TETRAHYDROQUINOLINE ANALOGUES AS MUSCARINIC AGONISTS

• US 20090239903A1
• Filed: 05/27/2009
• Published: 09/24/2009
• Est. Priority Date: 12/28/2001
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Skjaerback, Niels, Tolf, Bo-Ragnar, Koch, Kristian Norup, Friberg, Bo Lennart Mikael
• Granted Patent: US 8,680,115 B2
• Time in Patent Office: Days
• US Class Current: 514/305
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 451/02 containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 451/04 with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 451/06 Oxygen atoms

Abstract

The present invention relates to tetrahydroquinoline compounds as muscarinic receptor agonists; compositions comprising the same; methods of inhibiting an activity of a muscarinic receptor with said compounds; methods of treating a disease condition associated with a muscarinic receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.

Claims

1. A compound of formula (I), and salts and isomers thereof

wherein:

m is 0, 1 or 2;

C₃-C₄ is CH₂—

CR¹R⁹ or CH═

CR¹ or C₄ is CR¹R⁹ and C₃ is absent;

each R¹ and each R⁹ is separately selected from the group consisting of hydrogen, halogen, hydroxy, straight- or branched-chain optionally substituted C_1-6 alkyl, straight- or branched-chain optionally substituted C_2-6 alkenyl, straight- or branched-chain optionally substituted C_2-6 alkynyl, straight- or branched-chain optionally substituted C_1-6 alkylidene, straight- or branched-chain optionally substituted C_1-6 alkoxy, straight- or branched-chain optionally substituted C_1-6 heteroalkyl, straight- or branched-chain optionally substituted C_1-6 aminoalkyl, straight- or branched-chain optionally substituted C_1-6 haloalkyl, straight- or branched-chain optionally substituted C_1-6 alkoxycarbonyl, straight- or branched-chain optionally substituted C_1-6 hydroxyalkoxy, straight- or branched-chain optionally substituted C_1-6 hydroxyalkyl, straight- or branched-chain optionally substituted C_1-6 alkylthio, straight- or branched-chain optionally substituted —

O—

C_2-6 alkenyl, straight- or branched-chain optionally substituted —

O—

C_2-6 alkynyl, straight- or branched-chain optionally substituted C_3-6 alkenylalkoxy, straight- or branched-chain optionally substituted C_1-6 alkyloxyimino, straight- or branched-chain optionally substituted C_1-6 alkyloxyamino, optionally substituted —

O—

CH₂—

C_5-6 aryl, —

C(O)NR¹⁰R¹¹, —

CR¹⁰R¹¹R¹², —

OC(O)R¹⁰, straight- or branched-chain optionally substituted —

(O)(CH₂)_sNR¹¹R¹², straight- or branched-chain optionally substituted —

(CH₂)_sNR¹¹R¹², straight- or branched-chain optionally substituted OC(O)O(CH₂)_sCH₃, straight- or branched-chain optionally substituted —

S—

C_1-6-alkyl, straight- or branched-chain optionally substituted —

S—

C_2-6-alkenyl, and straight- or branched-chain optionally substituted —

S—

C_2-6-alkynyl, each of which may be optionally substituted with one or more substituents R_x;

each R¹⁰ is separately selected from the group consisting of hydrogen, straight- or branched-chain C_1-6 alkyl, straight- or branched-chain C_2-6 alkenyl, straight- or branched-chain C_2-6 alkynyl, straight- or branched-chain C_2-6 heteroalkyl, straight- or branched-chain C_2-6 aminoalkyl, straight- or branched-chain C_2-6 haloalkyl, straight- or branched-chain C_1-6 alkoxycarbonyl, straight- or branched-chain C_2-6 hydroxyalkyl, C_3-8 cycloalkyl, —

C(O)—

C_5-6 aryl substituted with C_1-3 alkyl or halo, C_5-6 aryl, C_5-6 heteroaryl, C_5-6 cycloalkyl, C_5-6 heterocycloalkyl, —

C(O)NR¹¹R¹², —

CR¹¹R¹²R¹³, and straight- or branched-chain —

(CH₂)_sNR¹¹R¹²;

each s is separately selected to be an integer from 1 to 8;

each R¹¹ and each R¹² is separately selected from the group consisting of hydrogen, straight- or branched-chain C_1-6 alkyl, C_3-6 cycloalkyl, and C_5-6 heteroaryl, or each R¹¹ and R¹² together form a C_3-8 cycloalkyl or C_3-8 heterocycloalkyl;

R¹³ is selected from the group consisting of hydrogen, halogen, straight- or branched-chain C_1-6 alkyl, formyl, and C_3-6 cycloalkyl;

each R_x is separately selected from the group consisting of hydrogen, halogen, hydroxy, straight- or branched-chain optionally substituted C_1-6 alkyl, straight- or branched-chain optionally substituted C_1-6 alkoxy, optionally substituted C_3-8 cycloalkyl, optionally substituted C_3-8 heterocyclyl, and straight- or branched-chain optionally substituted C_1-6 alkylidene;

R² and R³ are separately selected from the group consisting of hydrogen, optionally substituted C_1-6 alkyl, optionally substituted O—

C_1-6 alkyl, halogen, hydroxy or selected such that R² and R³ are covalently linked together to form a ring system;

each R⁴ and each R⁵ are separately selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C_1-6-alkyl, optionally substituted O—

C_1-6alkyl, optionally substituted aryl-C_1-6alkyl, and optionally substituted arylheteroalkyl;

L¹ and L² are separately biradicals having the formula —

C(R⁶)═

C(R⁷)—

;

Y is selected from the group consisting of O, S, and H₂; and

X is a biradical selected from the group consisting of —

C(R⁶)(R⁷)—

C(R⁶)(R⁷)— and

—

C(R⁶)═

C(R⁷)—

,

wherein R⁶ and R⁷ are separately selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NR^NR^N, N(R^N)—

C(O)N(R^N), optionally substituted C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, optionally substituted O—

C_1-6-alkyl, optionally substituted O-aryl, optionally substituted O—

C_2-6-alkenyl, optionally substituted O—

C_2-6-alkynyl,

wherein R^N is selected from the group consisting of hydrogen, and optionally substituted C_1-6-alkyl.

2. The compound of claim 1, wherein:

at least one of R₁ or R₉ is selected from the group consisting of hydroxy, straight- or branched-chain optionally substituted C_1-6 alkoxy, straight- or branched-chain optionally substituted C_1-6 alkyl, straight- or branched-chain optionally substituted C_2-6 alkenyl, straight- or branched-chain optionally substituted C_3-6 alkenylalkoxy, straight- or branched-chain optionally substituted C_1-6 alkyloxyimino, and straight- or branched-chain optionally substituted —

OC(O)O(CH₂)_sCH₃; and

R_x is selected from the group consisting of halogen, optionally substituted C_3-8 cycloalkyl, optionally substituted straight- or branched-chain C_1-6 alkyl, optionally substituted C_1-6 alkoxy and optionally substituted straight- or branched-chain C_2-6 alkenyl

3. The compound of claim 2, wherein:

the at least one of R¹ or R⁹ is selected from the group consisting of hydroxyl methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, ethenylmethoxy, ethenylethoxy, ethenylpropoxy, iminobutoxy, iminomethoxy, iminoethoxy, iminopropoxy, iminobutoxy; and

—

OC(O)O(CH₂)₂CH₃; and

R_x is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogen, and ethenyl.

4. The compound of claim 1, wherein:

each R⁶ and each R⁷ are separately selected from the group consisting of H, halogen, methyl, and methoxy.

5. The compound according to claim 1, wherein R², R³, R⁹, m, and C₃-C₄ are selected such that

is selected from the group consisting of

wherein R⁸ is present 0, 1, or 2 times and is independently selected from the group consisting of optionally substituted C_1-6 alkyl, optionally substituted O—

C_1-6 alkyl, halogen, hydroxy.

6. The compound according to claim 1, wherein C₃-C₄, m, R², R³, and R⁹ are hydrogen or selected such that R² and R³ together form a ring system such that

is selected from the group consisting of

7. The compound according to claim 1, wherein R² and R³ are separately selected from the group consisting of hydrogen, optionally substituted C_1-6 alkyl, optionally substituted O—

C_1-6 alkyl, halogen and hydroxy.

8. The compound according to claim 1, wherein m is 1.

9. The compound according to claim 1, wherein m is 0, C₃ is absent, and C₄ is CH such that

10. The compound according to claim 1 wherein X is —

C(R⁶)(R⁷)—

C(R⁶)(R⁷)—

.

11. The compound according to claim 1 wherein Y is selected from the group consisting of O and H₂.

12. The compound according to claim 1, wherein R¹ is selected from the group consisting of:

13. The compound according to claim 12, wherein the compound is selected from the group consisting of:

14. The compound according to claim 1, wherein the compound is selected from the group consisting of:

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1,2,3,4-tetrahydro-quinoline;

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-methyl-1,2,3,4-tetrahydro-quinoline;

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-1,2,3,4-tetrahydro-quinoline;

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-8-methyl-1,2,3,4-tetrahydro-quinoline;

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline;

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline;

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methoxy-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-3,4-dihydro-1H-quinolin-2-one;

6-Fluoro-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-3,4-dihydro-1H-quinolin-2-one;

(R,S)-6-Fluoro-1-[3-(4-propoxypiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-3,4-dihydro-1H-quinolin-2-one;

6-Methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-7-methyl-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one;

6,7-Difluoro-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one;

(R,S)-6,7-Difluoro-1-[3-(4-propoxypiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one;

6-Fluoro-7-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one;

(R,S)-6-Fluoro-7-methyl-1-[2-methyl-3-(4-propoxypiperidin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butyl-piperidin-1-yl)propyl]-6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one;

6-Fluoro-5-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

(R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;

(R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

(R)-1-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;

(R)-1-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;

(R)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-1H-quinolin-2-one;

1-[3-(4-Propoxypiperidin-1-yl)propyl]-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-1H-quinolin-2-one;

1-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-1H-quinolin-2-one;

1-[3-(4-Butyl-piperidin-1-yl)propyl]-7-methyl-1H-quinolin-2-one;

(R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-1H-quinolin-2-one;

(R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)-propyl]-1H-quinolin-2-one;

1-[3-(4-Allyloxypiperidin-1-yl)propyl]-1H-quinolin-2-one;

(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;

(R,S)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;

(R,S)-1-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;

(R,S)-1-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one; and

(R,S)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-one.

15. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof.

16. A method of treating a disease in a mammal, wherein modulation of the activity of a cholinergic receptor is associated with a physiologically beneficial response in said disease of said mammal,

said method comprising administering an effective amount of a compound according to claim 1.

17. The method according to claim 16, wherein the cholinergic receptor is a muscarinic receptor.

18. The method according to claim 16, wherein the cholinergic receptor is selected from the group consisting of a muscarinic M₁-receptor subtype and a muscarinic M₄-receptor subtype.

19. The method according to claim 16, wherein the physiologically beneficial response is associated with the selective modulation of the muscarinic M₁-receptor subtype in relation to the muscarinic M₂- or M₃-receptor subtypes.

20. The method according to claim 16, wherein the compound is a muscarinic agonist.

21. A method of increasing an activity of a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound according to claim 1.

22. A method of treating or preventing or alleviating the symptoms associated with a disorder in a mammal, comprising the administration of an effective amount of at least one compound according to claim 1, said disorder associated with a muscarinic receptor, such as M₁ muscarinic receptor subtype.

23. The method of claim 22, wherein the disorder is selected from the group consisting of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, increased intraocular pressure, neurodegenerative diseases, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, schizophrenia, Huntington'"'"'s chorea, Friederich'"'"'s ataxia, Gilles de la Tourette'"'"'s Syndrome, Downs Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, sudden infant death syndrome, and glaucoma.

24. The method according to claim 22, wherein the disease or disorder is a mental disorder and the physiologically beneficial response is due to modulation in terms of M₁ agonism;

M₁ and M₄ agonism;

both M₁ agonism and D₂ antagonism;

or M₁ and M₄ agonism and D₂ antagonism.