Water-soluble triazole fungicide

• US 20040198790A1
• Filed: 08/20/2003
• Published: 10/07/2004
• Est. Priority Date: 02/22/2001
• Status: Active Grant

• Current Assignee: Sankyo Company Limited (Daiichi Sankyo Company Limited)
• Original Assignee: Sankyo Company Limited (Daiichi Sankyo Company Limited)
• Inventors: Mori, Makoto, Konosu, Toshiyuki, Kagoshima, Yoshiko, Shibayama, Takahiro, Uchida, Takuya
• Granted Patent: US 7,230,023 B2
• Time in Patent Office: Days
• US Class Current: 514/383
• CPC Class Codes: A61P 31/10 Antimycotics
• 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 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• 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 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07F 9/6518 Five-membered rings
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom

Abstract

A triazole compound of the formula (I) or a pharmacologically salt thereof:

wherein X represents a group of formula X—OH which has antifungal activity, L represents an -(adjacently substituted C₆-C₁₀ aryl)-CH₂ group and R represents a —P(═O)(OH)₂ group.

Claims

1. A triazole compound of a formula (I) or a pharmacologically acceptable salt thereof:

2. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein L^a represents a C₆-C₁₀ aryl group which is unsubstituted or substituted with 1 to 3 of the same or different groups selected from the group consisting of the Substituent group α

, a heterocyclic group which is unsubstituted or substituted with 1 to 3 of the same or different groups selected from the group consisting of the Substituent group α

, or a C₃-C₇ cycloalkyl group which is unsubstituted or substituted with 1 to 3 of the same or different groups from the Substituent group α

.

3. The triazole compound or a pharmacologically acceptable salt thereof according to claim 2, wherein the carbon atom in the group of -L^a- to which the group of formula X—

O—

C(═

O)—

is bonded and the carbon atom in the group of -L^a- to which the group of formula -L^b-O—

R is bonded are adjacent to each other.

4. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein L^b represents an unsubstituted methylene group or a methylene group which is substituted with 1 or 2 of the same or different groups from the Substituent group α

.

5. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein L represents an unsubstituted -(o-phenylene)-CH₂—

group or an -(o-phenylene)-CH₂—

group which is substituted with one group from the Substituent group α

.

6. The triazole compound or a pharmacologically acceptable salt thereof according to claim 5, wherein L represents an -(o-phenylene)-CH₂—

group which is substituted with one group from the Substituent group α

.

7. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein R represents a hydrogen atom.

8. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein R represents a C₁-C₆ alkanoyl group which is unsubstituted or substituted with 1 to 3 of the same or different groups from the Substituent group β

.

9. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein R represents a —

P(═

O)(OH)₂ group.

10. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the Substituent group α

represents a Substituent group α

1 which is selected from the group consisting of a methyl group, a methoxy group, a halogen atom, a cyano group and a —

CH₂—

O—

P(═

O)(OH)₂ group.

11. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the Substituent group β

represents a Substituent group β

1 which is selected from the group consisting of an amino group, a C₁-C₆ alkylamino group and a di C₁-C₆ alkylamino group.

12. The triazole compound or a pharmacologically acceptable salt thereof according to claim 11, wherein the Substituent group β

represents a di C₁-C₆ alkylamino group.

13. The triazole compound or a pharmacologically acceptable salt thereof according to claim 12, wherein the Substituent group β

represents an N,N-dimethylamino group.

14. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the Substituent group β

represents a carboxy group.

15. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the Substituent group β

represents a 4- to 7-membered heterocyclic group containing one or more nitrogen atoms, said heterocyclic group containing one or more nitrogen atoms is unsubstituted or substituted with 1 or 2 C₁-C₆ alkyl groups which are the same or different.

16. The triazole compound or a pharmacologically acceptable salt thereof according to claim 15, wherein the Substituent group β

represents a 4- to 7-membered heterocyclic group containing one or more nitrogen atoms, said heterocyclic group containing one or more nitrogen atoms is substituted with 1 or 2 C₁-C₆ alkyl groups which are the same or different.

17. The triazole compound or a pharmacologically acceptable salt thereof according to claim 16, wherein Substituent group β

represents a 4-methyl-1-piperazinyl group.

18. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the Substituent group β

represents a group of formula —

C(O)—

W, wherein W represents a 4- to 7-membered heterocyclic group containing one or more nitrogen atoms, said heterocyclic group containing one or more nitrogen atoms is unsubstituted or substituted with 1 or 2 C₁-C₆ alkyl groups which are the same or different.

19. The triazole compound or a pharmacologically acceptable salt thereof according to claim 18, wherein Substituent group β

represents a group of formula —

C(O)—

W¹, wherein W¹ represents a 4- to 7-membered heterocyclic group containing one or more nitrogen atoms, said heterocyclic group containing one or more nitrogen atoms is substituted with 1 or 2 of the same or different C₁-C₆ alkyl groups.

20. The triazole compound or a pharmacologically acceptable salt thereof according to claim 19, wherein the Substituent group β

represents a (4-methyl-1-piperazinyl)carbonyl group.

21. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (III),

22. The triazole compound or a pharmacologically acceptable salt thereof according to claim 21, wherein Ar² represents a phenyl group which is unsubstituted or substituted with 1 to 5 of the same or different groups from the Substituent group γ

, or a monocyclic heteroaryl group which is unsubstituted or substituted with 1 to 5 of the same or different groups from the Substituent group γ

,

E represents a formula —

S(O)_n1—

group, wherein n1 is an integer from 0 to 2,

R⁴ represents a C₁-C₄ alkyl group,

R⁵ represents a hydrogen atom or a C₁-C₄ alkyl group,

G represents a group of a formula (Ga′

)

—

(CO)_p′

—

(R^6′

C═

CR^7′

)_q′

—

(C≡

C)_r′

—

(R^8′

C═

CR^9′

)_s′

—

 

 

(Ga′

)

wherein R^6′

, R^7′

, R^8′

and R^9′

independently represent a hydrogen atom or a C₁-C₆ alkyl group which is unsubstituted or substituted with 1 to 5 of the same or different halogen atoms,

p′

is an integer 0 or 1, and

q′

, r′ and

s′

independently are an integer from 0 to 2.

23. The triazole compound or a pharmacologically acceptable salt thereof according to claim 22, wherein X represents a group of a formula (IV)

24. The triazole compound or a pharmacologically acceptable salt thereof according to claim 21, wherein

E represents a methylene group,

A¹ represents a group selected from the group consisting of

G represents a group of a formula (Ga″

)

—

(HC═

CH)_q″

—

(C≡

C)_r″

—

(HC═

CH)_s″

—

 

 

(Ga″

)

wherein, q″

is an integer from 0 to 3, and r″ and

s″

independently are an integer from 0 to 2, provided that total of q″

, r″ and

s″

is 3 or less.

25. The triazole compound or a pharmacologically acceptable salt thereof according to claim 24, wherein X represents a group of a formula (V)

26. The triazole compound or a pharmacologically acceptable salt thereof according to claim 21, wherein

Ar² represents a naphthyl group which is unsubstituted or substituted with 1 to 5 of the same or different groups selected from the group consisting of the Substituent group γ

, and a fused bicyclic heteroaryl group which is unsubtituted or substituted with 1 to 5 of the same or different groups from Substituent group γ

,

E represents a formula —

S(O)_n1—

group, wherein n1 is an integer from 0 to 2,

R⁴ represents a C₁-C₆ alkyl group,

R⁵ represents a hydrogen atom,

G represents a group of a formula (Ga′

)

—

(CO)_p′

—

(R^6′

C═

CR^7′

)_q′

—

(C≡

C)_r′

—

(R^8′

C═

CR^9′

)_s′

—

 

 

(Ga′

)

wherein R^6′

, R^7′

, R^8′

and R^9′

independently represent a hydrogen atom or a C₁-C₆ alkyl group which is unsubtituted or substituted with 1 to 5 of the same or different halogen atoms,

p′

is an integer 0 or 1, and

q′

, r′ and

s′

independently are an integer from 0 to 2.

27. The triazole compound or a pharmacologically acceptable salt thereof according to claim 21, wherein

Ar² represents a phenyl group which may is unsubtituted or substituted with 1 to 5 of the same or different groups selected from the group consisting of the Substituent group γ

, and a naphthyl group which is unsubtituted or substituted with 1 to 5 of the same or different groups from the Substituent group γ

,

E represents a methylene group or a sulfur atom,

R⁵ represents a hydrogen atom, and

G represents a group of a formula (Gb)

-Φ

-CO—

NR^ψ

-T- 

 

(Gb)

wherein φ

represents a phenylene group which is unsubtituted or substituted with 1 or 2 of the same or different groups selected from the group consisting of a fluorine atom and a chlorine atom, or a naphthylene group which is unsubtituted or substituted with 1 or 2 of the same or different groups selected from the group consisting of a fluorine atom and a chlorine atom,

R^ψ

represents a hydrogen atom or a C₁-C₆ alkyl group, and

T represents a single bond or a straight or branched chain C₁-C₈ alkylene group.

28. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (VI)

29. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (VII)

30. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (VIII)

31. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (IX)

32. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (X)

33. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (XI)

34. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (XII)

35. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein X represents a group of a formula (XIII)

36. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the compound is dihydrogen 4-cyano-2-[[(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propoxy]carbonyl]benzyl phosphate.

37. The triazole compound or a pharmacologically acceptable salt thereof according to claim 1, wherein the compound is (1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 5-cyano-2-(hydroxymethyl)benzoate.

38. The triazole compound or a pharmaceutically acceptable salt according to thereof according to claim 23, wherein L is

39. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein R is a —

P(═

O)(OH)₂ group.

40. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 38, wherein R is a —

P(═

O)(OH)₂ group.

41. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein R is a hydrogen atom.

42. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 38, wherein R is a hydrogen atom.

43. The triazole compound or a pharmacologically acceptable salt thereof according to claim 38, wherein R represents a C₁-C₆ alkanoyl group which is unsubstituted or substituted with 1 to 3 of the same or different groups from the substituent group β

.

44. The triazole compound or a pharmacologically acceptable salt thereof according to claim 23, wherein R represents a C₁-C₆ alkanoyl group which is unsubstituted or substituted with 1 to 3 of the same or different groups from the substituent group β

.

45. The triazole compound or a pharmacologically acceptable salt thereof according to claim 22, wherein L is an (o-phenylene)-CH₂—

group which is substituted with one group from the Substituent group α

.

46. The triazole compound or a pharmacologically acceptable salt thereof according to claim 45, wherein R represents a hydrogen atom.

47. The triazole compound or a pharmacologically acceptable salt thereof according to claim 45, wherein R represents a C₁-C₆ alkanoyl group which is unsubstituted or substituted with 1 to 3 of the same or different groups from the substituent group β

.

48. The triazole compound or a pharmacologically acceptable salt thereof according to claim 45, wherein R represents a —

P(═

O)(OH)₂ group.

49. The triazole compound or a pharmacologically acceptable salt thereof according to claim 21, wherein L represents an unsubstituted -(o-phenylene)-CH₂—

group which is substituted with one group from the substituent group a.

50. The triazole compound or a pharmacologically acceptable salt thereof according to claim 49, wherein R represents a hydrogen atom.

51. The triazole compound or a pharmacologically acceptable salt thereof according to claim 49, wherein R represents a C₁-C₆ alkanoyl group which is unsubstituted or substituted with 1 to 3 of the same or different groups from the substituent group β

.

52. The triazole compound or a pharmacologically acceptable salt thereof according to claim 49, wherein R represents a —

P(═

O)(OH)₂ group.

54. A composition for treating or preventing a fungal infection comprising a pharmaceutically effective amount of the triazole compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 53 in combination with a pharmaceutically acceptable carrier.

55. A method for treating or preventing a fungal infection in a warm-blooded animal comprising administering to the warm-blooded animal an effective antifungal amount of the triazole compound or pharmaceutically acceptable salt thereof according to claim 1.

56. A method for treating or preventing a fungal infection in a human comprising administering to the human an effective antifungal amount of the triazole compound or pharmaceutically acceptable salt according to any one of claims 1 to 53.

57. A method according to claim 56, wherein the method is for treating a fungal infection;

the administering is by injection; and

the fungal infection is caused by a fungus of a genus selected from the group consisting of Candida, Aspergillus, Cryptococcus, Mucor, Histoplasma, Blastomyces, Coccidioides, Paracoccidioides, Trichophyton, Epidermophyton, Microsporum, Malassezia, Pseudallescheria, Sporothrix, Rhinosporidium, Fonsecaea, Wangiella, Phialophora, Exophiala, Cladosporium, Alternaria, Aureobasidium, Chaetomium, Curvularia, Drechslera, Mycocentrospora, Phoma, Hendersonula, Scytalidium, Corynespora, Leptosphaeria, Madurella, Neotestudina, Sedosporium, Pyrenochaeta, Geotrichum, Trichosporon, Chrysosporium, Coprinus, Schizophyllum, Pneumocystis, Conidiobolus, Basidiobolus, Paecilomyces, Penicilliun, Acremonium, Fusarium, Scopulariopsis, Saccharomyces, Cephalosporium, Loboa, Rhizopus, Rhizomucor and Absidia.

58. The method according to claim 57, wherein the injection is intravenous.

53. A triazole compound of a formula (I) or a pharmacologically acceptable salt thereof: