CN1292698A - Glycine transport inhibitors - Google Patents
Glycine transport inhibitors Download PDFInfo
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- CN1292698A CN1292698A CN998036471A CN99803647A CN1292698A CN 1292698 A CN1292698 A CN 1292698A CN 998036471 A CN998036471 A CN 998036471A CN 99803647 A CN99803647 A CN 99803647A CN 1292698 A CN1292698 A CN 1292698A
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- 239000004471 Glycine Substances 0.000 title claims abstract description 25
- 239000003112 inhibitor Substances 0.000 title description 2
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention is concerned with the use of glycine transport inhibiting [4,4-bis(4-fluorophenyl)butyl]-1-(piperazinyl and piperidinyl) derivatives for the preparation of medicaments for treating disorders of the central and peripheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. The invention further comprises novel compounds, their preparation and their pharmaceutical forms.
Description
The present invention relates to suppress [4 of glycine transmission, 4-is two-(4-fluoro phenyl) butyl]-1-(piperazinyl and piperidyl) derivant is used for the treatment of purposes in the medicine of maincenter and peripheral nervous system disorder in preparation, especially for the purposes of treatment psychosis, pain, epilepsy, neurodegenerative disease (AlzheimerShi disease), apoplexy, brain injury, multiple sclerosis etc.The present invention has also comprised the preparation and the pharmaceutical dosage form thereof of noval chemical compound further.
[4, two (the 4-fluoro phenyl) butyl of 4-]-1-(piperazine and piperidyl) derivant is well-known histamine and 5-hydroxytryptamine antagonist.Active and the preparation of these chemical compounds is disclosed in EP-A-0, and 151,826 and GB-1,055,100.
The chemical compound that the present invention relates to suppress the glycine transmission is used for the treatment of purposes in the medicine of maincenter and peripheral nervous system disorder in preparation, and the structural formula that described chemical compound has is:
Its N-oxide, three-dimensional chemical isomer and pharmaceutically acceptable addition salt, wherein
X represents CH or N;
L represents the group of following formula
Wherein n is 0 or 1;
M is 0 or 1;
Alk represents C
1-6Alkane two bases (alkanediyl);
A represents N or CH;
B
1Expression CH
2Or NH;
-a
1=a
2-a
3=a
4The divalent group of-expression following formula
-CH=CH-CH=CH-(a-1); Or
-N=CH-CH=CH-(a-2)；
R
1Expression is by C
1-4Alkoxyl, pyridine radicals, aryl, aryl carbonyl, thienyl, furyl, imidazole radicals [1,2-a] pyridine radicals, the optional C that replaces of thiazolyl
1-4Alkyl;
R
2Expression hydrogen or aryl;
R
3Expression hydrogen, C
1-6Alkyl or C
3-7Cycloalkyl;
R
4The group of expression thienyl, furyl, arylamino or following formula
R wherein
5Be hydrogen atom or aryl;
Aryl represents to be selected from C
1-4Alkyl, halo, hydroxyl, C
1-4The optional phenyl that replaces of 1 or 2 substituent group in the alkoxyl.
The invention still further relates to the method for treatment trouble maincenter and peripheral nervous system disorders homoiothermic animal, particularly for psychosis, pain, epilepsy, neurodegenerative disease (AlzheimerShi disease), apoplexy, brain injury, multiple sclerosis etc.Described Therapeutic Method comprises the mixture that is formed by the addition salts of the chemical compound of the structure formula I of signing an undertaking or its N-oxide form, pharmaceutically acceptable acid or alkali or its three-dimensional chemical isomer and pharmaceutical carrier of taking certain effectively therapeutic dose.
As at preamble with hereinafter relate to, halogenated classification has fluoro, chloro, bromo and iodo; C
3-7The type of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl; C
1-4Alkyl refers to the straight chain and the branched saturated hydrocarbon group of a tool 1-4 carbon atom, as methyl, ethyl, propyl group, butyl, 1-Methylethyl, 2-methyl-propyl, 2,2-dimethyl ethyl etc.; C
1-6Alkyl comprises C
1-4Alkyl and its have the more high-grade homologue of 5 or 6 carbon atoms, as amyl group, 2-methyl butyl, heptyl, 2-methyl amyl etc.; C
1-6Alkane two bases refer to the bivalence straight chain and the branched saturated hydrocarbon group of a tool 1-6 carbon atom, as 1, and 1-first two bases, 1,2-second two bases, 1,3-glyceryl, 1,4-fourth two bases, 1,5-penta 2 bases, 1,6-dihexyl, 1,2-glyceryl, 2,3-fourth two bases etc.
The pharmaceutically acceptable addition salt of above mentioning means and comprises alkali that can be formed by the formula I chemical compound, the tool therapeutic activity, nontoxic and acid-addition salts.The acid-addition salts form of formula I chemical compound can obtain by adopting the described free alkali of suitable acid treatment, can select mineral acid for use, as the acid of types such as halogen acids (example hydrochloric acid or hydrobromic acid), sulphuric acid, nitric acid, phosphoric acid; Also can select organic acid for use, as the acid of types such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, acetone acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexane sulfamic acid, salicylic acid, p-aminosallcylic acid, pamoic.
The formula I chemical compound that comprises acid proton can be converted into the addition salts form of its nontoxic alkali that therapeutic activity is arranged (as metal or amine), method be with suitable organic or inorganic alkali treatment they.Suitable base salt forms comprises, as ammonium salt, alkali metal and alkali salt (as lithium, sodium, potassium, magnesium, calcium salt etc.), organic alkali salt (as N, benzathine (benzatzhine), N-methyl D-glucamine, Compocillin salt) and the salt that become with aminoacid (as arginine, lysine etc.).
Conversely, described salt form also can be by being converted into free form with suitable alkali or acid treatment.
Addition salts one speech of above using also comprises the solvate that can be formed by formula I chemical compound and their salt, and these solvates are the chemical compounds as types such as hydrate, alcoholates.
The N-oxide form of formula I chemical compound refers to the formula I chemical compound that one or several nitrogen-atoms in the formula I chemical compound is oxidized to so-called N-oxide.
Preamble and the term " stereoptics isomer " used hereinafter comprise all possible stereoisomer that formula I chemical compound wherein can generate.If do not mention especially or illustrate that chemical compound promptly refers to the mixture of all possible three-dimensional chemical isomer, be racemic mixture specifically.All diastereomers and the enantiomer of described mixture inclusion compound basic structure.
The structure formula I obviously comprises three-dimensional chemical isomer and these mixture of isomers of formula I chemical compound.
Specifically, formula I chemical compound and some intermediate after this have a solid phase center at least in their structure.This solid phase center can exist with R or S configuration, and the service regeulations of described R and S sign and pure applied chemistry (1976,45,11-30) the middle unanimity of describing.
Some chemical compounds of formula I also can their tautomers form exist.Though this form clearly is not shown in the said structure formula, is contained within the scope of the present invention yet.
Below, all comprise its N-oxide, its pharmaceutically acceptable addition salt and all stereoisomers thereof in this term of formula I chemical compound.
When possessing following precondition, formula I chemical compound of the present invention can be thought new:
-represent CH as X; L is wherein B of formula (a)
1Expression-CH
2-, R
1Be pyridine-2-ylmethyl, thiophene-2-ylmethyl, furan-2-ylmethyl, when benzyl or 4-fluorobenzene methyl, then-a
1=a
2-a
3=a
4-do not represent-N=CH-CH=CH-;
-represent CH as X; L expression (a) is B wherein
1Expression-CH
2-, R
1When expression 4-anisyl methyl or thiazole-4-ylmethyl, then-a
1=a
2-a
3=a
4-do not represent-CH=CH-CH=CH-;
-represent N as X; L expression (a) wherein Alk represents 1, during the 3-glyceryl, and R then
4Do not represent phenyl.
The invention still further relates to the new formula I chemical compound of above mentioning, be used as medicine.
The important chemical compound of one class is wherein n=0 of formula I chemical compound, m=1; R
1For choosing wantonly by C
1-4The C that alkoxyl, aryl carbonyl or imidazo [1,2-a] pyridine radicals replaces
1-4Alkyl; R
4Be the group shown in thienyl, furyl or the formula (d-1).
Preferred chemical compound is wherein L expression (a) or a group (b) of formula I chemical compound.
Generally speaking, the formula I chemical compound can be according to EP-A-O, and 151,826 and GB-1, the reactions steps described in 055,100 and making more particularly, is the intermediate (W wherein by formula II
1Represent suitable leaving group such as halogen) get with the intermediate reaction of formula III.
Described reaction can in the dinethylformamide, in the presence of suitable alkali such as sodium carbonate, sodium bicarbonate or triethylamine, and be chosen wantonly in the presence of potassium iodide and carry out at atent solvent such as methyl iso-butyl ketone (MIBK), N,N-dimethylacetamide or N.
In this preparation and preparation hereinafter, if necessary, can come out product separation and purification from reaction medium.The method that is further purified can be according to methods that are generally known in the art, for example extraction method, crystallization process, the way of distillation, polishing and chromatography.
In addition, the formula I chemical compound also can make by reductive alkylation reaction.Then, the intermediate that makes the intermediate of formula IV and formula III is in reaction-inert solvent such as methanol, in the presence of Reducing agent as hydrogen, react in the presence of the palladium on the active carbon at suitable catalyst such as appendix, at the convenient time thiophene is added in the reactant mixture then.
Wherein X represents the formula I chemical compound of N, and described chemical compound (during the expression of I-a), the intermediate that can make formula (V) and formula make for the intermediate of (VI) reacts, wherein W with structural formula
1Be suitable leaving group, for example halogen.
Described reaction can in the dinethylformamide, at suitable alkali, exist down as sodium carbonate, sodium bicarbonate or triethylamine, and choose wantonly in the presence of potassium iodide and carry out at reaction-inert solvent such as methyl iso-butyl ketone (MIBK), N,N-dimethylacetamide or N.
The formula I chemical compound of the group of L expression (b) wherein, described chemical compound can be by formula (I-b) expression, but the isocyanate group derivatives reaction of the intermediate of through type (VII) and formula (VIII) and obtaining.
Described reaction can be carried out in reaction-inert solvent such as Di Iso Propyl Ether.
The formula I chemical compound also can transform mutually according to the known functional group method for transformation in field.
The employing field is known to be tervalent nitrogen transformation the method for its N-oxide form, and the formula I chemical compound also can be converted into its corresponding N-oxide form.The reaction of described N-oxide can make by reacting the starting material of formula I and 3-phenyl-2-(benzenesulfonyl) oxaziridine or with suitable organic or inorganic peroxide usually.Suitable inorganic peroxide comprises as hydrogen peroxide, alkali metal or alkaline earth metal peroxide (as sodium peroxide, potassium peroxide); Suitable organic peroxide can comprise peroxy acid (sour as 3-chloro benzenecarboperoxoic acid as benzenecarboperoxoic acid or halo benzenecarboperoxoic), peroxidating alkanoic acid (as peroxidating acetic acid), alkyl peroxide (as tert-butyl hydroperoxide); Appropriate solvent is as water, such as the mixture of low-level chain triacontanol, carbohydrate (as toluene, ketone such as 2-butanone), halo carbohydrate such as dichloromethane and these solvents of ethanol etc.
Some formula I chemical compounds and some intermediate of the present invention can comprise asymmetric carbon atoms.The pure form of three-dimensional chemical isomer of described chemical compound and described intermediate can obtain by the known method in employing field.For example, diastereomer can come by physical method for separation, and these methods comprise that selective crystallization or chromatographic separation technology such as adverse current distribute methods such as liquid chromatograph.Adopt selective crystallization or methods such as chromatographic separation technology such as liquid chromatography (LC), can at first above-mentioned racemic mixture and solvent such as chiral acid be converted into the mixture of diastereomeric salt or chemical compound, and from racemic mixture acquisition enantiomer; At last above-mentioned diastereomeric salt of separating or chemical compound are converted into corresponding enantiomer.Pure form of three-dimensional chemical isomer also can be obtained by the pure form of three-dimensional chemical isomer of suitable intermediate and starting material, and condition is that intermediate reaction is that stereospecificity ground takes place.
In addition, other method of separating the enantiomer of formula I chemical compound and intermediate also comprises liquid chromatography (LC), particularly uses the liquid chromatography (LC) of chiral stationary phase.
Some intermediate and raw material are known chemicals and can or can prepare according to the known method in field by commercially available acquisition.
Glycine is the amino acid neurotransmitter in maincenter and the peripheral nervous system (inhibition and excitatory synapse).The tangible function of these of glycine is receptor-mediated by two types, and each in them all interrelates with different glycine transport thing (transporter).The inhibition effect of glycine is by to causing the alkaloid of convulsions--the Glycine Receptors mediation of strychnine sensitivity, and therefore be known as " strychnine sensitivity ".The Glycine Receptors of strychnine sensitivity is found and mainly is present in spinal cord and the brain stem.
Glycine is by regulating glutamate, Glu--(Johnson and Ascher, nature, 325, the 529-531 (1987) of its function brought into play in the main effect of excitatory neurotransmitter in the irritability transmission in the nervous system; Fletcher etc., the glycine transmission. (Otterson and Storm-Mathisen, eds, 1990), pp.193-219).Specifically, glycine is a glutamate receptor--be also referred to as the single-minded analeptic altogether of N-methyl D-aspartic acid (NMDA) receptor.Nmda receptor is distributed widely in the brain, and distribution density is high especially in cerebral cortex and hippocampal formation.
The transhipment thing absorbs neurotransmitter from synapse, thereby has regulated the concentration of neurotransmitter in the synapse, and these have determined the intensity that synapse is transmitted jointly; By stoping the diffusion of neurotransmitter, the precision (fidelity) that the transhipment thing has kept synapse to transmit toward contiguous synapse; At last, the transhipment thing is discharged into the mediator in presynaptic gap by reuptake, makes mediator be reused.Extracellular sodium ion and potential difference in the cell membrane are depended in the neurotransmitter transhipment.Under special circumstances, for example during epilepsy, the transhipment thing can be brought into play antipodal effect, with the calcium outer mode release neurotransmitters (Attwell etc., neuron, 11,401-407 (1993)) of dependency acellular not.The regulating action of neurotransmitter transhipment thing provides a kind of adjusting synapse active mode, and this provides useful Therapeutic Method for maincenter and peripheral nervous system disorder.
Molecular cloning is learned to have disclosed and is had two types glycine transport thing, is referred to as GlyT-1 and GlyT-2 respectively.GlyT-1 is found and mainly is present in forebrain, its distribution consistent with the distribution of glutamatergic pathways and nmda receptor (Smith etc., neurocyte 8,927-935 (1992)).The different binding sites of it is now know that at least three GlyT-1 are called GlyT-1a, GlyT-1b and GlyT-1c (Kim etc., molecular pharmacology, 45,608-617 (1994)), each in them all shows a kind of distribution of uniqueness in brain and peripheral nervous tissue.On the contrary, GlyT-2 is found and mainly is present in brain stem and the spinal column, and distribution closely related (Liu etc., journal of biological chemistry, 268, the 22802-22808 (1993) of the Glycine Receptors of its distribution and strychnine sensitivity; Jursky and Nelson, neuro chemistry, 64,1026-1033 (1995)).Thus, people prediction, by regulating the synapse level of glycine, GlyT-1 and GlyT-2 can optionally regulate nmda receptor respectively and to the activity of the Glycine Receptors of strychnine sensitivity.
Therefore people expect that the chemical compound of using inhibition or activating the glycine transport thing changes the function of receptor, thereby provide therapeutical effect to numerous disease.Therefore, by suppressing GlyT-2, can strengthen the synapse level of glycine and lower the activity of the Glycine Receptors of tool strychnine sensitivity, thereby reduce (as nociceptive) information the transmission in spinal column relevant with the pain sensation, it is receptor-mediated with these having disclosed these mechanisms.Yaksh, pain, 37,111-123 (1989).In addition, the glycine that utilizes the Glycine Receptors of the strychnine sensitivity in the spinal cord to strengthen inhibition can transmit and can be used to reduce the muscle over-activity, this is for treating strong muscle contraction, disease as spasm, myoclonus and this class of epilepsy is useful (Truong etc., disorderly activity, 3,77-87 (1988); Becker, FASEB J, 4,2767-2774 (1990)).Can be relevant with the situation of epilepsy, apoplexy, brain injury, multiple sclerosis, spinal injury, myodystonia and other neural diseases and damage by the spasm that the adjusting Glycine Receptors is treated.
Nmda receptor participates in memory and study (Rison and Stanton, Neurosci.Biobehav.Rev., 19,533-552 (1995); Danysz etc., behavioral pharmacology, 6,455-474 (1995)); The appearance (Olney and Farber, Archives General Psychiatry, 52,998-1007 (1996)) that as if can cause the schizophrenia symptom that weakens by the neurotransmission function of NMDA mediation.Therefore, suppress GlyT-1 and the active material of glycine that increases nmda receptor can be used as the novel drugs of psychosis and dementia, be used for the treatment of the disease of cognitive process damage, as absent minded and organic brain syndrome.On the contrary, the excessive activation of nmda receptor is also relevant with numerous disease, particularly with apoplexy, brain injury and may be with neurodegenerative disease relevant nerve cell death, as Alzheimer ' s disease, many-infarct dementia, AIDS dementia, Huntington ' s disease, parkinson, the disease of nerve cell death appears in amyotrophic lateral sclerosis side sclerosis or other.Coyle﹠Puttfarcken, science, 262,689-695 (1993); Lipton and Rosenberg, New England Journal of Medicine, 330,613-622 (1993); Choi, neuron, 1,623-634 (1988).Therefore, strengthen the glycine activity that the active medicine of GlyT-1 can reduce nmda receptor.This effect can be used for treating above-mentioned disease and with the morbid state of these disease associations.Equally, the medicine of directly blocking glycine site on the nmda receptor also can be used to treat above-mentioned disease and with the morbid state of these disease associations.
For ease of taking of medicine, described herein chemical compound can be mixed with many kinds of pharmaceutical compositions, and it comprises pharmaceutically acceptable carrier and as the effectively noval chemical compound of the formula I of therapeutic dose active component, certain.For preparing pharmaceutical compositions of the present invention, can adopt with the form of addition salts or free acid or free alkali special compound that exist, certain effective dose, closely mix with pharmaceutically acceptable carrier as active component, its carrier form widely exists, and this depends on which kind of the medicine of preparation adopts take mode.These pharmaceutical compositions are to be suitable for making single dosage form, preferably oral, percutaneous or parenteral drug administration by injection mode.For example, the compositions of preparation peroral dosage form, all common pharmacy media all can be used, and as water, ethylene glycol, oil, alcohol etc., the oral liquid formulation form comprises as suspension, syrup, elixir and solution; With solid carrier such as starch, sugar, Kaolin, lubricant, binding agent, disintegrating agent etc., can be used under the situation of powder, ball, capsule and tablet.Tablet and capsule are the peroral dosage forms of taking most convenient, wherein obviously need to use the solid pharmaceutical carriers.For the compositions without enteral administration, its carrier comprises disinfectant usually, and it can help dissolving at least to a great extent.Also can prepare the solution by the injection of other composition, used carrier comprises saline solution, for example, and wherein glucose solution or saline and glucose mixed solution.The Injectable solution that contains the formula I chemical compound can be mixed with oily to prolong action time, and available for this reason suitable oil comprises as Oleum Arachidis hypogaeae semen, Oleum sesami, Oleum Gossypii semen, Semen Maydis oil, soybean oil, synthetic long-chain fat acid glyceride and these oily mixture that becomes with other line of oils.Also injectable suspension can be prepared, wherein suitable liquid carrier, suspending agent etc. can be used.In being suitable for the compositions of percutaneous dosing, carrier can be chosen wantonly and comprise penetration enhancers and/or suitable wetting agent, and they are mixing than small scale and various proper additive are optional, and these additives do not cause any tangible illeffects to skin.The administration that described additive can promote skin also/or help to prepare the compositions that seeks out, these compositionss can have many kinds of route of administration, as transdermal patch, a spot-on or ointment.Because the addition salts of (I) water solublity for their corresponding free alkalis or free acid form strengthens, they obviously are more suitable for being used for preparing fluid composition.
With the above-mentioned Pharmaceutical composition unit of being prepared into and uniformly dosage form so that to take be particularly advantageous.Be used in the description of this paper and this term of the unit dosage form in the claim refer to be suitable as unit dose, discontinuous unit physically, per unit all comprise be predetermined quantity, can produce the active component of required therapeutical effect and blended with it required carrier as calculated.The form of the example of this unit dosage form such as tablet (comprising cut sheet or coated tablet), capsule, ball, packed powder, thin slice, injectable solution or suspension, a soupspoon amount, tablespoonful etc. and so on, and their the multiple dose form of separating.
The following examples are used for illustrating the present invention.
Experimental section
Embodiment A .1
With 1-chloro-4, two (4-fluorophenyl) butane (5.6g) of 4-, 4-(1,2,3,4-tetrahydrochysene-2-oxo-3-quinazolyl) piperidines (3.5g), sodium carbonate (6.36g), contain the crystalline methyl-isobutyl alcohol/ketone mixtures of a spot of KI (160ml) and stir and refluxed 2 days, add entry (250ml) after the cooling, isolated organic layer drying, filtration, evaporating solvent.Residue is recrystallization from methyl iso-butyl ketone (MIBK) (80ml), obtains the 3-[1-[4 of 3g, two (4-methyl fluoride) butyl of 4-]-the 4-piperidyl]-3,4-dihydro-2 (1H)-quinolinone; Mp.199-200.5 ℃ (chemical compound 1).
Analog also can prepare:
4-[2-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] acetyl group]-3,4-dihydro-3-phenyl-2 (1H)-quinokysalines ethanedioic acid ester (1: 1); Mp.190.8 ℃ (chemical compound 2);
N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-1-(imidazo [1,2-a] pyridine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-amine; Mp.160.1 ℃ (chemical compound 3);
2-[[4-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 1-piperazinyl] methyl]-3-(2-ethoxyethyl)-3H-imidazo [4,5-b] pyridine ethanedioic acid esters (1: 2); Mp.173.2 ℃ (chemical compound 4);
3-[1-[4, two (4-methyl fluoride) butyl of 4-]-the 4-piperidyl]-3,4-dihydro-pyrrolo-[2,3-d]-2 (1H)-pyrimidone dihydrochlorides; Mp.220-222 ℃ (chemical compound 5);
Embodiment A .2
With 4-fluoro-γ-(4-fluorophenyl) phenylbutyraldehyde (2.6g), 1-(4-fluorophenyl)-3-[2-(4-piperidine methyl)-1H-benzimidazole-1-y1]-1-acetone dibromide monohydrate (5.5g), 3% alcoholic solution (1g) of thiophene, the mixture of potassium acetate (3g) and methanol (200ml) normal pressure and 50 ℃ down with 10% the palladium catalyst hydrogenation (2g) on the Linesless charcoal of investing.After the hydrogen of as calculated amount was ingested, the elimination catalyst evaporated filtrate, and water is joined the oily residue, with the ammonium hydroxide alkalization, extracted product, extract drying, filtration and evaporation with 4-methyl-2 pentanone.The oil residue is by purification by silica gel column chromatography, and as eluant, oily residue is converted into ethanedioic acid ester salt in acetonitrile and 4-methyl-2 pentanone with the mixture of chloroform and methanol (95: 5 volume ratios).This salt is crystallized out, and product obtains the 3-[2-[[1-[4 of 5g (63.3%) after filtration and drying, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] methyl]-1H-benzimidazole-1-yl]-1-(fluorophenyl)-1-acetone ethanedioic acid ester (1: 2); Mp.156.4 ℃ (chemical compound 6).
Embodiment A .3
With 1-[4, two (the 4-fluoro phenyl) butyl of 4-]-piperazine (6.9g), 4-chloro-1-(2-thienyl)-butanone (4.1g), sodium carbonate (3.18g), 4-methyl-2 pentanone solution (200ml) mixture that contains a spot of KI is through refluxing 24 hours, and then add 4-chloro-1-(2-the thienyl)-butanone (4.1g) of second portion, and stir and refluxed other 36 hours, add entry (100ml) after the cooling.Separate organic layer, with the potassium carbonate drying, more after filtration and evaporation.Make oily residue be dissolved in absolute ether (480ml), filtering solution, and hydrogen chloride gas imported filtrate, the elimination deposited salt, with 2-propanol (320ml) crystallization, obtain 4-[4,4-two (4-fluoro phenyl) butyl]-the 1-piperazinyl]-1-(2-thienyl)-butanone; Mp.227.5-230 ℃ (chemical compound 7).
Embodiment A .4
To stirring 1-[4, two (the 4-fluoro phenyl) butyl of 4-]-N-(4-anisyl)-4-piperidinamine (6.75g) 2, the solution of 2 '-oxygen, two propane (105ml) and oxolane (45ml) drips 2 of 2-isocyano group propane (1.36g), the solution of 2 '-oxygen, two propane (35ml), after adding finishes, stirred at first at room temperature lasting 1 day, and stirred one hour down at about 50 ℃ then.Evaporation reaction mixture.
Residue crystallizes out in the mixed liquor of 2 '-oxygen, two propane and 2-propanol from 2, obtains N-[1-4, two (4-fluorophenyl) butyl of 4-]-the 4-piperidyl]-N-(4-anisyl)-N '-(1-methyl-ethyl) urea (4.8g, 59%); Mp.170.9 ℃ (chemical compound 8).
Analog also can prepare
N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N '-butyl-N-(4-anisyl) urea; Mp.101.9 ℃ (chemical compound 9);
N-[1-4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N-(4-anisyl)-N '-propyl group-urea; Mp.124.1 ℃ (chemical compound 10);
N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N '-cyclohexyl-N-(4-anisyl) urea; Mp.128.2 ℃ (chemical compound 11);
N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N '-ethyl-N-(4-tolyl) urea; Mp.129.1 ℃ (chemical compound 12);
N-[1-[4,4-two (4-fluoro phenyl) butyl]-the 4-piperidyl]-N '-(1-Methylethyl)-N-(4-tolyl) urea; Mp.167.2 ℃ (chemical compound 13); And
N-[1-[4,4-two (4-fluoro phenyl) butyl]-the 4-piperidyl]-N'-(4-chlorphenyl)-N '-(1-Methylethyl) urea; Mp.157.4 ℃ (chemical compound 14);
Pharmacological examples
The transhipment test of Embodiment B .1:GlyT1 transhipment thing
The HEK293-GlyT1 cell (being a cell line of stably express people glycine transport thing 1) of minute junction is implanted Cytostar T plate, every hole 100 μ l DMEM culture medium (are replenished with 10% newborn calf serum in the DulbeccoShi improvement Eagle culture medium, the 1mM Sodium Pyruvate, the 2mM glutamine, 100u penicillin/ml and 0.1mg/ml streptomycin) in contain 50,000 cells.Cell is at 37 ℃, 5%CO
2, cultivated 48 hours under 95% humidity.
At the 3rd day, the washer that adopts the control of TecanPW96 microprocessor was with uptake buffer (25mM Hepes, 5.4mM potassium gluconate, 1.8mM calcium gluconate, 0.8mMMgSO
4, 140mMNaCl, the 5mM glucose, the 5mM alanine is transferred pH to 7.5 with 2Mtris liquid) and wash the cell in all 96 holes of little culture plate simultaneously, regulate TecanPW96 and make washed cell totally 5 times, and the only surplus 75 μ l in every hole.Test compounds is dissolved in the Concentraton gradient of the different micromole's level of formation among the DMSO.Every hole adds 1 μ l test solution, and cell was at room temperature cultivated 5-10 minute, adds 30 μ M[U with 25 μ l of uptake buffer dilution then
14C] glycine.After cell is at room temperature cultivated 1 hour,, measure [U with the little culture plate scintillation counter of Packard (Top Count) with the flat board sealing
14C] picked-up of glycine.From the result of each testing drug gained of different concentration, can calculate 50% inhibition concentration (IC of glycine uptake
50).Test compounds of the present invention be expressed as pIC
50(IC
50Negative log value) data calculated see Table 1.
Chemical compound 15 is 2-[[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] methyl]-3-(2-picolyl)-3H-imidazo [4,5-b] pyridine ethanedioic acid esters (1: 2);
Chemical compound 16 is 2-[[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] methyl]-the 3-[(4-fluorophenyl) methyl]-3H-imidazo [4,5-b] pyridine ethanedioic acid esters (1: 2);
Chemical compound 17 is 2-[[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] methyl]-3-(benzyl)-3H-imidazo [4,5-b] pyridine ethanedioic acid esters (1: 2);
Chemical compound 18 is 2-[[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] methyl]-3-(2-thenyl)-3H-imidazo [4,5-b] pyridine ethanedioic acid esters (1: 1);
Chemical compound 19 is 2-[[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] methyl]-3-(furfuryl)-3H-imidazo [4,5-b] pyridine ethanedioic acid esters (1: 2);
Chemical compound 20 is 2-[[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] methyl]-3-[(4-methoxyl group-phenyl) methyl]-1H-benzimidazole ethanedioic acid ester (1: 2);
Chemical compound 21 is 2-[[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-methyl]-3-(4-thiazolyl-methyl)-1H-benzimidazole ethanedioic acid ester (1: 2); As EP-A-0,151,826 announcements;
And chemical compound 22 is 1-[4, two (the 4-fluoro phenyl) butyl of 4-]-4-[3-[(anilino-carbonyl)-propyl group]-piperazine dihydrochloride, as GB-1,055,100 is disclosed, also tested.
Table 1
C. compositions embodiment
| Compound number | PIC 50 |
| 1 | 6．61 |
| 2 | 6．34 |
| 3 | 6．14 |
| 4 | 6．81 |
| 5 | 6．26 |
| 6 | 6．44 |
| 7 | 6．29 |
| 8 | 6．51 |
| Compound number | PIC 50 |
| 9 | 6．15 |
| 10 | 6．12 |
| 11 | 6．28 |
| 12 | 6．02 |
| 13 | 6．18 |
| 14 | 6．18 |
| 15 | 6．65 |
| 16 | 6．55 |
| Compound number | PIC 50 |
| 17 | 6．42 |
| 18 | 6．26 |
| 19 | 6．15 |
| 20 | 6．09 |
| 21 | 6．07 |
| 22 | 6．33 |
Following prescription is for example understood the typical Pharmaceutical composition that is fit to whole body drug treatment infected animal of the present invention and people.
Used among all these embodiment " active component " (A.I.) refer to formula I chemical compound or their pharmaceutically acceptable addition salt.
Embodiment C .1: Film coated tablets
The preparation of label is with the A.I. of 100g, and the mixture of the lactose of 570g and 200g starch fully mixes, and is dissolved in about 200ml water formed solution with the mixture moistening with 5g sodium lauryl sulphate and 10g polyvinylpyrrolidone then.Wet powdered mixture through sieve, dry, sieve once more, and then add 100g microcrystalline Cellulose and 15g hydrogenated vegetable oil, fully mixed and be pressed into tablet, obtain 10,000, every contains the 10mg active component.
Coating adds the 150ml dichloromethane solution of 5g ethyl cellulose in the 75ml of 10g methylcellulose denatured ethyl alcohol solution.And then adding 75ml dichloromethane and 2.5ml1,2, the 3-glycerol.Fusing 10g Polyethylene Glycol is dissolved in the 75ml dichloromethane then.The latter solution is joined the former, and then add 2.5g Dolomol, the spissated dye suspensions of the polyvinylpyrrolidone of 5g and 30ml.Behind the uniform mixing, just in the coating machine, carry out the coating of label with thus obtained mixture.
Claims (10)
1. the chemical compound that suppresses glycine transport is used for the treatment of purposes in the medicine of maincenter and diseases in peripheral nerve system in preparation, and above-claimed cpd has following formula:
Its N-oxide, form of three-dimensional chemical isomer or its pharmaceutically acceptable addition salt, wherein
X represents CH or N;
L represents a following formula group
Wherein n is 0 or 1;
M is 0 or 1;
Alk represents C
1-6Alkane two bases;
A represents N or CH;
B
1Expression CH
2Or NH;
-a
1=a
2-a
3=a
4The divalent group of-expression following formula
-CH=CH-CH=CH-(a-1); Or
-N=CH-CH=CH-(a-2)；
R
1Expression is optional by C
1-4The C that alkoxyl, pyridine radicals, aryl, aryl carboxyl, thienyl, furyl, imidazo [1,2-a] pyridine radicals, thiazolyl replace
1-4Alkyl;
R
2Expression hydrogen or aryl;
R
3Expression hydrogen, C
1-6Alkyl or C
3-7Cycloalkyl;
R
4Expression thienyl, furyl, alkyl amino or following formula group
R wherein
5Be hydrogen or aryl; Aryl is represented by from C
1-4Alkyl, halo, hydroxyl, C
1-4The optional phenyl that replaces of 1 or 2 substituent group selecting in the alkoxyl.
2. the purposes of claim 1, wherein L is formula (a) or group (b).
3. the purposes of claim 1, disease wherein refers to psychosis (psychoses), pain, epilepsy, neurodegenerative disease, apoplexy, brain injury or multiple sclerosis.
4. claim 1 or 2 defined formula I chemical compounds, condition is
-represent CH as X; The group of L expression (a), wherein B
1Expression-CH
2-group, R
1Expression pyridine-2-ylmethyl, thiophene-2-ylmethyl, furan-2-ylmethyl, when benzyl or 4-fluoro benzyl, then-a
1=a
2-a
3=a
4-do not represent-N=CH-CH=CH-;
-represent CH as X; The group of L expression (a), wherein B
1Expression-CH
2-group, R
1When expression 4-anisyl or thiazole-4-ylmethyl, then-a
1=a
2-a
3=a
4-do not represent-group of CH=CH-CH=CH-;
-represent N as X; The group of L expression (a), wherein Alk represents 1, during 3-propane two base, R then
4Do not represent phenyl amino.
5. the chemical compound in the claim 4, n=0 wherein, m=1; R
1Expression is by optional C
1-4Alkoxyl, fragrant carbonyl or imidazo [1, the 2-a] C that pyridine radicals replaced
1-4Alkyl; R
4Expression thienyl, furyl or formula (d-1) group.
6. the chemical compound in the claim 4, wherein chemical compound is 3-[1-[4, two (fluoro methyl) butyl of 4-]-the 4-piperidyl]-3,4-dihydro-2 (1H)-quinolinone; 4-[2-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] acetyl group]-3,4-dihydro-3-phenyl-2 (1H)-quinokysalines; N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-1-(imidazo [1,2-a] pyridine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-amine; 2-[[4-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 1-piperazinyl] methyl]-3-(2-ethoxyethyl)-3H-imidazo [4,5-b] pyridine; 3-[1-[4, two (4-methyl fluoride) butyl of 4-]-the 4-piperidyl]-3,4-dihydro-pyrido [2,3-d]-2 (1H)-pyrimidones; 3-[2-[[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl] methyl]-1H-benzimidazole-1-yl]-1-(4-fluorophenyl)-1-acetone 4-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 1-piperazinyl]-1-(2-thienyl)-butanone; N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N-(4-anisyl)-N '-(1-methyl-ethyl) urea; N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N '-butyl-N-(4-anisyl) urea; N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N-(4-anisyl)-N '-propyl group-urea; N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N '-thiacyclohexane base-N-(4-anisyl) urea; N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N '-ethyl-N-(4-aminomethyl phenyl) urea; N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N '-(Methylethyl)-N-(4-tolyl) urea; N-[1-[4, two (the 4-fluoro phenyl) butyl of 4-]-the 4-piperidyl]-N '-(4-chlorphenyl)-N '-(1-Methylethyl) urea;
And their N-oxide, form of three-dimensional chemical isomer or pharmaceutically acceptable addition salt.
7. Pharmaceutical composition, it comprises pharmaceutically acceptable carrier and as each the chemical compound in the claim 4 to 6 active component, dose therapeutically effective.
Preparation claim 7 with learning method for compositions, it is characterized in that, with effective therapeutic dose, each chemical compound fully mixes with pharmaceutical carrier in the claim 4 to 6.
9. each chemical compound is used as medicine in the claim 4 to 6.
10. the method for the chemical compound of preparation claim 4 is characterized in that
A) by making the intermediate of formula II, wherein W
1Represent suitable leaving group, with the intermediate of formula III in reaction-inert solvent, at suitable alkali with choose wantonly in the presence of potassium iodide and react:
B) intermediate that makes the intermediate of formula III and formula IV is in atent solvent, at Reducing agent with choose wantonly and carry out standard reductive alkylation react in the presence of suitable catalyst;
C) intermediate of through type (V) and the intermediate of formula VI, wherein W
1Leaving group for suitable reacts in atent solvent, thereby the chemical compound of the formula of obtaining (I-a) is reflected at suitable alkali and chooses wantonly in the presence of potassium iodide and carries out:
D) the isocyanate group derivant of the intermediate of through type (VII) and formula (VIII) reacts in atent solvent, thus the chemical compound of the formula of formation (I-b)
And if desired, can be by the formula I chemical compound being converted into acid-addition salts with acid treatment, or by being converted into base addition salts with alkali treatment, perhaps conversely, by the acid-addition salts form being changed into free alkali with alkali treatment, or by with acid treatment the base addition salts form being transformed into free acid; And, if desired, can prepare their N-oxide and/or form of three-dimensional chemical isomer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98200701.5 | 1998-03-06 | ||
| EP98200701 | 1998-03-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1292698A true CN1292698A (en) | 2001-04-25 |
Family
ID=8233444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN998036471A Pending CN1292698A (en) | 1998-03-06 | 1999-02-26 | Glycine transport inhibitors |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1059922A2 (en) |
| JP (1) | JP2002505277A (en) |
| KR (1) | KR20010032968A (en) |
| CN (1) | CN1292698A (en) |
| AU (1) | AU3408999A (en) |
| BG (1) | BG104685A (en) |
| BR (1) | BR9907951A (en) |
| CA (1) | CA2322164A1 (en) |
| EE (1) | EE200000482A (en) |
| HR (1) | HRP20000523A2 (en) |
| HU (1) | HUP0101048A2 (en) |
| IL (1) | IL138228A0 (en) |
| NO (1) | NO20004431L (en) |
| PL (1) | PL343435A1 (en) |
| SK (1) | SK13082000A3 (en) |
| TR (1) | TR200002567T2 (en) |
| WO (1) | WO1999044596A2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100341871C (en) * | 2005-06-03 | 2007-10-10 | 复旦大学 | Organic sulfur compound containing piperidine structure, its preparation and use |
| CN101072762B (en) * | 2004-12-09 | 2010-06-23 | 弗·哈夫曼-拉罗切有限公司 | Phenyl-piperazin methanone derivatives |
| CN101137363B (en) * | 2005-01-07 | 2010-09-15 | 弗·哈夫曼-拉罗切有限公司 | [4-(heteroaryl)piperazin-1-yl]-(2,5-substituted -phenyl)methanone derivatives as glycine transporter 1 (Glyt-1) inhibitors for the treatment of neurological and neuropsychiatric disorders |
| CN101141959B (en) * | 2005-01-18 | 2010-12-15 | 弗·哈夫曼-拉罗切有限公司 | 2,5-disubstituted phenyl methanone derivatives as glycine transporter 1 (Glyt-1) inhibitors for the treatment of neurological and neuropsychiatric disorders |
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| CN1171887C (en) | 1999-06-28 | 2004-10-20 | 詹森药业有限公司 | Respiratory syncytial virus replication inhibitors |
| UA73749C2 (en) * | 1999-11-01 | 2005-09-15 | Diarylenines | |
| CA2406652A1 (en) * | 2000-04-20 | 2001-11-01 | Nps Allelix Corp. | Aminopiperidines for use as glyt-1 inhibitors |
| DE10040016A1 (en) * | 2000-08-16 | 2002-02-28 | Boehringer Ingelheim Pharma | Novel beta-amyloid inhibitors, process for their preparation and their use as pharmaceuticals |
| AU2001288896A1 (en) | 2000-09-08 | 2002-03-22 | Gliatech, Inc. | Substituted hydrazine derivatives |
| AU2001290786A1 (en) * | 2000-09-14 | 2002-03-26 | Gliatech, Inc. | Nitrogen-containing compounds and their use as glycine transport inhibitors |
| AR032653A1 (en) | 2001-02-09 | 2003-11-19 | Telik Inc | HYPERCYCLIC INHIBITORS OF THE GLICINE TRANSPORTER 2 PHARMACEUTICAL COMPOSITIONS, USE AND METHODS. |
| US7030150B2 (en) | 2001-05-11 | 2006-04-18 | Trimeris, Inc. | Benzimidazole compounds and antiviral uses thereof |
| EP1703909B1 (en) * | 2003-09-09 | 2009-04-15 | F. Hoffmann-La Roche Ag | 1-benzoyl-piperazine derivatives as glycine uptake inhibitors for the treatment of psychoses |
| PL1663232T3 (en) | 2003-09-09 | 2008-05-30 | Hoffmann La Roche | 1-(2-amino-benzoyl)-piperazine derivatives as glycine uptake inhibitors for the treatment of psychoses |
| WO2005058885A2 (en) * | 2003-12-18 | 2005-06-30 | Glaxo Group Limited | Piperidine derivatives and their use as glycine transporter inhibitors |
| TW200630337A (en) | 2004-10-14 | 2006-09-01 | Euro Celtique Sa | Piperidinyl compounds and the use thereof |
| CN100586951C (en) | 2004-12-15 | 2010-02-03 | 弗·哈夫曼-拉罗切有限公司 | Bi- and tricyclic substituted benzophenones as glycine transporter l(GlyT-1) inhibitors for the treatment of alzheimer's disease. |
| PE20061156A1 (en) | 2004-12-23 | 2006-12-16 | Glaxo Group Ltd | BENZAMIDE DERIVATIVES AS INHIBITING AGENTS OF THE GLYCINE TRANSPORTER |
| GB0428233D0 (en) * | 2004-12-23 | 2005-01-26 | Glaxo Group Ltd | Compounds |
| US7485637B2 (en) | 2005-01-04 | 2009-02-03 | Hoffmann-La Roche Inc. | Benzoyl-tetrahydropiperidine derivatives |
| EP1836178A1 (en) * | 2005-01-06 | 2007-09-26 | F. Hoffmann-Roche AG | Sulfanyl substituted phenyl methanones as glycine transporter 1 (glyt-1) inhibitors for the treatment of neurological and neuropsychiatric disorders |
| JP4829900B2 (en) | 2005-01-26 | 2011-12-07 | エフ．ホフマン−ラ ロシュ アーゲー | Phenylmethanone derivatives and their use as glycine transporter 1 inhibitors |
| DK1848694T3 (en) | 2005-02-07 | 2010-01-25 | Hoffmann La Roche | Heterocyclic substituted phenylmethanones as inhibitors of glycine transport |
| WO2007110449A1 (en) | 2006-03-29 | 2007-10-04 | Euro-Celtique S.A. | Benzenesulfonamide compounds and their use |
| WO2007118854A1 (en) | 2006-04-13 | 2007-10-25 | Euro-Celtique S.A. | Benzenesulfonamide compounds and the use thereof |
| US8791264B2 (en) | 2006-04-13 | 2014-07-29 | Purdue Pharma L.P. | Benzenesulfonamide compounds and their use as blockers of calcium channels |
| EP2079485B1 (en) * | 2006-11-01 | 2012-06-13 | Purdue Pharma LP | Phenylpropionamide compounds and the use thereof |
| FR2910321B1 (en) | 2006-12-21 | 2009-07-10 | Galderma Res & Dev S N C Snc | CREAM GEL COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE |
| FR2910320B1 (en) * | 2006-12-21 | 2009-02-13 | Galderma Res & Dev S N C Snc | EMULSION COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE |
| US8399486B2 (en) | 2007-04-09 | 2013-03-19 | Purdue Pharma L.P. | Benzenesulfonyl compounds and the use thereof |
| WO2009040659A2 (en) | 2007-09-28 | 2009-04-02 | Purdue Pharma L.P. | Benzenesulfonamide compounds and the use thereof |
| WO2009075857A2 (en) * | 2007-12-12 | 2009-06-18 | Amgen Inc. | Glycine transporter-1 inhibitors |
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| US4219559A (en) * | 1979-01-10 | 1980-08-26 | Janssen Pharmaceutica N.V. | N-Heterocyclyl-4-piperidinamines |
| CA1140119A (en) * | 1978-04-03 | 1983-01-25 | Joseph Torremans | N-heterocyclyl-4-piperidinamines |
| PH23995A (en) * | 1984-01-09 | 1990-02-09 | Janssen Pharmaceutica Nv | 4((bicycle heterocyclyl)-methyl and hetero)piperidines |
| US4695575A (en) * | 1984-11-13 | 1987-09-22 | Janssen Pharmaceutica, N.V. | 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines |
| WO1999025353A1 (en) * | 1997-11-13 | 1999-05-27 | Merck Sharp & Dohme Limited | Therapeutic uses of triazolo-pyridazine derivatives |
-
1999
- 1999-02-26 EE EEP200000482A patent/EE200000482A/en unknown
- 1999-02-26 SK SK1308-2000A patent/SK13082000A3/en unknown
- 1999-02-26 HU HU0101048A patent/HUP0101048A2/en unknown
- 1999-02-26 CN CN998036471A patent/CN1292698A/en active Pending
- 1999-02-26 KR KR1020007006315A patent/KR20010032968A/en not_active Application Discontinuation
- 1999-02-26 BR BR9907951-8A patent/BR9907951A/en not_active Application Discontinuation
- 1999-02-26 TR TR2000/02567T patent/TR200002567T2/en unknown
- 1999-02-26 WO PCT/EP1999/001309 patent/WO1999044596A2/en not_active Application Discontinuation
- 1999-02-26 CA CA002322164A patent/CA2322164A1/en not_active Abandoned
- 1999-02-26 PL PL99343435A patent/PL343435A1/en not_active Application Discontinuation
- 1999-02-26 JP JP2000534198A patent/JP2002505277A/en not_active Withdrawn
- 1999-02-26 AU AU34089/99A patent/AU3408999A/en not_active Abandoned
- 1999-02-26 IL IL13822899A patent/IL138228A0/en unknown
- 1999-02-26 EP EP99915541A patent/EP1059922A2/en not_active Withdrawn
-
2000
- 2000-08-02 HR HR20000523A patent/HRP20000523A2/en not_active Application Discontinuation
- 2000-08-11 BG BG104685A patent/BG104685A/en unknown
- 2000-09-05 NO NO20004431A patent/NO20004431L/en not_active Application Discontinuation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101072762B (en) * | 2004-12-09 | 2010-06-23 | 弗·哈夫曼-拉罗切有限公司 | Phenyl-piperazin methanone derivatives |
| CN101137363B (en) * | 2005-01-07 | 2010-09-15 | 弗·哈夫曼-拉罗切有限公司 | [4-(heteroaryl)piperazin-1-yl]-(2,5-substituted -phenyl)methanone derivatives as glycine transporter 1 (Glyt-1) inhibitors for the treatment of neurological and neuropsychiatric disorders |
| CN101141959B (en) * | 2005-01-18 | 2010-12-15 | 弗·哈夫曼-拉罗切有限公司 | 2,5-disubstituted phenyl methanone derivatives as glycine transporter 1 (Glyt-1) inhibitors for the treatment of neurological and neuropsychiatric disorders |
| CN100341871C (en) * | 2005-06-03 | 2007-10-10 | 复旦大学 | Organic sulfur compound containing piperidine structure, its preparation and use |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010032968A (en) | 2001-04-25 |
| PL343435A1 (en) | 2001-08-13 |
| NO20004431D0 (en) | 2000-09-05 |
| HUP0101048A2 (en) | 2001-10-28 |
| JP2002505277A (en) | 2002-02-19 |
| HRP20000523A2 (en) | 2001-02-28 |
| EE200000482A (en) | 2002-02-15 |
| TR200002567T2 (en) | 2000-11-21 |
| SK13082000A3 (en) | 2001-03-12 |
| WO1999044596A2 (en) | 1999-09-10 |
| CA2322164A1 (en) | 1999-09-10 |
| BR9907951A (en) | 2001-01-30 |
| WO1999044596A3 (en) | 2000-02-17 |
| IL138228A0 (en) | 2001-10-31 |
| AU3408999A (en) | 1999-09-20 |
| BG104685A (en) | 2001-04-30 |
| NO20004431L (en) | 2000-10-30 |
| EP1059922A2 (en) | 2000-12-20 |
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