Selective AT2 receptor agonists for use in treatment of cachexia

Patent metadata

Field	Value
Publication number	US-10016397-B2
Application number	US-201414908165-A
Country	US
Kind code	B2
Filing date	Jul 17, 2014
Priority date	Jul 29, 2013
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

The present invention is directed to selective AT2 receptor agonist or a pharmaceutically acceptable salt thereof for use in treatment of cachexia, preferably for use in treatment of cancer cachexia.

First claim

The invention claimed is:

1. A method of treatment of cachexia, wherein a patient in need of such therapy is administered an effective dose of a selective AT2 receptor agonist or a pharmaceutically acceptable salt thereof, wherein the selective AT2 receptor agonist is a compound of formula I:

wherein
one of X 1 and X 2 represents —N— and the other represents —C(R 1 )—;
X 3 represents —N— or —C(R 2 )—;
X 4 represents —N— or —C(R 3 )—;
R 1 , R 2 and R 3 independently represent H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 -alkyl or halo;
provided that, when X 1 represents —C(R 1 )—, X 3 represents —C(R 2 )— and X 4 represents —C(R 3 )—, then R 1 represents H;
Y 1 , Y 2 , Y 3 and Y 4 independently represent CH— or —CF;
Z 1 represents —CH—, —O—, —S—, —N— or —CH═CH—;
Z 2 represents —CH—, —O—, —S— or —N—;
provided that:
(a) Z 1 and Z 2 are not the same;
(b) when Z 1 represents —CH═CH—, then Z 2 may only represent —CH— or N—; and
(c) other than in the specific case in which Z 1 represents —CH═CH—, and Z 2 represents —CH—, when one Z 1 and Z 2 represents —CH—, then the other represents —O— or —S—;

R 4 represents —S(O) 2 N(H)C(O)R 6 , —S(O) 2 N(H)S(O) 2 R 6 , —C(O)N(H)S(O) 2 R 6 , or, when Z 1 represents —CH═CH—, R 4 may represent —(H)S(O) 2 N(H)C(O)R 7 or —N(H)C(O)N(H)S(O) 2 R 7 ;
R 5 represents C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 -alkyl or di-C 1-3 alkylamino-C 1-4 -alkyl;
R 6 represents C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 -alkyl, C 1-3 alkoxy-C 1-6 -alkoxy, C 1-6 alkylamino or di-C 1-6 alkylamino; and
R 7 represents C 1-6 alkyl,
wherein
alkyl groups, and the alkyl parts of alkoxy, alkoxyalkyl, alkoxyalkoxy, alkylamino and alkylaminoalkyl groups, as defined herein may be straight-chain or, when there is a minimum of three carbon atoms, be branched-chain, and/or cyclic; or when there is a minimum of four carbon atoms, such groups may also be part cyclic/acyclic; or alkyl groups, and alkyl parts of alkoxy, alkoxyalkyl, alkoxyalkoxy, alkylamino and alkylaminoalkyl groups, may also be saturated or, when there is a minimum of two carbon atoms, be unsaturated; or such groups may also be substituted by one or more halo, and especially fluoro, atoms.

2. The method of claim 1 , wherein X1 represents —C(R1)-, X2 represents N, X3 represents —C(R2)-, and X4 represents —C(R3)-.

3. The method of claim 1 , wherein R 1 , R 2 and R 3 are all H.

4. The method of claim 1 , wherein Y 1 , Y 2 , Y 3 and Y 4 all represent —CH—.

5. The method of claim 1 , wherein Z 1 represents —S— and Z 2 represents —CH—.

6. The method of claim 1 , wherein R 4 represents —S(O) 2 N(H)C(O)R 6 , R 5 represents iso-butyl, and R 6 represents n-butoxy.

7. The method of claim 1 , wherein X 2 represents N, X 1 , X 3 and X 4 all represent —CH—; Y 1 , Y 2 , Y 3 and Y 4 all represent —CH—; Z 1 represents —S—; Z 2 represents —CH—; R 4 represents —S(O) 2 N(H)C(O)R 6 ; R 5 represents iso-butyl; and R 6 represents n-butoxy.

8. A method of treatment of cachexia, wherein a patient in need of such therapy is administered an effective dose of a selective AT2 receptor agonist or a pharmaceutically acceptable salt thereof in combination with at least one further active pharmaceutical agent, wherein the selective AT2 receptor agonist is a compound of formula I:

wherein
one of X 1 and X 2 represents —N— and the other represents —C(R 1 )—;
X 3 represents —N— or —C(R 2 )—;
X 4 represents —N— or —C(R 3 )—;
R 1 , R 2 and R 3 independently represent H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 -alkyl or halo;
provided that, when X 1 represents —C(R 1 )—, X 3 represents —C(R 2 )— and X 4 represents —C(R 3 )—, then R 1 represents H;

Y 1 , Y 2 , Y 3 and Y 4 independently represent —CH— or —CF;
Z 1 represents —CH—, —O—, —S—, —N— or —CH═CH—;
Z 2 represents —CH—, —O—, —S— or —N—;
provided that:
(a) Z 1 and Z 2 are not the same;
(b) when Z 1 represents —CH═CH—, then Z 2 may only represent —CH— or N—; and
(c) other than in the specific case in which Z 1 represents —CH═CH—, and Z 2 represents —CH—, when one Z 1 and Z 2 represents —CH—, then the other represents —O— or —S—;

R 4 represents —S(O) 2 N(H)C(O)R 6 , —S(O) 2 N(H)S(O) 2 R 6 , —C(O)N(H)S(O) 2 R 6 , or, when Z 1 represents —CH═CH—, R 4 may represent —(H)S(O) 2 N(H)C(O)R 7 or —N(H)C(O)N(H)S(O) 2 R 7 ;
R 5 represents C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 -alkyl or di-C 1-3 alkylamino-C 1-4 -alkyl;
R 6 represents C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 -alkyl, C 1-3 alkoxy-C 1-6 -alkoxy, C 1-6 alkylamino or di-C 1-6 alkylamino; and
R 7 represents C 1-6 alkyl,
wherein
alkyl groups, and the alkyl parts of alkoxy, alkoxyalkyl, alkoxyalkoxy, alkylamino and alkylaminoalkyl groups, as defined herein may be straight-chain or, when there is a minimum of three carbon atoms, be branched-chain, and/or cyclic; or when there is a minimum of four carbon atoms, such groups may also be part cyclic/acyclic; or alkyl groups, and alkyl parts of alkoxy, alkoxyalkyl, alkoxyalkoxy, alkylamino and alkylaminoalkyl groups, may also be saturated or, when there is a minimum of two carbon atoms, be unsaturated; or such groups may also be substituted by one or more halo, and especially fluoro, atoms.

9. The method of claim 8 , wherein said at least one further active pharmaceutical agent is an angiotensin converting enzyme (ACE) inhibitor.

10. The method of claim 8 , wherein the ACE inhibitor is one of captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, ceronapril, delepril, moveltipril, and/or combinations thereof.

11. The method of claim 8 , wherein said at least one further active pharmaceutical agent is a selective AT1 receptor antagonist.

12. The method of claim 8 , wherein said at least one further active pharmaceutical agent is one of azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, ripiasartan, saprisartan, tasosartan, telmisartan, valsartan and/or combinations thereof.

13. The method of claim 1 , wherein cachexia is cachexia associated with cancer, AIDS, liver cirrhosis, liver failure, chronic renal failure, chronic infection, diabetes, heart disease, chronic obstructive lung disease, multiple sclerosis, tuberculosis, familial amyloid polyneuropathy, heavy metal poisoning, arthritis, motor neuron diseases, burns and hormonal deficiency syndromes.

14. The method of claim 1 , wherein cachexia is cancer cachexia.

15. The method of claim 8 , wherein X1 represents —C(R1)-, X2 represents N, X3 represents —C(R2)-, and X4 represents —C(R3)-.

16. The method of claim 8 , wherein R 1 , R 2 and R 3 are all H.

17. The method of claim 8 , wherein Y 1 , Y 2 , Y 3 and Y 4 all represent —CH—.

18. The method of claim 8 , wherein Z 1 represents —S— and Z 2 represents —CH—.

19. The method of claim 8 , wherein R 4 represents —S(O) 2 N(H)C(O)R 6 , R 5 represents iso-butyl, an

Assignees

• Univ Berlin Charite
• Charite—Universitaetsmedizn Berlin

Inventors

• Springer Jochen
• Anker Stefan
• Coats Andrew Js

Classifications

• A61P43/00

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

• A61K31/417

  Imidazole-alkylamines, e.g. histamine, phentolamine · CPC title

• C07D409/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/4178 Primary

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title