US 2004/0176348 A1 · Arylvinylazacycloalkane compounds and methods of preparation and use thereof

Abstract

Novel vinylazacycloalkane compounds of Formula (I) are disclosed. The compounds are ligands of various nAChRs. The compounds and their pharmaceutically acceptable salts can be used to prepare pharmaceutical compositions and/or medicaments intended to prevent or treat disorders associated with dysfunction of nAChRs, especially within the central nervous system or the gastrointestinal system. Examples of types of disorders that can be treated include neurodegenerative disorders, including central nervous system disorders such as Alzheimer's disease, cognitive disorders, motor disorders such as Parkinson's disease, drug addiction, behavioral disorders and inflammatory disorders within the gastrointestinal system. The compounds can also serve as analgesics in the treatment of acute, chronic or recurrent pain.

Claims34

Dependent claims

A compound of the formula:

4
wherein:
the wavy line represents variable geometry (E or Z) about the double bond;
X is nitrogen or C—R2;
R1 is hydrogen, C1-6-alkyl, halogen, —OR4, —NR4R5, or —SR4 when X is C—R2 and hydrogen, C1-6 alkyl, —OR4, or —NR4R5 when X is nitrogen;
R2 is hydrogen, C1-6-alkyl, aryl, aryl-C1-6-alkyl, C1-6-alkyl-aryl, heteroaryl, heteroaryl C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, polycycloalkyl, —OR6, —NR6R7, —SR6, —SOR6, or —SO2R6, each of which can optionally be substituted with 1 or more substituents selected from halogen, —CN, —NO2, —NH2, —OH, —OR6, —COOH, —C(O)OR6, —O—C(O)R6, —NR6R7, —NHC(O)R6, —C(O)NR6R7, —SR6, —S(O)R6, —SO2R6, —NHSO2R6, —SO2NR6R6, —C(S)NR6R6, —NHC(S)R6, —O—SO2R6, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and C1-6alkyl;
R3 is hydrogen, C1-6-alkyl, aryl C1-6-alkyl, heteroaryl C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl;
m is between 1 and 4;
n is between 1 and 3;
R4 and R5 are, independently, hydrogen or C1-6-alkyl;
R6 and R7 are, independently, hydrogen, C1-6-alkyl (including cycloalkyl containing alkyl), aryl, aryl-C1-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl, heterocyclyl, heterocycloalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, —CN, —NO2, —NH2, —OH, —COOH, —COO—C1-6 alkyl, —CONH2, formyl, trifluoromethyl and trifluoromethoxy,
wherein the C1-6-alkyl, heterocyclic, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R8, —NR8R9, —CF3, —CN, —NO2, —C2R8, —N3, —SO2CH3, —OR8, —SR8, —C(═O)NR8R9, —NR8C(═O)R8, —C(═O)R8, —C(═O)OR8, —(CH2)qOR8, —OC(═O)R8, OC(═O)NR8R9 and —NR8C(═O)OR8,
where R8 and R9 are individually hydrogen, C1-C6 alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R6 and R7 or R8 and R9 can form a C1-10 cycloalkyl functionality,
and isomers, mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.

11 more elements

A compound selected from the group consisting of

(R)- and (S)-3-((E)-2-pyrrolidin-3-ylvinyl)-5-(tetrahydropyran-4-yloxy)pyridine
(R)- and (S)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine
(R)- and (S)-2-chloro-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine
(R)- and (S)-3-isopropoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine
(R)- and (S)-3-isopropoxy-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine
(R)- and (S)-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyrimidine
(R)- and (S)-2-chloro-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine
(R)- and (S)-5-((E)-2-piperidin-3-ylvinyl)pyrimidine
(R)- and (S)-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyrimidine
(R)- and (S)-2-chloro-5-((E)-2-piperidin-3-ylvinyl)pyridine
(R)- and (S)-2-chloro-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyridine
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyridine
5-((E)-2-piperidin-4-ylvinyl)pyrimidine
5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyrimidine
2-chloro-5-((E)-2-piperidin-4-ylvinyl)pyridine
2-chloro-5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyridine
3-cyclopropylmethoxy-5-((E)-2-piperidin-4-ylvinyl)pyridine
3-cyclopropylmethoxy-5-((E)-2-(1-methylpiperidyinyyl)pyridine
5-((E)-2-azetidin-31-ylvinyl)pyrimidine
5-((E)-2-(1-methylazetidin-3-yl)vinyl)pyrimidine
5-((E)-2-azetidin-3-ylvinyl)-2-chloropyridine
5-((E)-2-(1-methylazetidin-3-yl)vinyl)-2-chloropyridine
3-((E)-2-azetidin-3-ylvinyl)-5-cyclopropylmethoxypyridine
3-((E)-2-(1-methylazetidin-3-yl)vinyl)-5-cyclopropylmethoxypyridine
(R)- and (S)-3-phenoxy-5-((E)-2-piperidin-3-ylvinyl) pyridine
(R)- and (S)-3-phenoxy-5-((E)-2-(1-methylpiperidin-3-y l)vinyl)pyridine
3-phenoxy-5-((E)-2-piperidin-4-ylvinyl)pyridine
3-phenoxy-5-((E)-2-(1-methylpiperidin-4-y l)vinyl)pyridine
3-phenoxy-5-((E)-2-azetidin-3-ylvinyl)pyridine
3-phenoxy-5-((E)-2-(1-methylazetidin-3-yl)vinyl)pyridine
isomers thereof, mixtures thereof, including racemic mixtures, enantiomers, and tautomers thereof, and pharmaceutically acceptable salts thereof.

31 more elements

A method of treating neurodegenerative disorders comprising administering to a patient in need thereof an effective amount of a compound of the formula:

5
wherein:
the wavy line represents variable geometry (E or Z) about the double bond;
X is nitrogen or C—R2;
R1 is hydrogen, C1-6-alkyl, halogen, —OR4, —NR4R5, or —SR4 when X is C—R2 and hydrogen, C1-6alkyl, —OR4, or —NR4R5 when X is nitrogen;
R2 is hydrogen, C1-6-alkyl, aryl, aryl-C1-6-alkyl, C1-6-alkyl-aryl, heteroaryl, heteroaryl C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, polycycloalkyl, —OR6, —NR6R7, —SR6, —SOR6, or —SO2R6, each of which can optionally be substituted with 1 or more substituents selected from halogen, —CN, —NO2, —NH2, —OH, —OR6, —COOH, —C(O)OR6, —O—C(O)R6, —NR6R7, —NHC(O)R6, —C(O)NR6R7, —SR6, —S(O)R6, —SO2R6, —NHSO2R6, —SO2NR6R6, —C(S)NR6R6, —NHC(S)R6, —O—SO2R6, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and C1-6alkyl;
R3 is hydrogen, C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl;
m is between 1 and 4;
n is between 1 and 3;
R4 and R5 are, independently, hydrogen or C1-6-alkyl;
R6 and R7 are, independently, hydrogen, C1-6-alkyl (including cycloalkyl containing alkyl), aryl, aryl C1-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, —CN, —NO2, —NH2, —OH, —COOH, —COO—C1-6 alkyl, —CONH2, formyl, trifluoromethyl and trifluoromethoxy,
wherein the C1-6-alkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R8, —NR8R9, —CF3, —CN, —NO2, —C2R8, —N3, —SO2CH3, —OR8, —SR8, —C(═O)NR8R9, —NR8C(═O)R8, —C(═O)R8, —C(═O)OR8, —(CH2)qOR8, —OC(═O)R8, —OC(═O)NR8R9 and —NR8C(═O)OR8,
where R8 and R9 are individually hydrogen, C1-C6 alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R6 and R7 or R8 and R9 can form a C1-10 cycloalkyl functionality,
and isomers, mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.

11 more elements

A method of providing analgesia and/or treating inflammatory gastrointestinal disorders comprising administering to a patient in need thereof an effective amount of a compound of the formula:

6
wherein:
the wavy line represents variable geometry (E or Z) about the double bond;
X is nitrogen or C—R2;
R1 is hydrogen, C1-6-alkyl, halogen, —OR4, —NR4R5, or —SR4 when X is C—R2 and hydrogen, C1-6alkyl, —OR4, or —NR4R5 when X is nitrogen;
R2 is hydrogen, C1-6-alkyl, aryl, aryl C1-6-alkyl, C1-6-alkyl-aryl, heteroaryl, heteroaryl C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, polycycloalkyl, —OR6, —NR6R7, —SR6, —SOR6, or —SO2R6, each of which can optionally be substituted with 1 or more substituents selected from halogen, —CN, —NO2, —NH2, —OH, —OR6, —COOH, —C(O)OR6, —O—C(O)R6, —NR6R7, —NHC(O)R6, —C(O)NR6R7, —SR6, —S(O)R6, —SO2R6, —NHSO2R6, —SO2NR6R6, —C(S)NR6R6, —NHC(S)R6, —O—SO2R6, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and C1-6alkyl;
R3 is hydrogen, C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl;
m is between 1 and 4;
n is between 1 and 3;
R4 and R5 are, independently, hydrogen or C1-6-alkyl;
R6 and R7 are, independently, hydrogen, C1-6-alkyl (including cycloalkyl containing alkyl), aryl, aryl C1-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, —CN, —NO2, —NH2, —OH, —COOH, —COO—C1-6 alkyl, —CONH2, formyl, trifluoromethyl and trifluoromethoxy,
wherein the C1-6-alkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R8, —NR8R9, —CF3, —CN, —NO2, —C2R8, —N3, —SO2CH3, —OR8, —SR8, —C(═O)NR8R9, —NR8C(═O)R8, —C(═O)R8, —C(═O)OR8, —(CH2)qOR8, —OC(═O)R8, —OC(═O)NR8R9 and —NR8C(═O)OR8,
where R8 and R9 are individually hydrogen, C1-C6 alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R6 and R7 or R8 and R9 can form a C1-10 cycloalkyl functionality,
and isomers, mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.

11 more elements

A method of providing analgesia and/or treating inflammatory disorders comprising administering to a patient in need thereof an effective, anti-inflammatory amount of a compound selected from the group consisting of

(R)- and (S)-3-((E)-2-pyrrolidin-3-ylvinyl)-5-(tetrahydropyran-4-yloxy)pyridine
(R)- and (S)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine
(R)- and (S)-2-chloro-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine
(R)- and (S)-3-isopropoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine
(R)- and (S)-3-isopropoxy-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine
(R)- and (S)-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyrimidine
(R)- and (S)-2-chloro-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-(1-methylpyrrolidin-3-yl)vinyl)pyridine
(R)- and (S)-5-((E)-2-piperidin-3-ylvinyl)pyrimidine
(R)- and (S)-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyrimidine
(R)- and (S)-2-chloro-5-((E)-2-piperidin-3-ylvinyl)pyridine
(R)- and (S)-2-chloro-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyridine
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine
(R)- and (S)-3-cyclopropylmethoxy-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyridine
5-((E)-2-piperidin-4-ylvinyl)pyrimidine
5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyrimidine
2-chloro-5-((E)-2-piperidin-4-ylvinyl)pyridine
2-chloro-5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyridine
3-cyclopropylmethoxy-5-((E)-2-piperidin-4-ylvinyl)pyridine
3-cyclopropylmethoxy-5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyridine
5-((E)-2-azetidin-3-ylvinyl)pyrimidine
5-((E)-2-(1-methylazetidin-3-yl)vinyl)pyrimidine.
5-((E)-2-azetidin-3-ylvinyl)-2-chloropyridine
5-((E)-2-(1-methylazetidin-3-yl)vinyl)-2-chloropyridine
3-((E)-2-azetidin-3-ylvinyl)-5-cyclopropylmethoxypyridine
3-((E)-2-(1-methylazetidin-3-yl)vinyl)-5-cyclopropylmethoxypyridine
(R)- and (S)-3-phenoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine
(R)- and (S)-3-phenoxy-5-((E)-2-(1-methylpiperidin-3-yl)vinyl)pyridine
3-phenoxy-5-((E)-2-piperidin-4-ylvinyl)pyridine
3-phenoxy-5-((E)-2-(1-methylpiperidin-4-yl)vinyl)pyridine
3-phenoxy-5-((E)-2-azetidin-3-ylvinyl)pyridine
3-phenoxy-5-((E)-2-(1-methylazetidin-3-yl)vinyl)pyridine
isomers thereof, mixtures thereof, including racemic mixtures, enantiomers, and tautomers thereof, and the pharmaceutically acceptable salts thereof, to a patient in need of treatment thereof.

31 more elements

A method of preparing compounds of the formula:

7
wherein:
the wavy line represents variable geometry (E or Z) about the double bond;
X is nitrogen or C—R2;
R1 is hydrogen, C1-6-alkyl, halogen, —OR4, —NR4R5, or —SR4 when X is C—R2 and hydrogen, C1-6alkyl, —OR4, or —NR4R5 when X is nitrogen;
R2 is hydrogen, C1-6-alkyl, aryl, aryl C1-6-alkyl, C1-6-alkyl-aryl, heteroaryl, heteroaryl C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, polycycloalkyl, OR6, NR6R7, SR6, SOR6, or SO2R6, each of which can optionally be substituted with 1 or more substituents selected from halogen, —CN, —NO2, —NH2, —OH, —OR6, COOH, —C(O)OR6, —O—C(O)R6, —NR6R7, —NHC(O)R6, —C(O)NR6R7, —SR6, —S(O)R6, —SO2R6, —NHSO2R6, —SO2NR6R6, —C(S)NR6R6, —NHC(S)R6, —O—SO2R6, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and C1-6alkyl;
R3 is hydrogen, C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl;
m is between 1 and 4;
n is between 1 and 3;
R4 and R5 are, independently, hydrogen or C1-6-alkyl;
R6 and R7 are, independently, hydrogen, C1-6-alkyl (including cycloalkyl containing alkyl), aryl, aryl C1-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl, heterocyclyl, heterocycloalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, —CN, —NO2, —NH2, —OH, —COOH, —COO—C1-6 alkyl, —CONH2, formyl, trifluoromethyl and trifluoromethoxy,
wherein the C1-6-alkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R8, —NR8R9, —CF3, —CN, —NO2, —C2R8, —N3, —SO2CH3, —OR8, —SR8, —C(═O)NR8R9, —NR8C(═O)R8, —C(═O)R8, —C(═O)OR8, —(CH2)qOR8, —OC(═O)R8, —OC(═O)NR8R9 and —NR8C(═O)OR8,
where R8 and R9 are individually hydrogen, C1-C6 alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R6 and R7 or R8 and R9 can form a C1-10 cycloalkyl functionality, and
and isomers, mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof,
comprising:
a) reacting an aldehyde of formula:
8
where m is between 1 and 4 and n is between 1 and 3;
with a phosphorane ylide of the formula
PPh3═CH2
to yield a vinylazacycloalkane of the formula
9
b) reacting the resulting vinylazacycloalkane with a heteroaryl halide of the formula:
10
where X and R1 are as defined above and Y is a halogen, and
c) removing any remaining protecting groups.

23 more elements

Dependencies are inferred from the claim text.

Arylvinylazacycloalkane compounds and methods of preparation and use thereof

Life of this patent

Arylvinylazacycloalkane compounds and methods of preparation and use thereof

Life of this patent

Abstract

Claims34