Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive alloesteric modulator activity for the treatment of Alzheimers disease

• US 10,457,670 B2
• Filed: 12/04/2017
• Issued: 10/29/2019
• Est. Priority Date: 04/23/2014
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Yamada, Masami, Suzuki, Shinkichi, Sugimoto, Takahiro, Nakamura, Minoru, Sakamoto, Hiroki, Kamata, Makoto
• Primary Examiner(s): Rozof, Timothy R
• Application Number:
  US15/830,634
• Publication Number:
  US 20180346452A1
• Time in Patent Office: 694 Days
• CPC Class Codes: A61K 31/045 Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4406 only substituted in position 3, e.g. zimeldine nicotinic acid A61K31/455
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• 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 25/16 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/46 with an oxygen atom in position 1
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention provides a compound having a cholinergic muscarinic M1 receptor positive allosteric modulator activity and useful as an agent for the prophylaxis or treatment of Alzheimer'"'"'s disease, schizophrenia, pain, sleep disorder, Parkinson'"'"'s disease dementia, dementia with Lewy bodies, and the like.

The present invention relates to a compound represented by the formula (I) or a salt thereof.

wherein each symbol is as described in the specification,
or a salt thereof.

Claims

1. A method for a treatment of Alzheimer'"'"'s disease, schizophrenia, cognitive impairment associated with schizophrenia, pain, sleep disorder, Parkinson'"'"'s disease dementia, Parkinson'"'"'s disease, or dementia with Lewy bodies, in a mammal, which comprises administering to the mammal an effective amount of a compound represented by formula (I) below:

2. The method according to claim 1, wherein R¹ is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C_5-6 cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclic group,

(4) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, or

(5) an optionally substituted C_1-6 alkyl group.

3. The method according to claim 1, wherein R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C_1-6 alkyl group,

(4) an optionally substituted C_1-6 alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group.

4. The method according to claim 1, wherein Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents, in addition to R⁴,

selected from

(a) a halogen atom,

(b) a C_1-6 alkyl group, and

(c) a C_1-6 alkoxy group.

5. The method according to claim 1, wherein

R¹ is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C_5-6 cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclic group,

(4) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, or

(5) an optionally substituted C_1-6 alkyl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) an optionally substituted C_1-6 alkyl group;

R³ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) an optionally substituted C_1-6 alkyl group,

(5) a C_1-6 alkoxy group, or

(6) a C_3-6 cycloalkyl group;

R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C_1-6 alkyl group,

(4) an optionally substituted C_1-6 alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group; and

Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents, in addition to R⁴, selected from

(a) a halogen atom,

(b) a C_1-6 alkyl group, and

(c) a C_1-6 alkoxy group.

6. The method according to claim 1, wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom, and

(ii) a cyano group,

(2) a C_5-6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group,

(ii) a C_1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and

(iii) a C_1-6 alkoxy group,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups,

(4) a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms, or

(5) a C_1-6 alkyl group optionally substituted by from 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group;

R² is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) a C_1-6 alkyl group;

R³ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) a C_1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(5) a C_1-6 alkoxy group, or

(6) a C_3-6 cycloalkyl group;

R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C_1-6 alkyl group,

(4) a C_1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,

(5) a carbamoyl group,

(6) a mono- or di-C_1-6 alkyl-carbamoyl group, or

(7) a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 C_1-6 alkyl groups; and

Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents, in addition to R⁴, selected from

(a) a halogen atom,

(b) a C_1-6 alkyl group, and

(c) a C_1-6 alkoxy group.

7. The method according to claim 6, wherein the partial structure represented by the following formula:

8. The method according to claim 1, wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituents selected from

(i) a halogen atom, and

(ii) a cyano group,

(2) a C_5-6 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups, or

(4) a C_1-6 alkyl group optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group;

R² is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) a C_1-6 alkyl group;

R³ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) a C_1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(5) a C_1-6 alkoxy group, or

(6) a C_3-6 cycloalkyl group;

R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C_1-6 alkyl group,

(4) a C_1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,

(5) a mono- or di-C_1-6 alkyl-carbamoyl group, or

(6) a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 C_1-6 alkyl groups; and

Ring A is a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents, in addition to R⁴, selected from

(a) a halogen atom, and

(b) a C_1-6 alkoxy group.

9. The method according to claim 8, wherein the partial structure represented by the following formula:

10. The method according to claim 1, wherein

R¹ is

(1) a C_5-6 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, or

(2) a 5- or 6-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups;

R² is

(1) a halogen atom, or

(2) a C_1-6 alkyl group;

R³ is a C_1-6 alkyl group;

R⁴ is

(1) a C_1-6 alkyl group,

(2) a C_1-6 alkoxy group, or

(3) a 5- or 6-membered monocyclic aromatic heterocyclic group; and

Ring A is a benzene ring or a pyridine ring, each of which is unsubstituted, in addition to R⁴.

11. The method according to claim 10, wherein the partial structure represented by the following formula:

12. The method according to claim 1, wherein

R¹ is

(1) a cyclohexyl group substituted by one hydroxy group, or

(2) a tetrahydropyranyl group substituted by one hydroxy group;

R² is

(1) a halogen atom, or

(2) a C_1-6 alkyl group;

R³ is a C_1-6 alkyl group;

R⁴ is

(1) a C_1-6 alkyl group,

(2) a C_1-6 alkoxy group, or

(3) a pyrazolyl group; and

Ring A is a benzene ring or a pyridine ring, each of which is unsubstituted, in addition to R⁴.

13. The method according to claim 12, wherein the partial structure represented by the following formula: