NITROGEN-CONTAINING SPIROCYCLIC COMPOUNDS AND PHARMACEUTICAL USES THEREOF
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:
(1) CH═CH,
(2) N═CH, or
(3) CH═N,
X is:
(1) nitrogen atom, or
(2) C—R d wherein R d is hydrogen atom or halogen 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, provided that when X a ═X b is CH═CH, then X is C—R d wherein R d is hydrogen atom or halogen atom.
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:
(1) nitrogen atom, or
(2) C—R d wherein R d is halogen 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 c2 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 the general 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 . (canceled)
9 . 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.
10 . 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.
11 . 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.
12 . 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.
13 . 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.
14 . The compound as claimed in claim 10 , wherein R a is methyl or fluorine atom, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.
15 . 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.
16 . The compound as claimed in claim 15 , 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.
17 . 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.
18 . The compound as claimed in claim 17 , 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.
19 - 20 . (canceled)
21 . 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.
22 - 27 . (canceled)
28 . 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.
29 . The method as claimed in claim 28 , wherein the Janus kinase is Janus kinase 3.
30 . The method as claimed in claim 28 , wherein the Janus kinase is Janus kinase 2.
31 . 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.
32 . 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.
33 . 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.
34 - 39 . (canceled)
40 . A method for treating 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.
41 . 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.