Tetrahydroquinoline analogues as muscarinic agonists

• US 7,307,075 B2
• Filed: 12/23/2002
• Issued: 12/11/2007
• Est. Priority Date: 12/28/2001
• Status: Expired due to Fees

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Tolf, Bo-Ragnar, Koch, Kristian Norup, Skjaerbaek, Niels, Friberg, Bo Lennart Mikael
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US10/329,455
• Publication Number:
  US 20030176418A1
• Time in Patent Office: 1,814 Days
• Field of Search: 514/230.5, 544/105
• US Class Current: 514/230.5
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• 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 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 513/04 Ortho-condensed systems

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, or a salt or isomer thereof

2. The compound according to claim 1, wherein R¹ is selected from the group consisting of optionally substituted C_1-6-alkyl, optionally substituted C_1-6-alkylidene, and optionally substituted O—

C_1-6-alkyl.

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

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

C_1-6 alkyl, halogen and hydroxy.

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

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

7. The compound according to claim 1 wherein Y is selected from the group consisting of 0 and H₂.

8. The compound according to claim 1, of formula Ia

9. The compound claim 8, wherein the optionally substituted C_1-6-alkyl is selected from the group consisting of unsubstituted C_1-6-alkyl, and C_1-6-alkoxyalkyl;

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

X is C(R⁶)(R⁷)—

O—

; and

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

C_1-6alkyl.

10. The compound according to claim 1 selected from the group consisting of

4-[3-(4-butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

6-acetyl-4-[3-(4-butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butyl-piperidin-1-yl)-propyl]-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-[3-(4-butyl-piperidin-1-yl)-propyl]-6-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine;

4-[3-(4-butylpiperidin-1-yl)propyl]-6,8-dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butyl-piperidin-1-yl)propyl]-6,8-dimethyl-4H-benzo[1,4]oxazin-3-one;

6-tert-butyl-4-[3-(4-butyl-piperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-5-methyl-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-7-methyl-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-6-chloro-7-nitro-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-7-chloro-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-7,8-difluoro-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

4-[3-(3-butylidene-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-6,8-dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one;

6-bromo-4-[3-(4-butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one;

4-[3-(4-butylpiperidin-1-yl)propyl]-8-isopropyl-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-hydroxy-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one;

(−

)-4-[3-(4-butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin)-2-methoxypropyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-fluoropropyl]-4H-benzo[1,4]oxazin-3-one;

(S)-4-[3-(4-butyl-piperidin-1-yl)-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[2-methyl-3-(4-propoxypiperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(3-butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-6-fluoro-4-[2-methyl-3-(4-propoxy-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylidenepiperidin-1-yl)-2-methyl-propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

(R)-6-fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylpiperidin-1-yl)2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;

(R)-7-fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;

(R)-7-fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylpiperidin-1-yl)-2-methyl-propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;

(R)-6-methoxy-4-[2-methyl-3-(3-pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-6-methoxy-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-6-methyl-4-[2-methyl-3-(4-propoxypiperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R)-4-[3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-6-fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-6-fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-7-fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-7-fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[2-methyl-3-(4-propoxypiperidin-1-yl)-6-methoxy]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylidenepiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(3-butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;

(R,S)-1-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(4-butylpiperidin-1-yl)-2-methylpropyl]-6,7-difluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-6,7-difluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(3-butoxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-6-fluoro-4-{3-[3-(2-methoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(3-butylazetidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;

(R,S)-6-fluoro-4-[2-methyl-3-(3-propoxyazetidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;

(R,S)-4-[3-(3-butylazetidin-1-yl)-2-methoxypropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one; and

4-[3-(4-butyl-3-fluoropiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one.

11. A composition comprising

i) one or more compounds of formula I, as defined in claim 1, and

ii) at least one pharmaceutically acceptable excipient or carrier.

12. 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 of formula I, as defined in claim 1, and

wherein said disease is selected from the group consisting of Alzheimer'"'"'s disease, Parkinson'"'"'s disease, schizophrenia, Huntington'"'"'s chorea, Friedreich'"'"'s ataxia, Gilles de la Tourette'"'"'s Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.

13. The method according to claim 12, wherein the cholinergic receptor is a muscarinic receptor.

14. The method according to claim 12, wherein the cholinergic receptor is a muscarinic M₁-receptor subtype.

15. The method according to claim 12, wherein the cholinergic receptor is the muscarinic M₄-receptor subtype.

16. The method according to claim 12, 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.

17. The method according to claim 12 wherein the compound is a muscarinic agonist.

18. A method of treating a disease or condition in a mammal, said disease or condition 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, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, schizophrenia, Huntington'"'"'s chorea, Friedreich'"'"'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, comprising contacting a cholinergic receptor with an effective amount of at least one compound as defined in claim 1.

19. A method of treating or alleviating the symptoms associated with a disorder in a mammal, comprising the administration of an effective amount of at least one compound as defined in claim 1, said disorder associated with a muscarinic M₁-receptor subtype, wherein said 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, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, schizophrenia, Huntington'"'"'s chorea, Friedreich'"'"'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.

20. The method according to claim 12, wherein 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.