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US 7,459,451 B2Granted
Pyrazolopyridine derivatives
AssigneeAstellas Pharma Inc.
InventorsYoshito Abe, Kazuhiko Ohne, Kentaro Sato, Makoto Inoue, Mitsuaki Okumura
Life of this patent
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Abstract
The invention relates to compound of the formula (I) or its salt, in which R1, R2, R3 and R4 are as defined in the description, their use of as medicament, the process for their preparation and use for the treatment of PDE-IV or TNF-α mediated diseases.
Claims12
A compound of formula (I):
- in which
- R1 is (1) lower alkyl optionally substituted by halogen, cyclo(lower)alkyl, lower alkoxy, hydroxy, protected hydroxy, cyclo(lower)alkyloxy, aryloxy, hydroxyimino, carbamoyloxy optionally substituted by lower alkyl, or substituted or unsubstituted heterocyclyl, wherein said lower alkoxy is optionally substituted by cyclo(lower)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
- (2) lower alkenyl optionally substituted by cyano or carbamoyl optionally substituted by aryl which may have halogen,
- (3) cyclo(lower)alkyl,
- (4) acyl,
- (5) cyano,
- (6) substituted or unsubstituted aryl, or
- (7) substituted or unsubstituted heteroaryl;
- R2 is hydroxy, protected hydroxy, cyano, carboxy, hydroxyimino(lower)alkyl,—CONR6R7 or -(A1)p-X-A2-R5,
- wherein
- p is 0 or 1
- A1 is (C1-C2)alkylene or —CH═CH—;
- A2 is a divalent heterocyclic group, or —(CH2)n— or —(CH═CH)m—, wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3;
- X is single bond, —CH2— or —O—, and
- R5 is protected hydroxy, cyano, carboxy, protected carboxy, hydroxyimino(lower)alkyl, or —CONR6R7
- wherein R6 is hydrogen or lower alkyl, and R7 is hydrogen or —(CH2)q—Y—R8, wherein q is 0, 1, 2 or 3, Y is bond, —O—, or —CH(R9)—CH2—, wherein R9 is lower alkyl, carboxy or protected carboxy, and R8 is (1) lower alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heteroaryl, (4) substituted or unsubstituted heterocyclyl, or (5) substituted or unsubstituted cyclo(lower)alkyl), or alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent substituted or unsubstituted azaheterocyclyl group;
- R3 is (1) substituted or unsubstituted aryl,
- (2) substituted or unsubstituted heteroaryl,
- (3) substituted or unsubstituted heterocyclyl,
- (4) cyclo(lower)alkyl, or
- (5) lower alkyl optionally substituted by (a) cyclo(lower)alkyl, (b) substituted or unsubstituted heterocyclyl, (c) substituted or unsubstituted aryl, or (d) substituted or unsubstituted heteroaryl;
- and
- R4 is lower alkyl,
- or a pharmaceutically acceptable salt thereof.
21 more elements
A process for preparing a pyrazolpyridine compound of formula (I-2), or a salt thereof:
- wherein
- R1 is (1) lower alkyl optionally substituted by halogen, cyclo(lower)alkyl, lower alkoxy, hydroxy, protected hydroxy, cyclo(lower)alkyloxy, aryloxy, hydroxyimino, carbamoyloxy optionally substituted by lower alkyl, or substituted or unsubstituted heterocyclyl, wherein said lower alkoxy is optionally substituted by cyclo(lower)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
- (2) lower alkenyl optionally substituted by cyano or carbamoyl optionally substituted by aryl which may have halogen,
- (3) cyclo(lower)alkyl,
- (4) acyl,
- (5) cyano,
- (6) substituted or unsubstituted aryl, or
- (7) substituted or unsubstituted heteroaryl;
- R3 is (1) substituted or unsubstituted aryl,
- (2) substituted or unsubstituted heteroaryl,
- (3) substituted or unsubstituted heterocyclyl,
- (4) cyclo(lower)alkyl, or
- (5) lower alkyl optionally substituted by (a) cyclo(lower)alkyl, (b) substituted or unsubstituted heterocyclyl, (c) substituted or unsubstituted aryl, or (d) substituted or unsubstituted heteroaryl;
- and
- R4 is lower alkyl;
- which process comprises subjecting a compound of formula (I-1), or a salt thereof, to Wittig reaction to give the compound of formula (1-2),
- wherein R1, R3 and R 4 are each as defined above.
14 more elements
A process for preparing a pyrazolpyridine compound of formula I-4), or a salt thereof:
- wherein
- R1 is (1) lower alkyl optionally substituted by halogen, cyclo(lower)alkyl, lower alkoxy, hydroxy, protected hydroxy, cyclo(lower)alkyloxy, aryloxy, hydroxyimino, carbamoyloxy optionally substituted by lower alkyl, or substituted or unsubstituted heterocyclyl, wherein said lower alkoxy is optionally substituted by cyclo(lower)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
- (2) lower alkenyl optionally substituted by cyano or carbamoyl optionally substituted by aryl which may have halogen,
- (3) cyclo(lower)alkyl,
- (4) acyl,
- (5) cyano,
- (6) substituted or unsubstituted aryl, or
- (7) substituted or unsubstituted heteroaryl;
- R2b is a carboxy or -(A1)p-X-A2-R5,
- wherein
- p is 0 or 1
- A1 is (C1-C2)alkylene or —CH═CH—;
- A2 is a divalent heterocyclic group, or —(CH2)n— or —(CH═CH)m—, wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3;
- X is single bond, —CH2— or —O—, and
- R5 is carboxy or —CONR6R7
- wherein R6 is hydrogen or lower alkyl, and R7 is —(CH2)q—Y—R8, wherein q is 0, 1, 2 or 3, Y is —CH(R9)—CH2—, wherein R9 is carboxy, and R8 is (1) lower alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heteroaryl, (4) substituted or unsubstituted heterocyclyl, or (5) substituted or unsubstituted cyclo(lower)alkyl;
- R3 is (1) substituted or unsubstituted aryl,
- (2) substituted or unsubstituted heteroaryl,
- (3) substituted or unsubstituted heterocyclyl,
- (4) cyclo(lower)alkyl, or
- (5) lower alkyl optionally substituted by (a) cyclo(lower)alkyl, (b) substituted or unsubstituted heterocyclyl, (c) substituted or unsubstituted aryl, or (d) substituted or unsubstituted heteroaryl;
- and
- R4 is lower alkyl;
- which process comprises subjecting a compound of formula (I-3), or a salt thereof, to hydrolysis to give the compound of formula (I-4)
- wherein R1, R3 and R4 are each as defined above, and
- R2a is a protected carboxy or -(A1)p-X-A2-R5,
- wherein
- p is 0 or 1
- A1 is (C1-C2)alkylene or —CH═CH—;
- A2 is a divalent heterocyclic group, or —(CH2)n— or —(CH═CH)m—, wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3;
- X is single bond, —CH2— or —O—, and
- R5 is protected carboxy or —CONR6R7
- wherein R6 is hydrogen or lower alkyl, and R7 is —(CH2)q—Y—R8, wherein q is 0, 1, 2 or 3, Y is —CH(R9)—CH2—, wherein R9 is protected carboxy, and R8 is (1)lower alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heteroaryl, (4) substituted or unsubstituted hererocyclyl, or (5) substituted or unsubstituted cyclo(lower)alkyl.
30 more elements
A process for preparing a pyrazolpyridine compound of formula (I-5), or a salt thereof:
- wherein
- R1 is (1) lower alkyl optionally substituted by halogen, cyclo(lower)alkyl, lower alkoxy, hydroxy, protected hydroxy, cyclo(lower)alkyloxy, aryloxy, hydroxyimino, carbamoyloxy optionally substituted by lower alkyl, or substituted or unsubstituted heterocyclyl, wherein said lower alkoxy is optionally substituted by cyclo(lower)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
- (2) lower alkenyl optionally substituted by cyano or carbamoyl optionally substituted by aryl which may have halogen,
- (3) cyclo(lower)alkyl,
- (4) acyl,
- (5) cyano,
- (6) substituted or unsubstituted aryl, or
- (7) substituted or unsubstituted heteroaryl;
- R2c is a —CONRR6R7 or -(A1)p-X-A2-R5,
- wherein
- p is 0 or 1
- A1 is (C1-C2)alkylene or —CH═CH—;
- A2 is a divalent heterocyclic group, or —(CH2)n— or —(CH═CH)m—, wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3;
- X is single bond, —CH2— or —O—, and
- R5 is —CONRR6R7,
- wherein R6 is hydrogen or lower alkyl, and R7 is hydrogen or —(CH2)q—Y—R8, wherein q is 0, 1, 2 or 3, Y is bond, —O—, or —CH(R9)—CH2—, wherein R9 is lower alkyl, carboxy or protected carboxy, and R8 is (1) lower alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heteroaryl, (4) substituted or unsubstituted heterocyclyl, or (5) substituted or unsubstituted cyclo(lower)alkyl, or
- alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent substituted or unsubstituted azaheterocyclyl group;
- R3 is (1) substituted or unsubstituted aryl,
- (2) substituted or unsubstituted heteroaryl,
- (3) substituted or unsubstituted heterocyclyl,
- (4) cyclo(lower)alkyl, or
- (5) lower alkyl optionally substituted by (a) cyclo(lower)alkyl, (b) substituted or unsubstituted heterocyclyl, (c) substituted or unsubstituted aryl, or (d) substituted or unsubstituted heteroaryl;
- and
- R4 is lower alkyl;
- which process comprises amidating a compound of formula (I-4), or a salt thereof to give the compound of formula (I-5)
- wherein R1, R3 and R4 are each as defined, and
- R2b is a carboxy or -(A1)p-X-A2-R5,
- wherein
- p is 0 or 1
- A1 is (C1-C2)alkylene or —CH═CH—;
- A2 is a divalent heterocyclic group, or —(CH2)n— or —(CH═CH)m—, wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3;
- X is single bond, —CH2— or —O—, and
- R5 is carboxy.
30 more elements
A process for preparing a pyrazolpyridine compound of formula (I-7), or a salt thereof:
- wherein
- R1 is (1) lower alkyl optionally substituted by halogen, cyclo(lower)alkyl, lower alkoxy, hydroxy, protected hydroxy, cyclo(lower)alkyloxy, aryloxy, hydroxyimino, carbamoyloxy optionally substituted by lower alkyl, or substituted or unsubstituted heterocyclyl, wherein said lower alkoxy is optionally substituted by cyclo(lower)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
- (2) lower alkenyl optionally substituted by cyano or carbamoyl optionally substituted by aryl which may have halogen,
- (3) cyclo(lower)alkyl,
- (4) acyl,
- (5) cyano,
- (6) substituted or unsubstituted aryl, or
- (7) substituted or unsubstituted heteroaryl;
- R2e is -(A1)p-X-A2-R5,
- wherein
- p is 0 or 1
- A1 is (C1-C2)alkylene;
- A2 is a divalent heterocyclic group or —(CH2)n—, wherein n is integer which may range from 1 to 6;
- X is single bond, —CH2— or —O—, and
- R5 is protected hydroxy, cyano, carboxy, protected carboxy,
- hydroxyimino(lower)alkyl, or —CONR6R7
- wherein R6 is hydrogen or lower alkyl, and R7 is hydrogen or —(CH2)q—Y—R8,
- wherein q is 0, 1, 2 or 3, Y is bond, —O—, or —CH(R9)—CH2—, wherein R9 is lower alkyl, carboxy or protected carboxy, and R8 is (1) lower alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heteroaryl, (4) substituted or unsubstituted heterocyclyl, or (5) substituted or unsubstituted cyclo(lower)alkyl, or
- alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent substituted or unsubstituted azaheterocyclyl group;
- R3 is (1) substituted or unsubstituted aryl,
- (2) substituted or unsubstituted heteroaryl,
- (3) substituted or unsubstituted heterocyclyl,
- (4) cyclo(lower)alkyl, or
- (5) lower alkyl optionally substituted by (a) cyclo(lower)alkyl, (b) substituted or unsubstituted heterocyclyl, (c) substituted or unsubstituted aryl, or (d) substituted or unsubstituted heteroaryl;
- and
- R4 is lower alkyl;
- which process comprises reducting a compound of formula (I-6), or a salt thereof, to give the compound of formula (I-7)
- wherein R1, R3 and R4 are each as defined above, and
- R2d is -(A1)p-X-A2-R5,
- wherein
- p is 0 or 1
- A1 is (C1-C2)alkylene or —CH═CH—;
- A2 is a divalent heterocyclic group, or —(CH2)n— or —(CH═CH)m—, wherein n is integer which may range from 1 to 6 and m is integer which may range from 1 to 3;
- X is single bond, —CH2— or —O—, and
- R5 is protected hydroxy, cyano, carboxy, protected carboxy, hydroxyimino(lower)alkyl, or —CONR6R
- wherein R6 is hydrogen or lower alkyl and R7 is hydrogen or —(CH2)q—Y—R8,
- wherein q is 0, 1, 2 or 3, Y is bond, —O—, or —CH(R9)—CH2—, wherein R9 is lower alkyl, carboxy or protected carboxy, and R8 is (1) lower alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heteroaryl, (4) substituted or unsubstituted heterocyclyl, or (5) substituted or unsubstituted cyclo(lower)alkyl, or
- alternatively R6 and R7, together with the nitrogen atom to which they are attached, represent substituted or unsubstituted azaheterocyclyl group;
- provided that A1 is —CH═CH— or A2 is —(CH═CH)m—.
36 more elements
Dependencies are inferred from the claim text.