Novel amide compounds

• US 20040087798A1
• Filed: 12/27/2002
• Published: 05/06/2004
• Est. Priority Date: 03/14/2000
• Status: Abandoned Application

• Current Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Original Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Yamada, Akira
• Application Number:
  US10/221,554
• Publication Number:
  US 20040087798A1
• Time in Patent Office: Days
• US Class Current: 546/336
• 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: C07C 205/12 the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms
• CPC Class Codes: C07C 233/75 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 257/18 having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
• 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: 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 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/30 Oxygen atoms
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/65 attached in position 3 or 5
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• 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 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 235/18 : with aryl radicals directly attached in position 2
• 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 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 249/14 : Nitrogen atoms
• CPC Class Codes: C07D 253/07 : 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 ring carbon atoms
• 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 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/30 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 277/42 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 277/64 : with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 285/135 : Nitrogen atoms
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 311/22 : with oxygen or sulfur atoms directly attached in position 4
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• 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 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings

Abstract

A compound of the formula (I):

R¹-A-X-NHCO—Y—R²

wherein

R¹ is heterocyclic group which may have suitable substituents, or phenyl which may have suitable substituents,

R² is condensed phenyl which may have suitable substituents, phenyl which may have suitable substituents, or thienyl which may have suitable substituents,

A is a group of the formula:

—(CH₂)_t—(O)_m—

or

 which R³ and R⁴ are each hydrogen or linked together to form imino,

R⁵ is hydrogen or lower alkyl,

t is 0, 1 or 2,

p, m and n are each 0 or 1,

X is phenylene which may have suitable substituents, or bivalent heterocyclic group containing nitrogen which may have suitable substituents,

Y is bond, lower alkylene, or lower alkenylene,

and a salt thereof.

Claims

1. A compound of the formula (I):

R¹-A-X-NHCO—

Y—

R²

wherein

R¹ is heterocyclic group which may have suitable substituents, or phenyl which may have suitable substituents,

R² is condensed phenyl which may have suitable substituents, phenyl which may have suitable substituents, or thienyl which may have suitable substituents,

A is a group of the formula;

—

(CH₂)_t—

(O)_m—

or

 

in which R³ and R⁴ are each hydrogen or linked together to form imino,

R⁵ is hydrogen or lower alkyl,

t is 0, 1 or 2,

p, m and n are each 0 or 1,

X is phenylene which may have suitable substituents, or bivalent heterocyclic group containing nitrogen which may have suitable substituents,

Y is bond, lower alkylene, or lower alkenylene,

and a salt thereof.

2. The compound of claim 1, wherein

R¹ is imidazolyl;

imidazolyl which have 1 to 3 lower alkyl;

imidazolyl which have 1 to 3 lower alkanoyl;

imidazolyl which have 1 to 3 halogen and/or lower alkyl;

pyridyl;

pyridyl which have 1 to 3 lower alkyl;

pyridyl which have 1 to 3 lower alkoxy;

pyridyl which have 1 to 3 halogen;

pyridyl which have 1 to 3 halogen and/or trihalo(lower)alkyl;

phenyl;

phenyl which have 1 to 3 lower alkyl;

phenyl which have 1 to 3 lower alkylamino;

phenyl which have 1 to 3 lower alkanoylamino;

phenyl which have 1 to 3 lower alkylsulfonylamino;

phenyl which have 1 to 3 halogen;

phenyl which have 1 to 3 lower alkoxy;

phenyl which have 1 to 3 halogen and/or lower alkoxy;

phenyl which have unsaturated heteromonocyclic group containing 1 to 4 nitrogen atom(s);

phenyl which have unsaturated heteromonocyclic group containing 1 or 2 salfur atom(s) and 1 to 3 nitrogen atom(s);

phenyl which have unsaturated heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s);

phenyl which have oxidopyridyloxy;

oxochromenyl;

piperazinyl;

triazolyl

triazolyl which have 1 to 3 lower alkyl;

triazolyl which have 1 to 3 thioxo and/or lower alkyl;

triazolyl which have unsaturated heteromonocyclic group containing 1 to 4 nitrogen atom(s);

pyrimidinyl;

pyrazinyl;

quinolinyl;

isoquinolinyl;

thienyl;

thiazolyl which have 1 to 3 halogen;

benzothiazolyl;

isoxazolyl which have 1 to 3 lower alkyl;

triazinyl which have 1 to 3 lower alkyl;

pyridazinyl which have 1 to 3 halogen;

thiadiazolyl;

benzimidazolyl which have 1 to 3 lower alkyl;

benzimidazolyl which have 1 to 3 halogen;

benzimidazolyl which have 1 to 3 lower alkoxy;

benzisoxazolyl;

indolyl which have 1 to 3 lower alkyl,

R2 is fluorenyl;

indolyl which have 1 to 3 lower alkyl;

phenyl;

phenyl which have 1 to 3 halogen;

phenyl which have 1 to 3 lower alkyl;

phenyl which have 1 to 3 lower alkoxy;

phenyl which have 1 to 3 trihalo(lower)alkyl;

phenyl which have 1 to 3 cyano;

phenyl which have halophenyl;

phenyl which have phenyl;

phenylsulfanyl;

phenyl which have lower alkylphenyl;

phenyl which have thienyl;

phenyl which have halothienyl;

pyridyl;

thienyl which have phenyl;

carbazolyl;

carbazolyl which have 1 to 3 halogen;

carbazolyl which have 1 to 3 trihalo(lower)alkyl and/or lower alkyl;

naphthyl;

2,3-dihydorobenzo[b]oxepinyl;

2,3-dihydorobenzo[b]oxepinyl which have 1 to 3 lower alkyl;

2,3-dihydorobenzo[b]oxepinyl which have 1 to 3 halogen;

2,3-dihydoro-benzo[b]oxepinyl which have 1 to 3 lower alkanesulfonyl;

2,3-dihydoro-benzo[b]oxepinyl which have 1 to 3 lower alkoxy;

2,3-dihydoro-benzo[b]thiepinyl which have dioxo;

8,9-dihydoro-benzocycloheptyl;

chromenyl which have 1 to 3 halogen;

indolyl;

indolyl which have 1 to 3 trihalo(lower)alkyl and/or lower alkyl,

A is a group of the formula;

—

(CH₂)_t—

(O)_m—

or

 

in which R³ and R⁴ are each hydrogen or linked together to form imino,

R⁵ is hydrogen or lower alkyl,

t is 0, 1 or 2,

p, m and n are each 0 or 1,

X is phenylene;

phenylene which have 1 to 3 halogen;

phenylene which have 1 to 3 cyano;

phenylene which have 1 to 3 lower alkyl;

phenylene which have 1 to 3 lower alkoxy;

phenylene which have 1 to 3 lower alkylsulfonylamino;

phenylene which have 1 to 3 halogen and/or lower alkoxy;

phenylene which have saturated heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s);

pyridinylene;

pyridinylene which have 1 to 3 halogen;

pyridinylene which have 1 to 3 trihalo(lower)alkyl;

pyridinylene which have 1 to 3 lower alkyl;

pyridinylene which have saturated heteromonocyclic group containing 1 to 4 nitrogen atom(s);

piperadinylene which have unsaturated heteromonocyclic group containing 1 to 4 nitrogen atom(s);

pyrimidinylene;

isoindolinylene,

Y is vinylene;

1-propenylene;

methylene;

ethylene.

12. A pharmaceutical composition, which has a compound of claim 1 and a pharmaceutically acceptable carriers or excipients.

13. A process for preparing a pharmaceutical composition, which comprises a compound of claim 1 in admixture with a pharmaceutically acceptable carriers or excipients.

14. A use of a compound of claim 1 as a medicament.

15. A use of a compound of claim 1 as a 5-HT antagonist.

16. A use of a compound of claim 1 as a 5-HT_2C antagonist.

17. A use of a compound of claim 1 for preparing a medicament for treating 5-HT-mediated diseases.

18. A method for treating 5-HT-mediated diseases which comprises administering a compound of claim 1 to human or animals.

3. A compound of the formula (I):

R¹-A-X-NHCO—

Y—

R²

wherein

R¹ is phenyl,

R² is phenyl which have trihalo(lower)alkyl,

A is a group of the formula;

 

in which R³ and R⁴ are linked together to form imino,

R⁵ is hydrogen,

p is 1,

n is 0,

X is phenylene which have halogen and lower alkoxy,

Y is vinylene,

and a salt thereof.

4. A compound of the formula (I):

R¹-A-X—

N HCO—

Y—

R²

wherein

R¹ is unsaturated heteromonocyclic group containing 1 to 4 nitrogen atom(s) which have 1 to 3 lower alkyl,

R² is indolyl which have 1 to 3 lower alkyl,

A is bond,

X is phenylene which have 1 to 3 halogen,

Y is bond,

and a salt thereof.

5. The compound of claim 4, wherein

R¹ is 4,5-di(lower alkyl)imidazolyl,

R² is 2,3-di(lower alkyl)indolyl,

X is phenylene which have 1 halogen.

6. A compound of the formula (I):

R¹-A-X-NHCO—

Y—

R²

wherein

R¹ is unsaturated heteromonocyclic group containing 1 to 4 nitrogen atom(s) which have 1 to 3 lower alkyl,

R² is carbazolyl,

A is bond,

X is phenylene which have 1 to 3 lower alkoxy,

Y is bond,

and a salt thereof.

7. The compound of claim 6, wherein

R¹ is 4,5-di(lower alkyl)imidazolyl,

X is phenylene which have 1 lower alkoxy.

8. A process for preparing a compound of the formula:

R¹-A-X-NHCO—

Y—

R²

or a salt thereof,

subjecting a compound of the formula;

R¹-A-X—

NH₂

or a salt thereof,

to amidation reaction with a compound of the formula;

HOOC—

Y—

R²

or a salt thereof,

wherein

R¹ is heterocyclic group which may have suitable substituents, or phenyl which may have suitable substituents,

R² is condensed phenyl which may have suitable substituents, phenyl which may have suitable substituents, or thienyl which may have suitable substituents,

A is a group of the formula;

—

(CH₂)_t—

(O)_m—

or

in which R³ and R⁴ are each hydrogen or linked together to form imino,

R⁵ is hydrogen or lower alkyl,

t is 0, 1 or 2,

p, m and n are each 0 or 1,

X is phenylene which may have suitable substituents, or bivalent heterocyclic group containing nitrogen which may have suitable substituents,

Y is bond, lower alkylene, or lower alkenylene.

9. A process for preparing a compound of the formula:

10. A process for preparing a compound of the formula:

11. A process for preparing a compound of the formula:

R¹—

NH—

CH₂—

X-NHCO—

Y—

R²

or a salt thereof,

subjecting a compound of the formula;

R¹—

NH₂

or a salt thereof,

to reaction with a compound of the formula;

or a salt thereof,

wherein

R¹ is heterocyclic group which may have suitable substituents, or phenyl which may have suitable substituents,

R² is condensed phenyl which may have suitable substituents, phenyl which may have suitable substituents, or thienyl which may have suitable substituents,

X is phenylene which may have suitable substituents, or bivalent heterocyclic group containing nitrogen which may have suitable substituents,

Y is bond, lower alkylene, or lower alkenylene.