Pyrazole derivative

• US 20010011090A1
• Filed: 02/02/2001
• Published: 08/02/2001
• Est. Priority Date: 10/13/1997
• Status: Active Grant

• Current Assignee: Astellas Pharma Incorporated
• Original Assignee: Astellas Pharma Incorporated
• Inventors: Takeuchi, Makoto, Okamoto, Yoshinori, Kubota, Hirokazu, Ishikawa, Jun, Yonetoku, Yasuhiro, Kawazoe, Souichirou, Sugasawa, Keizo, Toyoshima, Akira, Funatsu, Masashi
• Granted Patent: US 6,958,339 B2
• Time in Patent Office: Days
• US Class Current: 514/230.5
• 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

Drugs, in particular, pyrazole derivatives represented by the following general formula (I) which have a calcium release-dependent calcium channel inhibitory effect and medicinal compositions, in particular, calcium release-dependent calcium channel inhibitors containing the above compounds as the active ingredient,

(in the formula, each symbol has the following meaning:

B: phenylene, a nitrogen-containing, divalent, saturated ring group, or a monocyclic, divalent heteroaromatic ring group which may be substituted with Alk,

X: —NR¹—CR²R³—, —CR²R³—NR¹—, —NR¹SO₂—, —SO₂—NR¹— or —CR⁴═CR⁵—, and

A: benzene ring which may have one or more substituents; mono-, di- or tricyclic fused heteroaryl which may have one or more substituents; cycloalkyl which may have one or more substituents; a nitrogen-containing, saturated ring group which may have one or more substituents; lower alkenyl which may have one or more substituents; lower alkynyl which may have one or more substituents; or Alk which may have one or more substituents).

Claims

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

(in the formula, each symbol has the following meaning;

D;

pyrazolyl which may have 1 to 3 substituents selected from the group consisting of —

Alk, —

lower alkenyl, —

lower alkynyl, —

halogeno—

lower alkyl, —

Alk—

cycloalkyl, —

Alk—

O—

Alk, —

cycloalkyl, —

O—

Alk, —

COOH, —

COO—

Alk and —

Hal,

n;

0 or 1,

B;

phenylene, a nitrogen-containing, divalent, saturated ring group, or a monocyclic, divalent heteroaromatic ring group which may be substituted with Alk,

X;

—

NR—

CR²R³—

, —

CR²R³—

NR¹—

, —

NR¹—

SO₂—

, —

SO₂—

N¹—

or —

CR⁴′

CR⁵—

,

R¹;

—

H, —

OH, —

Alk, —

O—

Alk or —

CO—

Alk,

R² and R³;

the same or different from each other and each represents —

H or —

Alk, or R² and R³ together form ═

O or ═

S,

R⁴ and R⁵;

the same or different from each other and each represents —

H, —

Hal, —

halogeno—

lower alkyl or —

Alk, and

A;

benzene ring which may have one or more substituents;

mono-, di- or tricyclic fused heteroaryl which may have one or more substituents;

cycloalkyl which may have one or more substituents;

a nitrogen-containing, saturated ring group which may have one or more substituents;

lower alkenyl which may have one or more substituents;

lower alkynyl which may have one or more substituents;

or Alk which may have one or more substituents,

or A and X may together form a group represented by a formula

(wherein A² is a nitrogen-containing hetero ring selected from the group consisting of 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, 3,4-dihydro-2H-1, 4-benzoxazin-4-yl and indolinyl, wherein said hetero ring may have one or more substituents), 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-methyl-5-trifluoromethyl-1H-pyrazol-3-yl, n is 0, B is thiophene-2,5-diyl and X is CONH, A is a group other than 4-chlorophenyl,

(3) when D is 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl, n is 0, B is thiophene-2,5-diyl and X is CONH, A is a group other than benzyl,

(4) when D is 4-ethoxycarbonyl-5-trifluoromethyl-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and Y is NHCO, A is a group other than trichlorovinyl,

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

(6) when n is 1, D is 1H-pyrazol-5-yl substituted with at least one trifluoromethyl group or 1H-pyrazol-1-yl substituted with at least one trifluoromethyl group).

2. The pyrazole derivative or pharmaceutically acceptable salt thereof according to

claim 1

, wherein A is phenyl which may have one or more substituents of F group;

mono-, di- or tricyclic fused heteroaryl which may have one or more substituents of F group;

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

a nitrogen-containing, saturated ring group which may have one or more substituents of F group;

lower alkenyl which may have one or more substituents of G group;

lower alkynyl which may have one or more substituents of G group;

or Alk which may have one or more substituents of G group, wherein the F group is a group consisting of —

Alk, —

lower alkenyl, —

lower alkynyl, —

Hal, —

NH₂, —

NH (Alk) , —

N (Alk) ₂, —

No₂, —

CN, —

OH, —

0—

Alk, —

0—

CO—

Alk, —

SH, —

S—

Alk, —

COOH, —

COO—

Alk, —

CO—

Alk, —

CHO, —

CONH₂, —

CONH(Alk), —

CON(Alk)₂, —

SO—

Alk, —

SO₂—

Alk, —

SO₂NH₂, —

SO₂NH—

(Alk) , —

SO₂N (Alk) 2, —

aryl, —

cycloalkyl, —

O—

Alk—

O—

, —

halogeno—

lower alkyl, —

Alk—

NH₂, —

Alk—

NH(Alk), —

Alk—

N(Alk),, —

Alk—

OH, —

Alk—

O—

Alk, —

Alk—

SH, —

Alk—

S—

Alk, —

Alk—

COOH, —

Alk—

COO—

Alk, —

Alk—

CO—

Alk, —

Alk—

CHO, —

Alk—

CONH₂, —

Alk—

CONH(Alk), —

Alk—

CON(Alk)₂, —

Alk—

SO—

Alk, —

Alk—

SO₂—

Alk, —

Alk—

SO₂NH₂, —

Alk—

SO₂NH(Alk), —

Alk—

SO₂N(Alk)₂, —

Alk—

aryl and —

Alk—

cycloalkyl, and the G group is a group consisting of —

Hal, —

NH₂, —

NH(Alk), —

N(Alk)₂, —

NO₂, —

CN, —

OH, —

O—

Alk, —

O—

CO—

Alk, —

SH, —

S—

Alk, —

COOH, —

COO—

Alk, —

CO—

Alk, —

CHO, —

CONH₂, —

CONH(Alk), —

CON(Alk)₂, —

SO—

Alk, —

SO₂—

Alk, —

SO₂NH₂, —

SO₂NH—

(Alk), —

SO₂N(Alk)₂, aryl which may have one or more substituents of F group;

mono-, di- or tricyclic fused heteroaryl which may have one or more substituents of F group;

cycloalkyl which may have one or more substituents of F group and a nitrogen-containing, saturated ring group which may have one or more substituents of F group,

or A and X may together form a group represented by a formula

(wherein A² is a nitrogen-containing hetero ring selected from the group consisting of 1-pyrrolidinyl, pyrazolidinyl, piperidino, 1-piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl, wherein said hetero ring may have one or more substituents of F group).

3. The pyrazole derivative or pharmaceutically acceptable salt thereof according to

claim 2

, wherein B is phenylene;

piperidine-1,4-diyl;

or a monocyclic, divalent heteroaromatic ring group selected from the class consisting of thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, pyridine, pyrazine, pyridazine and pyrimidine, which may be substituted with Alk, X is —

NH—

CO—

, —

NH—

CH₂—

, —

N(OH)—

CO—

, —

N(Alk)—

CO—

, —

CO—

NH—

, —

CH₂—

NH—

, —

CO—

N (OH)—

, —

CO—

N (Alk)—

, —

SO₂NH—

, —

NHSO₂—

or —

CH═

C (Hal)—

,

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

mono-, di- or tricyclic 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, imidazopyridyl, quinazolinyl and cinnolinyl, which may have one or more substituents of group F;

cycloalkyl;

a nitrogen-containing, saturated ring selected from the group consisting of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl, which may be substituted with one or more Alk;

lower alkynyl which may be substituted with one or more Hal;

lower alkenyl which may be substituted with one or more Hal;

or Alk which may be substituted with one or more Hal, and

the F group is a group consisting of —

Alk, —

lower alkenyl, —

lower alkynyl, —

Hal, —

NH₂, —

NH(Alk), —

N(Alk) 2, —

NO₂, —

CN, —

OH, —

O—

Alk, —

O—

CO—

Alk, —

SH, —

S—

Alk, —

COOH, —

COO—

Alk, —

CO—

Alk, —

CHO, —

CONH₂, —

CONH(Alk), —

CON(Alk)₂, —

SO—

Alk, —

SO₂—

Alk, —

SO₂NH₂, —

SO₂NH—

(Alk) and —

SO₂N(Alk)₂,

or A and X may together form a group represented by a formula

4. The pyrazole derivative or pharmaceutically acceptable salt thereof according to

claim 3

, wherein

n is 0, D is pyrazolyl which may have 1 to 3 substituents selected from —

Alk, —

halogeno—

lower alkyl, —

COOH and —

COO—

Alk,

B is phenylene or a monocyclic, divalent heteroaromatic ring group selected from the class consisting of thiophene, furan, thiazole, pyridine and pyrimidine, which may be substituted with Alk,

X is —

NH—

CO—

, —

N(OH)—

CO—

, —

CO—

NH—

, —

CH₂—

NH—

or —

CO—

N(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-, di- or tricyclic 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 Alk;

cycloalkyl;

lower alkenyl which may be substituted with one or more Hal;

or Alk.

5. The pyrazole derivative or pharmaceutically acceptable salt thereof according to

claim 1

, wherein D is pyrazolyl substituted with at least one trifluoromethyl group.

6. The pyrazole derivative or pharmaceutically acceptable salt thereof according to

claim 1

, wherein D is 1H-pyrazol-5-yl substituted with at least one trifluoromethyl group or 1H-pyrazol-1-yl substituted with at least one trifluoromethyl group.

7. The pyrazole derivative or pharmaceutically acceptable salt thereof according to

claim 1

, wherein X is —

NH—

CO—

or —

CO—

NH—

.

8. The pyrazole derivative or pharmaceutically acceptable salt thereof according to

claim 1

, wherein D is 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl and A is phenyl which may be substituted with Hal.

9. The pyrazole derivative 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 Alk.

10. A pharmaceutical composition which comprises a pyrazole derivative represented by the following general formula (I′

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

(in the formula, each symbol has the following meaning;

D;

pyrazolyl which may have 1 to 3 substituents selected from the group consisting of —

Alk, —

lower alkenyl, —

lower alkynyl, —

halogeno—

lower alkyl, —

Alk—

cycloalkyl, —

Alk—

O—

Alk, —

cycloalkyl, —

O—

Alk, —

COOH, —

COO—

Alk and —

Hal,

n;

0 or 1,

B;

phenylene, a nitrogen—

containing, divalent, saturated ring group, or a monocyclic, divalent heteroaromatic ring group which may be substituted with Alk,

X;

—

NR¹—

CR²R³—

, —

CR²R³—

NR¹—

, —

NR¹—

SO₂—

, —

SO₂—

NR¹—

or —

CR⁴═

CR⁵—

,

R¹;

—

H, —

OH, —

Alk, —

0—

Alk or —

CO—

Alk,

R² and R³;

the same or different from each other and each represents —

H or —

Alk, or R² and R³ together form ═

O or ═

S,

R⁴ and R⁵;

the same or different from each other and each represents —

H, —

Hal, —

halogeno—

lower alkyl or —

Alk, and

A;

benzene ring which may have one or more substituents;

mono-, di- or tricyclic fused heteroaryl which may have one or more substituents;

cycloalkyl which may have one or more substituents;

a nitrogen-containing, saturated ring group which may have one or more substituents;

lower alkenyl which may have one or more substituents;

lower alkynyl which may have one or more substituents;

or Alk which may have one or more substituents,

or A and X may together form a group represented by a formula

(wherein A² is a nitrogen-containing hetero ring selected from the group consisting of 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino,. 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl, wherein said hetero ring may have one or more substituents), with the proviso that when n is 1, D is 1H-pyrazol-5-yl substituted with at least one trifluoromethyl group or 1H-pyrazol-1-yl substituted with at least one trifluoromethyl group).

11. The pharmaceutical composition according to

claim 10

, which is a calcium release-dependent calcium channel inhibitor.

12. The pharmaceutical composition according to

claim 11

, which is an IL-2 production inhibitor.

13. The pharmaceutical composition according to

claim 12

, which is a preventive or therapeutic agent for allergic, inflammatory or autoimmune diseases.

14. The pharmaceutical composition according to

claim 13

, which is a preventive or therapeutic agent for bronchial asthma or rheumatoid arthritis.

15. The pharmaceutical composition according to

claims 10

to

14

, wherein D is pyrazolyl substituted with at least one trifluoromethyl group.

16. The pharmaceutical composition according to

claims 10

to

14

, wherein D is 1H-pyrazol-5-yl substituted with at least one trifluoromethyl group or 1H-pyrazol-1-yl substituted with at least one trifluoromethyl group.

17. The pharmaceutical composition according to

claims 10

to

14

, wherein X is —

NH—

CO—

or —

CO—

NH—

.

18. The pharmaceutical composition according to

claims 10

to

14

, wherein D is 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl and A is phenyl which may be substituted with Hal.

19. The pharmaceutical composition according to

claims 10

to

14

, 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.