Pyrazole derivative

• US 6,958,339 B2
• Filed: 02/02/2001
• Issued: 10/25/2005
• Est. Priority Date: 10/13/1997
• Status: Expired due to Fees

• Current Assignee: Astellas Pharma Incorporated
• Original Assignee: Astellas Pharma Incorporated
• Inventors: Takeuchi, Makoto, Kubota, Hirokazu, Ishikawa, Jun, Yonetoku, Yasuhiro, Kawazoe, Souichirou, Sugasawa, Keizo, Toyoshima, Akira, Funatsu, Masashi
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US09/773,736
• Publication Number:
  US 20010011090A1
• Time in Patent Office: 1,726 Days
• Field of Search: 548/127, 548/200, 548/236, 548/312.4, 548/364.1, 548/365.7, 548/375.1, 546/211, 546/275.4, 544/405, 514/255.05, 514/326, 514/341, 514/361, 514/365, 514/374, 514/397, 514/406
• US Class Current: 514/255.05
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 37/00 Drugs for immunological or allergic disorders
• 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 231/14 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 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• 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
• CPC Class Codes: C07D 417/04 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 417/14 containing three or more hetero rings

Abstract

The present invention is directed to drugs, in particular, pyrazole derivatives represented by the following general formula (I)
which have a calcium release-activated calcium channel inhibitory effect and medicinal compositions, in particular, calcium release-activated calcium channel inhibitors containing the above compounds as the active ingredient, wherein each substituent is defined in the specification.

The present invention also relates to a pharmaceutical composition containing an effective amount of the compound of formula (I) and a pharmaceutically effective carrier.

The present invention further relates to methods of treatment of diseases associated with calcium release-activated calcium channels, diseases associated with IL-2 production, and methods of treatment of allergic, inflammatory or auto-immune diseases.

Claims

1. A pyrazole compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof

wherein each symbol has the following meaning,

D:

1H-pyrazol-1-yl, which may have 1 to 2 substituents selected from the group consisting of -lower alkyl (“

Alk”

), -lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalkyl, —

O-Alk, —

COO-Alk and -halogen atom (“

Hal”

),

n;

0,

B;

1,4-phenylene,

X;

—

NH—

CO—

, and

A;

aryl which may have one or more substituents of group F;

mono- or di-cyclic fused heteroaryl selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, isoquinolyl, quinolyl, quinoxanyl, phthalazinyl, imidazo[1,2-a]pyridyl, quinazolinyl and cinnolinyl which may have one or more substituents of group F;

cycloalkyl;

or Alk, wherein the F group is;

-Alk, -lower alkenyl, -lower alkynyl, -Hal, —

NH₂, —

NH(Alk), —

N(Alk)₂, —

NO₂, —

CN, —

OH, —

O-Alk, —

O—

CO-Alk, —

SH, —

S-Alk, —

COO-Alk, —

CO-Alk, —

CONH₂, —

CONH(Alk), —

CON(Alk)₂, —

SO-Alk, —

SO₂-Alk, and —

SO₂NH₂,

with the proviso that,

(1) when D is 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than 4-methyl-1,2,3-thiadiazol-5-yl,

(2) when D is 1 H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than methyl,

(3) when D is 3,5-dimethyl-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than methyl, and

(4) when D is 3-methyl-4-bromo-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than methyl.

2. The pyrazole compound or pharmaceutically acceptable salt thereof according to claim 1, wherein

D is 1H-pyrazol-1-yl, which may have 1 to 2 substituents selected from -Alk, halogeno-lower alkyl- and —

COO-Alk, and

A is phenyl which may have one or more substituents selected from the group consisting of -Alk, -Hal, —

NH₂, —

N(Alk)₂, —

NO₂, —

CN, —

OH, —

O-Alk and —

COO-Alk;

mono- or di-cyclic fused heteroaryl selected from the group consisting of thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl and isoquinolyl, which may be substituted with one or more Alk;

cycloalkyl;

or Alk.

3. The pyrazole compound or pharmaceutically acceptable salt thereof according to claim 1, wherein D is 1H-pyrazol-1-yl, substituted with at least one trifluoromethyl group.

4. The pyrazole compound or pharmaceutically acceptable salt thereof according to claim 1, wherein D is 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl and A is monocyclic heteroaryl selected from the group consisting of thiazolyl, thiadiazolyl, thienyl and pyridyl, which may be substituted with one or more Alk.

5. The pyrazole compound 4′

-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-4-methylthiazole-5-carboxanilide.

6. A pharmaceutical composition which comprises a pharmaceutically effective amount of a pyrazole compound represented by the following general formula (I′

) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier

wherein each symbol has the following meaning,

D;

1H-pyrazol-1-yl, which may have 1 to 2 substituents selected from the group consisting of -Alk, -lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalkyl, —

O-Alk, —

COO-Alk and -Hal,

n;

0,

B;

1,4-phenylene,

X;

—

NH—

CO—

, and

A;

aryl which may have one or more substituents of group F;

mono- or di-cyclic fused heteroaryl selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyt, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, isoquinolyl, quinolyl, quinoxanyl, phthalazinyl, imidazo[1,2-a]pyridyl, quinazolinyl and cinnolinyl which may have one or more substituents of group F;

cycloalkyl;

or Alk, wherein the F group is;

-Alk, -lower alkenyl, -lower alkynyl, -Hal, —

NH₂, —

NH(Alk), —

N(Alk)₂, —

NO₂, —

CN, —

OH, —

O-Alk, —

O—

CO-Alk, —

SH, —

S-Alk, —

COO-Alk, —

CO-Alk, —

CONH₂, —

CONH(Alk), —

CON(Alk)₂, —

SO-Alk, —

SO₂-Alk, and —

SO₂NH₂,

with the proviso that

(1) when D is 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than 4-methyl-1,2,3-thiadiazol-5-yl,

(2) when D is 1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than methyl,

(3) when D is 3,5-dimethyl-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than methyl, and

(4) when D is 3-methyl-4-bromo-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than methyl.

7. The pharmaceutical composition according to claim 6, wherein D is 1H-pyrazol-1-yl substituted with at least one trifluoromethyl group.

8. The pharmaceutical composition according to claim 6, wherein D is 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl and A is monocyclic heteroaryl selected from the group consisting of thiazolyl, thiadiazolyl, thienyl and pyridyl, which may be substituted with Alk.

9. The pharmaceutical composition which comprises a pyrazole compound according to claim 6, wherein the pyrazole compound is 4′

-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-4-methylthiazole-5-carboxanilide.

10. A method for treating bronchial asthma, which comprises administering a pharmaceutical composition comprising a pyrazole compound represented by the following general formula (I′

)

wherein each symbol has the following meaning,

D;

1H-pyrazol-1-yl, which may have 1 to 2 substituents selected from the group consisting of -Alk, -lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalkyl, —

O-Alk, —

COO-Alk and -Hal,

n;

0,

B;

1,4-phenylene,

X;

—

NH—

CO—

, and

A;

aryl which may have one or more substituents of group F;

mono- or di-cyclic fused heteroaryl selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, isoquinolyl, quinolyl, quinoxanyl, phthalazinyl, imidazo[1,2-a]pyridyl, quinazolinyl and cinnolinyl which may have one or more substituents of group F;

cycloalkyl;

or Alk, wherein the F group is;

-Alk, -lower alkenyl, -lower alkynyl, -Hal, —

NH₂, —

NH(Alk), —

N(Alk)₂, —

NO₂, —

CN, —

OH, —

O-Alk, —

O—

CO-Alk, —

SH, —

S-Alk, —

COO-Alk, —

CO-Alk, —

CONH₂, —

CONH(Alk), —

CON(Alk)₂, —

SO-Alk, —

SO₂-Alk, and —

SO₂NH₂,

with the proviso that

when D is 3,5-bis(trifluoromethyl-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than 4-methyl-1,2,3-thiadiazol-5-yl,

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in an effective amount for treating said disease in a patient suffering from or susceptible to said disease.

11. The method for treating bronchial asthma according to claim 10, wherein

D is 1H-pyrazol-1-yl, which may have 1 to 2 substituents selected from the group consisting of -Alk, -lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalkyl, —

O-Alk, —

COO-Alk and -Hal,

B is 1,4-phenylene, and

X is —

NH—

CO—

.

12. The method for treating bronchial asthma which comprises administering a pharmaceutical composition comprising a pyrazole compound according to claim 10, wherein the pyrazole compound is 4′

-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-4-methyithiazole-5-carboxanilide.

13. A method for treating rheumatoid arthritis, which comprises administering a pharmaceutical composition comprising a pyrazole compound represented by the following general formula (I′

)

wherein each symbol has the following meaning,

D;

1H-pyrazol-1-yl, which may have 1 to 2 substituents selected from the group consisting of -Alk, -lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalcyl, —

O-Alk, —

COO-Alk and -Hal,

n;

0,

B;

1,4-phenylene,

X;

—

NH—

CO—

, and

A;

aryl which may have one or more substituents of group F;

mono- or di-cyclic fused heteroaryl selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, isoquinolyl, quinolyl, quinoxanyl, phihalazinyl, imidazo[1,2-a]pyridyl, quinazolinyl and cinnolinyl which may have one or more substituents of group F;

cycloalkyl;

or -Alk, wherein the F group is;

-Alk, -lower alkenyl, -lower alkynyl, -Hal, —

NH₂, —

NH(Alk), —

N(Alk)₂, —

NO₂, —

CN, —

OH, —

O-Alk, —

O—

CO-Alk, —

SH, —

S-Alk, —

COO-Alk, —

CO-Alk, —

CONH₂, —

CONH(Alk), —

CON(Alk)₂, —

SO-Alk, —

SO₂-Alk, and —

SO₂NH₂,

with the proviso that

when D is 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than 4-methyl-1,2,3-thiadiazol-5-yl,

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in an effective amount for treating said disease in a patient suffering from or susceptible to said disease.

14. The method for treating rheumatoid arthritis according to claim 13, wherein

D is 1H-pyrazol-1-yl, which may have 1 to 2 substituents selected from the group consisting of -Alk, -lower alkenyl, -lower alkynyl, halogeno-lower alkyl-, -cycloalkyl, —

O-Alk, —

COO-Alk and -Hal,

B is 1,4-phenylene, and

X is —

NH—

CO—

.

15. The method for treating rheumatoid arthritis which comprises administering a pharmaceutical composition comprising a pyrazole compound according to claim 13, wherein the pyrazole compound is 4′

-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-4-methylthiazole-5-carboxanilide.