Claims for Patent: 8,609,647

Summary for Patent: 8,609,647

Title:	Nitrogen-containing spirocyclic compounds and pharmaceutical uses thereof
Abstract:	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.
Inventor(s):	Satoru Noji, Makoto Shiozaki, Tomoya Miura, Yoshinori Hara, Hiroshi Yamanaka, Katsuya Maeda, Akimi Hori, Masafumi Inoue, Yasunori Hase
Assignee:	Japan Tobacco Inc
Application Number:	US12/847,025
Patent Claims:	1. A compound of formula [I]: wherein Ra is the same or different and each is: (1) C1-6 alkyl, or (2) halogen atom, n1 is an integer selected from 0 to 4, Rb is the same or different and each is: (1) C1-6 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, Xa=Xb is CH═CH, X is a nitrogen atom, Rc is a group selected from the following (1) to (6): (1) hydrogen atom, (2) C1-6 alkyl optionally substituted by the same or different 1 to 5 substituents selected from the following Group A, (3) —C(═O)—Rc1, (4) —C(═O)—O—Rc2, (5) —C(═O)—NRc3Rc4 in which Rc1, Rc2, Rc3 and Rc4 are the same or different and each is: (i) hydrogen atom, or (ii) C1-6 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 Ya is a group selected from the following (i) to (iii): (i) C1-6 alkylene, (ii) —C(═O)—, and (iii) —C(═O)—O—, Ring T is: (i) C6-10 aryl, (ii) C3-10 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, Rc5 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) C1-6 alkoxy, (c) cyano, (d) C1-6 alkoxycarbonyl, (e) C1-6 alkylcarbonyloxy, and (f) C2-6 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, Rc is a group selected from the following (1) to (6): (1) hydrogen atom, (2) C1-6 alkyl substituted by one substituent selected from the following Group A, (3) —C(═O)—Rc1, (4) —C(═O)—O—Rc2, (5) —C(═O)—NRc3Rc4 in which Rc1 is C1-6 alkyl optionally substituted by one substituent selected from the following Group A, Rc2 is C1-6 alkyl, Rc3 is C1-6 alkyl optionally substituted by one substituent selected from the following Group A, Rc4 is (i) hydrogen atom, or (ii) C1-6 alkyl, and (6) a group of formula: in which Ya is a group selected from the following (i) to (iii): (i) C1-6 alkylene, (ii) —C(═O)—, and (iii) —C(═O)—O—, Ring T is: (i) phenyl, (ii) C3-6 cycloalkyl, or (iii) pyrrolidinyl, Rc5 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) C1-6 alkoxy, (c) cyano, (d) C1-6 alkoxycarbonyl, (e) C1-6 alkylcarbonyloxy, and (f) C2-6 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 Ra 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 Rc is —C(═O)—Rc1, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 15. The compound as claimed in claim 14, wherein Rc1 is C1-6 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 Rc is —C(═O)—NRc3Rc4, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 17. The compound as claimed in claim 16, wherein Rc3 is C1-6 alkyl substituted by one cyano group, and Rc4 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.