Isoxazole compounds as inhibitors of heat shock proteins

Patent metadata

Field	Value
Publication number	US-9718793-B2
Application number	US-201313929098-A
Country	US
Kind code	B2
Filing date	Jun 27, 2013
Priority date	Feb 11, 2003
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers:

wherein R 1 , is a group of formula (IA): —Ar 1 -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q, wherein in any compatible combination Ar 1 is an optionally substituted aryl or heteroaryl radical, Alk 1 and Alk 2 are optionally substituted divalent C 1 -C 6 alkylene or C 2 -C 6 alkenylene radicals, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NR A —, —C(═S)NR A —, —SO 2 NR A —, —NR A C(═O)—, —NR A SO 2 — or —NR A — wherein R A is hydrogen or C 1 -C 6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R 2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk 1 )p-(Z) r -(Alk 2 ) s -Q wherein Q, Alk 1 , Alk 2 , Z, p, r and s are as defined above in relation to group (IA); and R 3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, or C 1 -C 6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

First claim

The invention claimed is:

1. A method of inhibiting Heat Shock Protein 90 (HSP90) activity in mammals comprising administering to the mammal an amount of a compound of formula (A) or (B) or a salt, N-oxide, hydrate or solvate thereof, or a prodrug thereof effective to inhibit HSP90 activity:

wherein
R 1 is a group of formula (IB)

wherein in any compatible combination
R represents one or more optional substituents,
Alk 1 and Alk 2 are optionally substituted divalent C 1 -C 6 alkylene or C 2 -C 6 alkenylene radicals,
p, r and s are independently 0 or 1,
Z is —O—, —S—, —(C═O )—, —(C═S)—, —SO 2 —, —C(═O )O—, —C(═O )NR A —,
—C(═S)NR A —, —SO 2 NR A —, —NR A C(═O)—, —NR A SO 2 — or NR A — wherein R A is hydrogen or C 1 -C 6 alkyl, and
Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
R 2 is (i) a group of formula (IA):
—Ar 1 -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q  (IA)

wherein in any compatible combination
Ar 1 is an optionally substituted aryl or heteroaryl radical, and
Alk 1 , Alk 2 , p, r, s, Z, R A and Q are as defined in relation to R 1 ;
(ii) a carboxamide radical; or
(iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula —(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q wherein Q, Alk 1 , Alk 2 , Z, p, r and s are as defined above in relation to group (IA); and
R 3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, or C 1 -C 6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

2. The method as claimed in claim 1 wherein the compound has formula (ID) or the formula B regioisomer thereof,

wherein each R independently represents an optional substituent and R 3 represents a carboxamide group.

3. The method as claimed in claim 1 wherein the compound has formula (IE) or the formula B regioisomer thereof,

wherein R 3 represents a carboxamide group; R 9 represents —CH 2 NR 10 R 11 or —NR 10 R 11 wherein the substituted amino group —NR 10 R 11 is a solubilising group; and R 8 represents an optional substituent.

4. The method as claimed in claim 1 wherein the compound is selected from:
5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-piperidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
4-(4-Diethylaminomethyl-phenyl)-5-(2,4-dihydroxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(2,4-Dihydroxy- 5-isopropyl-phenyl)-4- [4-(4-methyl-piperazin- 1 -ylmethyl)-phenyl]- isoxazole-3-carboxylic acid ethylamide
5-(2,4-Dihydroxy-5 -isopropyl-phenyl)-4-(4-ethylaminomethyl-phenyl)-isoxazole-3 -carboxylic acid ethylamide
5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-[4-(isopropylamino-methyl)-phenyl]-isoxazole-3-carboxylic acid ethylamide
4-(4-Cyclohexylaminomethyl-phenyl)-5-(2,4-dihydroxy-5 -isopropyl-phenyl)-isoxazole-3 -carboxylic acid ethylamide
4-[4-(tert-Butylamino-methyl)-phenyl]-5-(2,4-dihydroxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-{4-[(2-methoxy-ethylamino)-methyl]-phenyll}-isoxazole-3-carboxylic acid ethylamide
5 -(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3 -carboxylic acid isopropylamide
5-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid isopropylamide
5-(5-tert-Butyl-2,4-dihydroxy-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid ethylamide
5-(5-tert-Butyl-2,4-dihydroxy-phenyl)-4-(4-piperidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(4-piperidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(5-tert-Butyl-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(5-tert-Butyl-2,4-dihydroxy-phenyl)-4-(4-diethylaminomethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
3-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazo1e-5-carboxylic acid ethylamide
4-(4-Diethylaminomethyl-phenyl)-5-(4,6-dihydroxy-2′-methyl-biphenyl-3-yl)-isoxazole-3-carboxylic acid ethylamide
4-(4-Diethylaminomethyl-phenyl)-5-(4′-fluoro-4,6-dihydroxy-biphenyl-3-yl)-isoxazole-3-carboxylic acid ethylamide
4-(4-Diethylaminomethyl-phenyl)-5-(4,6-dihydroxy-biphenyl-3-yl)-isoxazole-3-carboxylic acid ethylamide
5-(2′-Fluoro-4,6-dihydroxy-biphenyl-3-yl)-4-(4-pyrrolidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(4,6-Dihydroxy-biphenyl-3-yl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(2,4-Dihydroxy-5-phenethyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-piperidin-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid isopropylamide
4-(4-Diethylaminomethyl-phenyl)-5-(5-ethyl-2,4-dihydroxy-phenyl)-isoxazole-3-carboxylic acid ethylamide
5-(5-Ethyl-2,4-dihydroxy-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid ethylamide
5 -(5-Ethyl-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3 -carboxylic acid ethylamide
5 -(5 -Chloro-2,4-dihydroxy-phenyl)-4-(4-diethylaminomethyl-phenyl)-isoxazole-3 -carboxylic acid ethylamide
5-(5-Chloro-2,4-dihydroxy-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole-3-carboxylic acid ethylamide
5-(5 -Chloro-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3 -carboxylic acid ethylamide
and salts, hydrates, solvates and prodrugs thereof.

5. The method as claimed in claim 1 wherein the radical Ar 1 present in R 1 has formula (1B)

wherein Alk 1 , Alk 2 , p, r, s, Z and Q are as defined in claim 1 , and R represents one or more optional substituents.

6. The method as claimed in claim 5 wherein that the ring carbon atom adjacent the hydroxyl group in radical (IB) is unsubstituted.

7. The method as claimed in claim 1 wherein, in R 1 , each of p, r, and s is 0, and Q is hydrogen.

8. The method as claimed in claim 7 wherein R 1 is optionally substituted phenyl.

9. The method as claimed in claim 7 wherein R 1 is 2-hydroxyphenyl, optionally further substituted by one or more of hydroxy, methyl, ethyl, methoxy, ethoxy , chloro, or bromo.

10. The method as claimed in claim 7 wherein R 1 is 2,4-dihydroxyphenyl, substituted in the 5-position by a small lipophilic substituent.

11. The method as claimed in claim 10 wherein the small lipophilic substituent methyl, ethyl, isopropyl, isobutyl, tert-butyl, chloro, or bromo.

12. The method as claimed in claim 10 wherein the hydroxyl groups in R 1 are protected by groups which are cleaved in the body to release the hydroxyl groups.

13. The method as claimed in claim 12 wherein the protecting groups are methylcarbonyloxy, or isopropylamino-carbonyloxy.

14. The meth

Assignees

• Vernalis R&D Ltd
• Cancer Res Tech Ltd
• The Inst Of Cancer Res
• Vernalis R&D Ltd

Inventors

• Drysdale Martin James
• Dymock Brian William
• Finch Harry
• Webb Paul
• Mcdonald Edward
• James Karen Elizabeth
• Cheung Kwai Ming
• Matthews Thomas Peter

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title