Substituted pyrazole derivatives and use thereof

• US 20090270361A1
• Filed: 03/25/2009
• Published: 10/29/2009
• Est. Priority Date: 03/26/2008
• Status: Abandoned Application

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Tomita, Naoki, Ito, Mitsuhiro, Kaku, Tomohiro, Suzaki, Tomohiko
• Application Number:
  US12/383,502
• Publication Number:
  US 20090270361A1
• Time in Patent Office: Days
• US Class Current: 514/210.180
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/26 Androgens
• 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 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic 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 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention aims to provide a novel pyrazole derivative and a pharmaceutical agent containing the same. The present invention provides a compound represented by the formula (I′)

wherein

• R¹′ is
• (1) a hydrogen atom,
• (2) a group via a carbon atom,
• (3) a group via a nitrogen atom,
• (4) a group via an oxygen atom or
• (5) a group via a sulfur atom;
• R²′ is an aromatic ring group optionally having substituent(s);
• R³′ is
• (1) a hydrogen atom,
• (2) a group via a carbon atom,
• (3) a group via a nitrogen atom,
• (4) a group via an oxygen atom or
• (5) a group via a sulfur atom;
• R⁴′ is a cyanophenyl group optionally having substituent(s);
• X′ is
• (1) —Y′—CR⁵′R⁶′-Z′-
• wherein R⁵′ and R⁶′ are the same or different and each is a hydrogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom, or —CR⁵′R⁶′— is —C(alkylidene)-;
• Y′ is a bond, —COCO—, —CONH—, —COCONH— or —O—; and
• Z′ is a bond, —CH₂—, —CONH—, —O—, —OCH₂—, —S—, —SO—, —SO₂—, —CON(C₆H₅)— or

• (2) —CO(CONH)_n— wherein n is 0 or 1,
• (3) —NHCO—,
• (4) —CONH—,
• (5) —O—,
• (6) —CH═CH— or
• (7) —O(C_1-3 alkylene)O—; (excluding the compounds indicated to be excluded from the specification), or a salt thereof.

Claims

1. A compound represented by the formula (I′

)

wherein

R¹′

is

(1) a hydrogen atom,

(2) a group via a carbon atom,

(3) a group via a nitrogen atom,

(4) a group via an oxygen atom or

(5) a group via a sulfur atom;

R²′

is an aromatic ring group optionally having substituent(s);

R³′

is

(1) a hydrogen atom,

(2) a group via a carbon atom,

(3) a group via a nitrogen atom,

(4) a group via an oxygen atom or

(5) a group via a sulfur atom;

R⁴′

is a cyanophenyl group optionally having substituent(s);

X′

is

(1) —

Y′

—

CR^5′

R^6′

-Z′

-

wherein R^5′

and R^6′

are the same or different and each is a hydrogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom, or

—

CR^5′

R^6′

—

is —

C(alkylidene)-;

Y′

is a bond, —

COCO—

, —

CONH—

, —

COCONH—

or —

O—

; and

Z′

is a bond, —

CH₂—

, —

CONH—

, —

O—

, —

OCH₂—

, —

S—

, —

SO—

, —

SO₂—

, —

CON(C₆H₅)—

or

(2) —

CO(CONH)_n—

wherein n is 0 or 1,

(3) —

NHCO—

,

(4) —

CONH—

,

(5) —

O—

,

(6) —

CH═

CH—

or

(7) —

O(C_1-3 alkylene)O—

;

excluding the following compounds;

a compound represented by the formula;

wherein one of R^d, R^d1 and R^d2 is a cyano group and the other two groups are the same or different and each is a hydrogen atom, a chlorine atom or a methyl group and

a compound represented by the formula;

wherein R^e1 is a methyl group, an ethyl group or a methoxymethyl group, one of R^e2 and R^e3 is a cyano group, and the other is a hydrogen atom,

or a salt thereof.

25. A prodrug of the compound of claim 1.

26. A pharmaceutical agent comprising the compound of claim 1 or a prodrug thereof.

27. The pharmaceutical agent of claim 26, which is an androgen receptor antagonist.

28. The pharmaceutical agent of claim 27, wherein the androgen receptor is a normal androgen receptor and/or a mutant androgen receptor.

29. The pharmaceutical agent of claim 26, which is an agent for the prophylaxis or treatment of hormone sensitive cancer in the androgen-dependent phase and/or the androgen-independent phase.

30. The pharmaceutical agent of claim 26, which is an agent for the prophylaxis or treatment of prostate cancer.

31. A method of antagonizing an androgen receptor, comprising administering an effective amount of the compound of claim 1 or a prodrug thereof to a mammal.

32. A method of preventing or treating hormone sensitive cancer in the androgen-dependent phase and/or the androgen-independent phase, comprising administering an effective amount of the compound of claim 1 or a prodrug thereof to a mammal.

33. A method of preventing or treating prostate cancer, comprising administering an effective amount of the compound of claim 1 or a prodrug thereof to a mammal.

34. Use of the compound of claim 1 or a prodrug thereof for the production of an androgen receptor antagonist.

35. Use of the compound of claim 1 or a prodrug thereof for the production of an agent for the prophylaxis or treatment of hormone sensitive cancer in the androgen-dependent phase and/or the androgen-independent phase.

36. Use of the compound of claim 1 or a prodrug thereof for the production of an agent for the prophylaxis or treatment of prostate cancer.

2. A compound represented by the formula (I)

wherein

R¹ is

(1) a hydrogen atom,

(2) a group via a carbon atom,

(3) a group via a nitrogen atom,

(4) a group via an oxygen atom or

(5) a group via a sulfur atom;

R² is an aromatic ring group optionally having substituent(s);

R³ is

(1) a hydrogen atom,

(2) a group via a carbon atom,

(3) a group via a nitrogen atom,

(4) a group via an oxygen atom or

(5) a group via a sulfur atom;

R⁴ is a cyanophenyl group optionally having substituent(s);

X is

(1) —

Y—

CR⁵R⁶-Z-

wherein R⁵ and R⁶ are the same or different and each is a hydrogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom, or

—

CR⁵R⁶—

is —

C(alkylidene)-;

Y is a bond, —

COCO—

, —

CONH—

, —

COCONH—

or —

O—

; and

Z is a bond, —

CH₂—

, —

CONH—

, —

O—

, —

OCH₂—

, —

S—

, —

SO—

or —

SO₂—

,

(2) —

CO(CONH)_n—

wherein n is 0 or 1,

(3) —

NHCO—

,

(4) —

CONH—

,

(5) —

O—

or

(6) —

CH═

CH—

;

excluding the following compounds;

a compound represented by the formula;

wherein one of R^d, R^d1 and R^d2 is a cyano group and the other two groups are the same or different and each is a hydrogen atom, a chlorine atom or a methyl group and

a compound represented by the formula;

wherein R^e1 is a methyl group, an ethyl group or a methoxymethyl group, one of R^e2 and R^e3 is a cyano group, and the other is a hydrogen atom,

or a salt thereof.

3. The compound of claim 2, wherein X is —

CH₂—

, —

CH(CH₃)—

, —

CH(OH)—

, —

CH(OCOC₆H₅)—

, —

C(CH₃)(OH)—

, —

C(CH₂CH₃)(OH)—

, —

CO—

, —

C(═

CH₂)—

, —

O—

, —

CH₂O—

, —

CH₂S—

, —

CH(CH₃)S—

, —

CH₂CH₂—

, —

CH₂SO₂—

, —

CH═

CH—

, —

NHCO—

, —

CONH—

, —

C(CH₃)(OH)CH₂—

, —

OCH₂—

, —

COCONH—

, —

C(CH₃)(OH)CONH—

, —

CONHCH₂—

, —

CH₂OCH₂—

, —

COCOCH₂SO₂—

or —

COCONHCH₂.

4. The compound of claim 2, wherein R¹ is an acyl group or a C_1-6 alkyl group optionally substituted by a hydroxy group.

5. The compound of claim 2, wherein R² is

(1) a phenyl group optionally having substituent(s),

(2) a pyridyl group optionally having substituent(s),

(3) a pyrazolyl group,

(4) an imidazolyl group,

(5) an oxazolyl group,

(6) a furyl group,

(7) a thienyl group,

(8) a thiazolyl group,

(9) an isoxazolyl group,

(10) a pyrimidinyl group,

(11) an indolyl group or

(12) a quinolyl group.

6. The compound of claim 2, wherein R³ is a C_1-6 alkyl-carbonyloxy group, an acyl group or a C_1-6 alkyl group optionally substituted by a hydroxy group.

7. The compound of claim 2, wherein R⁴ is a 4-cyanophenyl group optionally having substituent(s) selected from a cyano group, a halogen atom and a C_1-6 alkyl group optionally substituted by a halogen atom.

8. The compound of claim 2, wherein

R¹ is an acyl group or a C_1-6 alkyl group optionally substituted by a hydroxy group;

R² is

(1) a phenyl group optionally having substituent(s),

(2) a pyridyl group optionally having substituent(s),

(3) a pyrazolyl group,

(4) an imidazolyl group,

(5) an oxazolyl group,

(6) a furyl group,

(7) a thienyl group,

(8) a thiazolyl group,

(9) an isoxazolyl group,

(10) a pyrimidinyl group,

(11) an indolyl group or

(12) a quinolyl group;

R³ is a C_1-6 alkyl-carbonyloxy group, an acyl group or a C_1-6 alkyl group optionally substituted by a hydroxy group;

R⁴ is a 4-cyanophenyl group optionally having substituent(s) selected from a cyano group, a halogen atom and a C_1-6 alkyl group optionally substituted by a halogen atom; and

X is —

CH₂—

, —

CH(CH₃)—

, —

CH(OH)—

, —

CH(OCOC₆H₅)—

, —

C(CH₃)(OH)—

, —

C(CH₂CH₃)(OH)—

, —

CO—

, —

C(═

CH₂)—

, —

O—

, —

CH₂O—

, —

CH₂S—

, —

CH(CH₃)S—

, —

CH₂CH₂—

, —

CH₂SO₂—

, —

CH═

CH—

, —

NHCO—

, —

CONH—

, —

C(CH₃)(OH)CH₂—

, —

OCH₂—

, —

COCONH—

, —

C(CH₃)(OH)CONH—

, —

CONHCH₂—

, —

CH₂OCH₂—

, —

COCOCH₂SO₂—

or —

COCONHCH₂—

.

9. The compound of claim 2, wherein

R¹ is a C_1-6 alkyl group optionally having substituent(s);

R² is a phenyl group optionally having substituent(s), a pyrazolyl group optionally having substituent(s), an imidazolyl group optionally having substituent(s), a furyl group optionally having substituent(s), an isoxazolyl group optionally having substituent(s), an oxazolyl group optionally having substituent(s), a pyridyl group optionally having substituent(s), a thienyl group optionally having substituent(s), a thiazolyl group optionally having substituent(s), a pyrimidinyl group optionally having substituent(s), an indolyl group optionally having substituent(s) or a quinolyl group optionally having substituent(s);

R³ is a C_1-6 alkyl group optionally having substituent(s), a C_1-6 alkyl-carbonyloxy group optionally having substituent(s) or a C_1-6 alkoxy-carbonyloxy group optionally having substituent(s);

R⁴ is a 4-cyanophenyl group optionally having substituent(s); and

,

X is —

CH₂—

, —

CH(CH₃)—

, —

CH(OH)—

, —

CH(OCOC₆H₅)—

, —

C(CH₃)(OH)—

, —

C(CH₂CH₃)(OH)—

, —

CO—

, —

C(═

CH₂)—

, —

O—

, —

CH₂O—

, —

CH₂S—

, —

CH(CH₃)S—

, —

CH₂CH₂—

, —

CH₂SO₂—

, —

CH═

CH—

, —

NHCO—

, —

CONH—

, —

C(CH₃)(OH)CH₂—

, —

OCH₂—

, —

COCONH—

, —

C(CH₃)(OH)CONH—

, —

CONHCH₂—

, —

CH₂OCH₂—

, —

COCOCH₂SO₂—

or —

COCONHCH₂—

.

11. The compound of claim 2, which is represented by the formula (Ib)

wherein

R^b is a hydrogen atom, a halogen atom, a cyano group or a C_1-6 alkyl group optionally having 1 to 3 halogen atoms;

X^b is —

CH₂—

, —

C₂H₄—

, —

O—

, —

O(C_1-2 alkylene)-, —

CH(OH)—

, —

OCH(CH₃)—

, —

OCH(CONH₂)—

, —

O—

CH₂CONH—

, —

CH(CH₃)—

, —

CH(OCOC₆H₅)—

, —

C(CH₃)(OH)—

, —

C(CH₂CH₃)(OH)—

, —

CO—

, —

C(═

CH₂)—

, —

CH₂O—

, —

CH₂S—

, —

CH(CH₃)S—

, —

CH₂SO₂—

, —

CH═

CH—

, —

NHCO—

, —

CONH—

, —

C(CH₃)(OH)CH₂—

, —

O(CH₂)—

, —

COCONH—

, —

C(CH₃)(OH)CONH—

, —

CONHCH₂—

, —

CH₂OCH₂—

, —

COCOCH₂SO₂—

, —

COCONHCH₂—

or —

C(CH₃)(OH)CH₂—

;

R^1b is an acyl group or a C_1-6 alkyl group optionally substituted by a hydroxy group;

R^2b is

(1) an aromatic hydrocarbon group optionally having substituent(s),

(2) a 5- to 7-membered mono-cyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which optionally has substituent(s) or

(3) a 8- to 12-membered condensed aromatic heterocyclic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which optionally has substituent(s);

R^3b is a C_1-6 alkyl-carbonyloxy group, an acyl group or a C_1-6 alkyl group optionally substituted by a hydroxy group, provided that when X^b is —

O—

, then R^1b and R^3b are groups other than an ethyl group.

12. The compound of claim 11, wherein R^2b is a phenyl group optionally having substituent(s), a pyridyl group optionally having substituent(s), a pyrimidinyl group optionally having substituent(s), a pyrazolyl group optionally having substituent(s), an imidazolyl group optionally having substituent(s), a thiazolyl group optionally having substituent(s), an oxazolyl group optionally having substituent(s), an oxadiazolyl group optionally having substituent(s), a pyrazolyl group optionally having substituent(s), a thienyl group optionally having substituent(s) or a thiazolyl group optionally having substituent(s).

13. The compound of claim 11, wherein R^2b is

(1) a phenyl group optionally having substituent(s) selected from an oxadiazolyl group optionally having substituent(s), a carbamoyl group optionally having substituent(s) and an acyl group or

(2) a pyridyl group optionally having substituent(s) selected from a C_1-6 alkyl-carbonylamino group and a carbamoyl group optionally having substituent(s).

14. The compound of claim 11, wherein

R^b is a halogen atom or a C_1-6 alkyl group optionally having 1 to 3 halogen atoms;

X is —

CH₂—

, —

C₂H₄—

or —

O—

;

R^1b and R^3b are each a C_1-6 alkyl group; and

R^2b is a phenyl group or pyridyl group optionally having substituent(s) selected from

(1) an oxadiazolyl group optionally having a carbamoyl group,

(2) a carbamoyl group substituted by a C_1-6 alkyl group optionally having a hydroxy group,

(3) a C_1-6 alkylcarbonyl-amino group,

(4) a dioxidothiomorpholinocarbonyl group,

(5) a morpholinocarbonyl group,

(6) a piperidinylcarbonyl group optionally having a hydroxy group and

(7) an azetidinylcarbonyl group optionally having a hydroxy group.

15. The compound of claim 2, which is represented by the formula (Ic)

wherein

X^c is —

CH₂—

, —

C₂H₄—

or —

O—

;

R^1c and R^3c are the same or different and each is a C_1-6 alkyl group;

W is a nitrogen atom or CH;

ring A is a benzene ring further optionally having 1 to 3 halogen atoms; and

R^c is

(1) an oxadiazolyl group optionally having a carbamoyl group,

(2) a carbamoyl group optionally having a C_1-6 alkyl group optionally having a hydroxy group,

(3) a C_1-6 alkylcarbonyl-amino group,

(4) a dioxidothiomorpholinocarbonyl group,

(5) a morpholinocarbonyl group,

(6) a piperidinylcarbonyl group optionally having a hydroxy group or

(7) an azetidinylcarbonyl group optionally having a hydroxy group.

16. The compound of claim 2, which is represented by the formula (Id)

wherein

X^d is —

O—

or —

CH₂—

W is a nitrogen atom or CH

R^da is a halogen atom,

R^1d and R^3d are each a methyl group, and

R^d is

(1) an oxadiazolyl group having a carbamoyl group,

(2) a C_1-6 alkyl-carbamoyl group optionally having a hydroxy group,

(3) a C_1-6 alkylcarbonyl-amino group,

(4) a dioxidothiomorpholinocarbonyl group,

(5) a morpholinocarbonyl group,

(6) a piperidinylcarbonyl group having a hydroxy group or

(7) an azetidinylcarbonyl group having a hydroxy group.

10. A compound represented by the formula (Ia)

wherein

R^a is a hydrogen atom, a halogen atom, a cyano group or a C_1-6 alkyl group optionally having 1 to 3 halogen atoms;

X^a is C_1-3 alkylene, —

O—

, —

O(C_1-3 alkylene)-, —

CH(OH)—

, —

OCH(CH₃)—

, —

OCH(CONH₂)—

, —

O—

CH₂CONH—

, —

CH(CH₃)—

, —

CH(OCOC₆H₅)—

, —

C(CH₃)(OH)—

, —

C(CH₂CH₃)(OH)—

, —

CO—

, —

C(═

CH₂)—

, —

CH₂O—

, —

CH₂S—

, —

CH(CH₃)S—

, —

CH₂SO₂—

, —

CH═

CH—

, —

NHCO—

, —

CONH—

, —

C(CH₃)(OH)CH₂—

, —

COCONH—

, —

C(CH₃)(OH)CONH—

, —

CONHCH₂—

, —

CH₂OCH₂—

, —

COCOCH₂SO₂—

, —

COCONHCH₂—

, —

C(CH₃)(OH)CH₂—

, —

O(C_1-3 alkylene)O—

, —

OCH₂CON(C₆H₅)—

or

R^1a is an acyl group or a C_1-6 alkyl group optionally substituted by a hydroxy group;

R^2a is

(1) an aromatic hydrocarbon group optionally having substituent(s),

(2) a 5- to 7-membered mono-cyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which optionally has substituent(s),

(3) a 8- to 12-membered condensed aromatic heterocyclic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which optionally has substituent(s), or

(4) a nonaromatic heterocyclic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which optionally has substituent(s); and

R^3a is a C_1-6 alkyl-carbonyloxy group, an acyl group or a C_1-6 alkyl group optionally substituted by a hydroxy group, provided that when X^a is —

O—

, then R^1a and R^3a are groups other than an ethyl group, and R^2a is a group other than a cyanophenyl group,

or a salt thereof.

17. 5-(4-{[1-(3-Chloro-4-cyanophenyl)-3,5-dimethyl-1H-pyrazol-4-yl]methyl}phenyl)-1,3,4-oxadiazole-2-carboxamide or a salt thereof.

18. N-tert-Butyl-4-{[1-(3-chloro-4-cyanophenyl)-3,5-dimethyl-1H-pyrazol-4-yl]methyl}benzamide or a salt thereof.

19. 2-Chloro-4-(4-{4-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-3,5-dimethyl-1H-pyrazol-1-yl)benzonitrile or a salt thereof.

20. 4-{[1-(3-Chloro-4-cyanophenyl)-3,5-dimethyl-1H-pyrazol-4-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzamide or a salt thereof.

21. 2-Chloro-4-{3,5-dimethyl-4-[4-(morpholin-4-ylcarbonyl)phenoxy]-1H-pyrazol-1-yl}benzonitrile or a salt thereof.

22. 2-Chloro-4-(4-{4-[(3-hydroxyazetidin-1-yl)carbonyl]benzyl}-3,5-dimethyl-1H-pyrazol-1-yl)benzonitrile or a salt thereof.

23. 2-Chloro-4-(4-{4-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]phenoxy}-3,5-dimethyl-1H-pyrazol-1-yl)benzonitrile or a salt thereof.

24. N-(6-{[1-(3-Chloro-4-cyanophenyl)-3,5-dimethyl-1H-pyrazol-4-yl]oxy}pyridin-3-yl)-2,2-dimethylpropanamide or a salt thereof.