Amine Derivative Having NPY Y5 Receptor Antagonistic Activity

• US 20100063027A1
• Filed: 04/25/2007
• Published: 03/11/2010
• Est. Priority Date: 04/28/2006
• Status: Active Grant

• Current Assignee: Shionogi & Co., Ltd.
• Original Assignee: Shionogi & Co., Ltd.
• Inventors: Okuno, Takayuki, Kouyama, Naoki, Sakagami, Masahiro
• Granted Patent: US 9,150,507 B2
• Time in Patent Office: Days
• US Class Current: 514/211.50
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• 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 25/16 Anti-Parkinson drugs
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/08 : the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2602/10 : the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2603/18 : Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 311/05 : to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07C 311/07 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/08 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/20 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/21 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/37 : having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/39 : having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/43 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 317/36 : with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 207/325 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 213/38 : having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 215/38 : Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/14 : other than aralkyl radicals
• CPC Class Codes: C07D 217/22 : 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 to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 219/10 : attached in position 9
• CPC Class Codes: C07D 231/38 : Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 233/58 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
• CPC Class Codes: C07D 233/61 : with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
• CPC Class Codes: C07D 235/30 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 237/20 : Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 237/22 : Nitrogen and oxygen atoms
• CPC Class Codes: C07D 237/34 : with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/20 : Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 261/14 : Nitrogen atoms
• CPC Class Codes: C07D 261/20 : condensed with carbocyclic rings or ring systems
• 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 265/30 : not condensed with other rings
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 267/14 : condensed with one six-membered ring
• CPC Class Codes: C07D 275/02 : not condensed with other rings
• CPC Class Codes: C07D 277/28 : Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/62 : Benzothiazoles
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 295/12 : substituted by singly or doubly bound nitrogen atoms nitro radicals C07D295/06
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/18 : by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: C07D 333/40 : Thiophene-2-carboxylic acid
• CPC Class Codes: C07D 333/66 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/72 : Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

This invention provides a compound of the formula (I):

a pharmaceutically acceptable salt or solvate thereof,
wherein
R¹ is optionally substituted lower alkyl,
Y is —S(O)_n— wherein n is 1 or 2, or —CO—,
R² is hydrogen or lower alkyl,
R⁷ is hydrogen or lower alkyl,
X is lower alkylene, lower alkenylene, arylene, cycloalkylene or the like, and
Z is lower alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl or the like.

Claims

1. A compound of the formula (I):

a pharmaceutically acceptable salt or solvate thereof,

wherein

R¹ is optionally substituted lower alkyl,

Y is —

S(O)_n—

wherein n is 1 or 2, or —

CO—

,

R² is hydrogen or optionally substituted lower alkyl,

R¹ and R² taken together may form lower alkylene,

R⁷ is hydrogen or optionally substituted lower alkyl,

X is optionally substituted lower alkylene,

optionally substituted lower alkenylene,

optionally substituted —

CO-lower alkylene,

optionally substituted —

CO-lower alkenylene or a group of the formula;

wherein

R³, R⁴, R⁵ and R⁶ are each independently hydrogen or optionally substituted lower alkyl, a group of the formula;

is optionally substituted cycloalkylene, optionally substituted cycloalkenylene, optionally substituted bicycloalkylene, optionally substituted arylene or optionally substituted heterocyclyldiyl,

p and q are each independently an integer between 0 and 2, either p or q is not 0, provided that a group of the formula;

is not a group of the formula;

wherein R¹⁴ is optionally substituted phenyl, —

NR²—

X—

may be a group of the formula;

wherein a group of the formula;

is piperidinediyl, piperazinediyl, pyridindiyl, pyrazinediyl, pyrrolidinediyl or pyrrolediyl,

U is lower alkylene or lower alkenylene, and

Z is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted lower alkoxy, optionally substituted carbocyclyl or optionally substituted heterocyclyl,

provided that Z is not fused heterocyclyl consisting of three rings, optionally substituted thiazolyl or optionally substituted quinazolinyl, and

provided that a compound wherein X is a group of the formula;

a group of the formula;

is optionally substituted cycloalkylene, q is 1, q is 0 and Z is optionally substituted pyrimidinyl is excluded.

2. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein R¹ is lower alkyl.

3. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein Y is —

S(O)₂—

.

4. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein Z is optionally substituted carbocyclyl or optionally substituted heterocyclyl.

5. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X is a group of the formula:

and

R¹ is optionally substituted C2 to C10 alkyl.

6. The compound, pharmaceutically acceptable salt or solvate thereof of claim 5, wherein Z is optionally substituted heterocyclyl.

7. The compound, pharmaceutically acceptable salt or solvate thereof of claim 5, wherein a group of the formula:

is optionally substituted cycloalkylene, optionally substituted cycloalkenylene, optionally substituted bicycloalkylene or optionally substituted piperidinylene.

8. The compound, pharmaceutically acceptable salt or solvate thereof of claim 5, wherein a group of the formula:

is optionally substituted cyclohexylene or optionally substituted piperidinylene,

p and q are each independently 0 or 1, and either p or q is not 0.

9. The compound, pharmaceutically acceptable salt or solvate thereof of claim 7 or 8, wherein Z is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted oxadiazolyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl or optionally substituted fused heterocycle consisting of two rings.

10. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X is a group of the formula:

and p+q is 1 or 2.

11. The compound, pharmaceutically acceptable salt or solvate thereof of claim 10, wherein p+q is 1.

18. A pharmaceutical composition comprising the compound, pharmaceutically acceptable salt or solvate thereof of any one of claims 1 to 17 as an active ingredient.

19. A NPY Y5 receptor antagonist comprising the compound, pharmaceutically acceptable salt or solvate thereof of any one of claims 1 to 17 as an active ingredient.

12. A compound of the formula (I):

a pharmaceutically acceptable salt or solvate thereof,

wherein

R¹ is optionally substituted lower alkyl,

Y is —

S(O)₂—

,

R² is hydrogen or optionally substituted lower alkyl,

R⁷ is hydrogen or optionally substituted lower alkyl,

X is a group of the formula;

wherein

R⁵ and R⁶ are each independently hydrogen,

a group of the formula;

is optionally substituted cycloalkylene,

p is 0, and

q is 1 or 2,

Z is optionally substituted carbocyclyl or optionally substituted heterocyclyl, and provided that a compound wherein Z is fused heterocyclyl consisting of three rings or optionally substituted pyrimidinyl is excluded.

13. The compound, pharmaceutically acceptable salt or solvate thereof of claim 12, wherein Z is optionally substituted phenyl, optionally substituted indanyl, optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted oxadiazolyl or optionally substituted fused heterocycle consisting of two rings.

14. The compound, pharmaceutically acceptable salt or solvate thereof of claim 12, wherein Z is optionally substituted isoquinolyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl, optionally substituted benzopyridyl, optionally substituted benzopyridadiyl, optionally substituted benzimidazolyl, optionally substituted thiazolopyridyl, optionally substituted isoxazolinonyl, optionally substituted oxazolinonyl, optionally substituted benzoxadinonyl or optionally substituted benzoxyazepinonyl.

15. A compound of the formula (I):

a pharmaceutically acceptable salt or solvate thereof,

wherein

R¹ is optionally substituted lower alkyl,

Y is —

S(O)₂—

,

R² is hydrogen or optionally substituted lower alkyl,

R⁷ is hydrogen or optionally substituted lower alkyl,

X is a group of the formula;

wherein R³ and R⁴ are each independently hydrogen,

a group of the formula;

is optionally substituted cycloalkylene,

p is 1 or 2,

q is 0, and

provided that a group of the formula;

is not a group of the formula;

wherein R¹⁴ is optionally substituted phenyl,

Z is optionally substituted carbocyclyl or optionally substituted heterocyclyl, and provided that a compound wherein Z is fused heterocyclyl consisting of three rings, optionally substituted thiazolyl or optionally substituted quinazolinyl is excluded.

16. The compound, pharmaceutically acceptable salt or solvate thereof of claim 15, wherein Z is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted quinolyl, optionally substituted isoquinolyl, optionally substituted benzothiazolyl, optionally substituted benzimidazolyl, optionally substituted benzoxazolyl, optionally substituted thiazolopyridyl or optionally substituted oxazolopyridyl.

17. A compound of the formula (I):

a pharmaceutically acceptable salt or solvate thereof,

wherein

R¹ is optionally substituted lower alkyl,

Y is —

S(O)₂—

,

R² is hydrogen or optionally substituted lower alkyl,

R⁷ is hydrogen or optionally substituted lower alkyl,

X is a group of the formula;

wherein R³ and R⁴ are each independently hydrogen,

a group of the formula;

is optionally substituted cycloalkylene,

p is 1 or 2, and

q is 0, and

Z is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted quinolyl, optionally substituted isoquinolyl, optionally substituted benzothiazolyl, optionally substituted benzimidazolyl, optionally substituted benzoxazolyl, optionally substituted thiazolopyridyl or optionally substituted oxazolopyridyl.

20. A compound of the formula:

a salt or solvate thereof,

wherein R¹ is ethyl or tert-butyl.

21. A compound of the formula:

a salt or solvate thereof,

wherein R¹ is ethyl, isopropyl or tert-butyl.

22. A compound of the formula:

a salt or solvate thereof,

wherein Z is optionally substituted carbocyclyl or optionally substituted heterocyclyl.

23. A compound of the formula:

a salt or solvate thereof,

wherein

R¹⁵ is NH₂ or OH, and

Z is optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted quinolyl, optionally substituted isoquinolyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl, optionally substituted benzopyridyl, optionally substituted benzopyridadiyl, optionally substituted benzimidazolyl, optionally substituted benzoxazolyl, optionally substituted thiazolopyridyl optionally substituted isoxazolinonyl, optionally substituted oxazolinonyl, optionally substituted benzoxadinonyl or optionally substituted benzoxyazepinonyl.