Trk-inhibiting compound

Patent metadata

Field	Value
Publication number	US-9242977-B2
Application number	US-201314397070-A
Country	US
Kind code	B2
Filing date	Apr 25, 2013
Priority date	Apr 26, 2012
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

An object of the present invention is to provide a drug containing a compound having Trk-inhibiting activity as an active ingredient in prophylaxis and/or therapy of diseases such as pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease. A compound represented by the general formula (I):

(wherein all symbols represent the same meanings as described in the specification), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof is useful as a drug component having Trk-inhibiting activity in prophylaxis and/or therapy of diseases such as pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease.

First claim

The invention claimed is:

1. A compound represented by the general formula (I):

wherein:
a ring Cy 1 represents a C3-10 monocyclic carbocycle or bicyclic carbocycle or a 4- to 10-membered monocyclic heterocycle or bicyclic heterocycle;
R 1 represents:
(1) a halogen;
(2) a C1-6 alkyl group optionally substituted with a halogen or an oxo group;
(3) a C3-6 cycloalkyl group optionally substituted with a halogen or a C1-3 alkyl group;
(4) a C1-6 alkyl group having an oxygen atom substituting for a carbon atom and optionally substituted with a halogen or an oxo group; or
(5) a C3-6 cycloalkyl group having an oxygen atom substituting for a carbon atom and optionally substituted with a halogen or a C1-3 alkyl group;
R 2 represents:
(1) a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group optionally substituted with a substituent selected from the group consisting of:
(i) a halogen;
(ii) a hydroxy group;
(iii) —NH(C1-3 alkyl);
(iv) —N(C1-3 alkyl) 2 ;
(v) an amino group;
(vi) a cyano group;
(vii) a nitro group;
(viii) a C1-4 alkylsulfonyl group,
(ix) a sulfonamide group;
(x) a C1-4 alkylsulfonamide group;
(xi) an oxo group;
(xii) a carboxyl group;
(xiii) —C(O)(O—C1-4 alkyl);
(xiv) a phosphonooxy group;
(xv) —OP(O)(O—C1-4 alkyl) 2 ;
(xvi) a carbamoyl group;
(xvii) a C1-4 alkylamide group; and
(xviii) a C1-4 alkylcarbamate group;

(2) a hydrogen atom;
(3) a hydroxy group;
(4) a carboxyl group;
(5) —C(O)(O—C1-4 alkyl);
(6) a phosphonooxy group;
(7) —OP(O)(O—C1-4 alkyl) 2 ;
(8) an amino group;
(9) a cyano group;
(10) a nitro group;
(11) a C1-4 alkylsulfonyl group;
(12) a sulfonamide group;
(13) a C1-4 alkylsulfonamide group;
(14) an oxo group;
(15) a carbamoyl group;
(16) a C1-4 alkylamide group;
(17) a C1-4 alkylcarbamate group; or
(18)

wherein an arrow a represents binding to the ring Cy 1 ;
X represents a bond, an oxygen atom, C═O or NH;
a ring Cy 2 represents a C3-10 monocyclic carbocycle or bicyclic carbocycle or a 4- to 10-membered monocyclic heterocycle or bicyclic heterocycle;
R 6 represents:
(1) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a C3-6 cycloalkyl group optionally substituted with a substituent selected from the group consisting of:
(i) a halogen;
(ii) a hydroxy group;
(iii) an oxo group;
(iv) —NH(C1-3 alkyl);
(v) —N(C1-3 alkyl) 2 ;
(vi) a C1-6 alkoxy group;
(vii) an amino group;
(viii) a cyano group;
(ix) a nitro group;
(x) a C1-4 alkylsulfonyl group;
(xi) a sulfonamide group;
(xii) a C1-4 alkylsulfonamide group;
(xiii) a carboxyl group;
(xiv) —C(O)(O—C1-4 alkyl);
(xv) a phosphonooxy group;
(xvi) —OP(O)(O—C1-4 alkyl) 2 ;
(xvii) a carbamoyl group;
(xviii) a C1-4 alkylamide group; and
(xix) a C1-4 alkylcarbamate group;

(2) a halogen;
(3) a C1-4 alkoxy group;
(4) a phosphonooxy group;
(5) —OP(O)(O—C1-4 alkyl) 2 ;
(6) a sulfonamide group;
(7) an oxo group;
(8) —NH(C1-3 alkyl);
(9) —N(C1-3 alkyl) 2 ;
(10) a carboxyl group;
(11) —C(O)(O—C1-4 alkyl);
(12) a carbamoyl group;
(13) a C1-4 alkylamide group;
(14) a hydroxy group;
(15) an amino group;
(16) a cyano group;
(17) a nitro group;
(18) a C1-4 alkylsulfonyl group;
(19) a C1-4 alkylsulfonamide group; or
(20) a C1-4 alkylcarbamate group;
A 1 and A 2 respectively and independently represent ═CR 3 —, ═CH— or ═N—;
A 3 , A 4 , A 5 and A 6 respectively and independently represent ═CR 4 — or ═N—;
R 3 represents:
(1) a halogen; or
(2) a C1-3 alkyl group or C1-3 alkoxy group optionally substituted with a halogen;
R 4 represents
(1) a halogen;
(2) a C1-3 alkyl group or C1-3 alkoxy group optionally substituted with a halogen; or
(3) a hydrogen atom;
Y represents an oxygen atom, an optionally oxidized sulfur atom, a methylene group or C═O;
Z represents:

or a group:

having an oxygen atom substituting for a carbon atom forming the ring;
R 5 represents a halogen, a hydroxy group or a C1-4 alkyl group optionally substituted with a hydroxy group;
R 7 respectively and independently represents:
(1) a C1-6 alkyl group, a C3-6 cycloalkyl group, a C1-6 alkyl group having an oxygen atom substituting for a carbon atom or a C3-6 cycloalkyl group having an oxygen atom substituting for a carbon atom, all of which may be optionally substituted with:
(i) a halogen;
(ii) a C3-6 cycloalkyl group;
(iii) a hydroxy group;
(iv) an oxo group; and
(v) a 4- to 6-membered monocyclic heterocycle; or

(2) a hydrogen atom;
arrows b, c, d and e represent binding to the thiazole ring;
p represents an integer of 0 to 5;
q represents an integer of 0 to 7;
r represents an integer of 0 to 2;
w represents an integer of 1 to 5; and
u represents an integer of 0 to 2;
provided that when p, q, r and u respectively represent an integer of 2 or more, R 1 , R 3 , R 5 and R 6 groups may be respectively and independently the same or different; a salt thereof, an N-oxide thereof, or a solvate thereof.

2. The compound according to claim 1 , wherein the general formula (I) is:

wherein all symbols represent the same meanings as those described in claim 1 .

3. The compound according to claim 2 , wherein the general formula (I-1) is:

4. The compound according to claim 2 , wherein the ring Cy 1 is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle.

5. The compound according to claim 1 , wherein one of A 1 and A 2 is ═N— and the other is ═CH— or both are ═N— and A 3 , A 4 , A 5 and A 6 are ═CH—.

6. The compound according to claim 1 , wherein the general formula (I) is:

wherein pa represents an integer of 0 to 4; pb represents an integer of 0 to 3; and other symbols represent the same meanings as those described in claim 1 , provided that when pa and pb respectively represent an integer of 2 or more, R 1 groups may be the same or different.

7. The compound according to claim 6 , wherein one of A 1 and A 2 is ═N—and the other is ═CH— or both are ═N— and A 3 , A 4 , A 5 and A 6 are ═CH—.

8. The compound according to claim 1 , wherein the general formula (I) is:

wherein all symbols represent the same meanings as those described in claim 1 and claim 6 .

9. The compound according to claim 8 , wherein one of A 1 and A 2 is ═N—and the other is ═

Assignees

• Ono Pharmaceutical Co

Inventors

• Takeuchi Jun
• Ikura Masahiro
• Higashino Masato
• Iwahashi Maki
• Hashimura Kazuya

Classifications

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

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