Substituted 5-membered ring compounds and their use

• US 20060235058A1
• Filed: 06/24/2004
• Published: 10/19/2006
• Est. Priority Date: 06/27/2003
• Status: Active Grant

• Current Assignee: Cancer Research Technology Limited (Cancer Research UK), Institute of Cancer Research, Vernalis R&D Ltd (Invesco Limited)
• Original Assignee: Cancer Research Technology Limited (Cancer Research UK), Institute of Cancer Research, Vernalis R&D Ltd (Invesco Limited)
• Inventors: Dymock, Brian William, Drysdale, Martin James, McDonald, Edward, Cheung, Kwai Ming
• Granted Patent: US 7,728,016 B2
• Time in Patent Office: Days
• US Class Current: 514/359
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders

Abstract

Compound of a compound of formula (1) or a salt, N-oxide, hydrate or solvate thereof, in the preparation of a composition for inhibition of HSP90 activity: wherein ring A is an aromatic or non-aromatic carbocyclic or heterocyclic ring having 5 ring atoms, for example 1,2,3-triazolyl or a 1,2,4-triazolyl or a tetrazolyl ring; and R₁ R₂ R₃ are as defined in the specification are inhibitors of HSP90 and therefore of use in the treatment of, for example, cancers, viral disease, inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis, Type I diabetes, lupus, psoriasis and inflammatory bowel disease; cystic fibrosis angiogenesis-related disease such as diabetic retinopathy, haemangiomas, and endometriosis; or for protection of normal cells against chemotherapy-induced toxicity; or diseases where failure to undergo apoptosis is an underlying factor, or protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart and brain; scrapie /CJD, Huntingdon'"'"'s and Alzheimer'"'"'s disease.

Claims

1. A compound of formula (I) or a salt, N-oxide, hydrate or solvate thereof, for use in human or veterinary medicine:

2. The compound as claimed in claim 1 wherein the group the ring A is aromatic.

3. The compound as claimed in claim 1 wherein both R₁ and R₂ are attached to ring carbon atoms.

4. The compound as claimed in claim 1 wherein one of R₁ and R₂ is attached to a ring carbon atom and the other to a ring nitrogen atom.

5. The compound as claimed in claim 1 wherein the ring A is a 1,2,4-tetrazolyl ring or a 1,2,3-triazole ring.

6. The compound as claimed in claim 1 wherein the compound of formula (I) has formula (IE) or (IF)

7. The compound as claimed in claim 1 wherein in the compound of formula (I) R₁ has formula (II):

8. The compound as claimed in claim 1 wherein in the group R₁ of the compound of formula (I) each of p, r and s is 0, and Q is hydrogen.

9. The compound as claimed in claim 8 wherein R₁ is 2-hydroxyphenyl optionally further substituted by one or more of hydroxy, methyl, ethyl, methoxy, ethoxy, chloro, or bromo.

10. The compound as claimed in claim 1 wherein in the compound of formula (I) R₁ has formula (IIA):

11. The compound as claimed in claim 1 wherein in the group R₁ of the compound of formula (I) one or more of p, r and s is 1.

12. The compound as claimed in claim 11 wherein p and/or s is/are 1 and r is 0.

13. The compound as claimed in claim 11 wherein each of p, r, and s is 1.

14. The compound as claimed in claim 11 wherein p and s are 0 and r is 1.

15. The compound as claimed in claim 1 wherein R₂ is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl, or thiazolyl, optionally substituted by one or more of methoxy, ethoxy, methylenedioxy, ethylenedioxy, fluoro, chloro, bromo, or trifluoromethyl.

16. The compound as claimed in claim 1 wherein R₂ is optionally substituted phenyl.

17. The compound as claimed in claim 1 wherein R₂ is a carboxamide radical of formula —

CONR^B(Alk)_nR^A wherein

Alk is an optionally substituted divalent alkylene, alkenylene or alkynylene radical, n is 0 or 1,

R is hydrogen or a C₁-C₆ alkyl or C₂-C₆ alkenyl group,

R^A is hydroxy or an optionally substituted carbocyclic or heterocyclic ring,

or R^A and R^B taken together with the nitrogen to which they are attached form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may optionally be substituted on one or more ring C or N atoms.

18. The compound as claimed claim 17 wherein

Alk is an optionally substituted —

CH₂—

, —

CH₂CH₂—

, —

CH₂CH₂CH₂—

, CH₂CH═

CH—

, or —

CH₂CCCH₂—

radical.

n is 0 or 1,

R^B is hydrogen, methyl, ethyl, n- or iso-propyl, or allyl,

R^A is hydroxy, hydroxy and/or chloro-substituted phenyl, 3,4 methylenedioxyphenyl, pyridyl, furyl, thienyl, N-piperazinyl, or Nmorpholinyl,

or R^A and R^B taken together with the nitrogen to which they are attached form a morpholino, piperidinyl, piperazinyl or N-phenylpiperazinyl ring.

19. The compound as claimed in claim 17 wherein n is 0, R^B is hydrogen and R^A is hydroxy or an optionally substituted carbocyclic or heterocyclic ring.

20. The compound as claimed in claim 1 wherein R₃ is hydrogen, methyl, ethyl, n- or iso-propyl, trifluoromethyl, or hydroxyethyl.

21. The compound as claimed in claim 1 wherein R₃ is a carboxamide group —

CONR^B(Alk)_nR^A wherein

Alk is an optionally substituted divalent alkylene, alkenylene or alkynylene radical, n is 0 or 1,

R^B is hydrogen or a C₁-C₆ alkyl or C₇-C₆ alkenyl group.

R^A is hydroxy or an optionally substituted carbocyclic or heterocyclic ring.

or R^A and R^B taken together with the nitrogen to which they are attached form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may optionally be substituted on one or more ring C or N atoms.

22. A method of treatment of diseases or conditions mediated by excessive or inappropriate HSP90 activity in mammals which method comprises administering to the mammal an amount of a compound of formula (I) as defined in claim 1, or a salt, hydrate or solvate thereof, effective to inhibit said HSP90 activity.

23. The method as claimed claim 21 for immunosuppression or the treatment of cancer;

viral disease, inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis, Type I diabetes, lupus, psoriasis and inflammatory bowel disease;

cystic fibrosis angiogenesis-related disease such as diabetic retinopathy, haemangiomas, and endometriosis;

or for protection of normal cells against chemotherapy-induced toxicity;

or diseases where failure to undergo apoptosis is an underlying factor;

or protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart and brain;

scrapie/CJD, Huntingdon'"'"'s and Alzheimer'"'"'s disease.

25. A pharmaceutical or veterinary composition comprising a compound as defined in claim 1, or a salt hydrate or solvate thereof, together with a pharmaceutically or veterinarily acceptable carrier.

24. (canceled)