CA2008571A1 - Pyridazino[4,5-b]indolizines - Google Patents
Pyridazino[4,5-b]indolizinesInfo
- Publication number
- CA2008571A1 CA2008571A1 CA002008571A CA2008571A CA2008571A1 CA 2008571 A1 CA2008571 A1 CA 2008571A1 CA 002008571 A CA002008571 A CA 002008571A CA 2008571 A CA2008571 A CA 2008571A CA 2008571 A1 CA2008571 A1 CA 2008571A1
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- CA
- Canada
- Prior art keywords
- indolizin
- pharmaceutically acceptable
- acceptable salt
- methylpyridazino
- amine
- Prior art date
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Abstract of the Disclosure The compound of the formula:
in which R1 is hydrogen, alkoxy, cyano, halo, nitro, amino, or mono- or dialkylamino;
R2 is hydrogen, alkyl, phenyl, benzyl, 2-thienyl, 3-thienyl or 2-, 3- or 4-pyridinyl; R3 is hydrogen, alkyl or phenyl; R4 is N-methyl-pyrrolidin-2-yl, 2-, 3- or 4-pyridinyl, 3-quinuclidinyl or where n is 1 to 5; m is 0 to 3; and R8 is hydrogen or alkyl of 1 to 6 carbon atoms; or R4 is
in which R1 is hydrogen, alkoxy, cyano, halo, nitro, amino, or mono- or dialkylamino;
R2 is hydrogen, alkyl, phenyl, benzyl, 2-thienyl, 3-thienyl or 2-, 3- or 4-pyridinyl; R3 is hydrogen, alkyl or phenyl; R4 is N-methyl-pyrrolidin-2-yl, 2-, 3- or 4-pyridinyl, 3-quinuclidinyl or where n is 1 to 5; m is 0 to 3; and R8 is hydrogen or alkyl of 1 to 6 carbon atoms; or R4 is
Description
` 12 December 1989 3ED1 :OCO:RKJ:rlk PATENT
X6~5'7~L
PYRTDAZ~NOr4,5.blTNDOLTZ~NES
Back~round of ~he ~nvention Although some forms of dementia can be treated (~, dementias resulting from cardiovascular disease, chemical toxins, depression, or head trauma) no effective therapy currently exists for the major form of dementia, senile dementia of the Alzheimer's type (SDAT), which accounts for more than half of all dementias, Moos et al., Med. Res. Reviews ~(3),353 (1988). The reason for this is that the etiology of the disease has not yet been confirrned, though many theories exist, Henderson, ActaPsychiat. Scand. 78, 257 (1988), Marx, Science 243, 1664 (1989). One theory which has gained wide acceptance is that the cognitive decline observed in patients with Alzheimer's disease and other forms of dementia is related to hypofunction of the cholinergic system, Bartus et al., Science 217 408 (1982), Collerton, Neuroscience 19(1) 1 (1986) and Whitehouse et al., Ann. Neurol., ~0 122 (1981). A study comparing patients with Alzheimer's disease (50), other dementias (10), and age-matched controls (20) found that 50-76% of the Alzheimer's patients had a statistically significant loss of cholinergic neurons in the basal forebrain. Other studies have -revealed that loss of presynaptic cholinergic neurons in the amygdala, hippocampus and neocortex related to hypofunction of the basal forebrain cholinergic system is also found in Parkinson's disease, Down's syndrome, dementia pugelistica, and some other forrns of dementia, Whitehouse et al., Adv. Behav. Biology, 29 85 (1985).
The neurotransmitter of the cholinergic system is acetylcholine. Receptor binding studies on brain tissue from animals (e.g. rats) and humans have identified two major types of acetylcholine (muscarinic) receptors, presynaptic receptors 011 nerve terminals (M2) and postsynaptic receptors (Ml). Postmortem examinatioll of braill tissue from Alzheimer's patients has shown that while postsynaptic Ml receptors remain intact, there is a reduction in the number of presynaptic M2 receptors, Marx, ibid. In fact, there is good correlation between the degree of presynaptic neuronal loss and the severity of the dementia, Marx, ibid, Collerton, ibid.
Degeneration of presynaptic cholinergic neurons results in insufficient production of acetylcholine and understimulated postsynaptic M1 receptors. Memory loss in normal humans, Bartus et al., ibid and Drachman et al., Arch. Neurol. 30 113 (1974) and animals (e.g. cat, rat, and monkey), Bartus et al., ibid and Collerton, ibid .
- - ~ ~ : . ~ ' .. ' 12December 1989 3ED2:0CO:RKJ :rlk PATENT
X6~5'7~L
PYRTDAZ~NOr4,5.blTNDOLTZ~NES
Back~round of ~he ~nvention Although some forms of dementia can be treated (~, dementias resulting from cardiovascular disease, chemical toxins, depression, or head trauma) no effective therapy currently exists for the major form of dementia, senile dementia of the Alzheimer's type (SDAT), which accounts for more than half of all dementias, Moos et al., Med. Res. Reviews ~(3),353 (1988). The reason for this is that the etiology of the disease has not yet been confirrned, though many theories exist, Henderson, ActaPsychiat. Scand. 78, 257 (1988), Marx, Science 243, 1664 (1989). One theory which has gained wide acceptance is that the cognitive decline observed in patients with Alzheimer's disease and other forms of dementia is related to hypofunction of the cholinergic system, Bartus et al., Science 217 408 (1982), Collerton, Neuroscience 19(1) 1 (1986) and Whitehouse et al., Ann. Neurol., ~0 122 (1981). A study comparing patients with Alzheimer's disease (50), other dementias (10), and age-matched controls (20) found that 50-76% of the Alzheimer's patients had a statistically significant loss of cholinergic neurons in the basal forebrain. Other studies have -revealed that loss of presynaptic cholinergic neurons in the amygdala, hippocampus and neocortex related to hypofunction of the basal forebrain cholinergic system is also found in Parkinson's disease, Down's syndrome, dementia pugelistica, and some other forrns of dementia, Whitehouse et al., Adv. Behav. Biology, 29 85 (1985).
The neurotransmitter of the cholinergic system is acetylcholine. Receptor binding studies on brain tissue from animals (e.g. rats) and humans have identified two major types of acetylcholine (muscarinic) receptors, presynaptic receptors 011 nerve terminals (M2) and postsynaptic receptors (Ml). Postmortem examinatioll of braill tissue from Alzheimer's patients has shown that while postsynaptic Ml receptors remain intact, there is a reduction in the number of presynaptic M2 receptors, Marx, ibid. In fact, there is good correlation between the degree of presynaptic neuronal loss and the severity of the dementia, Marx, ibid, Collerton, ibid.
Degeneration of presynaptic cholinergic neurons results in insufficient production of acetylcholine and understimulated postsynaptic M1 receptors. Memory loss in normal humans, Bartus et al., ibid and Drachman et al., Arch. Neurol. 30 113 (1974) and animals (e.g. cat, rat, and monkey), Bartus et al., ibid and Collerton, ibid .
- - ~ ~ : . ~ ' .. ' 12December 1989 3ED2:0CO:RKJ :rlk PATENT
2 2~S'~l can be artificially induced with a muscarinic antagonist, such as scopolamine. This deficit can be reversed by the anticholinesterase inhibitor, physostigmine, in both humans and monkeys, Marx ibid and by the muscarinic agonist arecoline in rats.
However, neither physostigmine nor arecoline have clinical efficacy due to undesirable 5 side-effects, a short duration of action and a narrow active dose range. Other therapies examined in clinical studies include treatment of Alzheimer's patients and healthy elderly patients with the acetylcholine precursors choline and lecithin. No significant improvement was observed on any cognitive test.
Over the next 50 years it is predicted that nearly 20% (55 million) of the population in the United States will be over 65 years of age, Moos et al., ibid. Couple this with the fact that Alzheimer's disease alone afflicts between 5 and 15% of individuals over 65 years of age, Collerton, ibid and it becomes obvious that dementia is a major health problem for which there is an urgent need for effective therapy.
15 Centrally acting muscarinic receptor agonists which have greater affinity for the Ml receptor than the M2 receptor as evidenced by in vitro receptor binding studies are useful for the treatment of Alzheimer's disease and other disorders associated with cortical cholinergic hypofunction. Ml receptor agonists have fewer undesirable side effects than muscarinic agonists which are not Ml selective since unwanted peripheral 20 effects are usually associated with agonism of the M2 receptor.
l~e~cription of the ~nvention In accordance with this invention, there is provided a group of novel 25 pyridazino[4,5-b]indolizine compounds which are selective agonists for central cholinergic Ml receptors and useful for treatment of diseases involving hypofunction of the cholinergic system. In addition, some of these compounds inhibit platelet aggregation induced by collagen and are useful as antithrombotic agents.
The compounds of the present invention are characterized by the general formula:
12December 1989 -- 3ED3:0CO:RKJ:rlk PATENT
However, neither physostigmine nor arecoline have clinical efficacy due to undesirable 5 side-effects, a short duration of action and a narrow active dose range. Other therapies examined in clinical studies include treatment of Alzheimer's patients and healthy elderly patients with the acetylcholine precursors choline and lecithin. No significant improvement was observed on any cognitive test.
Over the next 50 years it is predicted that nearly 20% (55 million) of the population in the United States will be over 65 years of age, Moos et al., ibid. Couple this with the fact that Alzheimer's disease alone afflicts between 5 and 15% of individuals over 65 years of age, Collerton, ibid and it becomes obvious that dementia is a major health problem for which there is an urgent need for effective therapy.
15 Centrally acting muscarinic receptor agonists which have greater affinity for the Ml receptor than the M2 receptor as evidenced by in vitro receptor binding studies are useful for the treatment of Alzheimer's disease and other disorders associated with cortical cholinergic hypofunction. Ml receptor agonists have fewer undesirable side effects than muscarinic agonists which are not Ml selective since unwanted peripheral 20 effects are usually associated with agonism of the M2 receptor.
l~e~cription of the ~nvention In accordance with this invention, there is provided a group of novel 25 pyridazino[4,5-b]indolizine compounds which are selective agonists for central cholinergic Ml receptors and useful for treatment of diseases involving hypofunction of the cholinergic system. In addition, some of these compounds inhibit platelet aggregation induced by collagen and are useful as antithrombotic agents.
The compounds of the present invention are characterized by the general formula:
12December 1989 -- 3ED3:0CO:RKJ:rlk PATENT
3 ;~ i'7~L
R
N-(CH2)n-R4 R
~ N ~ N
in which R1 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, halo, nitro, amino, or mono- or dialkylamino in which the alkyl groups have 1 to 6 carbon atoms;
R2 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, 2-thienyl, 3-thienyl, or 2-, 3- or 4-pyridinyl;
R3 is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; :
R4 is N-methyl-pyrrolidin-2-yl, 2-,3- or 4-pyridinyl, 3-quinuclidinyl or ~N~
~CH2)m wherein .. ... .
n is 1 to 5;
misOto3;
and R8 is hydrogen or alkyl of 1 to 6 carbon atoms;
or ' ! , ' ' ' ', - , , ~ ~ , ' : ' ' ' : ' ' .
12 December 1989 3ED4:0CO:RKJ:rlk PATENT
R4iS
S wherein a) n is 2, R5 taken with R3 is ethylene and R6 is -CHO, alkyl of 1 to 6 carbon atoms, unsubstituted or substituted phenyl, pyrirnidinyl, pyridinyl, or pyrazinyl where the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, cyano, nitro or trifluoromethyl;
.
b) n is 1 to 5, and RS and R6 taken together are polymethylene of 4 to 6 carbon atoms which may be alkyl substituted with a group having from 1 to 6 carbon atoms or RS and R6 taken with the nitrogen atom to which they are attached are morpholino, 3-azabicyclo[3.2.2]nonan-3-yl, pyrrol-l-yl, pyrrolidin- 1 -yl, pyrrolidin-2-on- 1 -yl, pyrrolidin-2-thion- 1 -yl, imidazol-l-yl, aLkyl-piperidin-l-yl in which the alkyl group contains 1 to 6 carbon atoms, or a piperazin-l-yl moiety in the 4-position of which is hydrogen, -CHO, alkyl of 1 to 6 carbon atoms or unsubstituted or substituted phenyl, pyrimidinyl, pyridinyl, or pyrazinyl where the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, cyano, nitro or trifluoromethyl;
or c) n is 1 to 5, and RS and R6 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, 3-quinuclidinyl, 2-adamantyl, bicyclo[3.2.1]octan-2-yl, bicyclo[3.3.1]nonan-9-yl or 2-, 3- or 4-pyridinyl;
or a pharmaceutically acceptable salt thereof.
.
- ::
.:
.. .,~, . .. : ~ .; `''~
, ~.
.. . .
.
- . .
12December 1989 3ED5:0CO:RKJ:rlk PATENT
S
2`~85~1 :
Of these compounds, from the standpoint of availability of starting compounds ~ -and production economies, the preferred compounds are those of the formula:
N-(CH2)n-R4 ~N
N~N
s in which R2 is alkyl of 1 to 3 earbon atoms;
R3 is hydrogen or alkyl of 1 to 3 carbon atoms;
R4 is ~
'''~
whereln RS and R6 are, independently, hydrogen, alkyl of 1 to 3 earbon atoms or 3-quinuclidinyl or RS and R6, taken with the nitrogen atom to which they are attached are morpholino or a piperazin- 1-yl moiety in whieh the 4-position is substituted with an alkyl group of 1 to 3 earbon atoms or a 2-pyrirnidinyl group;
and n is one of the integers 2, 3, 4 or 5;
or a pharmaceutically acceptable salt thereof.
:
12 December 1989 3ED6:0CO:RKJ:rlk PATENT
6 2~ i'7~
From an activity profile, the most preferred compound is that of Example 1, infra.
The pharmaceutically acceptablç salts are those conventionally produced with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, toluene sulfonic, naphthalenesulfonie, formic, acetic, propionic, oxalic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvie, phenylacetic, benzoic, para-amino benzoic, para-hydroxybenzoic, salieylie, sulfanilie aeids, and the like. The term halo employed on the foregoing description of the invention is intended to embrace chlorine, bromine, iodine and fluorine, the chloro or bromo groups being preferred.
The compounds of this invention may be readily prepared by displacing the halogen from the l-position of an appropriately substituted 1-halo-pyridazino[4,5-b]indolizine with the desired amine, thusly halo R~ + H-N--(CH2)n--R4 ~,~N~N
N-(CH2)n-R4 R1 ~ N
~N~N
The amino reaetants are eornmerieally available or prepared by methods well known in the art. The l-halo-pyridazino[4,5-b]indolizine reaetants may be prepared by various .. .. - . ~
.
.. ' ; ' ., ' ' ~
- . , . .
- ~ .
~................. , 12 December 1989 3ED7:0CO:RKJ:rlk PATENT
7 Z~
methods known to the medicinal chemist. For example, 2-indolizinecarboxylic acidwhich may be variously substituted as desired [Bragg et al., J. Chem. Soc. 3277 (1963)] is converted to an ester (methanol treated with an acid such as HCI) and the product is acylated with either an acid anhydride or an acid halide [R4COCI or 5 (R4Co)2o] in the presence of an acid acceptor (triethylamine, etc.) or by means of the Vilsmeir-Haak reaction when R2 is hydrogen, to obtain the corresponding 3-acyl-2-indolizine carboxylic acid ester. This product is treated with hydrazine hydrate to afford the corresponding substituted 2H-pyridazino[4,5-b]indolizin-1-one.
O ' ' R1 ~ H2NNH2 1 ~ NH
~N IlR2 ~N~f N . ..
Halogenation with POC13, SOC12 and the like affords the corresponding 1-halo-pyridazino[4,5-b]indolizine reactant.
The reaction of the 1-halo-pyridazino[4,5-b]indolizine derivatives with the 15 desired amine is performed with an excess (10-30 equivalents) of the amine at reflux temperature if the boiling point of the amine is below about 150C, or up to about 160C in the melting range of the amine in an inert atmosphere. The reaction is readily followed by thin layer chromatography on silica gel (1:1 MeOH:EtOAc, 100% MeOH
or MeOH containing 1-5% triethylamine or ammonium hydroxide). The reaction takes20 from several hours to several days to go to completion. After the reaction is complete, the excess amine is removed by vacuum distillation or extraction (CH2C12 with water wash) as appropriate. The organic phase is dried (NR2SO4) and evaporated ln vacuo to obtain the crude product which is ehromatographically purified (silica gel; acetonitrile, methanol or 1:1 MeOH:EtOAc containing an NH40H gradient 0-7%). The product is 25 then converted to the desired salt conventionally.
The following examples of the preparation of several compound species are presented as illustrative rather than limitative elements of the invention.
.. . . ~ . . ~ . , 12December 1989 3ED8:0CO:RKJ:rlk LT
Example 1 1 -r(3'-DiethvlaminoDroDvl)aminol-4-methvlpvridazinor4.5-blindoli7ine S A stirred solution of 2-indolizinecairboxylic acid, methyl ester (91.42 g, 0.522 mole) and anhydrous sodium acetate (42.53 g, 0.52 mole) in acetic anhydride (1.1 L) was refluxed, under anhydrous conditions, for 48 hours. After cooling most of the acetic anhydride was evaporated in vacuo. The resulting residue (150 ml) was cooled in an ice water bath and methanol (140 ml) was added to destroy the remaining acetic anhydride. The resulting mixture was poured into water (1.1 L) and the product was extracted with diethyl ether, three times. The ethereal layer was washed with saturated sodium bicarbonate solution, three times, with water, two times, and was dried over magnesium sulfate. Evaporation of solvent yielded 112 g of crude 3-acetyl-2-indolizinecarboxylic acid, methyl ester which was chromatographed on silica gel (3 kg) using 10% acetone in benzene as eluant, to afford the pure compound (85.5 g). For analysis, the product was recrystallized from a mixture of diethyl ether and petroleum ether.
Elemental analysis for C12H11O3N
Calc'd: C, 66.35; H, 5.11; N, 6.45 Found: C, 66.21; H, 5.02; N, 6.42 A solution of the keto ester prepared in the preceding paragraph (25.97 g, 0.119mole) and 99% hydrazine hydrate (46 ml) in ethanol (250 ml) was refluxed for 18 hours. The resulting suspension was cooled, filtered and dried to yield (19.48 g).
Evaporation of the filtrate and trituration of the resulting residue with ethanol afforded 1.07 g of additional product (total 20.55 g). For analysis, the product was recrystallized from N,N-dimethylformamide.
30 Elemental analysis for CI lHgON3 Calc'd: C, 66.32; H, 4.55; N, 21.09 Found: C, 66.17; H, 4.55; N, 21.42 .,: ,, : - . , .. - ~ ~ . , 12 December 1989 - 3ED9:0CO:RKJ:rlk PATENT
9 ;~ '7 The stirred suspension of the 4-methyl-_H-pyridazino[4,5-b]indolizine-1-one (10.0 g, 0.050 mole) in phosphoryl chloride (75 ml) was refluxed under nitrogen for 3 hours. After cooling, the reaction mixture was poured into ice-water (1 L) with vigorous stirring. Then, the solution was made aLkaline (pH 8-9) by addition of a 50%
W/W sodium hydroxide solution (cooling). The suspension was filtered and the solid . .
was washed with water and dried to yield 1-chloro-4-methylpyridazino[4,5-b]indolizine (10.33 g). For analysis, a sample was recrystallized from dichloromethane and ether.
-. :
10 ElementalanalysisforCllHgN3CI
Calc'd: C, 60.70; H, 3.70; N, 19.31 Found: C, 60.47; H, 3.68; N, 18.98 A mixture of the chloropyridazino indolizine (500 mg, 2.3 mmoles) and 3-15 diethylaminopropylamine (10 ml) was refluxed for 4 hours. After cooling the excess of 3-diethylaminopropylamine was removed by distillation under high vacuum. The resulting residue (l.S g) was dissolved in a small amount of chloroform (10 ml).Diethyl ether was added and upon scratching the free base of the title compound crystallized slowly (370 mg). This was dissolved in a small amount of methanol and a 20 little excess of ethereal hydrogen chloride was added. Diethyl ether was added to precipitate the title product as the dihydrochloride which crystallized on scratching (457 mg), m.p. 293-295C (dec), 52% yield. For analysis, the product was recryatllized from methanol and diethyl ether.
25 Elemental analysis for C1gH2sNs-2HCI-1/4 H2O
Calc'd: C, SS.S9; H, 7.13; N, 18.01 Found: C, 55.57; H, 7.14; N, 17.86 .~ .
~ . : . . . .
.
' .: ~ , .
. -., ~
12December 1989 --~ 3EDlO:OCO:RKJ:rlk PATENT
2~2~ 7~
ExamDIe 2 N,~-Dimethvl-N'.(4.meth~ vridazinor4.5-blindoli7,in-l-vl-l~-ethane diamine l-Chloro-4-methylpyridazino[4,5-b]indolizine (10 g, 4.6 mmol) and N,N-dimethylethylenediamine (10.94 g, 124 mmol) were heated in a nitrogen atmosphereunder reflux overnight. Excess amine was removed on a rotary evaporator at <1 mm of Hg and the solid residue was dissolved in methanol and filtered through a short pad of 10 silica gel. The pad was washed with methanol (3 x 100 mL) and the product wasremoved by elution with 20% triethylamine in methanol. Rotary evaporation of methanol and triethylamine under aspirator vacuum gave 1.23 g (99%) of the free base as a yellow solid. The free base was dissolved in a minimum amount of methanol, treated with ethereal HCl and diluted with diethyl ether to precipitate the title compound 15 as a dihydrochloride salt 1.28 g (91%) as a yellow solid, mp. 250-254C, 240C
darken.
Elemental analysis for ClsHlgNs-2HCl Calc'd: C, 52.64; H, 6.18; N, 20.46 Found: C, 53.27; H, 6.72; N, 20.36 Following the procedure of the preceding paragraph with the exception that N-(2-pyridinyl)ethanediamine is employed rather than N,N-dimethylethylenediamine, affords N-(2-pyridinyl)-N' - (4-methylpyridazino[4,5-b] indolizin- 1 -yl- 1,2-25 ethanediamine.
Example 3 N.N-Dimethvl-N'-(4-meth~lp-~rida7~inor4.5-blindoli7in-J-vl)-I .3-prop~e ~d~ine l-Chloro-4-methylpyridazino[4,5-b]indolizine (l.Og, 4.6 mmol) and 3-dimethylaminopropylamine (4.7 g, 46 mmol) were combined and heated under reflux - ;-. , ~ ''-. . . ~ : . - .. . ::
12December 1989 3ED11:0CO:RKJ:rlk PATENT
1 1 ~@~5i~1 . . .
in a nitrogen atmosphere overnight. After stirring at room temperature for 2 days the excess amine was distilled off at <1 mm of Hg using a rotary evaporator. The residue -was dissolved in methanol and filtered through a pad of silica gel. The pad was rinsed with methanol (3 x 100 mL) and then with 1:1 methanol: triethylamine (4 x 100 mL).
The eight fractions were analyzed by thin layer chromatography on silica gel eluting with methanoVtriethylamine. Fractions 4 and 5 were combined and evaporated in vacuo to give the free base as a bright yellow oil. The free base was dissolved in a minimum amount of methanol, treated with ethereal HCl and diluted with diethyl ether to give 728 mg (46%) of the title compound as a dihydrochloride salt. To obtain an analytical sample, the salt was purified by HPLC (silica, methanol containing 0-3%
ammonium hydroxide) and reconverted to the dihydrochloride salt. The yield was 315 mg (20%) as yellow crystals, mp 260C.
Elemental analysis for C16H2lNs-2Hcl-H2o Calc'd: C, 51.34; H, 6.73; N, 18.71 Found: C, 51.01; H, 6.33; N, 18.37 Example 4 N-r2-(4-MorpholinYl)ethvll-4-methylpvrida7,inor4.5-blindoli7.in-l-amine Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 27 equivalents of 4-(2-aminoethyl)morpholine gave the title compound as the free base which was converted to the dihydrochloride 25 salt (MeOH/ethereal HCVdiethyl ether), mp 310C (dec.).
Elemental analysis for C17H21N5O~2HCL-H2O
Calc'd: C, ~0.75; H, 6.26; N, 17.41 Found: C, 50.78; H, 5.89; N, 17.51 - ~
,,, .: ~ : . ~ . . ,: ' . . :.
,, - .' 12 December 1989 -~ 3ED12.0CO:RKJ:rlk PATENl`
12 2~G~
Example 5 N-r3-(4-Morpholinvl)eroDvll-4-methvl~vridazinor4.~-blindoli7,in-l-s Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 4-(3-aminopropyl)morpholine gave the title compound as the free base which was converted to the dihydrochloride salt, mp. 295-296C (after recrystallization from ethanol).
Elemental analysis for C18H23Nso-2 HCl Calc'd: C, 54.27; H, 6.33; N, 17.58 Found: C, 53.90; H, 6.26; N, 17.41 Example 6 N-r(l-Ethvl-2-Dvrrolidinvl)methvll-4-methvlpvridazinor4.5-bl-indolizin-l-amine Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 27 equivalents of 2-(aminomethyl)-1-ethylpyrrolidine gave the title compound as the free base which was converted to the dihydrochloride salt, mp. 128C (dec.).
Elemental analysis for ClgH23Ns-2HCI-1.75 H2O
Calc'd: C, 52.24; H, 6.94; N, 16.92 Found: C, 52.30; H, 6.39; N, 16.55 : ~ . . :: :: - . ~ ; . , : .
:~
12 December 1989 3ED13:0CO:RKJ:rlk PATENT
Examele 7 4-Methvl-1 (4'-methvlpiDerazinvl)pvridazinor4.5-blindolizine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of l-methylpiperazine gave the title compound as the free base as a yellow solid, mp. 110C in 61% yield after flash chromatography (silica gel, 0-1.2% NH40H in acetonitrile). The free base was converted to the dihydrochloride salt (MeOH/ethereal HCVdiethyl ether), mp. 343-344C.
Elemental analysis for C16HlgNs-2HCl Calc'd: C, 52.24; H, 6.26; N, 19.77 Found: C, 53.92; H, 6.01; N, 19.41 Example 8 4-Methvl-N-r3-(1-piperidinvl)DroDvllovridazinor4.5-bl-indolizin-l -~mine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 1-(3-aminopropyl)piperidine at 130C gave the title compound as the free base (oil, 83%)after HPLC purification.
Trituration with hexane gave a yellow solid (50%), mp 130-134C. The free base was then converted to the dihydrochloride salt (MeC)H/ethereal HCUdiethyl ether), mp. 302-303C.
Elemental analysis for ClgH2sNs-2HCl-0.5 H2O
Calc'd: C, 56.30; H, 6.96; N, 17.28 Found: C, 55.97; H, 6.85; N, 16.94 Following the procedure of Example 8 with the exception that instead of 1-(3-aminopropyl)piperidine, 1-(3-aminopropyl)-2-methyl-piperidine, 1-(3-aminopropyl)pyrrolidine or 1-(4-aminobutyl)pyrrolidine are employed as the reactant to . . .
. . : . . ~ : . - :
12December 1989 3ED1 4:0CO:RKJ:rlk PATENT
14 .2~
obtain 4-methyl-N-[3-(2-methylpiperidin- 1 -yl)propyl]pyridazino[4,5-b]-indolizin- 1 -amine, or a pharmaceutically acceptable salt thereof; 4-methyl-N-[3-(1-pyrrolidinyl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof; or 4-methyl-N-[4-(1-pyrrolidinyl)butyl]pyridazino[4,5-b]-5 indoLizin-1-amine, or a pharmaceutically acceptable salt thereof.
~:xample 9 4 Methvl-N-r4'-methvl(1-piperazinvl)propvllpvrida7inor4.~-bl-indo~i7.in-l-amine Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 4-methyl-1-(3-aminopropyl)piperazine at 150C gave the title compound as the free base (yellow15 solid, 16% of theory) after purification by HPLC and trituration with i-propylether, mp 60C (foams). The free base was converted to the trihydrochloride salt mp. 280C, 275C shrink (hydroscopic).
Elemental analysis for C1gH26N6-3HCI-2.5 H20 Calc'd: C, 46.30; H, 6.95; N, 17.05 Found: C, 46.48; H, 7.20; N, 17.09 Example 10 25 4-Methvl-N-r4'-me~h, v~Ripera~invl)hutvllp~ri~a7~0r4.~-blilldoli7,in-l-nll~in~
Reaction of 1-chloro-4-methylpyridazino[4,5-b]indolizine (1.5 g, 6.89 mmol) and 4-methyl- 1-(4-aminobutyl)piperazine (11.80 g, 68.9 mmol) gave 0.810 g (34%) of 30 the title compound as the free base (yellow solid, mp 110- 111C) after HPLC
purification and trituration with acetone. The free base was converted to the trihydrochloride salt (MeOH/ethereal HCI/diethyl ether), mp 282-283C, 280C
shrinks.
. . - - , . :
' ,: . : . ' ' :.'. ........... " : : ,: :
,: . . .
12December 1989 3ED15:0CO:RKJ:rlk PATENT
Elemental analysis for C20H2gN6-3HCl-1.5 H20 Calc'd: C, 49.13; H, 7.01; N, 17.19 Found: C, 49.09; H, 6.82; N, 17.17 -ExamDIe 11 4-(4-Methvl~vrida~inor4.~-blindolizin-1 -vl)-pi,Q~azinecarboxaldehvde Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of piperazinecarboxaldehyde at 150C gave the title compound as the free base, which was purified by fiash chromatography (silica gel, 1 to 20% methanol:ethyl acetate) and converted to the dihydrochloride salt (MeOH/etheral HCVdiethyl ether), mp 325C.
Elemental analysis for Cl6Hl7Nso.2Hcl-H2o Calc'd: C, 49.75; H, 5.48; N, 18.13 Found: C, 49.51; H, 4.93; N, 17.85 Example 12 -A7~abicvclor2.2.2loct~3~vl)~Nl~(4~methvlpvrida~inor4.
hlindoli~in-l -vl)-1.2-ethanedia~ine To a solution of 3-quinuclidinone hydrochloride (600 mg, 3.7 mmol) in methanol (15 mL) was added a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine (900 mg, 3.7 mmol) in methanol (11 mL) over a one minute period at room temperature. After stirring for 5 to 10 rninutes, a solution of zinc modifled cyanoborohydride (8.7 mL of 0.50 M cyanoborohydride in methanol, 4.4 mmol) was added [Kim, et al., J. Org. Chem. 50, 1927 (1985)]. A yellow precipitate formed. After stirring for 4 days at room temperature, 50% sodium hydroxide (1 mL) was added and the solvent was evaporated. The residue was mixed with 4:1 chloroform:methanol (at 20 mL) and filtered through a plug of basic alumina. Thefiltrate was evaporated and the residue was purified by flash chromatography (alumina, . - . . . ' ~ ~ , . , ;: .-. ~
. - . . : ~ :
- . ., ; ~ :. - ,.
12 December 1989 -~ 3ED16:0CO:RKJ:rlk PATENT
16 2~517 4:1 chloroform:methanol to 100% methanol) to give the title compound as the free base which was converted to the fumaric acid salt (fumaric acid/ethanol), mp 205-208C.
Elemental analysis for C2~26N6.2C4H4O4 1 1/2 H20 S Calc'd: C, 55.16; H, 6.11; N, 13.78 Found: C, 55.50; H, 5.82; N, 13.85 Employing N-(4-methylpyridazino[4,5-b]indolizin- 1 -yl)- 1,2-propanediamine gives N-( l -azabicyclo[2.2.2]oct-3-yl)-N'-(4-methylpyridazino[4,5-b]indolizin- 1 -yl)-10 1,2-propanediamine, as the free base.
Example 1~
N-(l-Methv!p!~rida7,inor4.~-blindQli~n-4-vl~ '-(tricvclodec-l-vl~ 2-ethanediamine Following the procedure of Example 12, adamantanone (570 mg, 3.8 mmol) inmethanol (11 mL) was added to a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine in methanol (10 mL) to give after 24 hours at room temperature 20 the title compound as the free base. After purification by chromatography (neutral alumina, 99:1 chloroform:methanol) it was converted to the fumarate salt (fumaric acid/ethanol), mp >250C.
Elemental analysis for C23H2gNs-c4H4o4- 1 1/2 H2O
Calc'd: C, 62.53; H, 7.00; N, 13.51 Found: C, 62.28; H, 6.81; N, 13.54 Following the procedure of the preceding paragraph with the exception that bicyclo(3.3.1)non-9-one is employed rather than adamantanone affords N-30 (bicyclo(3.3.1)non-9-yl)-N'-(4-methylpyridazino[4,6-b]indo]izin- 1 -yl)- 1,2-ethanediamine as the free base. It is converted to the dihydrochloride 1.25 hydrate by conventional means.
.. . .. . ; , .
., . : : ; -, ~ !. - . : - : ' ~ ' ,, ' . ~ , , ,: . : ' . ' . ~.':' ' . .`'- :
12 December 1989 3ED17:0CO:RKJ:rlk PATENT
17 2~ !357~. :
Ex~le 14 4-Methvl-N.r2.r4-(2.evrimidinvl)-1-piJ)erazinvllethvll~vrida~inor4.~-blindo1izin-1 -amine 1-Chloro-4-methylpyridazine (2 g, 9 mmol) and 1-(2-pyrimidyl)-4-(2'-arninoethyl)piperazine (3.8 g, 18 mmol) in N-methylpyrrolidinone (1 mL) was heated at 150C for 1.5 days. After removal of the solvent under vacuum, the residue was partitioned between methylene chloride and water. The organic phase was washed with saturated sodium bicarbonate solution, dried, and evaporated to give the title compound as the free base. After purificadon by HPLC (silica, 0.2% methanol:ethyl acetate) the compound was converted to the trihydrochloride salt (methanol/etheral HClldiethyl ether) and recrystallized from methanoVisopropyl ether, mp 280-283C.
lS Elemental analysis for C2lH24Ns-3Hcl-3H2o Calc'd: C, 45.70; H, 6.06; N, 20.30 Found: C, 45.65; H, 5.28; N, 20.16 Example 15 N-r3-~4-A7.~.b,i~ çlor3.2.21non-3-YI~R~Y11-4-methvlpvridazinor4.5-blindoli7.in~1 -a~nin_ Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 3 equivalents of 3-(3-azabicyclo[3.2.2]non-3-yl)propylamine at 150C overnight gave the title compound as the free base which was purifled by chromatography (silica gel, 1:4 methanol: methylene chloride containing ammonium hydroxide) and converted to the dihydrochloride salt (ethanoVetheral HCI), mp 343C dec.
Elemental analysis for C22H2gNs-2Hcl-H2o Calc'd: C, 58.14; H, 7.32; N, 15.41 Found: C, 58.18; H, 7.25; N, 15.59 :, :. . , ,. -, . : ., .: ' ~
: , .: . . .
. .
12 December 1989 3ED1 8:0CO:RKJ:rL~
PATENT
E~xamDle J 6 N-~Ricv~!~3.2.1lQç~ VI)-M~ ~L4.5-blindoli7,in-l-vl) 1.2-ethanediamine s Following the procedure of Example 12, bicyclo[3.2.1]octan-2-one in methanol (3 to 4 mL) was added to a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediarnine hydrochloride in methanol/DMSO (90 mL:30 mL) which had been heated to boiling and then allowed to cool. After stirring at room temperature 10 overnight, the title compound was obtained as the free base after column ehromatography (siliea gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide) and recrystallized from isopropyl ether. The compound was converted to the dihydrochloride salt by ethanolic HCl, mp 339-344C.
Elemental analysis for C2lH27Ns-2Hcl-2H2o Calc'd: C, 59.21; H, 6.96; N, 16.44 Found: C, 59.22; H, 6.82; N, 16.52 Example 17 1-r~-r(l-Methv!~wrida7,inor4,~ Llizin-4-vl~aminol-propvl-2 Dvrrolidinone Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine, five equivalents of 1-(3-aminopropyl)pyrrolidinone, and one quivalent of ammonium chloride at reflux under nitrogen for 3 hours gave the title compound as the free base after flash columnchromatography (silica gel, methanol:ethyl acetate). This was converted to the hydrochloride salt, mp 257-258C.
Elemental analysis for C18H20Nso-Hcl-5l4H2o Calc'd: C, 56.59; H, 5.95; N, 18.05 Found: C, 56.69; H, 6.21; N, 18.37 . , . , , . . , ~ ,, .
.
- .
- ~ ~ , . . .
12 December 1989 3ED19:0CO:RKJ:rlk PATENT
19 Z~
Following the same procedure of the preceding paragraph, employing 1-(3-aminopropyl)-2-pyrrolidinethione, 1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl-2-pyrrolidinethione is obtained.
Similarly, employing 1-pyrrolylpropylamine affords 1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl pyrrole, or a pharrnaceutically acceptable salt thereof;
Example 1 ~
N-r4-(3-A7,abicvclor3.2.21non-3-vl)butvll-4-methvlpvrida7.inor4~-blindo!izin-l -amine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine, three equivalents of 4-(3-azabicyclo[3.2.2]non-3-yl)butylamine and one equivalent of ammonium chloride at 145C under nitrogen overnight gave the tide compound as the free base after flash column chromatography (silica gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide). This was converted to the dihydrochloride salt and recrystallized from ethanol, mp 257-258C.
Elemental analysis for C23H31Ns-2HCI-2.3H2O
Calc'd: C, 56.11; H, 7.71; N, 14.23 Found: C, 56.12; H, 7.75; N, 14.09 E;xarll~ 19 4-Methvl-N-r2-(1 -methvl-2-Dvrrolidinvl~ethvllDvridazinor4.~-blindolizin-1-amine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine, ten equivalents of 2-(1-methyl-2-pyrrolidinyl)ethylamine and one equivalent of arnmonium chloride under reflux in a ,. . .
.. , ~ - `
12 December 1989 3ED20:0CO:RKJ:rllc AHP-95 l 5 PATENT
;~, ~5~
nitrogen atmosphere for 3 to 4 hours gave the title compound as the free base after removal of excess amine in vacuo and treatement of the residue with boiling ethyl acetate. The solid collected upon filtration was converted to the hydrochloride salt (methanol/ethereal HCUether), mp 169C.
Elemental analysis for ClgClgNs-HCl-1/2H2O
Calc'd: C, 61.62; H, 6.03; N, 19.53 Found: C, 61.70; H, 5.92; N, 19.64 Following the procedure of the preceding paragraph, with the exception that, instead of 2-(1-methyl-2-pyrrolidinyl)ethylamine, 2-(1-methyl-2-pyrrolyl)ethylamine is employed yields 4-methyl-N-[2-(1-methyl-2-pyrrolyl)ethyl]pyridazino[4,5-b]indolizin-l-amine as the free base. The hydrochloride salt is obtained by conventional means.
Similarly, substitution of 2-pyridinylethylamine for 2-(1-methyl-2-pyrrolidinyl)ethylamine affords 4-methyl-N-[2-(2-pyridinyl)ethyl]pyridazino[4,5~b]indolizin-1-amine. :
Example 20 4-M~hvl-N-r3-(lH-imida~ol-l-vl~Dropvllpvrisl~?~ino~4~5-blindoli~ine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine, eight equivalents of 3-(lH-imidazol-l-yl)propylamine and one equivalent of ammonium chloride under reflux in a nitrogen atmosphere for 1 hour and at room temperature for 48 hours gave the title compound as the free base after removal of excess amine In vacuQ and purification by ilash chromatoraphy (silica gel, 10 to 40% methanol in ethyl acetate). The free base was converted to the dihydrochloride salt (methanol/ethereal HCI/diethyl ether), mp 162-163C.
Elemental analysis for Cl7,HI8N6-2HCl-3/4H2o Calc'd: C, 51.98; H, 5.52; N, 21.40 Found: C, 51.82; H, 5.30; N, 21.2;
1~ December 1989 - 3ED2 1 :()CO:RKJ:rlk PATENT
21 ;2~J'~17~L
Example 21 4-MorphQlinQ~I~utvl-4-methvlDvFi~lg~-hlindoli~in-1-amine s Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazinyl[4,5-b]indolizine and a large excess of 4-(4-aminobutyl)morpholine gives the title compound as the free base which may be converted to the dihydrochloride salt by conventional means.
E~mple 22 4-Metl~vl-N-r2-r4-(2-~?vrimidinvl)-]~j~ ~ll?ro~vllpvrida7~inQr4~5-blindolizin-l-amine Following the procedure of Example 14, 1-chloro-4-methylpyridazinyl[4,5-b]indolizine is reacted with 1-(2-pyrimidyl)-4-(2'-aminopropyl)piperazine in N-methylpyrrolidione to obtain the title compound as the free base. Conversion to the hydrochloride is accomplished conventionally.
F.xaml?~ 23 a~ N-r(1-Azabicv~lor2.2.2loct-3- I-methvll-4-methvlpvrida7.inor4.5-bl-indoli~in-l -amine b) N-r(l-A~nl?icvcl(?r2~2l2loct-~-vl ethvll 4 me~hvlDvritlazino~4~5-bl indolizin-l -nmine The title compounds are prepared following the procedure of Example 1, by 30 reaction of one equivalent of 1-chloro-4-methylpyridazinyl[4,5-b]indolizine with a large excess of quinuclidin-3-ylmethylamine or quinuclidin-3-ylethylamine, respectively to yield the free bases which are readily converted to the hydrochloride salts by conventional means.
12 December lg89 ~ 3ED22:0CO:RKJ:rlk 2~G~
The selective M1 muscarinic binding by ~he compounds of this invention was established by deterrnining the ICso concentration of the test compound that will cause a fifty percent inhibition of specific [3H]pirenzepine binding to rat brain tissue (ICso).
Similarly, the ICso value was determined for M2 receptor binding at cerebellum tissue 5 which contains a high portion of M2 receptors, relative to L3H]quinuclidinyl benzilate (QNB). Comparison of the results obtained in these in vitro studies indicates the relative selectivity of the test compound for binding at the post-synaptic cholinergic Ml receptors which are mainly found in the central nervous system. The results of these studies were as follows:
Table I
[3Hl-Pirenzepine Ml L3H]QNB M2 Compound IC50 ~M IC50 IlM M2~1 :' ' Example 1 0.098 4.1 42 Example 2 0.66 12 18 Example 3 0.6 9.5 24 Exarnple 4 2.45 19 8 Example 5 0.27 12 44 Example 6 0.26 6.2 24 Example 7 1.0 29 29 Example 8 0.11 1.4 13 Example9 0.15 2.8 19 Example 10 0.14 3.5 25 In addition, the compound of Example 1 was tested, as representative of the other compounds of the invention, to establish its ability to reduce scopolarnine-induced hyperactivity which is currently considered a muscarinic Ml-mediated effect. Thus, 30 after thirty minutes of habituation to locomotor activity chambers (Digiscan, Omnitech;
Columbus, Ohio), rats, employed as standard test animals, were given either vehicle alone, scopolamine alone (1.7 mg/lcg, s.c.), or both scopolamine and one dose of the compound being tesied and the animals were returned to the chambers for an additional hour.
, , ~, ~ : . '': . .
12 December 1989 `` 3ED23:0CO:RKJ:rL~
PATENT
23 2~57~.
The motor activity chambers utilize infrared detectors to assess movement in 3 axes. Total activity measures (vertical + horizontal activity) were collected in 15 minute intervals for 1 hour post-injection. Total activity measures were cumulated across all 5 time intervals for statistical analysis.
Scopolamine at the dose used produced a significant increase in the total activity measure. A test compound is considered active as an M1 agonist if it produces anattenuation of scopolamine-induced hyperactivity, i.e., if total activity is statistically 10 lower than scopolamine-only controls or does not differ from vehicle-only controls.
The compound of Example 1 was thereby established to be active at 30 and 54 mg/lcg doses i.p. to produce sufficient reduction in hyperactivity. That total activity did not differ from vehicle-only controls. Arecoline is active in this test procedure at about 15 5.4 mg/kg.
The compound of Example 1 was also studied in the radial arm maze test where male Sprague-Dawley (Charles River) rats on a 23-hour food deprivation schedule were trained in an eight arm radial maze with all arms baited. Each session consisted of 20 two maze exposures, with a time limit of 500 seconds for each exposure. After four correct choices (first exposure), each animal was removed from the maze for one hour then returned with only the remaining four arms baited (second exposure). Choiceerrors, consisting of delay errors (re-entry into any of the four arms chosen during the first exposure) and current errors (re-entry into any of the four arms chosen during the 25 second exposure), as well as total errors were recorded. Durations for each exposure were also recorded. Statistical analysis were preforrned ~Ising a One-Way Anova with Dunnetts T-Test comparisons.
In experiments to assess standards, scopolamine HBr (0.3 mg/lcg) was 30 administered subcutaneously 30 minutes prior to the test, while arecoline (10 mg/kg) and physostigmine (0.01 mg/kg) were administered intraperitoneally 15 mintues prior to the test. In a subsequent experiment, scopolamine HBr (().3 mg/kg, s.c.) and the compound of Example 1 (1, 3, 10 mg/kg, i.p.) were administered simultaneously 30minutes prior to the test. All compounds were solubilized in distilled water.
12December 1989 --~ 3ED24:0CO:RKJ:rlk PATENT
In the first experiment, the scopolamine only group produced a significant increase in delay, current and total errors versus vehicle, while the arecoline and 5 physostigmine groups did not (Table 2). In faet, arecoline and physostigmine produeed a signifieant reduetion in scopolamine impairment in delay, eurrent and total errors. Seopolamine treatment also increased all time measures eompared to vehicle.
Physostigmine produced a significant time reduction compared to seopolamine in both delay time (first exposure) and total time. The arecoline group showed a significant 10 time inerease versus vehicle with no significant time reduetion versus scopolamine.
In the experiment with the compound in Example 1 (Table 3), scopolamine significantly inereased total errors eompared to vehicle. The Example 1 eompoundredueed the impairment eaused by seopolamine (i.e., seopolamine plus drug not 15 different than vehiele), at all doses tested, but not so mueh that the drug groups were significantly different than the scopolamine only group. Delay errors showed no dose-related trend, however, eurrent and total errors demonstrated a definite dose-related decrease in scopolamine impairment with the 10 mg/kg dose being the most potent.Scopolamine also increased all time measures compared to vehicle. Delay time (first 20 exposure) scores were also significantly increased in the Example 1 3.0 mg/kg dose group. Current time (second exposure) was significantly increased in all groups. The total time was signifieantly increased in the 3.0 and 10 mg/kg dose groups but the 1.0 mg~cg dose produced a reduction in time impairment compared to scopolarnine.
These data demonstrate that the compound of Example I can reduce cognitive irnpairment due to cholinergie hypofunetion.
. - ................. , , .. . ~ . . , ~ - , .
: . ~ . - - : . -12 December 1989 3ED25:0CO:RKJ:rlk PATENT
2S 26~ 57~
Table 2 Mean Values for Arecoline and Phvsostigime S in Radial Arm Maze Mean Errors Mean Time (Min) Dose Treatment (m~ ) Delav Current Total Delav Current Total Vehicle - 0.70 0 0.70 0.74 0.99 1.96 Scopolamine0.3 2.75*3.63* 6.38* 2.28* 2.78* 5.27*
Arecoline 10.0 1.50+0.75+ 2.25~ 1.50 2.32* 4.06*
Physostigmine 0.01 1.13+ 0.88+ 2.00+ 1.14+ 2.01 3.25+
Table 3 Mean Values for Example 1 Compound in Radial Arm Maze Mean Errors Mean Time (Min) Dose Treatment (m~ ) Delav Current Total Delav CulTent Total Vehicle - 0.67 0 0.67 0.62 0.58 1.47 Scopolamine0.3 2.143.57 5.72* 2.01* 2.90* 5.14*
Example 1 1.0 1.832.00 3.67 1.03 1.83* 2.99+
Example 1 3.0 2.38*1.13 3.50 1.95* 2.92* 4.96*
Example 1 10.0 2.000.75 2.75 1.63 3.32* 5.15*
* Significantly different vs. vehicle at p <.05.
35 + Significantly different vs. scopolamine at p <.05.
' - 12December 1989 3ED26:0CO:RKJ:rlk PATENT
26 2~ S71 The compound of Example 1 was also shown by standard experimental procedures to inhibit blood platelet aggregation induced by collagen (EDso at about a 3 molar concentration). Thus, the property of this compound as an antithrombotic agent S is indicated as an additional advantage for use in patients suffering from dementia where the possibility of thrombus formation is to be avoided as in cardiovascular disease states, as well as head trauma, and the like.
To determine the effective amount of compound to be administered 10 prophylactically to arrest declining cognitive function as in Alzheimer's dementia, a subjective approach is taken by relating the drug dosage to improve memory responses or analogous desired responses which can be related to relief of undesirable symptoms.
Based upon the animal data obtained to date, the initial dosing will begin at about 30 mg/kg oral with incremental increases until the desired result is achieved.
, : ,. ., . ~ . . :
- , , . . ~ : , ~ .
R
N-(CH2)n-R4 R
~ N ~ N
in which R1 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, halo, nitro, amino, or mono- or dialkylamino in which the alkyl groups have 1 to 6 carbon atoms;
R2 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, 2-thienyl, 3-thienyl, or 2-, 3- or 4-pyridinyl;
R3 is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; :
R4 is N-methyl-pyrrolidin-2-yl, 2-,3- or 4-pyridinyl, 3-quinuclidinyl or ~N~
~CH2)m wherein .. ... .
n is 1 to 5;
misOto3;
and R8 is hydrogen or alkyl of 1 to 6 carbon atoms;
or ' ! , ' ' ' ', - , , ~ ~ , ' : ' ' ' : ' ' .
12 December 1989 3ED4:0CO:RKJ:rlk PATENT
R4iS
S wherein a) n is 2, R5 taken with R3 is ethylene and R6 is -CHO, alkyl of 1 to 6 carbon atoms, unsubstituted or substituted phenyl, pyrirnidinyl, pyridinyl, or pyrazinyl where the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, cyano, nitro or trifluoromethyl;
.
b) n is 1 to 5, and RS and R6 taken together are polymethylene of 4 to 6 carbon atoms which may be alkyl substituted with a group having from 1 to 6 carbon atoms or RS and R6 taken with the nitrogen atom to which they are attached are morpholino, 3-azabicyclo[3.2.2]nonan-3-yl, pyrrol-l-yl, pyrrolidin- 1 -yl, pyrrolidin-2-on- 1 -yl, pyrrolidin-2-thion- 1 -yl, imidazol-l-yl, aLkyl-piperidin-l-yl in which the alkyl group contains 1 to 6 carbon atoms, or a piperazin-l-yl moiety in the 4-position of which is hydrogen, -CHO, alkyl of 1 to 6 carbon atoms or unsubstituted or substituted phenyl, pyrimidinyl, pyridinyl, or pyrazinyl where the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, cyano, nitro or trifluoromethyl;
or c) n is 1 to 5, and RS and R6 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, 3-quinuclidinyl, 2-adamantyl, bicyclo[3.2.1]octan-2-yl, bicyclo[3.3.1]nonan-9-yl or 2-, 3- or 4-pyridinyl;
or a pharmaceutically acceptable salt thereof.
.
- ::
.:
.. .,~, . .. : ~ .; `''~
, ~.
.. . .
.
- . .
12December 1989 3ED5:0CO:RKJ:rlk PATENT
S
2`~85~1 :
Of these compounds, from the standpoint of availability of starting compounds ~ -and production economies, the preferred compounds are those of the formula:
N-(CH2)n-R4 ~N
N~N
s in which R2 is alkyl of 1 to 3 earbon atoms;
R3 is hydrogen or alkyl of 1 to 3 carbon atoms;
R4 is ~
'''~
whereln RS and R6 are, independently, hydrogen, alkyl of 1 to 3 earbon atoms or 3-quinuclidinyl or RS and R6, taken with the nitrogen atom to which they are attached are morpholino or a piperazin- 1-yl moiety in whieh the 4-position is substituted with an alkyl group of 1 to 3 earbon atoms or a 2-pyrirnidinyl group;
and n is one of the integers 2, 3, 4 or 5;
or a pharmaceutically acceptable salt thereof.
:
12 December 1989 3ED6:0CO:RKJ:rlk PATENT
6 2~ i'7~
From an activity profile, the most preferred compound is that of Example 1, infra.
The pharmaceutically acceptablç salts are those conventionally produced with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, toluene sulfonic, naphthalenesulfonie, formic, acetic, propionic, oxalic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvie, phenylacetic, benzoic, para-amino benzoic, para-hydroxybenzoic, salieylie, sulfanilie aeids, and the like. The term halo employed on the foregoing description of the invention is intended to embrace chlorine, bromine, iodine and fluorine, the chloro or bromo groups being preferred.
The compounds of this invention may be readily prepared by displacing the halogen from the l-position of an appropriately substituted 1-halo-pyridazino[4,5-b]indolizine with the desired amine, thusly halo R~ + H-N--(CH2)n--R4 ~,~N~N
N-(CH2)n-R4 R1 ~ N
~N~N
The amino reaetants are eornmerieally available or prepared by methods well known in the art. The l-halo-pyridazino[4,5-b]indolizine reaetants may be prepared by various .. .. - . ~
.
.. ' ; ' ., ' ' ~
- . , . .
- ~ .
~................. , 12 December 1989 3ED7:0CO:RKJ:rlk PATENT
7 Z~
methods known to the medicinal chemist. For example, 2-indolizinecarboxylic acidwhich may be variously substituted as desired [Bragg et al., J. Chem. Soc. 3277 (1963)] is converted to an ester (methanol treated with an acid such as HCI) and the product is acylated with either an acid anhydride or an acid halide [R4COCI or 5 (R4Co)2o] in the presence of an acid acceptor (triethylamine, etc.) or by means of the Vilsmeir-Haak reaction when R2 is hydrogen, to obtain the corresponding 3-acyl-2-indolizine carboxylic acid ester. This product is treated with hydrazine hydrate to afford the corresponding substituted 2H-pyridazino[4,5-b]indolizin-1-one.
O ' ' R1 ~ H2NNH2 1 ~ NH
~N IlR2 ~N~f N . ..
Halogenation with POC13, SOC12 and the like affords the corresponding 1-halo-pyridazino[4,5-b]indolizine reactant.
The reaction of the 1-halo-pyridazino[4,5-b]indolizine derivatives with the 15 desired amine is performed with an excess (10-30 equivalents) of the amine at reflux temperature if the boiling point of the amine is below about 150C, or up to about 160C in the melting range of the amine in an inert atmosphere. The reaction is readily followed by thin layer chromatography on silica gel (1:1 MeOH:EtOAc, 100% MeOH
or MeOH containing 1-5% triethylamine or ammonium hydroxide). The reaction takes20 from several hours to several days to go to completion. After the reaction is complete, the excess amine is removed by vacuum distillation or extraction (CH2C12 with water wash) as appropriate. The organic phase is dried (NR2SO4) and evaporated ln vacuo to obtain the crude product which is ehromatographically purified (silica gel; acetonitrile, methanol or 1:1 MeOH:EtOAc containing an NH40H gradient 0-7%). The product is 25 then converted to the desired salt conventionally.
The following examples of the preparation of several compound species are presented as illustrative rather than limitative elements of the invention.
.. . . ~ . . ~ . , 12December 1989 3ED8:0CO:RKJ:rlk LT
Example 1 1 -r(3'-DiethvlaminoDroDvl)aminol-4-methvlpvridazinor4.5-blindoli7ine S A stirred solution of 2-indolizinecairboxylic acid, methyl ester (91.42 g, 0.522 mole) and anhydrous sodium acetate (42.53 g, 0.52 mole) in acetic anhydride (1.1 L) was refluxed, under anhydrous conditions, for 48 hours. After cooling most of the acetic anhydride was evaporated in vacuo. The resulting residue (150 ml) was cooled in an ice water bath and methanol (140 ml) was added to destroy the remaining acetic anhydride. The resulting mixture was poured into water (1.1 L) and the product was extracted with diethyl ether, three times. The ethereal layer was washed with saturated sodium bicarbonate solution, three times, with water, two times, and was dried over magnesium sulfate. Evaporation of solvent yielded 112 g of crude 3-acetyl-2-indolizinecarboxylic acid, methyl ester which was chromatographed on silica gel (3 kg) using 10% acetone in benzene as eluant, to afford the pure compound (85.5 g). For analysis, the product was recrystallized from a mixture of diethyl ether and petroleum ether.
Elemental analysis for C12H11O3N
Calc'd: C, 66.35; H, 5.11; N, 6.45 Found: C, 66.21; H, 5.02; N, 6.42 A solution of the keto ester prepared in the preceding paragraph (25.97 g, 0.119mole) and 99% hydrazine hydrate (46 ml) in ethanol (250 ml) was refluxed for 18 hours. The resulting suspension was cooled, filtered and dried to yield (19.48 g).
Evaporation of the filtrate and trituration of the resulting residue with ethanol afforded 1.07 g of additional product (total 20.55 g). For analysis, the product was recrystallized from N,N-dimethylformamide.
30 Elemental analysis for CI lHgON3 Calc'd: C, 66.32; H, 4.55; N, 21.09 Found: C, 66.17; H, 4.55; N, 21.42 .,: ,, : - . , .. - ~ ~ . , 12 December 1989 - 3ED9:0CO:RKJ:rlk PATENT
9 ;~ '7 The stirred suspension of the 4-methyl-_H-pyridazino[4,5-b]indolizine-1-one (10.0 g, 0.050 mole) in phosphoryl chloride (75 ml) was refluxed under nitrogen for 3 hours. After cooling, the reaction mixture was poured into ice-water (1 L) with vigorous stirring. Then, the solution was made aLkaline (pH 8-9) by addition of a 50%
W/W sodium hydroxide solution (cooling). The suspension was filtered and the solid . .
was washed with water and dried to yield 1-chloro-4-methylpyridazino[4,5-b]indolizine (10.33 g). For analysis, a sample was recrystallized from dichloromethane and ether.
-. :
10 ElementalanalysisforCllHgN3CI
Calc'd: C, 60.70; H, 3.70; N, 19.31 Found: C, 60.47; H, 3.68; N, 18.98 A mixture of the chloropyridazino indolizine (500 mg, 2.3 mmoles) and 3-15 diethylaminopropylamine (10 ml) was refluxed for 4 hours. After cooling the excess of 3-diethylaminopropylamine was removed by distillation under high vacuum. The resulting residue (l.S g) was dissolved in a small amount of chloroform (10 ml).Diethyl ether was added and upon scratching the free base of the title compound crystallized slowly (370 mg). This was dissolved in a small amount of methanol and a 20 little excess of ethereal hydrogen chloride was added. Diethyl ether was added to precipitate the title product as the dihydrochloride which crystallized on scratching (457 mg), m.p. 293-295C (dec), 52% yield. For analysis, the product was recryatllized from methanol and diethyl ether.
25 Elemental analysis for C1gH2sNs-2HCI-1/4 H2O
Calc'd: C, SS.S9; H, 7.13; N, 18.01 Found: C, 55.57; H, 7.14; N, 17.86 .~ .
~ . : . . . .
.
' .: ~ , .
. -., ~
12December 1989 --~ 3EDlO:OCO:RKJ:rlk PATENT
2~2~ 7~
ExamDIe 2 N,~-Dimethvl-N'.(4.meth~ vridazinor4.5-blindoli7,in-l-vl-l~-ethane diamine l-Chloro-4-methylpyridazino[4,5-b]indolizine (10 g, 4.6 mmol) and N,N-dimethylethylenediamine (10.94 g, 124 mmol) were heated in a nitrogen atmosphereunder reflux overnight. Excess amine was removed on a rotary evaporator at <1 mm of Hg and the solid residue was dissolved in methanol and filtered through a short pad of 10 silica gel. The pad was washed with methanol (3 x 100 mL) and the product wasremoved by elution with 20% triethylamine in methanol. Rotary evaporation of methanol and triethylamine under aspirator vacuum gave 1.23 g (99%) of the free base as a yellow solid. The free base was dissolved in a minimum amount of methanol, treated with ethereal HCl and diluted with diethyl ether to precipitate the title compound 15 as a dihydrochloride salt 1.28 g (91%) as a yellow solid, mp. 250-254C, 240C
darken.
Elemental analysis for ClsHlgNs-2HCl Calc'd: C, 52.64; H, 6.18; N, 20.46 Found: C, 53.27; H, 6.72; N, 20.36 Following the procedure of the preceding paragraph with the exception that N-(2-pyridinyl)ethanediamine is employed rather than N,N-dimethylethylenediamine, affords N-(2-pyridinyl)-N' - (4-methylpyridazino[4,5-b] indolizin- 1 -yl- 1,2-25 ethanediamine.
Example 3 N.N-Dimethvl-N'-(4-meth~lp-~rida7~inor4.5-blindoli7in-J-vl)-I .3-prop~e ~d~ine l-Chloro-4-methylpyridazino[4,5-b]indolizine (l.Og, 4.6 mmol) and 3-dimethylaminopropylamine (4.7 g, 46 mmol) were combined and heated under reflux - ;-. , ~ ''-. . . ~ : . - .. . ::
12December 1989 3ED11:0CO:RKJ:rlk PATENT
1 1 ~@~5i~1 . . .
in a nitrogen atmosphere overnight. After stirring at room temperature for 2 days the excess amine was distilled off at <1 mm of Hg using a rotary evaporator. The residue -was dissolved in methanol and filtered through a pad of silica gel. The pad was rinsed with methanol (3 x 100 mL) and then with 1:1 methanol: triethylamine (4 x 100 mL).
The eight fractions were analyzed by thin layer chromatography on silica gel eluting with methanoVtriethylamine. Fractions 4 and 5 were combined and evaporated in vacuo to give the free base as a bright yellow oil. The free base was dissolved in a minimum amount of methanol, treated with ethereal HCl and diluted with diethyl ether to give 728 mg (46%) of the title compound as a dihydrochloride salt. To obtain an analytical sample, the salt was purified by HPLC (silica, methanol containing 0-3%
ammonium hydroxide) and reconverted to the dihydrochloride salt. The yield was 315 mg (20%) as yellow crystals, mp 260C.
Elemental analysis for C16H2lNs-2Hcl-H2o Calc'd: C, 51.34; H, 6.73; N, 18.71 Found: C, 51.01; H, 6.33; N, 18.37 Example 4 N-r2-(4-MorpholinYl)ethvll-4-methylpvrida7,inor4.5-blindoli7.in-l-amine Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 27 equivalents of 4-(2-aminoethyl)morpholine gave the title compound as the free base which was converted to the dihydrochloride 25 salt (MeOH/ethereal HCVdiethyl ether), mp 310C (dec.).
Elemental analysis for C17H21N5O~2HCL-H2O
Calc'd: C, ~0.75; H, 6.26; N, 17.41 Found: C, 50.78; H, 5.89; N, 17.51 - ~
,,, .: ~ : . ~ . . ,: ' . . :.
,, - .' 12 December 1989 -~ 3ED12.0CO:RKJ:rlk PATENl`
12 2~G~
Example 5 N-r3-(4-Morpholinvl)eroDvll-4-methvl~vridazinor4.~-blindoli7,in-l-s Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 4-(3-aminopropyl)morpholine gave the title compound as the free base which was converted to the dihydrochloride salt, mp. 295-296C (after recrystallization from ethanol).
Elemental analysis for C18H23Nso-2 HCl Calc'd: C, 54.27; H, 6.33; N, 17.58 Found: C, 53.90; H, 6.26; N, 17.41 Example 6 N-r(l-Ethvl-2-Dvrrolidinvl)methvll-4-methvlpvridazinor4.5-bl-indolizin-l-amine Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 27 equivalents of 2-(aminomethyl)-1-ethylpyrrolidine gave the title compound as the free base which was converted to the dihydrochloride salt, mp. 128C (dec.).
Elemental analysis for ClgH23Ns-2HCI-1.75 H2O
Calc'd: C, 52.24; H, 6.94; N, 16.92 Found: C, 52.30; H, 6.39; N, 16.55 : ~ . . :: :: - . ~ ; . , : .
:~
12 December 1989 3ED13:0CO:RKJ:rlk PATENT
Examele 7 4-Methvl-1 (4'-methvlpiDerazinvl)pvridazinor4.5-blindolizine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of l-methylpiperazine gave the title compound as the free base as a yellow solid, mp. 110C in 61% yield after flash chromatography (silica gel, 0-1.2% NH40H in acetonitrile). The free base was converted to the dihydrochloride salt (MeOH/ethereal HCVdiethyl ether), mp. 343-344C.
Elemental analysis for C16HlgNs-2HCl Calc'd: C, 52.24; H, 6.26; N, 19.77 Found: C, 53.92; H, 6.01; N, 19.41 Example 8 4-Methvl-N-r3-(1-piperidinvl)DroDvllovridazinor4.5-bl-indolizin-l -~mine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 1-(3-aminopropyl)piperidine at 130C gave the title compound as the free base (oil, 83%)after HPLC purification.
Trituration with hexane gave a yellow solid (50%), mp 130-134C. The free base was then converted to the dihydrochloride salt (MeC)H/ethereal HCUdiethyl ether), mp. 302-303C.
Elemental analysis for ClgH2sNs-2HCl-0.5 H2O
Calc'd: C, 56.30; H, 6.96; N, 17.28 Found: C, 55.97; H, 6.85; N, 16.94 Following the procedure of Example 8 with the exception that instead of 1-(3-aminopropyl)piperidine, 1-(3-aminopropyl)-2-methyl-piperidine, 1-(3-aminopropyl)pyrrolidine or 1-(4-aminobutyl)pyrrolidine are employed as the reactant to . . .
. . : . . ~ : . - :
12December 1989 3ED1 4:0CO:RKJ:rlk PATENT
14 .2~
obtain 4-methyl-N-[3-(2-methylpiperidin- 1 -yl)propyl]pyridazino[4,5-b]-indolizin- 1 -amine, or a pharmaceutically acceptable salt thereof; 4-methyl-N-[3-(1-pyrrolidinyl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof; or 4-methyl-N-[4-(1-pyrrolidinyl)butyl]pyridazino[4,5-b]-5 indoLizin-1-amine, or a pharmaceutically acceptable salt thereof.
~:xample 9 4 Methvl-N-r4'-methvl(1-piperazinvl)propvllpvrida7inor4.~-bl-indo~i7.in-l-amine Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 4-methyl-1-(3-aminopropyl)piperazine at 150C gave the title compound as the free base (yellow15 solid, 16% of theory) after purification by HPLC and trituration with i-propylether, mp 60C (foams). The free base was converted to the trihydrochloride salt mp. 280C, 275C shrink (hydroscopic).
Elemental analysis for C1gH26N6-3HCI-2.5 H20 Calc'd: C, 46.30; H, 6.95; N, 17.05 Found: C, 46.48; H, 7.20; N, 17.09 Example 10 25 4-Methvl-N-r4'-me~h, v~Ripera~invl)hutvllp~ri~a7~0r4.~-blilldoli7,in-l-nll~in~
Reaction of 1-chloro-4-methylpyridazino[4,5-b]indolizine (1.5 g, 6.89 mmol) and 4-methyl- 1-(4-aminobutyl)piperazine (11.80 g, 68.9 mmol) gave 0.810 g (34%) of 30 the title compound as the free base (yellow solid, mp 110- 111C) after HPLC
purification and trituration with acetone. The free base was converted to the trihydrochloride salt (MeOH/ethereal HCI/diethyl ether), mp 282-283C, 280C
shrinks.
. . - - , . :
' ,: . : . ' ' :.'. ........... " : : ,: :
,: . . .
12December 1989 3ED15:0CO:RKJ:rlk PATENT
Elemental analysis for C20H2gN6-3HCl-1.5 H20 Calc'd: C, 49.13; H, 7.01; N, 17.19 Found: C, 49.09; H, 6.82; N, 17.17 -ExamDIe 11 4-(4-Methvl~vrida~inor4.~-blindolizin-1 -vl)-pi,Q~azinecarboxaldehvde Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of piperazinecarboxaldehyde at 150C gave the title compound as the free base, which was purified by fiash chromatography (silica gel, 1 to 20% methanol:ethyl acetate) and converted to the dihydrochloride salt (MeOH/etheral HCVdiethyl ether), mp 325C.
Elemental analysis for Cl6Hl7Nso.2Hcl-H2o Calc'd: C, 49.75; H, 5.48; N, 18.13 Found: C, 49.51; H, 4.93; N, 17.85 Example 12 -A7~abicvclor2.2.2loct~3~vl)~Nl~(4~methvlpvrida~inor4.
hlindoli~in-l -vl)-1.2-ethanedia~ine To a solution of 3-quinuclidinone hydrochloride (600 mg, 3.7 mmol) in methanol (15 mL) was added a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine (900 mg, 3.7 mmol) in methanol (11 mL) over a one minute period at room temperature. After stirring for 5 to 10 rninutes, a solution of zinc modifled cyanoborohydride (8.7 mL of 0.50 M cyanoborohydride in methanol, 4.4 mmol) was added [Kim, et al., J. Org. Chem. 50, 1927 (1985)]. A yellow precipitate formed. After stirring for 4 days at room temperature, 50% sodium hydroxide (1 mL) was added and the solvent was evaporated. The residue was mixed with 4:1 chloroform:methanol (at 20 mL) and filtered through a plug of basic alumina. Thefiltrate was evaporated and the residue was purified by flash chromatography (alumina, . - . . . ' ~ ~ , . , ;: .-. ~
. - . . : ~ :
- . ., ; ~ :. - ,.
12 December 1989 -~ 3ED16:0CO:RKJ:rlk PATENT
16 2~517 4:1 chloroform:methanol to 100% methanol) to give the title compound as the free base which was converted to the fumaric acid salt (fumaric acid/ethanol), mp 205-208C.
Elemental analysis for C2~26N6.2C4H4O4 1 1/2 H20 S Calc'd: C, 55.16; H, 6.11; N, 13.78 Found: C, 55.50; H, 5.82; N, 13.85 Employing N-(4-methylpyridazino[4,5-b]indolizin- 1 -yl)- 1,2-propanediamine gives N-( l -azabicyclo[2.2.2]oct-3-yl)-N'-(4-methylpyridazino[4,5-b]indolizin- 1 -yl)-10 1,2-propanediamine, as the free base.
Example 1~
N-(l-Methv!p!~rida7,inor4.~-blindQli~n-4-vl~ '-(tricvclodec-l-vl~ 2-ethanediamine Following the procedure of Example 12, adamantanone (570 mg, 3.8 mmol) inmethanol (11 mL) was added to a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine in methanol (10 mL) to give after 24 hours at room temperature 20 the title compound as the free base. After purification by chromatography (neutral alumina, 99:1 chloroform:methanol) it was converted to the fumarate salt (fumaric acid/ethanol), mp >250C.
Elemental analysis for C23H2gNs-c4H4o4- 1 1/2 H2O
Calc'd: C, 62.53; H, 7.00; N, 13.51 Found: C, 62.28; H, 6.81; N, 13.54 Following the procedure of the preceding paragraph with the exception that bicyclo(3.3.1)non-9-one is employed rather than adamantanone affords N-30 (bicyclo(3.3.1)non-9-yl)-N'-(4-methylpyridazino[4,6-b]indo]izin- 1 -yl)- 1,2-ethanediamine as the free base. It is converted to the dihydrochloride 1.25 hydrate by conventional means.
.. . .. . ; , .
., . : : ; -, ~ !. - . : - : ' ~ ' ,, ' . ~ , , ,: . : ' . ' . ~.':' ' . .`'- :
12 December 1989 3ED17:0CO:RKJ:rlk PATENT
17 2~ !357~. :
Ex~le 14 4-Methvl-N.r2.r4-(2.evrimidinvl)-1-piJ)erazinvllethvll~vrida~inor4.~-blindo1izin-1 -amine 1-Chloro-4-methylpyridazine (2 g, 9 mmol) and 1-(2-pyrimidyl)-4-(2'-arninoethyl)piperazine (3.8 g, 18 mmol) in N-methylpyrrolidinone (1 mL) was heated at 150C for 1.5 days. After removal of the solvent under vacuum, the residue was partitioned between methylene chloride and water. The organic phase was washed with saturated sodium bicarbonate solution, dried, and evaporated to give the title compound as the free base. After purificadon by HPLC (silica, 0.2% methanol:ethyl acetate) the compound was converted to the trihydrochloride salt (methanol/etheral HClldiethyl ether) and recrystallized from methanoVisopropyl ether, mp 280-283C.
lS Elemental analysis for C2lH24Ns-3Hcl-3H2o Calc'd: C, 45.70; H, 6.06; N, 20.30 Found: C, 45.65; H, 5.28; N, 20.16 Example 15 N-r3-~4-A7.~.b,i~ çlor3.2.21non-3-YI~R~Y11-4-methvlpvridazinor4.5-blindoli7.in~1 -a~nin_ Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 3 equivalents of 3-(3-azabicyclo[3.2.2]non-3-yl)propylamine at 150C overnight gave the title compound as the free base which was purifled by chromatography (silica gel, 1:4 methanol: methylene chloride containing ammonium hydroxide) and converted to the dihydrochloride salt (ethanoVetheral HCI), mp 343C dec.
Elemental analysis for C22H2gNs-2Hcl-H2o Calc'd: C, 58.14; H, 7.32; N, 15.41 Found: C, 58.18; H, 7.25; N, 15.59 :, :. . , ,. -, . : ., .: ' ~
: , .: . . .
. .
12 December 1989 3ED1 8:0CO:RKJ:rL~
PATENT
E~xamDle J 6 N-~Ricv~!~3.2.1lQç~ VI)-M~ ~L4.5-blindoli7,in-l-vl) 1.2-ethanediamine s Following the procedure of Example 12, bicyclo[3.2.1]octan-2-one in methanol (3 to 4 mL) was added to a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediarnine hydrochloride in methanol/DMSO (90 mL:30 mL) which had been heated to boiling and then allowed to cool. After stirring at room temperature 10 overnight, the title compound was obtained as the free base after column ehromatography (siliea gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide) and recrystallized from isopropyl ether. The compound was converted to the dihydrochloride salt by ethanolic HCl, mp 339-344C.
Elemental analysis for C2lH27Ns-2Hcl-2H2o Calc'd: C, 59.21; H, 6.96; N, 16.44 Found: C, 59.22; H, 6.82; N, 16.52 Example 17 1-r~-r(l-Methv!~wrida7,inor4,~ Llizin-4-vl~aminol-propvl-2 Dvrrolidinone Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine, five equivalents of 1-(3-aminopropyl)pyrrolidinone, and one quivalent of ammonium chloride at reflux under nitrogen for 3 hours gave the title compound as the free base after flash columnchromatography (silica gel, methanol:ethyl acetate). This was converted to the hydrochloride salt, mp 257-258C.
Elemental analysis for C18H20Nso-Hcl-5l4H2o Calc'd: C, 56.59; H, 5.95; N, 18.05 Found: C, 56.69; H, 6.21; N, 18.37 . , . , , . . , ~ ,, .
.
- .
- ~ ~ , . . .
12 December 1989 3ED19:0CO:RKJ:rlk PATENT
19 Z~
Following the same procedure of the preceding paragraph, employing 1-(3-aminopropyl)-2-pyrrolidinethione, 1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl-2-pyrrolidinethione is obtained.
Similarly, employing 1-pyrrolylpropylamine affords 1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl pyrrole, or a pharrnaceutically acceptable salt thereof;
Example 1 ~
N-r4-(3-A7,abicvclor3.2.21non-3-vl)butvll-4-methvlpvrida7.inor4~-blindo!izin-l -amine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine, three equivalents of 4-(3-azabicyclo[3.2.2]non-3-yl)butylamine and one equivalent of ammonium chloride at 145C under nitrogen overnight gave the tide compound as the free base after flash column chromatography (silica gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide). This was converted to the dihydrochloride salt and recrystallized from ethanol, mp 257-258C.
Elemental analysis for C23H31Ns-2HCI-2.3H2O
Calc'd: C, 56.11; H, 7.71; N, 14.23 Found: C, 56.12; H, 7.75; N, 14.09 E;xarll~ 19 4-Methvl-N-r2-(1 -methvl-2-Dvrrolidinvl~ethvllDvridazinor4.~-blindolizin-1-amine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine, ten equivalents of 2-(1-methyl-2-pyrrolidinyl)ethylamine and one equivalent of arnmonium chloride under reflux in a ,. . .
.. , ~ - `
12 December 1989 3ED20:0CO:RKJ:rllc AHP-95 l 5 PATENT
;~, ~5~
nitrogen atmosphere for 3 to 4 hours gave the title compound as the free base after removal of excess amine in vacuo and treatement of the residue with boiling ethyl acetate. The solid collected upon filtration was converted to the hydrochloride salt (methanol/ethereal HCUether), mp 169C.
Elemental analysis for ClgClgNs-HCl-1/2H2O
Calc'd: C, 61.62; H, 6.03; N, 19.53 Found: C, 61.70; H, 5.92; N, 19.64 Following the procedure of the preceding paragraph, with the exception that, instead of 2-(1-methyl-2-pyrrolidinyl)ethylamine, 2-(1-methyl-2-pyrrolyl)ethylamine is employed yields 4-methyl-N-[2-(1-methyl-2-pyrrolyl)ethyl]pyridazino[4,5-b]indolizin-l-amine as the free base. The hydrochloride salt is obtained by conventional means.
Similarly, substitution of 2-pyridinylethylamine for 2-(1-methyl-2-pyrrolidinyl)ethylamine affords 4-methyl-N-[2-(2-pyridinyl)ethyl]pyridazino[4,5~b]indolizin-1-amine. :
Example 20 4-M~hvl-N-r3-(lH-imida~ol-l-vl~Dropvllpvrisl~?~ino~4~5-blindoli~ine Following the procedure of Example 1, reaction of one equivalent of l-chloro-4-methylpyridazino[4,5-b]indolizine, eight equivalents of 3-(lH-imidazol-l-yl)propylamine and one equivalent of ammonium chloride under reflux in a nitrogen atmosphere for 1 hour and at room temperature for 48 hours gave the title compound as the free base after removal of excess amine In vacuQ and purification by ilash chromatoraphy (silica gel, 10 to 40% methanol in ethyl acetate). The free base was converted to the dihydrochloride salt (methanol/ethereal HCI/diethyl ether), mp 162-163C.
Elemental analysis for Cl7,HI8N6-2HCl-3/4H2o Calc'd: C, 51.98; H, 5.52; N, 21.40 Found: C, 51.82; H, 5.30; N, 21.2;
1~ December 1989 - 3ED2 1 :()CO:RKJ:rlk PATENT
21 ;2~J'~17~L
Example 21 4-MorphQlinQ~I~utvl-4-methvlDvFi~lg~-hlindoli~in-1-amine s Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazinyl[4,5-b]indolizine and a large excess of 4-(4-aminobutyl)morpholine gives the title compound as the free base which may be converted to the dihydrochloride salt by conventional means.
E~mple 22 4-Metl~vl-N-r2-r4-(2-~?vrimidinvl)-]~j~ ~ll?ro~vllpvrida7~inQr4~5-blindolizin-l-amine Following the procedure of Example 14, 1-chloro-4-methylpyridazinyl[4,5-b]indolizine is reacted with 1-(2-pyrimidyl)-4-(2'-aminopropyl)piperazine in N-methylpyrrolidione to obtain the title compound as the free base. Conversion to the hydrochloride is accomplished conventionally.
F.xaml?~ 23 a~ N-r(1-Azabicv~lor2.2.2loct-3- I-methvll-4-methvlpvrida7.inor4.5-bl-indoli~in-l -amine b) N-r(l-A~nl?icvcl(?r2~2l2loct-~-vl ethvll 4 me~hvlDvritlazino~4~5-bl indolizin-l -nmine The title compounds are prepared following the procedure of Example 1, by 30 reaction of one equivalent of 1-chloro-4-methylpyridazinyl[4,5-b]indolizine with a large excess of quinuclidin-3-ylmethylamine or quinuclidin-3-ylethylamine, respectively to yield the free bases which are readily converted to the hydrochloride salts by conventional means.
12 December lg89 ~ 3ED22:0CO:RKJ:rlk 2~G~
The selective M1 muscarinic binding by ~he compounds of this invention was established by deterrnining the ICso concentration of the test compound that will cause a fifty percent inhibition of specific [3H]pirenzepine binding to rat brain tissue (ICso).
Similarly, the ICso value was determined for M2 receptor binding at cerebellum tissue 5 which contains a high portion of M2 receptors, relative to L3H]quinuclidinyl benzilate (QNB). Comparison of the results obtained in these in vitro studies indicates the relative selectivity of the test compound for binding at the post-synaptic cholinergic Ml receptors which are mainly found in the central nervous system. The results of these studies were as follows:
Table I
[3Hl-Pirenzepine Ml L3H]QNB M2 Compound IC50 ~M IC50 IlM M2~1 :' ' Example 1 0.098 4.1 42 Example 2 0.66 12 18 Example 3 0.6 9.5 24 Exarnple 4 2.45 19 8 Example 5 0.27 12 44 Example 6 0.26 6.2 24 Example 7 1.0 29 29 Example 8 0.11 1.4 13 Example9 0.15 2.8 19 Example 10 0.14 3.5 25 In addition, the compound of Example 1 was tested, as representative of the other compounds of the invention, to establish its ability to reduce scopolarnine-induced hyperactivity which is currently considered a muscarinic Ml-mediated effect. Thus, 30 after thirty minutes of habituation to locomotor activity chambers (Digiscan, Omnitech;
Columbus, Ohio), rats, employed as standard test animals, were given either vehicle alone, scopolamine alone (1.7 mg/lcg, s.c.), or both scopolamine and one dose of the compound being tesied and the animals were returned to the chambers for an additional hour.
, , ~, ~ : . '': . .
12 December 1989 `` 3ED23:0CO:RKJ:rL~
PATENT
23 2~57~.
The motor activity chambers utilize infrared detectors to assess movement in 3 axes. Total activity measures (vertical + horizontal activity) were collected in 15 minute intervals for 1 hour post-injection. Total activity measures were cumulated across all 5 time intervals for statistical analysis.
Scopolamine at the dose used produced a significant increase in the total activity measure. A test compound is considered active as an M1 agonist if it produces anattenuation of scopolamine-induced hyperactivity, i.e., if total activity is statistically 10 lower than scopolamine-only controls or does not differ from vehicle-only controls.
The compound of Example 1 was thereby established to be active at 30 and 54 mg/lcg doses i.p. to produce sufficient reduction in hyperactivity. That total activity did not differ from vehicle-only controls. Arecoline is active in this test procedure at about 15 5.4 mg/kg.
The compound of Example 1 was also studied in the radial arm maze test where male Sprague-Dawley (Charles River) rats on a 23-hour food deprivation schedule were trained in an eight arm radial maze with all arms baited. Each session consisted of 20 two maze exposures, with a time limit of 500 seconds for each exposure. After four correct choices (first exposure), each animal was removed from the maze for one hour then returned with only the remaining four arms baited (second exposure). Choiceerrors, consisting of delay errors (re-entry into any of the four arms chosen during the first exposure) and current errors (re-entry into any of the four arms chosen during the 25 second exposure), as well as total errors were recorded. Durations for each exposure were also recorded. Statistical analysis were preforrned ~Ising a One-Way Anova with Dunnetts T-Test comparisons.
In experiments to assess standards, scopolamine HBr (0.3 mg/lcg) was 30 administered subcutaneously 30 minutes prior to the test, while arecoline (10 mg/kg) and physostigmine (0.01 mg/kg) were administered intraperitoneally 15 mintues prior to the test. In a subsequent experiment, scopolamine HBr (().3 mg/kg, s.c.) and the compound of Example 1 (1, 3, 10 mg/kg, i.p.) were administered simultaneously 30minutes prior to the test. All compounds were solubilized in distilled water.
12December 1989 --~ 3ED24:0CO:RKJ:rlk PATENT
In the first experiment, the scopolamine only group produced a significant increase in delay, current and total errors versus vehicle, while the arecoline and 5 physostigmine groups did not (Table 2). In faet, arecoline and physostigmine produeed a signifieant reduetion in scopolamine impairment in delay, eurrent and total errors. Seopolamine treatment also increased all time measures eompared to vehicle.
Physostigmine produced a significant time reduction compared to seopolamine in both delay time (first exposure) and total time. The arecoline group showed a significant 10 time inerease versus vehicle with no significant time reduetion versus scopolamine.
In the experiment with the compound in Example 1 (Table 3), scopolamine significantly inereased total errors eompared to vehicle. The Example 1 eompoundredueed the impairment eaused by seopolamine (i.e., seopolamine plus drug not 15 different than vehiele), at all doses tested, but not so mueh that the drug groups were significantly different than the scopolamine only group. Delay errors showed no dose-related trend, however, eurrent and total errors demonstrated a definite dose-related decrease in scopolamine impairment with the 10 mg/kg dose being the most potent.Scopolamine also increased all time measures compared to vehicle. Delay time (first 20 exposure) scores were also significantly increased in the Example 1 3.0 mg/kg dose group. Current time (second exposure) was significantly increased in all groups. The total time was signifieantly increased in the 3.0 and 10 mg/kg dose groups but the 1.0 mg~cg dose produced a reduction in time impairment compared to scopolarnine.
These data demonstrate that the compound of Example I can reduce cognitive irnpairment due to cholinergie hypofunetion.
. - ................. , , .. . ~ . . , ~ - , .
: . ~ . - - : . -12 December 1989 3ED25:0CO:RKJ:rlk PATENT
2S 26~ 57~
Table 2 Mean Values for Arecoline and Phvsostigime S in Radial Arm Maze Mean Errors Mean Time (Min) Dose Treatment (m~ ) Delav Current Total Delav Current Total Vehicle - 0.70 0 0.70 0.74 0.99 1.96 Scopolamine0.3 2.75*3.63* 6.38* 2.28* 2.78* 5.27*
Arecoline 10.0 1.50+0.75+ 2.25~ 1.50 2.32* 4.06*
Physostigmine 0.01 1.13+ 0.88+ 2.00+ 1.14+ 2.01 3.25+
Table 3 Mean Values for Example 1 Compound in Radial Arm Maze Mean Errors Mean Time (Min) Dose Treatment (m~ ) Delav Current Total Delav CulTent Total Vehicle - 0.67 0 0.67 0.62 0.58 1.47 Scopolamine0.3 2.143.57 5.72* 2.01* 2.90* 5.14*
Example 1 1.0 1.832.00 3.67 1.03 1.83* 2.99+
Example 1 3.0 2.38*1.13 3.50 1.95* 2.92* 4.96*
Example 1 10.0 2.000.75 2.75 1.63 3.32* 5.15*
* Significantly different vs. vehicle at p <.05.
35 + Significantly different vs. scopolamine at p <.05.
' - 12December 1989 3ED26:0CO:RKJ:rlk PATENT
26 2~ S71 The compound of Example 1 was also shown by standard experimental procedures to inhibit blood platelet aggregation induced by collagen (EDso at about a 3 molar concentration). Thus, the property of this compound as an antithrombotic agent S is indicated as an additional advantage for use in patients suffering from dementia where the possibility of thrombus formation is to be avoided as in cardiovascular disease states, as well as head trauma, and the like.
To determine the effective amount of compound to be administered 10 prophylactically to arrest declining cognitive function as in Alzheimer's dementia, a subjective approach is taken by relating the drug dosage to improve memory responses or analogous desired responses which can be related to relief of undesirable symptoms.
Based upon the animal data obtained to date, the initial dosing will begin at about 30 mg/kg oral with incremental increases until the desired result is achieved.
, : ,. ., . ~ . . :
- , , . . ~ : , ~ .
Claims
1 -[(3-diethylaminopropyl)amino]-4-methylpyridazino[4,5-b]indolizine or a pharmaceutically acceptable salt thereof;
N,N-dimethyl-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl-1,2-ethane diamine, or a pharmaceutically acceptable salt thereof;
N,N-dimethyl-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,3-propanediamine, or a pharmaceutically acceptable salt thereof;
or N,N-dimethyl-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,4-butanediamine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
N-[2-(4-morpholinyl)ethyl]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or N-[3-(4-morpholinyl)propyl]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is N-(4-morpholino)butyl-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
N-[(1-ethyl-2-pyrrolidinyl)methy]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or 4-methyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
4-methyl-1-(4'-methylpiperazinyl)pyridazino[4,5-b]indolizine, or a pharmaceutically acceptable salt thereof;
or 4-(4-methylpyridazino[4,5-b]indolizin-1-yl)-piperazinecarboxaldehyde, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
4-methyl-N-[4'-methyl(1-piperazinyl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or 4-methyl-N-[4'-methyl(1-piperazinyl)butyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is 4-methyl-N-[2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is 4-methyl-N-[2-[4-(2-pyrimidinyl)-1-piperazinyl]propyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
4-methyl-N-[3-(1-piperidinyl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
N-[3-(4-azabicyclo[3.2.2]non-3-yl)propyl]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
N-[4-(3-azabicyclo[3.2.2]non-3-yl)butyl]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
4-methyl-N-[3-(2-methylpiperidin-1-yl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
4-methyl-N-[3-(1-pyrrolidinyl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or 4-methyl-N-[4-(1-pyrrolidinyl)butyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is N-(1-azabicyclo[2.2.2]oct-3-yl)-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is N-(1-azabicyclo[2.2.2]oct-3-yl)-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-propanediamine, or a pharmaceuticallyacceptable salt thereof.
A compound of Claim 1 which is:
N-[(1-azabicyclo[2.2.2]oct-3-yl-methyl]-4-methylpyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or N-[(1-azabicyclo[2.2.2]oct-3-yl-ethyl]-4-methylpyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
N-(1-methylpyridazino[4,5-b]indolizin-4-yl)-N'-(tricyclodec-1-yl)-1 ,2-ethanediamine, or a pharmaceutically acceptable salt thereof;
N-(bicyclo[3.2.1]oct-2-yl)-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl) 1,2-ethanediamine, or a pharmaceutically acceptable salt thereof;
or N-(bicyclo[3.3.1]non-9-yl-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl-1,2-ethanediamine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl-2-pyrrolidinone, or a pharmaceutically acceptable salt thereof;
4-methyl-N-[3-(1H-imidazol-1-yl)propyl]pyridazino[4,5-b]indolizine, or a pharmaceutically acceptable salt thereof;
4-methyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]pyridazino[4,5-b]indolizin-1- -amine, or a pharmaceutically acceptable salt thereof;
1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl-2-pyrrolidinethione, or a pharmaceutically acceptable salt thereof;
1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl pyrrole, or a pharmaceutically acceptable salt thereof;
or 4-methyl-N-[2-(1-methyl-2-pyrrolyl)ethyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
4-methyl-N-[2-(2-pyridinyl)ethyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or N-(2-pyridinyl)-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl-1,2-ethanediamine, or a pharmaceutically acceptable salt thereof.
N,N-dimethyl-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl-1,2-ethane diamine, or a pharmaceutically acceptable salt thereof;
N,N-dimethyl-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,3-propanediamine, or a pharmaceutically acceptable salt thereof;
or N,N-dimethyl-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,4-butanediamine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
N-[2-(4-morpholinyl)ethyl]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or N-[3-(4-morpholinyl)propyl]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is N-(4-morpholino)butyl-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
N-[(1-ethyl-2-pyrrolidinyl)methy]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or 4-methyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
4-methyl-1-(4'-methylpiperazinyl)pyridazino[4,5-b]indolizine, or a pharmaceutically acceptable salt thereof;
or 4-(4-methylpyridazino[4,5-b]indolizin-1-yl)-piperazinecarboxaldehyde, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
4-methyl-N-[4'-methyl(1-piperazinyl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or 4-methyl-N-[4'-methyl(1-piperazinyl)butyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is 4-methyl-N-[2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is 4-methyl-N-[2-[4-(2-pyrimidinyl)-1-piperazinyl]propyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
4-methyl-N-[3-(1-piperidinyl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
N-[3-(4-azabicyclo[3.2.2]non-3-yl)propyl]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
N-[4-(3-azabicyclo[3.2.2]non-3-yl)butyl]-4-methylpyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
4-methyl-N-[3-(2-methylpiperidin-1-yl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
4-methyl-N-[3-(1-pyrrolidinyl)propyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or 4-methyl-N-[4-(1-pyrrolidinyl)butyl]pyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is N-(1-azabicyclo[2.2.2]oct-3-yl)-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is N-(1-azabicyclo[2.2.2]oct-3-yl)-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-propanediamine, or a pharmaceuticallyacceptable salt thereof.
A compound of Claim 1 which is:
N-[(1-azabicyclo[2.2.2]oct-3-yl-methyl]-4-methylpyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or N-[(1-azabicyclo[2.2.2]oct-3-yl-ethyl]-4-methylpyridazino[4,5-b]-indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
N-(1-methylpyridazino[4,5-b]indolizin-4-yl)-N'-(tricyclodec-1-yl)-1 ,2-ethanediamine, or a pharmaceutically acceptable salt thereof;
N-(bicyclo[3.2.1]oct-2-yl)-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl) 1,2-ethanediamine, or a pharmaceutically acceptable salt thereof;
or N-(bicyclo[3.3.1]non-9-yl-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl-1,2-ethanediamine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl-2-pyrrolidinone, or a pharmaceutically acceptable salt thereof;
4-methyl-N-[3-(1H-imidazol-1-yl)propyl]pyridazino[4,5-b]indolizine, or a pharmaceutically acceptable salt thereof;
4-methyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]pyridazino[4,5-b]indolizin-1- -amine, or a pharmaceutically acceptable salt thereof;
1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl-2-pyrrolidinethione, or a pharmaceutically acceptable salt thereof;
1-[3-[(1-methylpyridazino[4,5-b]indolizin-4-yl)amino]-propyl pyrrole, or a pharmaceutically acceptable salt thereof;
or 4-methyl-N-[2-(1-methyl-2-pyrrolyl)ethyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof.
A compound of Claim 1 which is:
4-methyl-N-[2-(2-pyridinyl)ethyl]pyridazino[4,5-b]indolizin-1-amine, or a pharmaceutically acceptable salt thereof;
or N-(2-pyridinyl)-N'-(4-methylpyridazino[4,5-b]indolizin-1-yl-1,2-ethanediamine, or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002008571A CA2008571A1 (en) | 1990-01-12 | 1990-01-25 | Pyridazino[4,5-b]indolizines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/464,468 US4985560A (en) | 1990-01-12 | 1990-01-12 | Pyridazino(4,5-b)indolizines |
| CA002008571A CA2008571A1 (en) | 1990-01-12 | 1990-01-25 | Pyridazino[4,5-b]indolizines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2008571A1 true CA2008571A1 (en) | 1991-07-25 |
Family
ID=25673906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002008571A Abandoned CA2008571A1 (en) | 1990-01-12 | 1990-01-25 | Pyridazino[4,5-b]indolizines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2008571A1 (en) |
-
1990
- 1990-01-25 CA CA002008571A patent/CA2008571A1/en not_active Abandoned
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| Date | Code | Title | Description |
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| FZDE | Discontinued |