Nitrogen-containing spirocyclic compounds and pharmaceutical uses thereof
View Patent ↗A compound of the following general formula [I]: wherein each symbol has the same meaning as defined herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical use of the same in treating organ transplant rejection, graft versus host reaction after transplantation, autoimmune disease, allergic disease and chronic myeloproliferative disease.
1. A compound of formula [I]:
wherein R a is the same or different and each is:
(1) C 1-6 alkyl, or
(2) halogen atom,
n1 is an integer selected from 0 to 4,
R b is the same or different and each is:
(1) C 1-6 alkyl, or
(2) halogen atom,
n2 is an integer selected from 0 to 4,
m1 is an integer selected from 0 to 3,
m2 is an integer selected from 1 to 4,
X a =X b is
CH═CH,
X is
a nitrogen atom,
R c is a group selected from the following (1) to (6):
(1) hydrogen atom,
(2) C 1-6 alkyl optionally substituted by the same or different 1 to 5 substituents selected from the following Group A,
(3) —C(═O)—R c1 ,
(4) —C(═O)—O—R c2 ,
(5) —C(═O)—NR c3 R c4
in which R c1 , R c2 , R c3 and R c4 are the same or different and each is:
(i) hydrogen atom, or
(ii) C 1-6 alkyl optionally substituted by the same or different 1 to 5 substituents selected from the following Group A, and
(6) a group of formula:
in which Y a is a group selected from the following (i) to (iii):
(i) C 1-6 alkylene,
(ii) —C(═O)—, and
(iii) —C(═O)—O—,
Ring T is:
(i) C 6-10 aryl,
(ii) C 3-10 cycloalkyl, or
(iii) saturated monoheterocyclyl wherein the saturated monoheterocyclyl comprises 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom or sulfur atom as well as carbon atoms and the number of the constituent ring atoms is 3 to 7,
R c5 is the same or different and each is:
(i) cyano, or
(ii) nitro,
p is an integer selected from 0 to 4,
Group A is selected from the group consisting of:
(a) hydroxyl,
(b) C 1-6 alkoxy,
(c) cyano,
(d) C 1-6 alkoxycarbonyl,
(e) C 1-6 alkylcarbonyloxy, and
(f) C 2-6 alkenyloxy,
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
2. The compound as claimed in claim 1 , wherein n1 is an integer selected from 0 to 2,
n2 is an integer selected from 0 to 2,
m1 is an integer selected from 0 to 3,
m2 is an integer selected from 1 to 3,
X is
a nitrogen atom,
R c is a group selected from the following (1) to (6):
(1) hydrogen atom,
(2) C 1-6 alkyl substituted by one substituent selected from the following Group A,
(3) —C(═O)—R c1 ,
(4) —C(═O)—O—R c2 ,
(5) —C(═O)—NR c3 R c4
in which R c1 is C 1-6 alkyl optionally substituted by one substituent selected from the following Group A,
R c2 is C 1-6 alkyl,
R c3 is C 1-6 alkyl optionally substituted by one substituent selected from the following Group A,
R c4 is
(i) hydrogen atom, or
(ii) C 1-6 alkyl, and
(6) a group of formula:
in which Y a is a group selected from the following (i) to (iii):
(i) C 1-6 alkylene,
(ii) —C(═O)—, and
(iii) —C(═O)—O—,
Ring T is:
(i) phenyl,
(ii) C 3-6 cycloalkyl, or
(iii) pyrrolidinyl,
R c5 is
(i) cyano, or
(ii) nitro,
p is an integer selected from 0 or 1,
Group A is selected from the group consisting of:
(a) hydroxyl,
(b) C 1-6 alkoxy,
(c) cyano,
(d) C 1-6 alkoxycarbonyl,
(e) C 1-6 alkylcarbonyloxy, and
(f) C 2-6 alkenyloxy,
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
3. The compound as claimed in claim 1 , wherein m1 is an integer of 0 or 1 and m2 is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
4. The compound as claimed in claim 3 , wherein m1 is 1 and m2 is 2, which is a compound of formula [II]:
wherein each symbol has the same meaning as defined in claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
5. The compound as claimed in claim 3 , wherein m1 is 0 and m2 is 2, which is a compound of formula [III]:
wherein each symbol has the same meaning as defined in claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
6. The compound as claimed in claim 3 , wherein m1 is 0 and m2 is 1, which is a compound of formula [IV]:
wherein each symbol has the same meaning as defined in claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
7. The compound as claimed in claim 1 , wherein m1 is 0 and m2 is 3, or m1 is 2 and m2 is 1, or m1 is 2 and m2 is 2, or m1 is 3 and m2 is 2, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
8. The compound as claimed in claim 1 , wherein n1 is 0 and n2 is 0, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
9. The compound as claimed in claim 1 , wherein n1 is 1 and n2 is 0, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
10. The compound as claimed in claim 1 , wherein n1 is 0 and n2 is 1, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
11. The compound as claimed in claim 1 , wherein n1 is 2 and n2 is 0, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
12. The compound as claimed in claim 1 , wherein n1 is 0 and n2 is 2, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
13. The compound as claimed in claim 9 , wherein R a is methyl or fluorine atom, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
14. The compound as claimed in claim 1 , wherein R c is —C(═O)—R c1 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
15. The compound as claimed in claim 14 , wherein R c1 is C 1-6 alkyl substituted by one hydroxyl or cyano group, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
16. The compound as claimed in claim 1 , wherein R c is —C(═O)—NR c3 R c4 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
17. The compound as claimed in claim 16 , wherein R c3 is C 1-6 alkyl substituted by one cyano group, and R c4 is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
18. The compound as claimed in claim 1 selected from the following chemical structural formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
19. A pharmaceutical composition, comprising the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof, and a pharmaceutically acceptable carrier.
20. A method for inhibiting Janus kinase 2 or Janus kinase 3, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
21. The method as claimed in claim 20 , wherein the Janus kinase is Janus kinase 3.
22. The method as claimed in claim 20 , wherein the Janus kinase is Janus kinase 2.
23. A method for treating or preventing a disease selected from the group consisting of organ transplant rejection and graft versus host reaction after transplantation, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
24. A method for treating rheumatoid arthritis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
25. A method for treating psoriasis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
26. A method for treating dry eye, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
27. A method for treating or preventing atopic dermatitis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
28. The method of claim 20 , wherein said mammal is human.
29. The method of claim 23 , wherein said mammal is human.
30. The method of claim 24 , wherein said mammal is human.
31. The method of claim 25 , wherein said mammal is human.
32. The method of claim 26 , wherein said mammal is human.
33. The method of claim 27 , wherein said mammal is human.
34. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
35. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
36. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
37. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
38. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
39. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
40. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
41. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
42. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
43. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
44. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
45. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
46. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
47. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
48. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
49. The compound as claimed in claim 1 which is represented by the following formula:
or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
50. A pharmaceutical composition, comprising the compound as claimed in any one of claims 34 to 49 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof, and a pharmaceutically acceptable carrier.
51. A method for inhibiting Janus kinase 2 or Janus kinase 3, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 34 to 49 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
52. The method of claim 51 , wherein said mammal is human.
53. The method as claimed in claim 51 , wherein the Janus kinase is Janus kinase 3.
54. The method as claimed in claim 51 , wherein the Janus kinase is Janus kinase 2.
55. A method for treating or preventing a disease selected from the group consisting of organ transplant rejection and graft versus host reaction after transplantation, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 34 to 49 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
56. The method of claim 55 , wherein said mammal is human.
57. A method for treating rheumatoid arthritis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 34 to 49 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
58. The method of claim 57 , wherein said mammal is human.
59. A method for treating psoriasis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 34 to 49 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
60. The method of claim 59 , wherein said mammal is human.
61. A method for treating dry eye, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 34 to 49 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
62. The method of claim 61 , wherein said mammal is human.
63. A method for treating atopic dermatitis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 34 to 49 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
64. The method of claim 63 , wherein said mammal is human.
65. The compound as claimed in claim 1 which is represented by the following formula:
66. The compound as claimed in claim 1 which is represented by the following formula:
67. The compound as claimed in claim 1 which is represented by the following formula:
68. The compound as claimed in claim 1 which is represented by the following formula:
69. The compound as claimed in claim 1 which is represented by the following formula:
70. The compound as claimed in claim 1 which is represented by the following formula:
71. The compound as claimed in claim 1 which is represented by the following formula:
72. The compound as claimed in claim 1 which is represented by the following formula:
73. The compound as claimed in claim 1 which is represented by the following formula:
74. The compound as claimed in claim 1 which is represented by the following formula:
75. The compound as claimed in claim 1 which is represented by the following formula:
76. The compound as claimed in claim 1 which is represented by the following formula:
77. The compound as claimed in claim 1 which is represented by the following formula:
78. The compound as claimed in claim 1 which is represented by the following formula:
79. The compound as claimed in claim 1 which is represented by the following formula:
80. The compound as claimed in claim 1 which is represented by the following formula:
81. A pharmaceutical composition, comprising the compound as claimed in any one of claims 65 to 80 and a pharmaceutically acceptable carrier.
82. A method for inhibiting Janus kinase 2 or Janus kinase 3, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 65 to 80 .
83. The method of claim 82 , wherein said mammal is human.
84. The method as claimed in claim 82 , wherein the Janus kinase is Janus kinase 3.
85. The method as claimed in claim 82 , wherein the Janus kinase is Janus kinase 2.
86. A method for treating or preventing a disease selected from the group consisting of organ transplant rejection and graft versus host reaction after transplantation, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 65 to 80 .
87. The method of claim 86 , wherein said mammal is human.
88. A method for treating rheumatoid arthritis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 65 to 80 .
89. The method of claim 88 , wherein said mammal is human.
90. A method for treating psoriasis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 65 to 80 .
91. The method of claim 90 , wherein said mammal is human.
92. A method for treating dry eye, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 65 to 80 .
93. The method of claim 92 , wherein said mammal is human.
94. A method for treating atopic dermatitis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in any one of claims 65 to 80 .
95. The method of claim 94 , wherein said mammal is human.