the cells with the dye FLUO-4. After incubation, the cell plates are washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl2, 700 μM, NaH2PO4, 2 mM CaCl2, 5 mMNaHCO3, 8 mM HEPES, and 10 mM glucose, pH 7.4) and incubated with 3 μM FLUO-4 in 0.1 mL loading buffer for 90 min. The cells are then washed twice with 0.2 mL loading buffer, resuspended in 0.1 mL of loading buffer, and ttansfened to a FLIPR for measurement of calcium mobilization flux in the presence of glutamate and in the presence or absence of a Diaminoalkylene Compound. To measure calcium mobilization flux, fluoresence is monitored for about
15 s to establish a baseline and DMSO solutions containing various concentrations of a Diaminoalkylene Compound ranging from about 50 μM to about 0.8 nM diluted in loading buffer (0.05 mL of a 4X dilution) are added to the cell plate and fluoresence is monitored for about 2 min. 0.05 mL of a 4X glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 μM and fluoresence is monitored for about one additional min. The final DMSO concentration in the assay is 1%. In each experiment fluoresence is monitored as a function of time and the data is analyzed using a non-linear regression to determine the IC5o value. In each experiment each data point is determined twice. The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. A number of references have been cited, the entire disclosures of which are incorporated herein by reference.

Claims

What is claimed is: 1. A compound of formula:
Figure imgf000128_0001
or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2 or 3; Ri and Ri' are each independently -H or -(Cι-C )alkyl; (a) when n is 1 or 2, then R2 is -H, -(Ci-Cio)alkyl, -(C2-Cio)alkenyl, -(C2-Cio)alkynyl, -(C3-C10)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C8-C14)tticycloalkyl, -(C5-C1o)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heteroaryl, -(3- to 7-membered)heterocycle, -(7- to
10-membered)bicycloheterocycle, -phenyl, -naphthyl -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which, other than -H, is unsubstituted or substituted with one or more R4; or (b) when n is 3, then R2 is -H, -(C1-C1o)alkyl, -(C2-Cio)alkenyl, -(C2-Cio)alkynyl, -(C3-C10)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C8-C14)tticycloalkyl, -(C5-Cio)cycloalkenyl, -(C8-C1 )bicycloalkenyl, -(C8-C1 )tricycloalkenyl, -2-pyridyl, 4-pyridyl, -furyl, -thiophenyl, -pyπolyl, -oxazolyl, -imidazolyl, -thiazolyl, -isoxazolyl, -pyrazolyl, -isothiazolyl, -pyridazinyl, -pyrimidinyl, -pyrazinyl, -triazinyl, -morpholinyl, -pynolidinonyl, -pynolidinyl, -piperidinyl, -piperazinyl, -hydantoinyl, -valerolactamyl, -oxiranyl, -oxetanyl, -tettahydrofuranyl, -tetrahydropyranyl, -tetraliydropyrindinyl, -tetøahydropyrimidinyl, -tetrahydrothiophenyl, -tetrahydrothiopyranyl, -(3- to 7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle, -phenyl, -naphthyl -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which, other than -H, is unsubstituted or substituted with one or more R4 groups; each R3 is independently -H, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(C2- C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5- membered)heterocycle, -C(halo)3, -CH(halo)2, -OCH(halo)2, -CN, -OH, -halo, -N3, -NO2, -NH2, -N(H)(R4), -N(R4)2, -CH=NR4, -CH=NH, -NHOH, -NR4OH, -OR5, -COR5, -C(O)OR5, -OC(O)R5, -OC(O)OR5, -SR5, -S(O)R5 or -S(O)2R5; each R is independently -(Ci-C6)alkyl, -C(halo)3, -CH(halo)2, -OCH(halo)2, -CN, -OH, -halo, -NO2, -OR5, -COR5, -C(O)OR5, -OC(O)R5, or -OC(O)OR5; each R5 is independently -H, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(C2- C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5- membered)heterocycle, -C(halo)3, or -CH(halo)2; X is C(H) or N; Y is N, C(H), C(NO2), C(CN), C(halo), C(CH3), or C(CF3); Z is C(H) or N; and each halo is independently -F, -CI, -Br or -I.
2. The compound of claim 1, wherein: n is 1, 2 or 3; R2 is -(Ci-Cio)alkyl, -phenyl, -2-pyridyl or -4-pyridyl; each R3 is -H; X is C(H); and Y is -N, C(H) or C(NO2).
3. The compound of claim 2, wherein n is 2, R\ and Ri' are each -H, R2 is -phenyl, Y is C(NO2) and Z is N.
4. The compound of claim 2, wherein n is 3, R\ and Ri' are each -H, R2 is -phenyl, Y is C(NO2) and Z is N.
5. The compound of claim 2, wherein n is 2, R\ is -H, Ri' is -CH3, R is -phenyl, Y is C(NO2) and Z is N.
6. The compound of claim 2, wherein n is 2, R\ and Ri' are each -H, R2 is -phenyl, Y is N and Z is N.
7. The compound of claim 2, wherein n is 2, Ri and Ri' are each H, R2 is -phenyl, Y is C(NO2) and Z is C(H).
8. The compound of claim 2, wherein n is 2, Ri and Ri' are each H, R2 is -n-butyl, Y is C(NO2) and Z is C(H).
9. The compound of claim 2, wherein n is 2, Ri and Ri' are each H,
R2 is -2-pyridyl, Y is C(NO2) and Z is C(H).
10. The compound of claim 2, wherein n is 2, Ri and Ri' are each H, R2 is -4-pyridyl, Y is C(NO2) and Z is C(H).
11. The compound of claim 2, wherein n is 3, and R2 is -phenyl, -2-pyridyl or -4-pyridyl.
12. A composition comprising an effective amount of a compound of any of claims 1-11 and a pharmaceutically acceptable canier or excipient.
13. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of the compound of any of claims 1-11.
14. The method of claim 13, further comprising adjunctively administering to the animal an effective amount of another therapeutic agent.
15. A method for treating an addictive disorder in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of the compound of any of claims 1-11.
16. The method of claim 15, further comprising adjunctively administering to the animal an effective amount of another therapeutic agent.
17. A method for treating anxiety in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of the compound of any of claims 1-11.
18. The method of claim 17, further comprising adjunctively administering to the animal an effective amount of another therapeutic agent.
19. A method for treating Parkinson's disease in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of the compound of any of claims 1-11.
20. The method of claim 19, further comprising adjunctively administering to the animal an effective amount of another therapeutic agent.
21. A method for treating depression in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of the compound of any of claims 1-11.
22. The method of claim 21, further comprising adjunctively administering to the animal an effective amount of another therapeutic agent.
23. A method for treating schizophrenia in an animal, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of the compound of any of claims 1-11.
24. The method of claim 23, further comprising adjunctively administering to the animal an effective amount of another therapeutic agent.
25. A method for inhibiting mGluR5-receptor function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a compound or a pharmaceutically acceptable salt of the compound of any of claims 1- 11.
26. The method of claim 25, further comprising contacting the cell with an effective amount of another therapeutic agent.
27. A method for inhibiting mGluRl -receptor function in a cell, comprising contacting a cell capable of expressing mGluRl with an effective amount of a compound or a pharmaceutically acceptable salt of the compound of any of claims 1- 11.
28. The method of claim 27, further comprising contacting the cell with an effective amount of another therapeutic agent.
29. A method for preparing a composition, the method comprising admixing a compound or a pharmaceutically acceptable salt of the compound of any of claims 1-11 and a pharmaceutically acceptable canier or excipient.
30. A kit comprising a container containing the composition of claim 12.
PCT/US2004/033621 2003-10-09 2004-10-11 Therapeutic agents useful for treating pain WO2005035500A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51081003P 2003-10-09 2003-10-09
US60/510,810 2003-10-09

Publications (2)

Publication Number Publication Date
WO2005035500A2 true WO2005035500A2 (en) 2005-04-21
WO2005035500A3 WO2005035500A3 (en) 2005-05-19

Family

ID=34435130

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/033621 WO2005035500A2 (en) 2003-10-09 2004-10-11 Therapeutic agents useful for treating pain

Country Status (1)

Country Link
WO (1) WO2005035500A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005062986A1 (en) * 2005-12-28 2007-07-05 Grünenthal GmbH New substituted propiolic acid amides, useful for treatment and prevention of e.g. pain, anxiety and panic attacks, are inhibitors of the mGluR5 receptor
WO2007079958A1 (en) * 2005-12-28 2007-07-19 Grünenthal GmbH Substituted bis(hetero)aromatic n-ethylpropiolamides and use thereof for production of medicaments
WO2007079961A1 (en) * 2005-12-28 2007-07-19 Grünenthal GmbH Substituted thiazoles and their use for producing drugs
JP2009522222A (en) * 2005-12-28 2009-06-11 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Substituted thiazole and its use in the manufacture of a medicament

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003093236A1 (en) * 2002-05-02 2003-11-13 Euro-Celtique, S.A. 1-(pyrid-2-yl)-piperazine compounds as metabotropic glutamate receptor inhibitor
WO2004029044A1 (en) * 2002-09-24 2004-04-08 Euro-Celtique, S.A. Pyrimidine compounds as therapeutic agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003093236A1 (en) * 2002-05-02 2003-11-13 Euro-Celtique, S.A. 1-(pyrid-2-yl)-piperazine compounds as metabotropic glutamate receptor inhibitor
WO2004029044A1 (en) * 2002-09-24 2004-04-08 Euro-Celtique, S.A. Pyrimidine compounds as therapeutic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ISHIZUMI ET AL: "Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)- 1-piperazinylÜbutylÜ-2,3- bicyclo[2.2.1Üheptanedicarboximide (tandospirone) and related compounds" CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN. TOKYO, JP, vol. 39, no. 9, 1991, pages 2288-2300, XP002103452 ISSN: 0009-2363 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005062986A1 (en) * 2005-12-28 2007-07-05 Grünenthal GmbH New substituted propiolic acid amides, useful for treatment and prevention of e.g. pain, anxiety and panic attacks, are inhibitors of the mGluR5 receptor
WO2007079958A1 (en) * 2005-12-28 2007-07-19 Grünenthal GmbH Substituted bis(hetero)aromatic n-ethylpropiolamides and use thereof for production of medicaments
WO2007079961A1 (en) * 2005-12-28 2007-07-19 Grünenthal GmbH Substituted thiazoles and their use for producing drugs
JP2009522222A (en) * 2005-12-28 2009-06-11 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Substituted thiazole and its use in the manufacture of a medicament
JP2009522220A (en) * 2005-12-28 2009-06-11 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Substituted bis (hetero) aromatic N-ethylpropioramide and its use in the manufacture of a medicament
JP2009522223A (en) * 2005-12-28 2009-06-11 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Substituted thiazole and its use for the manufacture of a medicament
US8008304B2 (en) 2005-12-28 2011-08-30 Grüenthal GmbH Substituted propiolic acid amides and their use for producing drugs
US8318774B2 (en) 2005-12-28 2012-11-27 Gruenenthal Gmbh Compounds involving mGluR5 receptor regulation and methods of making the compounds

Also Published As

Publication number Publication date
WO2005035500A3 (en) 2005-05-19

Similar Documents

Publication Publication Date Title
US6864261B2 (en) Therapeutic agents useful for treating pain
CA2533509C (en) Piperidine compounds and pharmaceutical compositions containing them
KR100896497B1 (en) Therapeutic agents useful for treating pain
WO2005056524A2 (en) Therapeutic agents useful for treating pain
WO2004058754A1 (en) Benzoazolypiperazine derivatives having mglur1- and mglur5-antagonistic activity
WO2004011441A1 (en) Pyridazinylpiperazine derivatives for treating pain
EP1664041A1 (en) Phenyl-carboxamide compounds useful for treating pain
WO2004029031A2 (en) Therapeutic piperazine compounds
WO2005030753A2 (en) Therapeutic agents useful for treating pain
CA2534088C (en) 2,3-substituted pryidl compounds useful for treating pain
WO2004002983A2 (en) Therapeutic piperazine derivatives useful for treating pain
WO2003093236A1 (en) 1-(pyrid-2-yl)-piperazine compounds as metabotropic glutamate receptor inhibitor
KR100867188B1 (en) Piperazines useful for treating pain
WO2004029044A1 (en) Pyrimidine compounds as therapeutic agents
WO2005007641A1 (en) 2-pyridine alkyne derivatives useful for treating pain
WO2005035500A2 (en) Therapeutic agents useful for treating pain

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application