Diarylcycloalkyl derivatives, process for their preparation and their use as pharmaceuticals Number:7,160,911 from the United States Patent and Trademark Office (PTO) owispatent

Title: Diarylcycloalkyl derivatives, process for their preparation and their use as pharmaceuticals

Abstract: Diarylcycloalkyl derivatives, process for their preparation and their use as pharmaceuticalsThe invention relates to diarylcycloalkyl derivatives and to their physiologically acceptable salts, racemates and physiologically functional derivatives.What is described are compounds of the formula I, ##STR00001## in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparation. The compounds are suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistence is involved.

Patent Number: 7,160,911 Issued on 01/09/2007 to Goerlitzer,   et al.

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Inventors:	Goerlitzer; Jochen (Frankfurt am Main, DE), Glombik; Heiner (Hofheim, DE), Falk; Eugen (Frankfurt, DE), Gretzke; Dirk (Frankfurt, DE), Keil; Stefanie (Hofheim, DE), Schaefer; Hans-Ludwig (Hochheim, DE), Stapper; Christian (Mainz, DE), Wendler; Wolfgang (Selters, DE)
Assignee:	Sanofi-Aventis Deutschland GmbH (Frankfurt, DE)
Appl. No.:	10/789,019
Filed:	February 27, 2004

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Foreign Application Priority Data

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Feb 27, 2003 [DE]			103 08 353

Current U.S. Class:	514/374 ; 548/236
Current International Class:	A61K 31/421 (20060101); A61K 31/422 (20060101); C07D 263/34 (20060101); C07D 413/02 (20060101); C07D 413/04 (20060101)
Field of Search:	548/236 514/374

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References Cited [Referenced By]

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U.S. Patent Documents

	5411979		May 1995		Hirose et al.
	6221633		April 2001		Ertl
	6221897		April 2001		Frick
	6245744		June 2001		Frick
	6277831		August 2001		Frick
	6342512		January 2002		Kirsch
	6414002		July 2002		Cheng et al.
	6506781		January 2003		Cobb et al.
	6545009		April 2003		Sugiyama et al.
	6589969		July 2003		Tajima et al.
	6624185		September 2003		Glombik et al.
	2004/0198786		October 2004		Gretzke et al.
	2004/0209920		October 2004		Stapper et al.
	2004/0209931		October 2004		Holla et al.
	2004/0209932		October 2004		Goerlitzer et al.

Foreign Patent Documents

	10142734		Mar., 2003		DE
	0 462 884		Dec., 2001		EP
	1 354 879		Oct., 2003		EP
	WO 94/18183		Aug., 1994		WO
	WO 94/18184		Aug., 1994		WO
	WO 96/38428		Dec., 1996		WO
	WO 97/26265		Jul., 1997		WO
	WO 97/41097		Nov., 1997		WO
	WO 98/08871		Mar., 1998		WO
	WO 98/19998		May., 1998		WO
	WO 99/03861		Jan., 1999		WO
	WO 99/15525		Apr., 1999		WO
	WO 99/61431		Dec., 1999		WO
	WO 99/62871		Dec., 1999		WO
	WO 99/62872		Dec., 1999		WO
	WO 99/67278		Dec., 1999		WO
	WO 99/67279		Dec., 1999		WO
	WO 00/40569		Jul., 2000		WO
	WO 00/63208		Oct., 2000		WO
	WO 00/64888		Nov., 2000		WO
	WO 00/66585		Nov., 2000		WO
	WO 00/71549		Nov., 2000		WO
	WO 200064876		Nov., 2000		WO
	WO 00/78312		Dec., 2000		WO
	WO 01/04146		Jan., 2001		WO
	WO 01/09111		Feb., 2001		WO
	WO 01/21602		Mar., 2001		WO
	WO 01/40169		Jun., 2001		WO
	WO 01/40171		Jun., 2001		WO
	WO 01/72290		Oct., 2001		WO
	WO 01/81327		Nov., 2001		WO
	WO 01/83451		Nov., 2001		WO
	WO 01/85695		Nov., 2001		WO
	WO 01/91752		Dec., 2001		WO
	WO 01/94300		Dec., 2001		WO
	WO 02/38541		May., 2002		WO
	WO 02/50027		Jun., 2002		WO
	WO 02/051820		Jul., 2002		WO
	WO 02/096864		Dec., 2002		WO
	WO 2003020269		Mar., 2003		WO
	WO 03/040174		May., 2003		WO
	WO 03/084922		Oct., 2003		WO
	WO 03/084923		Oct., 2003		WO
	WO 03/104188		Dec., 2003		WO

Other References

Stein, E., "Managing Dyslipidemia in the High-Risk Patient," Am. J. Card., vol. 89(suppl.), pp. 50C-57C (2002), at p. 51C, col. 1, lines 15-16. cite- d by examiner . Asakawa A et al., Cocaine-Amphetamine-Regulated Transcript Influences Energy Metabolism Anxiety and Gastric Emptying in Mice, Hormone and Metabolic Reserch; vol. 33(9); 2001; pp. 554-558. cited by other . Berger Joel et al., The Mechanisms of Action of PPARs, Annul. Rev. Med.; vol. 53; 2002; pp. 409-435. cited by other . Fruchart Jean-Charles et al., PPARs, Metabolic Disease and Atherosclerosis, Pharmacological Research; vol. 44, No. 5; 2001' pp. 345-352. cited by other . Kersten Sander et al., Roles of PPARs in Health and Disease, Nature; vol. 405; May 25, 2000; pp. 421-424. cited by other . Kliewer Steven A et al., Peroxisome Proliferator-Activated Receptors: From Genes to Physiology, Recent Prog. Horm Res.; vol. 56; 2001; pp. 239-263. cited by other . Lee Daniel W et al., Leptin agonists as a potential approach to the treatment of obesity, Drugs of the Future; vol. 26(9); 2001; pp. 873-881. cited by other . Motojima Kiyoto, Peroxisome Proliferator-Activated Receptor (PPAR): Structure, Mechanisms of Activation and Diverse Functions, Cell Structure and Function; vol. 18; 1993; pp. 267-277. cited by other . Okada Hiroshi et al., Synthesis and Antitumor Activities of Prodrugs of Benzoylphenylureas, Chem. Pharm. Bull.; vol. 42(1); 1994; pp. 57-61. cite- d by other . Pineda Torra Ines et al., Peroxisome Proliferator-activated Receptors: from Transcriptional Control to Clinical Practice, Curr. Opin. Lipidol; vol. 12; 2001; pp. 245-254. cited by other . Pineda Torra Ines et al., Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging, Curr. Opin. Lipidol; vol. 10; 1999; pp. 151-159. cited by other . Stein E., Managing Dyslipidemia in the High-Risk Patient, Am. J. Card., vol. 89(suppl.), 2002, pp. 50C-57C. cited by other . Vidal-Puig A et al., Regulation of PPAR y Gene Expression by Nutrition and Obesity in Rodents, J. Clin. Invest.; vol. 97, No. 11, 1996; pp. 2553-2561. cited by other . Wilson Timothy M. et al., The PPARs: From Orphan Receptors to Drug Discovery, Journal of Medicinal Chemistry; vol. 43, No. 4; 2000; pp. 527-550. cited by other . Zunft H,. J. F. et al., Carob Pulp Preparation for Treatment of Hypercholesterolemia, Advances in Natural Therapy; vol. 18, No. 5; Sep.-Oct. 2001; pp. 230-236. cited by other.

Primary Examiner: McKane; Joseph K.
Assistant Examiner: Anderson; Rebecca L.
Attorney, Agent or Firm: Kurys; Barbara E.

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Claims

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What is claimed is:

1. A compound of the formula I ##STR00034## wherein Ring A is (C.sub.3 C.sub.8)-cycloalkanediyl or (C.sub.3 C.sub.8)-cycloalkenediyl, wherein one or more carbon atoms in said (C.sub.3 C.sub.8)-cycloalkanediyl and (C.sub.3 C.sub.8)-cycloalkenediyl groups is optionally replaced by oxygen atoms; Ring B is a) phenyl; or b) (C.sub.3 C.sub.8)-cycloalkyl, an 8-, 9-, 10, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S; R1 is a) in the case where ring B is selected from a) above: SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2--CF.sub.3, SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; c) in the case ring B is selected from a) above and R4 is phenyl: (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R2 is H or CF.sub.3; R4 is a) in the case where ring B is selected from a) above: phenyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; c) in the case ring B is selected from a) above and R1 is selected from a) above: (C.sub.1 C.sub.6)-alkyl; R5 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R3 is H or (C.sub.1 C.sub.6)-alkyl; X is (C.sub.1 C.sub.6)-alkanediyl, wherein one or more carbon atoms in said (C.sub.1 C.sub.6)-alkanediyl group are optionally replaced by oxygen atoms; Y is (C.sub.1 C.sub.6)-alkanediyl, wherein one or more carbon atoms in said (C.sub.1 C.sub.6)-alkanediyl group are optionally replaced by oxygen atoms; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein: Ring A is (C.sub.3 C.sub.8)-cycloalkanediyl or (C.sub.3 C.sub.8)-cycloalkenediyl, wherein one or more carbon atoms in said (C.sub.3 C.sub.8)-cycloalkanediyl and (C.sub.3 C.sub.8)-cycloalkenediyl groups are optionally replaced by oxygen atoms; Ring B is a) phenyl; or b) (C.sub.3 C.sub.8)-cycloalkyl, an 8-, 9-, 10, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S; R1 is a) in the case where ring B is selected from a) above: SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2--CF.sub.3, SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; c) in the case where ring B is selected from a) above and R4 is phenyl: (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R2 is H or CF.sub.3; R4 is a) in the case where ring B is selected from a) above: phenyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; c) in the case where ring B is selected from a) above and R1 is selected from a) above: (C.sub.1 C.sub.6)-alkyl; R5 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R3 is H or (C.sub.1 C.sub.6)-alkyl; X is CH.sub.2--O; Y is (C.sub.1 C.sub.6)-alkanediyl, wherein one or more carbon atoms in said (C.sub.1 C.sub.6)-alkanediyl group are optionally replaced by oxygen atoms.

3. The compound of claim 2 wherein: Ring A is (C.sub.3 C.sub.8)-cycloalkanediyl wherein one carbon atom therein is optionally replaced by an oxygen atom; Ring B is a) phenyl; or b ) (C.sub.3 C.sub.8)-cycloalkyl, an 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S; R1 is a) in the case where ring B is selected from a) above: SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2--CF.sub.3, SCF.sub.3, OCF.sub.2--CHF.sub.3, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; c) in the case where ring B is selected from a) above and R4 is phenyl: (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R2 is H or CF.sub.3; R4 is a) in the case where ring B is selected from a) above: phenyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; c) in the case where ring B is selected from a) above and R1 is selected from a) above: (C.sub.1 C.sub.6)-alkyl; R5 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R3 is H or (C.sub.1 C.sub.6)-alkyl; X is CH.sub.2--O; Y is CH.sub.2--O.

4. The compound of claim 1 which has the formula Ia ##STR00035## wherein ring A, ring B, R1, R2, R3, R4, R5, X and Y are as defined in claim 1.

5. The compound of claim 4 wherein: R3 is H; and R5 is methyl.

6. The compound of claim 5 wherein: Ring A is (C.sub.5 C.sub.7)-cycloalkanediyl; Ring B is a) phenyl; or b) (C.sub.3 C.sub.8)-cycloalkyl, an 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S; R1 is a) in the case where ring B is selected from a) above: SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2--CF.sub.3, SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; c) in the case where ring B is selected from a) above and R4 is phenyl: (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R2 is H or CF.sub.3; R4 is a) in the case where ring B is selected from a) above: phenyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; c) in the case where ring B is selected from a) above and R1 selected from a) above: (C.sub.1 C.sub.6)-alkyl; R5 is methyl; R3 is H; X is CH.sub.2--O; Y is CH.sub.2--O.

7. The compound of claim 6 wherein the central cycloalkanediyl ring is attached 1,3-cis.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of claim 1.

9. The pharmaceutical composition of claim 6 further comprising at least one additional active ingredient.

10. The pharmaceutical composition of claim 9 wherein said additional active ingredient has favorable effects on metabolic disturbances or disorders.

11. The pharmaceutical composition of claim 9 wherein said additional active ingredient is an antidiabetic.

12. The pharmaceutical composition of claim 9 wherein said additional active ingredient is a lipid modulator.

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Description

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The invention relates to diarylcycloalkyl derivatives and to their physiologically acceptable salts and physiologically functional derivatives.

Compounds of a similar structure have already been described in the prior art for the treatment of hyperlipidemia and diabetes (WO 2000/64876 and WO 03/020269).

The invention was based on the object of providing compounds which permit therapeutically utilizable modulation of lipid and/or carbohydrate metabolism and are thus suitable for the prevention and/or treatment of diseases such as type 2 diabetes and atherosclerosis and the diverse sequelae thereof.

A series of compounds which modulate the activity of PPA receptors has surprisingly been found. The compounds are suitable in particular for activating PPARalpha and PPARgamma, it being possible for the extent of the relative activation to vary depending on the compounds.

Accordingly, the invention relates to compounds of the formula I

##STR00002## in which Ring A is (C.sub.3 C.sub.8)-cycloalkanediyl or (C.sub.3 C.sub.8)-cycloalkenediyl, wherein one or more carbon atoms in said (C.sub.3 C.sub.8)-cycloalkanediyl and (C.sub.3 C.sub.8)-cycloalkenediyl groups is optionally replaced by oxygen atoms; Ring B is a) phenyl; or b) (C.sub.3 C.sub.8)-cycloalkyl, an 8-, 9-, 10, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S; R1 is a) in the case where ring B is selected from a) above: SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2--CF.sub.3, SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; c) in the case ring B is selected from a) above and R4 is phenyl: (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R2 is H or CF.sub.3; R4 is a) in the case where ring B is selected from a) above: phenyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; c) in the case ring B is selected from a) above and R1 is selected from a) above: (C.sub.1 C.sub.6)-alkyl; R5 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R3 is H or (C.sub.1 C.sub.6)-alkyl; X is (C.sub.1 C.sub.6)-alkanediyl, wherein one or more carbon atoms in said (C.sub.1 C.sub.6)-alkanediyl group are optionally replaced by oxygen atoms; Y is (C.sub.1 C.sub.6)-alkanediyl, wherein one or more carbon atoms in said (C.sub.1 C.sub.6)-alkanediyl group are optionally replaced by oxygen atoms; and pharmaceutically acceptable salts thereof.

Preference is given to compounds of the formula I wherein Ring A is (C.sub.3 C.sub.8)-cycloalkanediyl or (C.sub.3 C.sub.8)-cycloalkenediyl, wherein one or more carbon atoms in said (C.sub.3 C.sub.8)-cycloalkanediyl and (C.sub.3 C.sub.8)-cycloalkenediyl groups are optionally replaced by oxygen atoms; Ring B is a) phenyl; or b) (C.sub.3 C.sub.8)-cycloalkyl, an 8-, 9-, 10, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S; R1 is a) in the case where ring B is selected from a) above: SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2--CF.sub.3, SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; c) in the case where ring B is selected from a) above and R4 is phenyl: (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R is H or CF.sub.3; R4 is a) in the case where ring B is selected from a) above: phenyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; c) in the case where ring B is selected from a) above and R1 is selected from a) above: (C.sub.1 C.sub.6)-alkyl; R5 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R3 is H or (C.sub.1 C.sub.6)-alkyl; X is CH.sub.2--O; Y is (C.sub.1 C.sub.6)-alkanediyl, wherein one or more carbon atoms in said (C.sub.1 C.sub.6)-alkanediyl group are optionally replaced by oxygen atoms.

Preference is furthermore given to compounds of the formula I wherein: Ring A is (C.sub.3 C.sub.8)-cycloalkanediyl wherein one carbon atom therein is optionally replaced by an oxygen atom; Ring B is a) phenyl; or b) (C.sub.3 C.sub.8)-cycloalkyl, an 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two three or four heteroatoms selected from the group consisting of N, O and S; R1 is a) in the case where ring B is selected from a) above: SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2--CF.sub.3, SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; c) in the case where ring B is selected from a) above and R4 is phenyl: (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R2 is H or CF.sub.3; R4 is a) in the case where ring B is selected from a) above: phenyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; c) in the case where ring B is selected from a) above and R1 is selected from a) above: (C.sub.1 C.sub.6)-alkyl; R5 is H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R3 is H or (C.sub.1 C.sub.6)-alkyl; X is CH.sub.2--O; Y is CH.sub.2--O.

Particular preference is given to compounds of the formula Ia

##STR00003## in which ring A, ring B, R1, R2, R3, R4, R5, X and Y are as defined above.

Particular preference is furthermore given to compounds of the formula Ia wherein: R3 is H; and R5 is methyl.

Also preferred are compounds of the formula Ia wherein: Ring A is (C.sub.5 C.sub.7)-cycloalkanediyl; Ring B is a) phenyl; or b) (C.sub.3 C.sub.8)-cycloalkyl, an 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic ring, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heteroaromatic ring optionally containing one, two, three or four heteroatoms selected from the group consisting of N, O and S; R1 is a) in the case where ring B is selected from a) above: SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, OCF.sub.2--CF.sub.3, SCF.sub.3, OCF.sub.2--CHF.sub.2, O-phenyl, (C.sub.1 C.sub.6)-alkyl, O--(C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl-O--(C.sub.1 C.sub.3)-alkyl; c) in the case where ring B is selected from a) above and R4 is phenyl: (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; R2 is H or CF.sub.3; R4 is a) in the case where ring B is selected from a) above: phenyl; b) in the case where ring B is selected from b) above: H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 C.sub.6)-alkyl or O--(C.sub.1 C.sub.6)-alkyl; c) in the case where ring B is selected from a) above and R1 selected from a) above: (C.sub.1 C.sub.6)-alkyl; R5 is methyl; R3 is H; X is CH.sub.2--O; Y is CH.sub.2--O.

Very particular preference is given to compounds of the formulae I and Ia wherein the central cycloalkanediyl ring is attached 1,3-cis.

This invention also encompasses all combinations of preferred aspects of the invention described herein.

The alkyl radicals in the substituents R1, R2, R3, R4 and R5 may be either straight-chain or branched.

Aryl means an aromatic carbocyclic mono- or bicyclic ring system which comprises 6 to 10 atoms in the ring or rings.

Heteroaryl is a mono- or bicyclic aromatic ring system having 4 to 11 ring members, in which at least one atom in the ring system is a heteroatom from the series N, O and S.

The compounds of the formula I comprise at least two centers of asymmetry and may comprise more in addition. The compounds of the formula I may therefore exist in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and mixtures of diastereomers. The present invention encompasses all these isomeric forms of the compounds of the formula I. These isomeric forms can be obtained by known methods even if not specifically described in some cases.

Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.

As used herein, the following definitions apply:

"Patient" means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.

"Treat" or "treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

"Therapeutically effective amount" means a quantity of the compound which is effective in treating the named disorder or condition.

"Pharmaceutically acceptable carrier" is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.

The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57 61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.

The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.

All references to "compound(s) of formula I" hereinafter refer to compound(s) of the formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein.

Use

This invention relates further to the use of compounds of the formula I and their pharmaceutical compositions as PPAR ligands. The PPAR ligands of the invention are suitable as modulators of PPAR activity.

Peroxisome proliferator-activated receptors (PPAR) are transcription factors which can be activated by ligands and belong to the class of nuclear hormone receptors. There are three PPAR isoforms, PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K, Cell Struct Funct. 1993 October; 18(5): 267 77).

Two variants of PPARgamma exist, PPARgamma.sub.1 and gamma.sub.2, which are the result of alternative use of promoters and differential mRNA splicing (Vidal-Puig et al. J. Clin. Invest., 97:2553 2561, 1996). Different PPARs have different tissue distribution and modulate different physiological functions. The PPARs play a key role in various aspects of the regulation of a large number of genes, the products of which genes are directly or indirectly crucially involved in lipid and carbohydrate metabolism. Thus, for example, PPARalpha receptors play an important part in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARgamma is crucially involved for example in regulating adipose cell differentiation. In addition, however, PPARs are also involved in the regulation of many other physiological processes, including those which are not directly connected with carbohydrate or lipid metabolism. The activity of different PPARs can be modulated by various fatty acids, fatty acid derivatives and synthetic compounds to varying extents. For relevant reviews about functions, physiological effect and pathophysiology, see: Joel Berger et al., Annu. Rev. Med. 2002, 53, 409 435; Timothy Wilson et al. J. Med. Chem., 2000, Vol. 43, No. 4, 527 550; Steven Kliewer et al., Recent Prog Horm Res. 2001; 56: 239 63.

The present invention relates to compounds of the formula I suitable for modulating the activity of PPARs, especially the activity of PPARalpha and PPARgamma. Depending on the modulation profile, the compounds of the formula I are suitable for the treatment, control and prophylaxis of the indications described hereinafter, and for a number of other pharmaceutical applications connected thereto (see, for example, Joel Berger et al., Annu. Rev. Med. 2002, 53, 409 435; Timothy Wilson et al. J. Med. Chem., 2000, Vol. 43, No. 4, 527 550; Steven Kliewer et al., Recent Prog Horm Res. 2001; 56: 239 63; Jean-Charles Fruchart, Bart Staels and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345 52; 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL 405, 25 May 2000; 421 4; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staels: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001, 245 254).

Compounds of this type are particularly suitable for the treatment and/or prevention of 1. disorders of fatty acid metabolism and glucose utilization disorders disorders in which insulin resistance is involved 2. Diabetes mellitus, especially type 2 diabetes, including the prevention of the sequelae associated therewith.

Particular aspects in this connection are hyperglycemia, improvement in insulin resistance, improvement in glucose tolerance, protection of the pancreatic .beta. cells prevention of macro- and microvascular disorders 3. Dyslipidemias and their sequelae such as, for example, atherosclerosis, coronary heart disease, cerebrovascular disorders etc, especially those (but not restricted thereto) which are characterized by one or more of the following factors: high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations, low HDL cholesterol concentrations low ApoA lipoprotein concentrations high LDL cholesterol concentrations small dense LDL cholesterol particles high ApoB lipoprotein concentrations 4. Various other conditions which may be associated with the metabolic syndrome, such as: obesity (excess weight), including central obesity thromboses, hypercoagulable and prothrombotic states (arterial and venous) high blood pressure heart failure such as, for example (but not restricted thereto), following myocardial infarction, hypertensive heart disease or cardiomyopathy 5. Other disorders or conditions in which inflammatory reactions or cell differentiation may for example be involved are: atherosclerosis such as, for example (but not restricted thereto), coronary sclerosis including angina pectoris or myocardial infarction, stroke vascular restenosis or reocclusion chronic inflammatory bowel diseases such as, for example, Crohn's disease and ulcerative colitis pancreatitis other inflammatory states retinopathy adipose cell tumors lipomatous carcinomas such as, for example, liposarcomas solid tumors and neoplasms such as, for example (but not restricted thereto), carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, of the kidneys and the urinary tract, of the genital tract, prostate carcinomas etc acute and chronic myeloproliferative disorders and lymphomas angiogenesis neurodegenerative disorders Alzheimer's disease multiple sclerosis Parkinson's disease erythemato-squamous dermatoses such as, for example, psoriasis acne vulgaris other skin disorders and dermatological conditions which are modulated by PPAR eczemas and neurodermitis dermatitis such as, for example, seborrheic dermatitis or photodermatitis keratitis and keratoses such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or keratosis follicularis keloids and keloid prophylaxis warts, including condylomata or condylomata acuminata human papilloma viral (HPV) infections such as, for example, venereal papillomata, viral warts such as, for example, molluscum contagiosum, leukoplakia papular dermatoses such as, for example, Lichen planus skin cancer such as, for example, basal-cell carcinomas, melanomas or cutaneous T-cell lymphomas localized benign epidermal tumors such as, for example, keratoderma, epidermal naevi chilblains high blood pressure syndrome X polycystic ovary syndrome (PCOS) asthma osteoarthritis lupus erythematosus (LE) or inflammatory rheumatic disorders such as, for example, rheumatoid arthritis vasculitis wasting (cachexia) gout ischemia/reperfusion syndrome acute respiratory distress syndrome (ARDS) Formulations

The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per day and per kilogram of bodyweight, for example 0.1 10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.001 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one (or more) surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5to 2%.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).

The compounds of the formula I are distinguished by favorable effects on metabolic disorders. They beneficially influence lipid and sugar metabolism, in particular they lower the triglyceride level and are suitable for the prevention and treatment of type II diabetes and arteriosclerosis and the diverse sequalae thereof.

Combinations with Other Medicaments

The compounds of the invention can be administered alone or in combination with one or more further pharmacologically active substances which have, for example, favorable effects on metabolic disturbances or disorders frequently associated therewith. Examples of such medicaments are 1. medicaments which lower blood glucose, antidiabetics, 2. active ingredients for the treatment of dyslipidemias, 3. antiatherosclerotic medicaments, 4. antiobesity agents, 5. antiinflammatory active ingredients 6. active ingredients for the treatment of malignant tumors 7. antithrombotic active ingredients 8. active ingredients for the treatment of high blood pressure 9. active ingredients for the treatment of heart failure and active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.

They can be combined with the compounds of the invention of the formula I in particular for a synergistic improvement in the effect. Administration of the active ingredient combination can take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.

Examples which may be mentioned are:

Antidiabetics

Suitable antidiabetics are disclosed for example in the Rote Liste 2001, chapter 12 or in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. Antidiabetics include all insulins and insulin derivatives such as, for example, Lantus.RTM. (see www.lantus.com) or Apidra.RTM., and other fast-acting insulins (see U.S. Pat. No. 6,221,633), GLP-1 receptor modulators as described in WO 01/04146 or else, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S.

The orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, DPP-IV inhibitors, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which alter lipid metabolism and lead to a change in the blood lipid composition, compounds which reduce food intake, PPAR and PXR modulators and active ingredients which act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.

In one embodiment of the invention, the compounds of the formula I are administered in combination with substances which influence hepatic glucose production such as, for example, glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188)

In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of the formula I are administered in combination with a biguanide such as, for example, metformin.

In a further embodiment, the compounds of the formula I are administered in combination with a meglitinide such as, for example, repaglinide.

In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione such as, for example, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2- ,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered in combination with a DPPIV inhibitor as described, for example, in WO98/19998, WO99/61431, WO99/67278, WO99/67279, WO01/72290, WO02/38541, WO03/040174, in particular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98, LAF237 (1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile), TS021 ((2S, 4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2- -carbonitrile monobenzenesulfonate).

In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARgamma agonist such as, for example, rosiglitazone, pioglitazone.

In one embodiment, the compounds of the formula I are administered in combination with compounds with an inhibitory effect on SGLT-1 and/or 2, as disclosed directly or indirectly for example in PCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455.

In one embodiment, the compounds of the formula I are administered in combination with an .alpha.-glucosidase inhibitor such as, for example, miglitol or acarbose.

In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

Lipid Modulators

In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCOA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid reabsorption inhibitor (see, for example, U.S. Pat. Nos. 6,245,744, 6,221,897, 6,277,831, EP 0683 773, EP 0683 774).

In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor as described for example in WO 0250027, or ezetimibe, tiqueside, pamaqueside.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see, for example, U.S. Pat. No. 6,342,512).

In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax.RTM. (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 September October), 18(5), 230 6.) Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hoechst, 65926 Frankfurt/Main)). Combination with Caromax.RTM. is possible in one preparation or by separate administration of compounds of the formula I and Caromax.RTM.. Caromax.RTM. can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPARalpha agonist.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist such as, for example, AZ 242 (Tesaglitazar, (S)-3-(4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionic acid), BMS 298585 (N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)et- hoxy]phenyl]methyl]glycine) or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, WO96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I are administered in combination with nicotinic acid or niacin.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, e.g. CP-529, 414 (torcetrapib).

In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, implitapide.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist.

Antiobesity Agents

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor such as, for example, orlistat.

In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolic Research (2001), 33(9), 554 558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}amide hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin- -5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin antagonists (e.g. 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin4-ylurea hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-y- l)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropyla- mine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, .beta.3 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-- yloxy)ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcar- bamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquino- line-2-carboxylic acid tertiary butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873 881), DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-1.beta. agonists.

In one embodiment of the invention, the further active ingredient is leptin.

In one embodiment, the further active ingredient is dexamphetamine, amphetamine, mazindole or phentermine.

In one embodiment, the compounds of the formula I are administered in combination with medicaments having effects on the coronary circulation and the vascular system, such as, for example, ACE inhibitors (e.g. ramipril), medicaments which act on the angiotensin-renine system, calcium antagonists, beta blockers etc.

In one embodiment, the compounds of the formula I are administered in combination with medicaments having an antiinflammatory effect.

In one embodiment, the compounds of the formula I are administered in combination with medicaments which are employed for cancer therapy and cancer prevention.

It will be appreciated that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the protection conferred by the present invention.

The activity of the compounds was tested as follows:

Determination of EC50 Values of PPAR Agonists in the Cellular PPARalpha Assay

Principle

The potency of substances which bind to human PPARalpha and activate in an agonistic manner is analyzed using a stably transfected HEK cell line (HEK