Amine compound and use thereof for medical purposes

Patent metadata

Field	Value
Publication number	US-9657043-B2
Application number	US-201314396330-A
Country	US
Kind code	B2
Filing date	Apr 23, 2013
Priority date	Apr 23, 2012
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

The present invention provides a compound represented by the following formula (I):

wherein each symbol is as described in the DESCRIPTION, which has a superior peripheral blood lymphocyte decreasing action, and is useful for the treatment or prophylaxis of autoimmune diseases; prophylaxis or suppression of resistance or acute rejection or chronic rejection of transplantation of organ or tissue; treatment or prophylaxis of graft-versus-host (GvH) disease due to bone marrow transplantation; or treatment or prophylaxis of allergic diseases.

First claim

The invention claimed is:

1. An amine compound represented by the following formula (I)

wherein
R 1 is a hydrogen atom or P(═O)(OH) 2 ,
V is a C 1-4 alkylene or a C 2-4 alkenylene,
R 2 is a hydrogen atom, or a C 1-4 alkyl optionally substituted by a hydroxy group or a halogen atom,
R 3 and R 4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl,
X is a single bond, an oxygen atom, a sulfur atom, methylene, —CO—, —SO—, —SO 2 — or —NR 5 —
wherein R 5 is a hydrogen atom or a C 1-4 alkyl optionally having substituent(s),
A 1 and A 2 are the same or different and each is a single bond, an oxygen atom, a sulfur atom, —CO—, —SO—, —SO 2 — or —NR 6 — wherein R 6 is a hydrogen atom, a C 1-6 alkyl optionally having substituent(s), a C 1-7 acyl optionally having substituent(s) or a C 2-7 alkoxycarbonyl,
Y is C═O,
B 1 and B 2 are the same or different and each is a single bond, a C 1-10 alkylene optionally having substituent(s), a C 2-10 alkenylene optionally having substituent(s) or a C 2-10 alkynylene optionally having substituent(s),
C 1 and C 2 are the same or different and each is a hydrogen atom, a halogen atom, a C 6-10 aryl optionally having substituent(s), a heteroaryl with 5 to 10 ring-constituting atoms optionally having substituent(s), which contains 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms or 1 or 2 sulfur atoms as the ring-constituting atom(s), a C 3-7 cycloalkyl optionally having substituent(s), which is optionally fused with benzene optionally having substituent(s), or a heterocycloalkyl with 5 to 7 ring-constituting atoms optionally having substituent(s), which contains 1 or 2 nitrogen atoms or 1 or 2 oxygen atoms as the ring-constituting atoms, and is optionally fused with benzene optionally having substituent(s),
D is a hydrogen atom, a halogen atom or a C 1-4 alkyl optionally having substituent(s),
m is 0 or 1, and
n is 0 or 1,
or a pharmaceutically acceptable acid addition salt thereof.

2. The compound according to claim 1 , wherein both R 3 and R 4 are hydrogen atoms, or a pharmaceutically acceptable acid addition salt thereof.

3. The compound according to claim 1 , wherein n is 0, or a pharmaceutically acceptable acid addition salt thereof.

4. The compound according to claim 1 , wherein V is CH 2 CH 2 , or a pharmaceutically acceptable acid addition salt thereof.

5. The compound according to claim 1 , wherein C 1 is a hydrogen atom, a C 6-10 aryl optionally having substituent(s) or a heteroaryl with 5 to 10 ring-constituting atoms optionally having substituent(s), which contains 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms or 1 or 2 sulfur atoms as the ring-constituting atom(s), or a pharmaceutically acceptable acid addition salt thereof.

6. The compound according to claim 1 , wherein A 1 is a single bond, an oxygen atom, a sulfur atom or —CO—, or a pharmaceutically acceptable acid addition salt thereof.

7. The compound according to claim 1 , wherein R 2 is hydroxymethyl, or a pharmaceutically acceptable acid addition salt thereof.

8. The compound according to claim 1 , wherein R 1 is a hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof.

9. The compound according to claim 1 , wherein the compound of the formula (I) is any of the following a to hh, or a pharmaceutically acceptable acid addition salt thereof:
a. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-[3-(trifluoromethyl)phenoxy]-9H-thioxanthen-9-one,
b. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-(4-chlorophenoxy)-9H-thioxanthen-9-one,
c. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-7-[3-(trifluoromethyl)phenoxy]-9H-thioxanthen-9-one,
d. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-7-(3-chlorophenoxy)-9H-thioxanthen-9-one,
e. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-(4-fluorophenoxy)-9H-xanthen-9-one,
f. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-(4-methoxyphenoxy)-9H-xanthen-9-one,
g. 6-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-2-[3-(trifluoromethyl)phenoxy]-9H-xanthen-9-one,
h. 3-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-hexyloxy-9H-thioxanthen-9-one,
i. 6-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-2-[(1E)-hex- 1-en-1-yl]-9H-xanthen-9-one,
j. 3-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-(4-methoxyphenoxy)-9H-xanthen-9-one,
k. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-7-pentyloxy-9H-xanthen-9-one,
l. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-7-hexyloxy-9H-xanthen-9-one,
m. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-(3-chloro-4-fluorophenoxy)-9H-xanthen-9-one,
n. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-(trifluoromethyl)phenyl1-9H-xanthen-9-one,
o. 3-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-pentyloxy-9H-xanthen-9-one,
p. 2-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-6-[3-(trifluoromethoxy)phenyl]-9H-xanthen-9-one,
q. 6-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]-2-(3-chloro-4-fluorophenoxy)-9H-xanthen-9-one,
r. mono(2-amino-2-hydroxymethyl-4-{9-oxo-6-[3-(trifluoromethyl)phenoxy]-9H-thioxanthen-2-yl}butyl)phosphate,
s. mono{2-amino-4-[6-(4-chlorophenoxy)-9-oxo-9H-thioxanthen-2-yl]-2-hydroxymethylbutyl}phosphate,
t. mono(2-amino-2-hydroxymethyl-4-{9-oxo-7-[3-(trifluoromethyl)phenoxy]-9H-thioxanthen-2-yl}butyl)phosphate,
u. mono{2-amino-4-[7-(3-chlorophenoxy)-9-oxo-9H-thioxanthen-2-yl]-2-hydroxymethylbutyl}phosphate,
v. mono{2-amino-4-[6-(4-fluorophenoxy)-9-oxo-9H-xanthen-2-yl]-2-hydroxymethylbutyl}phosphate,
w. mono{2-amino-2-hydroxymethyl-4-[6-(4-methoxyphenoxy)-9-oxo-9H-xanthen-2-yl]butyl }phosphate,
x. mono(2-amino-2-hydroxymethyl-4-{9-oxo-7-[3-(trifluoromethyl)phenoxy]-9H-xanthen-3-yl}butyl)phosphate,
y. mono[2-amino-4-(6-hexyloxy-9-oxo-9H-thioxanthen-3-yl)-2-(hydroxymethyl)butyl]phosphate,
z. mono(2-amino-4-{7-[(1E)-hex-1-en-1-yl]-9-oxo-9H-xanthen-3-yl }-2-(hydroxymethyl)butyl)phosphate,
aa. mono{2-amino-2-hydroxymethyl-4-[6-(4-methoxyphenoxy)-9-oxo-9H-xanthen-3-yl]butyl}phosphate,
bb. mono[2-amino-2-hydroxymethyl-4-(9-oxo-7-pentyloxy-9H-xanthen-2-yl)butyl]phosphate,
cc. mono[2-amino-4-(7-hexyloxy-9-oxo-9H-xanthen-2-yl)-2-hydroxymethylbutyl]phosphate,
dd. mono{2-amino-4-[6(3-chloro-4-fluorophenoxy)-9-oxo-9H-xanthen-2-yl]-2-hydroxymethylbutyl}phosphate,
ee. mono{2-amino-2-hydroxymethyl-4-[9-oxo-6-[3-(trifluoromethyl)phenyl]-9H-xanthen-2-yl]butyl}phosphate,
ff. mono[2-amino-2-hydroxymethyl-4-(9-oxo-6-pentyloxy-9H-xanthen-3-yl)butyl]phosphate,
gg. mono(2-amino-2-hydroxymethyl-4-{9-oxo-6-[3-(trifluoromethoxy)phenyl]-9H-xanthen-2-yl}butyl)phosphate and
hh. mono{2-amino-4-[7-(3-chloro-4-fluorophenoxy)-9-oxo-9H-xanthen-3-yl]-2-(hydroxymethyl)butyl}phosphate.

10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.

11. A method for treating an autoimmune disease selected from the group consisting of rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis and Type I diabetes mellitus; suppressing resistance or acute rejection or chronic rejection of transplantation of organ or tissue; treating a graft-versus-host (GvH) disease due to bone marrow transplantation; or treating an allergic disease, comprising:
administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof to a patient in need thereof.

12. The method according to claim 11 , wherein the allergic

Assignees

• Mitsubishi Tanabe Pharma Corp

Inventors

• Hamada Maiko
• Tashiro Kaoru
• Sakashita Hiroshi
• Kiuchi Masatoshi
• Takeda Shuzo
• Adachi Kunitomo

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title