Benzimidazolidinone derivatives as muscarinic agents

• US 20040067931A1
• Filed: 04/03/2003
• Published: 04/08/2004
• Est. Priority Date: 10/02/2001
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Tolf, Bo-Ragnar, Koch, Kristian Norup, Kelly, Nicholas Michael
• Granted Patent: US 6,951,849 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 209/38 in positions 2 and 3, e.g. isatin
• CPC Class Codes: C07D 235/26 Oxygen atoms
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 277/68 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• 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 471/08 Bridged systems

Abstract

Benzimidazolidinone derivative compounds, which increase acetylcholine signaling or effect in the brain, and highly selective muscarinic agonists, particularly for the M₁ and/or M₄ receptor subtypes, pharmaceutical compositions comprising the same, as well as methods of treating psychosis using these compounds are disclosed.

Claims

1. A compound of Formula I

2. The compound of claim 1, wherein Z is N.

3. The compound of claim 2, wherein X is selected from the group consisting of N, S, and 0.

4. The compound of claim 3, wherein —

Y is ═

O.

5. The compound of claim 1, wherein N(R¹)R² is selected from the group consisting of a piperidine with at least one substituent R⁴ in the 2-position, a piperidine with at least one substituent R⁴ in the 3-position, a piperidine with at least one substituent R⁴ in the 4-position.

6. The compound of claim 5, wherein N(R¹)R² is selected from the group consisting of a piperidine with at least one substituent R⁴ in the 4-position.

7. The compound of claim 1, wherein N(R¹)R² is selected from the group consisting of

8. The compound of claim 1, wherein R⁴ is selected from the group consisting of hydroxy, C_1-8-alkyl, C_1-8-alkoxy, C_1-8-heteroalkyl, C_3-8-cycloalkyl, C_1-6-arylalkyl, C_1-8-alkylidene, each of which may be optionally substituted with a substituent R⁵.

9. The compound of claim 1, wherein R⁴ is selected from the group consisting of hydroxy, C_3-8-alkyl, C_3-8-alkoxy, C_5-10-aryl, and C_3-8-alkylidene, each of which may be optionally substituted with a substituent R⁵ wherein R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, C_1-8-alkoxy and C_1-8-alkyl.

10. The compound of claim 1, wherein R⁴ is selected from the group consisting of an optionally substituted ethyl, an optionally substituted butyl, an optionally substituted pentyl, an optionally substituted propyloxy, and 3-(C_1-8-alkyl)-butylidene.

11. The compound of claim 1, wherein N(R¹)R² is

12. The compound of claim 1, wherein

X is selected from the group consisting of O, N and S;

Z is N;

Y is =0 or tautomers thereof;

SPU is a spacer unit providing a distance d between Z and N wherein —

SPU—

is —

(CR⁶R⁷)_n-A-, n is 3, and A is absent;

N together with R¹ and R² form a piperidine ring substituted with one or more substituents R⁴ selected from the group consisting of hydroxy, halogen, C_1-8-alkyl, C_3-8-cycloalkyl, C_1-8-alkoxy, C_1-8-heteroalkyl, C_1-8-alkylcarbonyl, C_1-8-alkylidene, C_2-8-alkenyl, C_2-8-alkynyl, C_1-6-alkyloxyimino, and C_1-6-alkyloxyamino each of which may be optionally substituted with a substituent R⁵

R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, C_1-8-alkyl, C_1-8-alkoxy, C_3-8-cycloalkyl, C_3-8-heterocyclyl, C_1-8-alkylcarbonyl, C_1-8-alkylidene, C_2-8-alkenyl and C_2-8-alkynyl;

R^x may be absent or selected from the group consisting of hydrogen, optionally substituted C_1-8-alkyl

R³ may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C_1-8-alkyl, C_1-8-alkoxy, optionally substituted C_1-8-alkylidene, optionally substituted C_2-8-alkenyl, optionally substituted C_2-8-alkynyl optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C_3-8-cycloalkyl, optionally substituted C_3-8-heterocyclyl, and optionally substituted C_1-8-alkylcarbonyl; and

each R⁶ and each R⁷ is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C_1-8-alkyl, C_1-8-alkoxy, C_1-8-heteroalkyl, C_3-8-cycloalkyl.

13. A pharmaceutical composition comprising a compound according to claim 1, together with pharmaceutically acceptable carriers or excipients.

14. A method of treating or preventing mental disease or disorder in a mammal comprising identifying a mammal in need thereof and administering at least one compound of claim 1 to said mammal.

15. The method of claim 14, wherein the mental disorder is selected from the group consisting of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, sleep disorders, and psychosis.

16. The method of claim 14, wherein the mental disorder is selected from the group consisting of neurodegenerative diseases, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, schizophrenia, Huntington'"'"'chorea, Friederich'"'"'s ataxia, Gilles de la Tourette'"'"'s Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, and sudden infant death syndrome.

17. A method of treating or preventing a disease or disorder associated with increased intraocular pressure in a mammal comprising identifying a mammal in need thereof and administering at least one compound of claim 1 to said mammal.

18. 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 of claim 1.

19. The method of claim 18, wherein the compound is a cholinergic agonist.

20. The method of claim 19, wherein the compound is selective for one or both of the M₁ and M₄ muscarinic receptor subtypes.

21. The method of claim 18, wherein the compound further acts as a D₂ antagonist or D₂ inverse agonist.

22. A method of treating or preventing pain in a mammal, comprising administering an effective amount of a compound of claim 1 to said mammal.

23. A method of prophylactic or curative treatment of psychosis or alleviation of symptoms of psychosis in a mammal, comprising administering an effective amount of a compound of claim 1 to said mammal.

24. A method of modulating or preventing the progression or formation of amyloid plaques in an individual susceptible to or affected by Alzheimer'"'"'s Disease, comprising administering an effective amount of a compound of claim 1, said effective amount sufficient to modulate amyloid precursor protein processing.