COMPOUNDS AND THEIR USE

• US 20110172204A1
• Filed: 01/07/2011
• Published: 07/14/2011
• Est. Priority Date: 01/08/2010
• Status: Abandoned Application

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Buffham, William John, Pooni, Parminder Kaur, Merchant, Kevin John
• Application Number:
  US12/986,391
• Publication Number:
  US 20110172204A1
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

A compound of the formula:

• wherein:
• R₁ represents C_1-6 alkyl or H; Y represents —NR₂R₃ as depicted in formula (B), or a ring of formula (A)

• wherein ^a represents the point of attachment to the pyrimidinyl ring;
• R₂ represents C_1-4alkyl substituted by C_1-3 alkoxy; R₃ represents C_1-4 alkyl; W represents —(CH₂)_n—; W₁ represents —(CH₂)_p—; n represents 1 or 2 or 3; p represents 1 or 2; R₄ represents C_1-4 alkoxy, C_1-6 alkyl or halogen; and R₅ represents halogen or H, provided that, when R₄ represents halogen, R₅ is not H, or a pharmaceutically acceptable salt thereof. The compounds of the invention have been found to modulate the histamine H3 receptor.

Claims

1. A compound of the formula:

2. A compound according to claim 1 wherein Y represents a ring of formula (A).

3. A compound according to claim 1 wherein p is 1.

4. A compound according to claim 1 wherein R₁ is H, n is 2, p is 1, R₄ is methoxy and R₅ is H.

5. A compound according to claim 1 wherein R₁ is H, n is 1, p is 1, R₄ is methoxy and R₅ is H.

6. A compound according to claim 1 wherein R₄ represents C_1-4 alkoxy.

7. A compound according to claim 1 which is:

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl]-2-[(3R)-3-methoxypyrrolidin-1-yl]pyrimidine-5-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl]-2-[(3S)-3-methoxypyrrolidin-1-yl]pyrimidine-5-carboxamide;

N-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl)-2-(3-methoxyazetidin-1-yl)pyrimidine-5-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl]-2-(3,3-difluoropyrrolidin-1-yl)pyrimidine-5-carboxamide;

N-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl)-2-(4,4-difluoropiperidin-1-yl)pyrimidine-5-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl]-2-[(3S)-3-methoxypyrrolidin-1-yl]-N-methylpyrimidine-5-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl]-2-[(3R)-3-methoxypyrrolidin-1-yl]-N-methylpyrimidine-5-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl]-2-{[(2S)-2-methoxypropyl](methyl)amino}pyrimidine-5-carboxamide;

or

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)methyl]-2-{[(2R)-2-methoxypropyl](methyl)amino}pyrimidine-5-carboxamide,

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to claim 1, together with one or more pharmaceutically acceptable excipients.

9. A composition according to claim 8, comprising one or more additional, pharmaceutically active ingredients.

12. A method of treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity, the method comprising the administration, to a subject in need of such treatment or prevention, of a therapeutically effective amount of a compound according to claim 1.

13. A method according to claim 12, wherein the condition is a disorder of the central nervous system.

14. A method according to claim 12, wherein the condition is a disorder selected from schizophrenia, neurodegenerative disorders (such as Alzheimer'"'"'s Disease), cognitive disorders (such as dementia and schizophrenia), sleep disorders (such as narcolepsy and hypersomnia), pain, obesity, attentional disorders and epilepsy.

16. A method for preparing a compound according to claim 1, the method comprising the step of reacting an intermediate having the formula:

17. A method according to claim 16, wherein R₆ is OH or OR₇, R₇ being a carboxyl activating group.

10. (canceled)

11. (canceled)

15. (canceled)

18. A compound of formula (i) or (ii):