HK1152935A

HK1152935A - Annelated n-heterocyclic sulfonamides with oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals

Info

Publication number: HK1152935A
Application number: HK11107007.3A
Authority: HK
Inventors: Stefanie Keil; Matthias Urmann; Wolfgang Wendler; Maike Glien; Hans Matter; Eugen Falk
Original assignee: 赛诺菲-安万特
Priority date: 2008-06-09
Filing date: 2009-05-22
Publication date: 2012-03-16

Description

Cyclized N-heterocyclic sulfonamides with oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals

Technical Field

The invention relates to cyclized N-heterocyclic sulfonamides (annelated N-heterocyclic sulfonamides with oxadiazinone headgroup) and their physiologically acceptable salts and physiologically functional derivatives which exhibit PPAR delta agonist activity or PPAR delta and PPAR alpha agonist activity.

Background

PPAR delta agonists with sulfonamide groups are described in WO 2003/097607, WO2004/005253 and DE 10335449 and WO 2004/092117. Compounds containing oxadiazolone features are described in WO 2005/097786. Pyridopyrazine derivatives are described in WO 2007/130468.

The object of the present invention is to provide compounds which allow a therapeutically effective modulation of lipid and/or carbohydrate metabolism and are therefore suitable for the prevention and/or treatment of diseases such as type II diabetes and atherosclerosis and their various sequelae. It is another object of the invention to treat demyelinating and other neurodegenerative diseases in the central and peripheral nervous system.

A series of compounds have been found that modulate the activity of the PPA receptor. These compounds are particularly suitable for activating PPAR δ or activating PPAR δ and PPAR α, however it is possible that the relative activation will vary with the particular compound.

Disclosure of Invention

The compounds of the present invention are described by formula I:

wherein

Y is O, S, SO,SO₂(C0-C2) alkylene-N (R10), C (R3) (R4);

r1 is H, halogen, (C1-C8) alkyl, (C3-C7) cycloalkyl- (C0-C4) alkylene, (C5-C10) heteroaryl- (C0-C4) alkylene, (C0-C8) alkyl-O- (C0-C4) alkylene, (C6-C10) aryl- (C0-C4) alkylene, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r2 is H, (C1-C8) alkyl, halogen, (C0-C8) alkyl-O- (C0-C4) alkylene, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r3 is H, (C1-C8) alkyl, (C3-C7) cycloalkyl- (C0-C4) alkylene, (C6-C10) aryl- (C0-C4) alkylene, (C5-C10) heteroaryl- (C0-C4) alkylene, (C0-C4) alkylene-N (R10) (R11) wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r4 is H, (C1-C8) alkyl, (C3-C7) cycloalkyl- (C0-C4) alkylene, (C6-C10) aryl- (C0-C4) alkylene, (C5-C10) heteroaryl- (C0-C4) alkylene, (C0-C4) alkylene-N (R10) (R11) wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

or R3 and R4 together with the carbon atom to which they are attached form a (C3-C7) cycloalkyl ring in which one carbon atom is optionally replaced by one heteroatom selected from O, S or N;

r5 is H, (C1-C8) alkyl, (C3-C7) cycloalkyl- (C0-C4) alkylene, (C6-C10) aryl- (C0-C4) alkylene, (C5-C10) heteroaryl- (C0-C4) alkylene, (C0-C4) alkylene-N (R10) (R11) wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r6 is H, (C1-C8) alkyl, (C3-C7) cycloalkyl- (C0-C4) alkylene, (C6-C10) aryl- (C0-C4) alkylene, (C5-C10) heteroaryl- (C0-C4) alkylene, (C0-C4) alkylene-N (R10) (R11) wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

or R5 and R6 together with the carbon atom to which they are attached form a (C3-C7) cycloalkyl ring in which one carbon atom is optionally replaced by one heteroatom selected from O, S or N;

r7 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O- (C0-C4) alkylene-H, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r8 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O- (C0-C4) alkylene-H, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F, wherein R8 is only attached to carbon;

r9 is H, halogen, (C1-C8) alkyl, (C3-C7) cycloalkyl- (C0-C4) alkylene, (C0-C8) alkyl-O- (C0-C4) alkylene, (C6-C10) aryl- (C0-C4) alkylene, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r10 is H, (C1-C8) alkyl, (C0-C8) alkyl-O- (C0-C4) alkylene, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r11 is H, (C1-C8) alkyl, (C0-C8) alkyl-O- (C0-C4) alkylene, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

x1, X2, X3, X4 and X5 are independently N or CH;

the compounds are in all their stereoisomeric forms, mixtures in any ratio, physiologically acceptable salts and tautomeric forms.

Another embodiment of the present invention are compounds of formula I, wherein

Y is O, S, SO₂(C0-C2) alkylene-N (R10), C (R3) (R4);

r1 is H, halogen, (C1-C8) alkyl, (C3-C7) cycloalkyl- (C0-C4) alkylene, (C5-C10) heteroaryl- (C0-C4) alkylene, (C0-C8) alkyl-O- (C0-C4) alkylene, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r2 is H, (C1-C8) alkyl, halogen;

r3 is H, (C1-C8) alkyl, (C0-C4) alkylene-N (R10) (R11), wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r4 is H, (C1-C8) alkyl, (C0-C4) alkylene-N (R10) (R11), wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

or R3 and R4 together with the carbon atom to which they are attached form a (C3-C7) cycloalkyl ring;

r5 is H, (C1-C8) alkyl;

r6 is H, (C1-C8) alkyl;

or R5 and R6 together with the carbon atom to which they are attached form a (C3-C7) cycloalkyl ring;

r7 is H, halogen, (C1-C8) alkyl;

r8 is H, halogen, (C1-C8) alkyl;

r9 is H, halogen, (C1-C8) alkyl, (C0-C8) alkyl-O- (C0-C4) alkylene, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F;

r10 is H, (C1-C8) alkyl;

r11 is H, (C1-C8) alkyl;

one or two of X1, X2, X3, X4 and X5 are N, and the other of X1, X2, X3, X4 and X5 are CH.

Another embodiment of the present invention are compounds of formula I, wherein

Y is O, S, C (R3) (R4).

Another embodiment of the present invention are compounds of formula I, wherein

R1 is F, Cl, (C1-C4) alkyl, (C3-C6) cycloalkyl- (C0-C2) alkylene, (C5-C6) heteroaryl- (C0-C2) alkylene, (C1-C6) alkyl-O- (C0-C2) alkylene, wherein alkyl and alkylene are unsubstituted or substituted with 1 to 3F.

Another embodiment of the present invention are compounds of formula I, wherein

R2 is in the para position relative to R1.

Another embodiment of the present invention are compounds of formula I, wherein

R2 is H, (C1-C3) alkyl, F, Cl.

Another embodiment of the present invention are compounds of formula I, wherein

R3 is H, (C1-C4) alkyl, N (R10) (R11).

Another embodiment of the present invention are compounds of formula I, wherein

R4 is H, (C1-C4) alkyl.

Another embodiment of the present invention are compounds of formula I, wherein

R3 and R4 together with the carbon atom to which they are attached form a (C3-C6) cycloalkyl ring.

Another embodiment of the present invention are compounds of formula I, wherein

R5 is H, (C1-C4) alkyl.

Another embodiment of the present invention are compounds of formula I, wherein

R6 is H, (C1-C4) alkyl.

Another embodiment of the present invention are compounds of formula I, wherein

R5 and R6 together with the carbon atom to which they are attached form a (C3-C6) cycloalkyl ring.

Another embodiment of the present invention are compounds of formula I, wherein

R7 is H, F, Cl, (C1-C4) alkyl, preferably H.

Another embodiment of the present invention are compounds of formula I, wherein

R8 is H, F, preferably H.

Another embodiment of the present invention are compounds of formula I, wherein

R9 is H, Cl, (C1-C) alkyl, (C1-C4) alkyl-O-, wherein alkyl is unsubstituted or substituted with 1 to 3F, preferably CF₃。

Another embodiment of the present invention are compounds of formula I, wherein

R10 is H.

Another embodiment of the present invention are compounds of formula I, wherein

R11 is H.

Another embodiment of the present invention are compounds of formula I, wherein

One of X1, X2, X3 is N, the others of X1, X2, X3 are CH, and X4 and X5 are CH, or

X1, X2, X3 are CH, and one of X4 and X5 is N and the other of X4 and X5 is CH.

Another embodiment of the present invention are compounds of formula I, wherein

X1, X2, X3, X4 are CH, and X5 is N.

Another embodiment of the present invention are compounds of formula I, wherein

Y is O, S, SO₂、CR3R4、CH₂-NR10；

R1 is H, F, Cl, (C1-C4) alkyl, (C1-C4) alkyl-O-, (C3) cycloalkyl, (C5) heteroaryl, wherein alkyl is unsubstituted or substituted with 1 to 3F;

r2 is H, Cl;

r3 is H, (C1-C4) alkyl, NH₂；

R4 is H, (C1-C4) alkyl;

r5 is H, (C1-C4) alkyl;

r6 is H, (C1-C4) alkyl;

r7 is H;

r8 is H;

r9 is CF₃；

R10 is H;

x1, X4, X5 are independently CH or N;

x2 and X3 are CH.

Other embodiments of the invention are the following compounds:

3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [6- (6-trifluoromethyl-pyridin-3-yl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [4, 4-dimethyl-6- (6-trifluoromethyl-pyridin-3-yl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- {4- [ 4-amino-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -2-chloro-phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H- [1, 8] naphthyridin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [3, 2-b ] [1, 4] oxazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] thiazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- {2, 3-dichloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] thiazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [1, 1-dioxo-7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-1H-benzo [1, 4] thiazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3, 4, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-1-sulfonyl group]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-one;

3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H- [1, 5] naphthyridine-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [2, 2-dimethyl-7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] oxazin-4-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-bromo-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-cyclopropyl-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-isobutyl-phenyl } -4H- [1, 2, 4] oxadiazol-5-one

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2- (furan-3-yl) -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [2, 3-b ] [1, 4] oxazin-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [2, 3-b ] [1, 4] oxazin-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-fluoro-phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-methyl-phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-ethoxy-phenyl } -4H- [1, 2, 4] oxadiazol-5-one;

3- [4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2- (2, 2, 2-trifluoro-ethoxy) -phenyl ] -4H- [1, 2, 4] oxadiazol-5-one.

The invention also includes all combinations of the preferred aspects of the invention described herein.

The term "alkyl" as used herein is understood in a broad sense to mean a saturated hydrocarbon group which may be straight or branched. Unless otherwise specified, alkyl groups have 1 to 8 carbon atoms. Examples of "(C1-C8) -alkyl-" are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl, the isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2, 2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl. The term "(C0-C8) -alkyl-" is a hydrocarbon group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, wherein the term "C0-alkyl-" is a covalent bond. All of these definitions also apply to the term "alkylene".

The term "alkenyl" as used herein is understood in a broad sense to mean a hydrocarbon group having 1 to 4 double bonds and which may be straight or branched. Unless otherwise specified, alkenyl groups have 2 to 8 carbon atoms. Examples of "(C2-C8) -alkenyl-" are alkenyl groups having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl (═ allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1, 3-pentadienyl. All of these definitions also apply to the term "alkenylene".

The term "alkynyl" as used herein is understood in a broad sense to mean a hydrocarbon group having 1 to 4 triple bonds and which may be straight or branched. Unless otherwise specified, alkynyl groups have 2 to 8 carbon atoms. Examples of "(C2-C8) -alkynyl-" are alkynyl groups containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl (═ propargyl) or 2-butynyl. All of these definitions also apply to the term "alkynylene".

All these definitions apply also if alkyl is a substituent on another group, for example in alkyloxy, alkyloxycarbonyl or arylalkyl.

Unless otherwise indicated, alkyl and alkylene are unsubstituted or mono-, di-or trisubstituted independently of each other by suitable groups such as F, Cl, Br, I, CF₃，NO₂CN, COOH, CO-O- (C0-C4) alkylene- (C6-C10) aryl, CO-O- (C1-C4) alkyl, CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, CO-O- (C0-C4) alkylene- (C3-C15) heterocycle, CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C10) aryl, CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H, CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl, CO-N ((C0-C4) alkylene-H) - (C36 0-C4) alkylene 874 (C3-C15) heterocycle, (C0-C4) alkylene- (C3-C6) cycloalkyl, (C0-C4) alkylene- (C6-C10) aryl, (C0-C4) alkylene- (C3-C15) heterocycle, (C2-C6) -alkenyl, (C2-C6) -alkynyl, O- (C0-C6) -alkyl, O- (C0-C4) alkylene- (C6-C10) aryl, O- (C0-C4) alkylene- (C3-C12) cycloalkyl, O- (C0-C4) alkylene- (C3-C15) heterocycle, O-CO-O- (C0-C4) alkylene- (C6-C10) aryl, O-CO-O- (C1-C4) alkyl, O-CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, O-CO-O- (C0-C4) alkylene- (C3-C15) heterocycle, S- (C1-C4) alkyl, S- (C0-C4) alkylene- (C3-C13) cycloalkyl, S- (C0-C4) alkylene- (C6-C10) aryl, S- (C0-C4) alkylene- (C3-C15) heterocycle, SO- (C1-C4) alkyl, SO- (C0-C4) alkylene- (C3-C13) cycloalkyl, SO- (C0-C4) alkylene- (C6-C10) aryl, SO- (C0-C4) alkylene- (C3-C15) heterocycle, SO₂- (C1-C4) alkyl, SO₂- (C0-C4) alkylene- (C3-C13) cycloalkyl, SO₂- (C0-C4) alkylene- (C6-C10) aryl, SO₂- (C0-C4) alkylene- (C3-C15) heterocycle, SO₂N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C10) aryl, SO₂N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H, SO₂-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl, SO₂-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle, wherein said aryl ring or heterocycle is unsubstituted or mono-or di-substituted with: F. cl, Br, OH, CF₃、NO₂、CN、OCF₃O- (C1-C6) -alkyl, (C1-C6) -alkyl, N ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H; n ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H, N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H) - (C1-C6) cycloalkyl, N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkyl, n ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C3-C15) heterocycle, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkyl, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C4-C4) heterocycle N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene- (C6-C12) -aryl), N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkyl, N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle, wherein said aryl ring or heterocyclic ring is unsubstituted or mono-or di-substituted with：F、Cl、Br、I、OH、CF₃、NO₂、CN、OCF₃O- (C1-C6) -alkyl, (C1-C6) -alkyl, N ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H, SO₂-CH₃COOH, COO- (C1-C6) -alkyl, SF₅、CONH₂。

Unless otherwise indicated, the term "cycloalkyl" is understood to mean a saturated hydrocarbon ring containing from 3 to 13 carbon atoms in a monocyclic, bicyclic, fused, bridged or spiro ring. Examples of (C3-C13) -cycloalkyl are cycloalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl. The term "cycloalkyl" also includes bicyclic groups in which any of the above cycloalkyl rings is fused to a benzene ring, such as indane and 1, 2, 3, 4-tetrahydronaphthalene.

Unless otherwise indicated, cycloalkyl is unsubstituted or mono-, di-or trisubstituted by, independently of one another, suitable radicals such as F, Cl, Br, I, CF₃，NO₂CN, COOH, CO-O- (C0-C4) alkylene- (C6-C10) aryl, CO-O- (C1-C4) alkyl, CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, CO-O- (C0-C4) alkylene- (C3-C15) heterocycle, CO-N ((C0-C4) alkylene-H) - (C1-C6) alkylene-H, CO-N ((C0-C4) alkylene-H) - (C1-C6) cycloalkyl, CON ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C12) -aryl, (C0-C4) alkylene- (C3-C6) cycloalkyl, (C3-C6) alkyl, (C2-C6) -alkenyl, (C2-C6) -alkynyl, (C0-C4) alkylene- (C6-C10) aryl, (C0-C4) alkylene- (C3-C15) heterocycle, O- (C0-C6) -alkyl, (C6-C6) alkylene-O- (C6-C6) alkylene- (C6-C6) cycloalkyl, (C6-C6) alkylene-O- (C6-C6) alkylene- (C6-C6) aryl, (C6-C6) alkylene-O- (C6-C6) alkylene- (C6-C6) heterocycle, O-CO-O- (C6-C6) alkylene- (C6) aryl, O-CO-O- (C1-C4) alkyl, O-CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, O-CO-O- (C0-C4) alkylene- (C3-C15) heterocycle, O-CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C10) aryl, O-CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H, O-CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl), O-CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle, S- (C1-C4) alkyl, S- (C0-C4) alkylene- (C3-C13) alkylene, S- (C0-C4) alkylene- (C6-C10) aryl, S- (C0-C4) alkylene- (C3-C15) heterocycle, SO- (C1-C4) alkyl, SO- (C4-C4) alkylene- (C4-C4) cycloalkyl, SO- (C4-C4) alkylene- (C4-C4) aryl, SO- (C0-C4) alkylene- (C3-C15) heterocycle, SO₂- (C1-C4) alkyl, SO₂- (C0-C4) alkylene- (C3-C13) cycloalkyl, SO₂- (C0-C4) alkylene- (C6-C10) aryl, SO₂- (C0-C4) alkylene- (C3-C15) heterocycle, SO₂N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C10) aryl, SO₂N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H, SO₂-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl, SO₂-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle, wherein said aryl ring or heterocycle is unsubstituted or mono-or di-substituted with: F. cl, Br, OH, CF₃、NO₂、CN、OCF₃O- (C1-C6) -alkyl, (C1-C6) -alkyl, N ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H; n ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H, N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H) - (C1-C6) cycloalkyl, N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkyl, n ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C3-C15) heterocycle, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkyl, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C4-C4) heterocycle N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene- (C6-C12) -aryl), N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkyl, N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene-H) Alkylene- (C3-C15) heterocycle wherein the aryl ring or heterocycle is unsubstituted or mono-or di-substituted with: F. c1, Br, I, OH, CF₃、NO₂、CN、OCF₃O- (C1-C6) -alkyl, (C1-C6) -alkyl, N ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H, SO₂-CH₃COOH, COO- (C1-C6) -alkyl, SF₅、CONH₂。

The term "aryl" is understood to mean an aromatic hydrocarbon ring containing from 6 to 14 carbon atoms in a single ring or in two rings. Examples of (C6-C14) -aryl rings are phenyl, naphthyl (e.g.1-naphthyl and 2-naphthyl), biphenyl (e.g.2-biphenyl, 3-biphenyl and 4-biphenyl), anthracenyl or fluorenyl. A biphenyl ring, a naphthyl ring and in particular a phenyl ring are further embodiments of the aryl ring.

The term "heterocycle" is understood to mean a saturated (heterocycloalkyl), partially unsaturated (heterocycloalkenyl) or unsaturated (heteroaryl) hydrocarbon ring containing from 3 to 15 ring carbon atoms in a monocyclic, bicyclic, fused, bridged or spiro ring, and 1 to 5 of said 3 to 15 ring carbon atoms being replaced by a heteroatom, such as nitrogen, oxygen or sulfur, wherein said heteroatom may be further oxidized, for example N-O, S-O, SO₂. Examples of heterocycles are acridinyl, azaindole (1H-pyrrolopyridyl), azabenzimidazolyl, azaspirodecyl, azaA group, azetidine, aziridine, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiopyranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 4, 5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1, 3-dioxolanyl, 1, 3-dioxolyl, 3-dioxo [1, 3, 4-dihydrooxazolinyl]Oxathiazinyl, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b ]]Tetrahydrofuryl, furyl, furazanyl, imidazolidineAn imidazolyl group, an imidazolinyl group, an imidazolyl group, a 1H-indazolyl group, an indolinyl group, an indolizinyl group, an indolyl group, a 3H-indolyl group, an isobenzofuranyl group, an isochroman group, an isoindazolyl group, an isoindolyl group, an isoquinolyl group (a benzimidazolyl group), an isothiazolyl group, an isothiazolidinyl group, an isothiazolinyl group, an isoxazolinyl group, an isoxazolidinyl group, a 2-isoxazolinyl group, a ketopiperazinyl group, a morpholinyl group, a naphthyridinyl group, an octahydroisoquinolyl group, an oxadiazolyl group, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2-oxathiolanyl, 1, 4-oxazepanyl, 1, 4-oxaza.A group, 1, 2-oxazinyl, 1, 3-oxazinyl, 1, 4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, naphthyridinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinonyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, pteridinyl, purinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, tetrahydropyridyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, 1, 2-thiazinyl, 1, 3-thiazinyl, 1, 4-thiazinyl, 1, 3-thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenol, thienyl, thiopyranyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, 1, 2, 3-triazolyl, 1, 2, 3-triazole.A group selected from the group consisting of 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl and xanthyl.

The heterocyclic ring being unsubstituted or mono-, di-or trisubstituted by suitable groups, e.g. F, Cl, Br, I, CF₃，NO₂CN, COOH, CO-O- (C0-C4) alkylene- (C6-C10) aryl, CO-O- (C1-C4) alkyl, CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, CO-O- (C0-C4) alkylene- (C3-C15) heterocycle, CO-N ((C0-C4) alkylene-H) - (C1-C6) alkylene-H, CO-N ((C0-C4) alkylene-H) - (C1-C6) cycloalkyl, CON ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C12) -aryl, (C0-C4) alkylene- (C3-C6) cycloalkyl, (C3-C6) alkyl, (C2-C6) -alkenyl, (C2-C6) -alkynyl, (C0-C4) alkylene- (C6-C10) aryl, (C0-C4) alkylene- (C3-C15) heterocycle, O- (C0-C6) -alkyl, (C6-C6) alkylene-O- (C6-C6) alkylene- (C6-C6) cycloalkyl, (C6-C6) alkylene-O- (C6-C6) alkylene- (C6-C6) aryl, (C6-C6) alkylene-O- (C6-C6) alkylene- (C6-C6) heterocycle, O-CO-O- (C6-C6) alkylene- (C6) aryl, O-CO-O- (C1-C4) alkyl, O-CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, O-CO-O- (C0-C4) alkylene- (C3-C15) heterocycle, O-CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C10) aryl, O-CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H, O-CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl, O-CO-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle 38964 S- (C1-C4) alkyl, S- (C0-C4) alkylene- (C3-C13) cycloalkyl, S- (C0-C4) alkylene- (C6-C10) aryl, S- (C0-C4) alkylene- (C3-C15) heterocycle, SO- (C1-C4) alkyl, SO- (C0-C4) alkylene- (C3-C13) cycloalkyl, SO- (C0-C4) alkylene- (C6-C10) aryl, SO- (C0-C4) alkylene- (C3-C15) heterocycle, SO- (C0-C4) alkylene- (C3-C15) aryl₂- (C1-C4) alkyl, SO₂- (C0-C4) alkylene- (C3-C13) cycloalkyl, SO₂- (C0-C4) alkylene- (C6-C10) aryl, SO₂- (C0-C4) alkylene- (C3-C15) heterocycle, SO₂N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C10) aryl, SO₂N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H, SO₂-N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl, SO₂-N ((C0-C4) alkylene-H) - (C0-C4) ylideneAlkyl- (C3-C15) heterocycle, wherein said aryl ring or heterocycle is unsubstituted or mono-or di-substituted with: F. cl, Br, OH, CF₃、NO₂、CN、OCF₃O- (C1-C6) -alkyl, (C1-C6) -alkyl, N ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H; n ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H, N ((C0-C4) alkylene-H) - (C0-C4) alkylene-H) - (C1-C6) cycloalkyl, N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkyl, n ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C3-C15) heterocycle, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkylene- (C6-C12) -aryl, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkyl, N ((C0-C4) alkylene-H) -CO-O- (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO- (C0-C4) alkylene- (C4-C4) heterocycle N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene- (C6-C12) -aryl), N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkyl, N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene- (C3-C13) cycloalkyl, N ((C0-C4) alkylene-H) -CO-N ((C0-C4) -alkylene-H) - (C0-C4) alkylene- (C3-C15) heterocycle, wherein said aryl or heterocyclic ring is unsubstituted or mono-or di-substituted with: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃O- (C1-C6) -alkyl, (C1-C6) -alkyl, N ((C0-C4) -alkylene-H) - (C0-C4) -alkylene-H, SO₂-CH₃COOH, COO- (C1-C6) -alkyl, SF₅、CONH₂。

Halogen is fluorine, chlorine, bromine or iodine.

The optically active carbon atoms present in the compounds of the formula I can, independently of one another, have the R configuration or the S configuration. The compounds of the formula I may be present as pure enantiomers or pure diastereomers, or as mixtures of enantiomers and/or diastereomers, for example as racemates. The present invention relates to pure enantiomers and mixtures of enantiomers as well as pure diastereomers and mixtures of diastereomers. The present invention includes mixtures of two or more stereoisomers of formula I, and the present invention includes mixtures of the stereoisomers in all ratios. In the case where the compounds of the formula I can exist as E or Z isomers (either cis or trans isomers), the invention relates both to the pure E isomer and to the pure Z isomer and to the E/Z mixture in all ratios. The invention also includes all tautomeric forms of the compounds of formula I.

Diastereomers (including E/Z isomers) can be separated into the individual isomers, for example, by chromatography. The racemates can be separated into the two enantiomers by conventional methods, for example by chromatography on a chiral phase, or by resolution, for example by crystallization of diastereomeric salts obtained with optically active acids or optically active bases. Stereochemically identical compounds of formula I may also be obtained as follows: using stereochemically uniform starting materials or using stereoselective reactions.

The compounds of formula I may exist in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and mixtures of diastereomers and their tautomeric forms. The present invention includes all such stereoisomeric and tautomeric forms of the compounds of formula I. These isomeric forms can be obtained by known methods, even if not specifically stated in some cases.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical use because they are more water soluble than the original or parent compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention are salts with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and salts with the following organic acids: such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable base addition salts are ammonium salts, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. magnesium and calcium salts), tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol) salts, diethanolamine, lysine or ethylenediamine salts.

Salts with non-pharmaceutically acceptable anions such as trifluoroacetate are also within the scope of the invention, which are useful as intermediates in the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic applications such as in vitro applications.

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

Physiologically functional derivatives also include prodrugs of the compounds of the invention, see, e.g., h.okadaet al, chem.pharm.bull.1994, 42, 57-61. These prodrugs can be metabolized in vivo to the compounds of the invention. These prodrugs may themselves be active or inactive.

The compounds of the present invention may also exist in various polymorphic forms, such as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.

All references hereinafter to "compounds of formula I" refer to the above-mentioned compounds of formula I as well as their salts, solvates and physiologically functional derivatives as described herein.

Use of

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

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that can be activated by ligands and belong to the class of nuclear hormone receptors. There are three PPAR isoforms, PPAR α, PPAR γ and PPAR δ (the same as PPAR β), which are encoded by different genes (Peroxisome promoter-activated receptors (PPAR): structure, mechanisms of activation and reversion functions: Motojima K., Cell Structure function, 1993, 18(5), 267-77).

PPAR γ is present in three variants in humans, namely PPAR γ₁、γ₂And gamma₃They exist, derived from the alternative use of promoters and splicing of different mrnas. Different PPARs have different tissue distribution and modulate different physiological functions. PPARs play an important role in a number of aspects in the regulation of a wide variety of genes, the products of which are directly or indirectly decisively involved in lipid and carbohydrate metabolism. Thus, for example, the PPAR α receptor plays an important role in regulating fatty acid breakdown or lipoprotein metabolism in the liver, while PPAR γ is critically involved in, for example, regulation of adipocyte differentiation. However, PPARs are also involved in the regulation of a variety of other physiological processes, including those not directly related to carbohydrate or lipid metabolism. The activity of different PPARs can be modulated to varying degrees by various fatty acids, fatty acid derivatives and synthetic compounds. For relevant literature on function, physiological role and pathophysiology see Berger, j.et al, annu.rev.med., 2002, 53, 409-; wilson, t.et., j.med.chem., 2000, 43(4), 527-550; kliewer, s.et al, Recent Prog hormres, 2001, 56, 239-63; moller, d.e. and Berger, j.p., Int J Obes Relat metabiosd, 2003, 27Suppl 3, 17-21; ram, v.j., Drugs Today, 2003, 39(8), 609-32.

Of the three PPAR isoforms, the physiological function of PPAR δ has been long unknown. The first proposed pharmacological effect on PPAR δ was to modulate cholesterol homeostasis. PPAR delta ligand L-165041, which is somewhat selective, has been found to increase plasma cholesterol in animal models of diabetes (BergerJ. et al, J.biol. chem., 1999, 274, 6718-. In obese cynomolgus monkeys, a potent and selective PPAR δ ligand, GW501516, increased HDL-cholesterol, decreased plasma LDL-cholesterol, triglycerides and insulin levels (Oliver, w.et al, proc.natl.acad.sci., 2001, 98, 5306-. The dual PPAR δ/PPAR α agonist YM-16638 significantly reduces plasma lipids in macaques and cynomolgus monkeys (Goto, s.et al., br.j.pharm., 1996, 118, 174-178) and functions in a similar manner in two-week clinical trials in healthy volunteers (Shimokawa, t.et al., Drug dev.res., 1996, 38, 86-92).

Recent publications emphasize that PPAR Δ is an important target for the treatment of dyslipidemia, insulin resistance, type II diabetes, atherosclerosis and syndrome X (Wang, Y-X. et al., Cell, 2003, 113, 159-.

PPAR δ is known to play an important role in embryonic development, transplantation and bone formation in addition to its role as a modulator of lipid, glucose and cholesterol metabolism (Lim, H.and Dey, S.K., trends Endocrinol Meteb., 2000, 11(4), 137-42; Ding, N.Z.et al, Mol Reprod Dev., 2003, 66(3), 218-24; Man, H.et al, J Biol chem., 2000, 275(11), 8126-32).

Many publications demonstrate that PPAR δ triggers the proliferation and differentiation of keratinocytes, suggesting a role in skin disease and wound healing (Di-Poi, n.et al, J Steroid Biochem Mol biol., 2003, 85(2-5), 257-65; Tan, n.s.et al, Am J Clin dermatol., 2003, 4(8), 523-30; Wahli, w., Swiss Med wkly., 2002, 132(7-8), 83-91).

PPAR δ appears to be significantly expressed in the CNS; however, many of its functions are still unknown. Of particular interest, however, is the finding that PPAR δ is expressed in oligodendrocytes in rodents, the major lipid producing cells of the CNS (j.granneman, et al, j.neurosci.res., 1998, 51, 563-. In addition, PPAR δ selective agonists were also found to significantly increase oligodendrocyte myelin gene expression and myelin diameter in mouse cultures (i.sauja et al, gia, 2001, 33, 194-. Thus, PPAR δ activators are useful for the treatment of demyelinating diseases and dysmyelination. The use of peroxisome proliferator activated receptor delta agonists in the treatment of MS and other demyelinating diseases may be found in WO 2005/097098.

Demyelinating disease is demonstrated by the loss of myelin, which is a dense multilayer of lipids and proteins that coat many nerve fibers. These layers are provided by oligodendroglia in the Central Nervous System (CNS) and Schwann cells in the Peripheral Nervous System (PNS). In patients with demyelinating diseases, demyelination may be irreversible, which is usually accompanied or occurs after axonal degeneration, and usually accompanied or occurring after cellular degeneration. Demyelination can occur as a result of neuronal damage or damage to the myelin sheath itself, for whatever reason: abnormal immune responses, local injury, ischemia, metabolic disease, toxic substances or viral infection (Prineas and McDonald, Demyelinating diseases, in Greenfield's Neuropathology, 6.sup.th ed. (Edward Arnold: New York, 1997) 813-811; Beers and Berkow, eds., The Merck Manual of diagnosis Therapy, 17.sup.the d. (Whitehouse Station, N.J.: Merck research laboratories, 1999)1299, 1437, 1473-76, 1483).

Central demyelination (demyelination in the CNS) occurs in several cases where the etiology is generally uncertain and is known as a primary demyelinating disease. Among these primary demyelinating diseases, Multiple Sclerosis (MS) is the most prevalent. Other primary demyelinating diseases include Adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS vacuolar myelopathy, HTLV-associated myelopathy, Leber's hereditary optic atrophy (Leber's hereditary optic neuropathy), Progressive Multifocal Leukoencephalopathy (PML), subacute sclerosing panencephalitis, guillain-Barre syndrome (Guillian-Barre syndrome), and tropical spastic paraplegia. In addition, there are acute disorders in which demyelination can occur in the CNS, such as Acute Disseminated Encephalomyelitis (ADEM) and acute viral encephalitis. In addition, acute transverse myelitis, a syndrome in which acute spinal transection of unknown cause affects gray and white matter in one or more adjacent thoracic segments, can also lead to demyelination. In addition, diseases in which myelinating glial cells are damaged include spinal cord injury, neuropathy, and nerve injury.

The present invention relates to compounds of formula I which are suitable for modulating PPAR activity, particularly PPAR δ and PPAR α activity. Based on the regulatory properties, the compounds of formula I are suitable for the treatment, control and prevention of the indications described below, and for a variety of other pharmaceutical applications relating thereto (see, e.g., Berger, J., et al, Annu. Rev. Med., 2002, 53, 409-.

Such compounds are particularly suitable for the treatment and/or prophylaxis of:

1. fatty acid metabolism disorders and glucose utilization disorders.

Diseases involving insulin resistance

2. Diabetes, particularly type II diabetes, includes the prevention of its associated sequelae.

The specific aspects are as follows:

-hyperglycemia

Improvement of insulin resistance

Improvement of glucose tolerance

Protection of pancreatic beta cells

Prevention of macrovascular and microvascular disease

3. Dyslipidemia and its sequelae, such as atherosclerosis, coronary heart disease, cerebrovascular disease, etc., particularly but not exclusively those characterised by one or more of the following factors:

high plasma triglyceride concentration, high postprandial plasma triglyceride concentration

Low HDL cholesterol concentration

Low ApoA lipoprotein concentration

High LDL cholesterol concentration

Low density LDL cholesterol particles

High ApoB lipoprotein concentration

4. Various other conditions that may be associated with metabolic syndrome, such as:

obesity (overweight), including central obesity

Thrombosis, easy coagulation and pre-thrombotic states (arteries and veins)

-hypertension

Heart failure, such as but not limited to secondary myocardial infarction, hypertensive heart disease or cardiomyopathy

5. Diseases or conditions involving inflammatory reactions:

atherosclerosis, such as but not limited to coronary arteriosclerosis (including angina pectoris or myocardial infarction) or stroke

Restenosis or reocclusion of blood vessels

Chronic inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis

-asthma

Lupus Erythematosus (LE) or inflammatory rheumatic diseases, such as rheumatoid arthritis

NASH (non-alcoholic steatohepatitis)

Other inflammatory states

6. Diseases of the cell cycle or cell differentiation process:

-adipose cell tumors

Lipomas, e.g. liposarcoma

Solid tumors and neoplasms, such as but not limited to gastrointestinal cancer, liver cancer, biliary tract cancer, pancreatic cancer, endocrine tumors, lung cancer, kidney cancer, urinary tract cancer, birth canal cancer, prostate cancer and the like

Acute and chronic myeloproliferative diseases and lymphomas

Angiogenesis

7. Demyelinating and other neurodegenerative diseases in the central and peripheral nervous systems, including:

alzheimer's disease (Alzheimer's disease)

Multiple sclerosis

Parkinson's disease

Adrenoleukodystrophy (ALD)

-adrenomyeloneuropathy

AIDS syringomyelia

HTLV-related myelopathy

Leber's hereditary optic atrophy

Progressive Multifocal Leukoencephalopathy (PML)

Subacute sclerosing panencephalitis

Guillain-Barre syndrome

-tropical spastic paraparesis

Acute Disseminated Encephalomyelitis (ADEM)

Acute viral encephalitis

Acute transverse myelitis

Spinal cord and brain injury

-sand-horse-picture disease (Charcot-Marie-Tooth disease)

8. Skin diseases and/or disorders of the wound healing process:

erythematous-desquamatisms (erythro-dandruff dermatases), e.g. psoriasis

Acne vulgaris

Other skin diseases and skin conditions modulated by PPARs

-eczema and neurodermatitis

Dermatitis, such as seborrheic dermatitis or photodermatitis

Keratitis and keratoses, such as seborrheic keratosis, senile keratosis, actinic keratosis, light-induced keratosis or follicular keratosis

Keloid and keloid prevention

Warts, including condyloma or condyloma acuminata

Human Papillomavirus (HPV) infection, such as venereal papilloma, viral warts (e.g. molluscum contagiosum) or leukoplakia

Papulodermopathies, e.g. lichen planus

Skin cancer, such as basal cell carcinoma, melanoma or cutaneous T-cell lymphoma

Local benign epidermal tumors, e.g. keratoderma or epidermoid nevus verruciformis

Chilblain

Wound healing

9. Other diseases

-hypertension

-pancreatitis

Syndrome X

Polycystic ovarian syndrome (PCOS)

-asthma

-osteoarthritis

Vasculitis

Wasting disease (cachexia)

Gout (gout)

Ischemia/reperfusion syndrome

-Acute Respiratory Distress Syndrome (ARDS)

Preparation

The amount of a compound of formula I required to achieve a desired biological effect depends on a variety of factors, such as the particular compound selected, the intended use, the mode of administration, and the clinical condition of the patient. The daily dose is usually 0.001mg to 100mg (typically 0.01mg to 50mg) per day per kg body weight, for example 0.1 to 10 mg/kg/day. The intravenous dose may be, for example, from 0.001mg to 1.0mg/kg, which may suitably be administered as an infusion of from 10ng to 100 ng/kg/min. Infusion solutions suitable for these purposes may contain, for example, from 0.1ng to 10mg, typically 1ng to 10mg, of the active ingredient per ml. A single dose may contain, for example, from 1mg to 10g of active ingredient. Thus, ampoules for injection may contain, for example, from 1mg to 100mg of active ingredient, whereas single-dose preparations which can be administered orally, such as capsules or tablets, may contain, for example, from 0.05 to 1000mg, typically from 0.5 to 600mg, of active ingredient. For the treatment of the above conditions, the compounds of formula I may be used as the compounds themselves, but they are preferably used in the form of a pharmaceutical composition containing an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the health of the patient. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, e.g., a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may also be present, including other compounds of formula I. The pharmaceutical compositions of the present invention can be prepared by one of the known pharmaceutical methods, which essentially comprises mixing the ingredients with pharmacologically acceptable carriers and/or excipients.

The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each case on the severity of the condition to be treated and on the nature of the compound of the formula I used in each case. Coated formulations and coated sustained release formulations are also within the scope of the invention. Preferred are acid and gastric juice resistant formulations. Suitable gastro-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical formulations adapted for oral administration may be presented as discrete units, such as capsules, cachets, sucking tablets or tablets, each containing a given amount of a compound of formula I; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water or water-in-oil emulsion. These compositions may be prepared as described above by any suitable pharmaceutical process which includes a step in which the active ingredient is contacted with a carrier, which may contain one or more additional ingredients. The compositions are generally prepared as follows: the active ingredient is uniformly and homogeneously mixed with the liquid and/or finely divided solid carrier, and then the product is shaped, if desired. Thus, for example, a tablet can be prepared as follows: powders or granules of the compound and optionally one or more other ingredients are compacted or molded. Compressed tablets may be prepared as follows: the compound in free-flowing form, e.g. powder or granules, optionally mixed with a binder, a flow aid, an inert diluent and/or one (or more) surfactant/dispersant in a suitable apparatus, is tabletted. Molded tablets may be prepared as follows: the compound in powder form is molded, wetted with an inert liquid diluent in a suitable apparatus.

Pharmaceutical compositions suitable for oral (sublingual) administration include suckable tablets (lozenges) containing a compound of formula I together with a flavouring (usually sucrose and acacia or tragacanth), and lozenges comprising the compound in an inert base such as gelatin and glycerol or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, although administration by subcutaneous, intramuscular or intradermal injection is also possible. These formulations can preferably be prepared as follows: the compound is mixed with water and the resulting solution is sterilized and made isotonic with blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. These forms can be prepared as follows: the compound of formula I is mixed with one or more conventional solid carriers, such as cocoa butter, and the resulting mixture is shaped.

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

Transdermal administration may also be carried out. Pharmaceutical compositions suitable for transdermal use may be in the form of a single ointment suitable for long-term intimate contact with the epidermis of a patient. These pastes suitably contain the active ingredient in an optionally buffered aqueous solution in which it is dissolved and/or dispersed in an adhesive or dispersed in a polymer. Suitable concentrations of the active ingredient are about 1% to 35%, preferably about 3% to 15%. Active ingredients can be released in particular by electrotransport or iontophoresis, see for example Pharmaceutical Research, 2 (6): 318(1986).

The compounds of the formula I are characterized by advantageous effects on metabolic disorders. They advantageously influence lipid metabolism and sugar metabolism, in particular they reduce triglyceride levels, and are suitable for the prevention and treatment of type II diabetes and atherosclerosis and their various sequelae.

In combination with other drugs

The compounds of the present invention may be administered alone or in combination with one or more other pharmacologically active agents. In particular, the compounds of the present invention may be administered in combination with active ingredients having similar pharmacological effects. For example, they can be administered in combination with active ingredients which have a favourable effect on metabolic disorders or diseases which are usually associated with metabolic disorders. Examples of such drugs are:

1. drugs that lower blood sugar are anti-diabetic drugs,

2. an active component for treating the dyslipidaemia,

3. an anti-atherosclerotic drug composition comprises a combination of anti-atherosclerotic drugs,

4. an anti-obesity agent,

5. an anti-inflammatory active ingredient, which is,

6. an active component for treating malignant tumor,

7. the anti-blood test forms an active component,

8. an active component for treating high blood pressure,

9. an active ingredient for the treatment of heart failure,

10. active ingredients for the treatment and/or prophylaxis of complications which are caused by or associated with diabetes,

11. an active ingredient for the treatment of neurodegenerative diseases,

12. an active ingredient for treating central nervous system diseases,

13. active ingredients for the treatment of drug, nicotine or alcohol addiction, and

14. an analgesic.

They can be used in combination with the compounds of the formula I according to the invention, in particular for synergistically enhancing the activity. The combined administration of the active ingredients can be carried out as follows: the active ingredients are administered to the patient separately or in the form of a combination in which the active ingredients are present in one pharmaceutical preparation.

Other active ingredients suitable for the combination product are:

all antidiabetic agents mentioned in Rote Liste2005, chapter 12; all of the weight-reducing/appetite-suppressing agents mentioned in Rote list 2005, chapter 1; all lipid lowering agents mentioned in Rote Liste2005, chapter 58. They can be used in combination with the compounds of the formula I according to the invention, in particular for synergistically increasing the action. The combined administration of the active ingredients can be carried out as follows: the active ingredients are administered to the patient separately or in the form of a combination in which the active ingredients are present in one pharmaceutical preparation. Most of the active ingredients described below are described in USP Physicological of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetic agents include insulin and insulin derivatives, e.g.(see www.lantus.com) or HMR 1964 or(insulin destemir) or those described in WO 2005005477(Novo Nordisk), rapid-acting insulins (see US6,221,633), inhalation insulins, e.g.Or Oral insulin, e.g. IN-105(Nobex) or Oral-lyn^TM(Generex Biotechnology), GLP-1 derivatives and GLP-1 agonists such as exenatide (Exenatide), liraglutide (liraglutide), or those described in WO 98/08871, WO2005027978, WO 2006037811 or WO 2006037810(Novo Nordisk A/S), WO01/04156(Zealand) or WO 00/34331(Beaufour-Ipsen), pramlintide acetate (pramlintide acetate) (Symlin; Amylin Pharmaceuticals), BIM-51077, PC-DAC-exendin-4 (exendin-4 analogue covalently bound to recombinant human albumin), such as those described in D.n et al, Proc.Natl.Acad.Sci.USA 104 (943), those described in WO 2006124529, and components effective in lowering blood glucose levels orally.

Antidiabetic agents also include glucose dependent insulinotropic polypeptide (GIP) receptor agonists, such as those described in WO 2006121860.

The orally effective hypoglycemic active ingredients preferably comprise:

a sulfonylurea,

(ii) a biguanide compound(s),

(ii) a group of the meglitinides,

an oxadiazolidinedione compound which is a novel compound,

the thiazolidinediones are selected from the group consisting of thiazolidinediones,

a glucosidase inhibitor,

an inhibitor of a glycogen phosphorylase enzyme, which is capable of inhibiting glycogen phosphorylase activity,

an antagonist of glucagon is provided which is a glucagon antagonist,

an activator of a glucokinase which is capable of activating a glucokinase,

a fructose-1, 6-bisphosphatase inhibitor,

glucose carrier 4(GLUT4) modulators,

inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),

a GLP-1 agonist,

potassium channel openers such as pinadil, chromancarbine, diazoxide or those drugs described in the following references: carr et al, Diabetes 52, 2003, 2513.2518; hansen et al, Current medical Chemistry 11, 2004, 1595-; t.m.tagmose et al, j.med.chem.47, 2004, 3202-; m.j.coghlan et al, j.med.chem.44, 2001, 1627-; or WO 97/26265 and WO 99/03861(Novo Nordisk A/S),

dipeptidyl peptidase IV (DPP-IV) inhibitors,

an insulin sensitizer is provided,

liver enzyme inhibitors involved in the stimulation of gluconeogenesis and/or glycogenolysis,

glucose uptake modulators, glucose transport modulators and glucose reabsorption modulators,

an inhibitor of 11 beta-HSD 1,

inhibitors of protein tyrosine phosphatase 1B (PTP1B),

sodium-dependent glucose transporter 1 or 2(SGLT1 or SGLT2) modulators,

compounds which alter lipid metabolism, such as components having antihyperlipidemic activity and components having antilipidemic activity,

a compound that reduces the intake of food,

a compound that increases the production of heat,

PPAR and RXR modulators, and

an active ingredient having an effect on ATP-dependent potassium channels in beta-cells.

In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin or L-659699.

In one embodiment of the invention, a compound of formula I is administered in combination with a cholesterol absorption inhibitor, such as ezetimibe, tiquinan, pamoside, FM-VP4 (sitostanol/brassicasterol ascorbyl phosphate; Forbes Medi-Tech, WO 2005042692, WO 2005005453), MD-0727(Microbia Inc., WO 2005021497, WO 2005021495) or a compound described in: WO 2002066464, WO 2005000353(Kotobuki pharmaceutical Co. ltd.), WO 2005044256 or WO 2005062824(Merek & Co.), WO 2005061451 and WO 2005061452(AstraZeneca AB), WO 2006017257(Phenomix), WO2005033100(Lipideon Biotechnology AG), WO 2004097655, WO 2004000805, WO 2004000804, WO 2004000803, WO 2002050068, WO 2002050060, WO 2005047248, WO 2006086562, WO 2006102674, WO 2006116499, WO 2006121861, WO 2006122186, WO 2006122216, WO 2006127893, WO 2006137794, WO 2006137796, WO 2006137782, WO 2006137793, WO 2006137797, WO 2006137795, WO 2006137792 or WO 2006138163.

In one embodiment of the invention, the compound of formula I is administered in combination with VytorinTM, which is a fixed combination of ezetimibe and simvastatin.

In one embodiment of the invention, the compound of formula I and the fixed combination of ezetimibe and atorvastatin are administered in combination.

In one embodiment of the invention, the compound of formula I and the fixed combination of ezetimibe and fenofibrate are administered in combination.

In another embodiment of the invention, the compound of formula I and the fixed combination of fenofibrate and rosuvastatin are administered in combination.

In one embodiment of the invention, the compound of the formula I is administered in combination withThe latter is a fixed combination of fenofibrate and metformin.

In one embodiment of the invention, the compound of formula I is administered in combination with ISIS-301012, which is an antisense oligonucleotide capable of modulating the apolipoprotein B gene.

In one embodiment of the invention, a compound of formula I is administered in combination with a PPAR γ agonist, such as rosiglitazone, pioglitazone, JTT-501, G1262570, R-483, CS-011 (rivoglitazone).

In one embodiment of the invention, the compound of formula I is administered in combination with a compact^TMThe latter is a fixed combination of pioglitazone hydrochloride and metformin hydrochloride.

In one embodiment of the invention, the compound of formula I is administered in combination with a Tademact^TMThe latter is a fixed combination of pioglitazone and glimepiride.

In one embodiment of the invention, the compound of formula I and pioglitazone hydrochloride are administered in combination with a fixed combination of an angiotensin II agonist (e.g. TAK-536).

In one embodiment of the invention, a compound of formula I is administered in combination with a PPAR α agonist, such as GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945, LY-518674 or those described in WO 2001040207, WO 2002096894, WO 2005097076.

In one embodiment of the invention, a compound of formula I is administered in combination with a PPAR α/γ mixed agonist, for example, nateglinide (navaglitazar), LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (lobeglitazone sulfate) or the drugs described in WO 00/64888, WO 00/64876, WO03/020269 or J.P. Berger et al, TRENDS in pharmaceutical Sciences (28), (5), 244-.

In one embodiment of the invention, a compound of formula I is administered in combination with a PPAR8 agonist, such as GW-501516 or the drugs described in WO 2006059744, WO 2006084176, WO 2006029699, WO 2007039172, WO 2007039178.

In one embodiment, the compound of formula I is administered in combination with metoclopramide or MBX-2044 or other partial PPAR γ agonist/antagonist.

In one embodiment of the invention, the compound of formula I is administered in combination with a fibrate, e.g., fenofibrate, clofibrate or bezafibrate.

In one embodiment of the invention, the compound of formula I is administered in combination with an MTP inhibitor, such AS, for example, Enptapide (impliptaside), BMS-201038, R-103757, AS-1552133 or those described in WO 2005085226, WO 2005121091, WO 2006010423.

In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor, such as torcetrapib, JTT-705 or those described in WO 2006002342, WO2006010422, WO 2006012093, WO 2006073973, WO 2006072362, WO2006097169, WO 2007041494.

In one embodiment of the invention, the compound of formula I is administered in combination with a bile acid absorption inhibitor (see, for example, US6,245,744, US6,221,897 or WO 00/61568), such as HMR 1741 or those described in DE 102005033099.1, DE 102005033100.9, WO2007009655 and WO 2007009656.

In one embodiment of the invention, the compound of formula I is administered in combination with a bile acid polymer absorber, such as cholestyramine or colesevelam (colesevelam).

In one embodiment of the invention, the compound of formula I is administered in combination with an LDL receptor inducing agent (see US6,342,512), such as HMR1171, HMR1586 or those described in WO 2005097738.

In one embodiment of the invention, a compound of formula I is administered in combination with an ABCA1 expression enhancer, such as the agents described in WO 2006072393 for ABCA1 expression enhancer.

In another embodiment of the invention, a compound of formula I is administered in combination with an RNAi therapeutic agent directed against PCSK9 (protein convertase sublisisin/kexin type 9).

In one embodiment, the compound of formula I is administered in combination with(omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).

In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor, such as avasimibe (avasimibe) or SMP-797.

In one embodiment of the invention, the compound of formula I is administered in combination with an antioxidant, such as OPC-14117, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.

In one embodiment of the invention, the compound of formula I is administered in combination with a vitamin, such as vitamin B6 or vitamin B12.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein lipase modulator, for example, ibrolipi (NO-1886).

In one embodiment of the invention, the compound of formula I is administered in combination with an ATP citrate lyase inhibitor, such as SB-204990.

In one embodiment of the invention, the compound of the formula I is administered in combination with a squalene synthetase inhibitor, for example BMS-188494, TAK-475 or the drugs described in WO2005077907, JP 2007022943.

In one embodiment of the invention, a compound of formula I is administered in combination with a lipoprotein (a) antagonist, such as gemcabene (CI-1027).

In one embodiment of the invention, a compound of formula I is administered in combination with a GPR109A agonist (HM74A receptor agonist; NAR agonist (nicotinic acid receptor agonist)), such as nicotinic acid, extended release nicotinic acid binding to MK-0524A, or those described in WO 2006045565, WO 2006045564, WO2006069242, WO 2006124490, WO 2006113150, WO 2007017261, WO2007017262, WO 2007017265, WO 2007015744, WO 2007027532, the GPR109A agonist (HM74A receptor agonist; NAR agonist (nicotinic acid receptor agonist)).

In another embodiment of the invention, a compound of formula I is administered in combination with a GPR116 agonist as described, for example, in WO2006067531, WO 2006067532.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipase inhibitor, such as orlistat (orlistat) or cetilistat (cetilistat) (ATL-962).

In one embodiment of the invention, the compound of formula I is administered in combination with insulin.

In one embodiment, the compound of formula I is administered in combination with a sulfonylurea agent, such as tolbutamide, glyburide, glipizide, gliclazide or glimepiride.

In one embodiment, the compounds of formula I are administered in combination with an agent that increases insulin secretion, such as KCP-265(WO 2003097064) or those described in WO 2007026761.

In one embodiment, a compound of formula I is administered in combination with a glucose-dependent insulinotropic receptor (GDIR) agonist, e.g., APD-668.

In one embodiment, the compound of formula I is administered in combination with a biguanide, for example, metformin.

In another embodiment, the compound of formula I is administered in combination with a meglitinide, such as repaglinide, nateglinide, or mitiglinide.

In another embodiment, a compound of formula I and mitiglinide are administered in combination with a glitazone drug (glitazone), such as pioglitazone hydrochloride.

In another embodiment, a compound of formula I and mitiglinide are administered in combination with an α -glucosidase inhibitor.

In one embodiment, a compound of formula I is administered in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or a compound described in WO97/41097(dr. heavy's Research Foundation) (particularly 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxoquinazolin-2-ylmethoxy ] phenyl ] methyl ] -2, 4-thiazolidinedione).

In one embodiment, the compound of formula I is administered in combination with an α -glucosidase inhibitor, such as miglitol or acarbose.

In one embodiment, the compound of formula I is administered in combination with an active ingredient that has an effect on the ATP-dependent potassium channel in beta cells, such as tolbutamide, glyburide, glipizide, glimepiride or repaglinide.

In one embodiment, a compound of formula I is administered in combination with more than one of the above-mentioned compounds, e.g., sulfonylureas and metformin, sulfonylureas and acarbose, repaglinide and metformin, insulin and sulfonylureas, insulin and metformin, insulin and troglitazone, insulin and lovastatin, and the like.

In one embodiment, the compound of formula I is administered in combination with a glycogen phosphorylase inhibitor, such as PSN-357, FR-258900 or those described in WO 2003084922, WO 2004007455, WO 2005073229, WO 2005073230, WO 2005073231 or WO 2005067932.

In one embodiment, the compound of formula I is administered in combination with a glucagon receptor antagonist, such as A-770077, NNC-25-2504, or a drug described in WO 2004100875 or WO 2005065680.

In one embodiment, a compound of formula I is administered in combination with a glucokinase activator such as LY-2121260(WO 2004063179), PSN-105, PSN-110, GKA-50, or agents such as those described in: WO 2004072031, WO2004072066, WO 2005080360, WO 2005044801, WO 2006016194, WO2006058923, WO 2006112549, WO 2006125972, WO 2007017549, WO2007017649, WO 2007007910, WO 2007007040-42, WO 2007006760-61, WO 2007006814, WO 2007007886, WO 2007028135, WO 2007031739, WO 2007041365, WO 2007041366, WO 2007037534, WO 2007043638, WO 2007053345, WO 2007051846, WO 2007051845, WO 2007053765, WO 2007051847.

In one embodiment, a compound of formula I is administered in combination with a gluconeogenesis inhibitor, for example FR-225654.

In one embodiment, the compound of formula I is administered in combination with a fructose-1, 6-bisphosphatase (FBPase) inhibitor, such as CS-917(MB-06322), MB-07803 or those described in WO 2006023515, WO 2006104030, WO 2007014619.

In one embodiment, a compound of formula I is administered in combination with a glucose carrier 4(GLUT4) modulator, such as KST-48(D. -O.Lee et al.: Arzneim. -Forsch. drug Res.54(12), 835 (2004)).

In one embodiment, the compound of formula I is administered in combination with a glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitor, such as the one described in WO 2004101528.

In one embodiment, a compound of formula I is administered in combination with a dipeptidyl peptidase IV (DPP-IV) inhibitor, such as vildagliptin (LAF-237), sitagliptin (sitagliptin) (MK-0431), sitagliptin phosphate, saxagliptin (Saxagliptin) (BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP-104, DP-893, ABT-341, ABT-279, or salts thereof or those compounds described in: WO2003074500, WO 2003106456, WO 2004037169, WO 200450658, WO2005058901, WO 2005012312, WO 2005/012308, WO 2006039325, WO2006058064, WO 2006015691, WO 2006015701, WO 2006015699, WO2006015700, WO 2006018117, WO 2006099943, WO 2006099941, JP2006160733, WO 2006071752, WO 2006065826, WO 2006078676, WO2006073167, WO 2006068163, WO 2006090915, WO 2006104356, WO2006127530, WO 2006111261, WO20070 2007015767, WO 2007024993, WO 2007029086.

In one embodiment, the compound of formula I is administered in combination with JanumetTM, which is a fixed combination of sitagliptin phosphate and metformin hydrochloride.

In one embodiment, a compound of formula I is administered in combination with an 11 β -hydroxysteroid dehydrogenase 1(11 β -HSD1) inhibitor, such as BVT-2733, JNJ-25918646, INCB-13739 or such as those described in the following references: WO 200190090-94, WO 200343999, WO 2004112782, WO 200344000, WO 200344009, WO 2004112779, WO 2004113310, WO 2004103980, WO2004112784, WO 2003065983, WO 2003104207, WO 2003104208, WO2004106294, WO 2004011410, WO 2002007251, WO 2004011410, WO2004089367, WO 2004011410-71, WO 2004011410, WO2005016877, WO 2004011410, WO2006012173, WO 2004011410, WO2006051662, WO 2004011410, WO2006050908, WO 2004011410, WO2006074244, WO 2004011410, WO 20061481, WO 3634481, WO 2004011410, WO 20036613872, WO 20036584, WO 36695, WO 366672, WO 200607472, WO 36695, WO 2004011410, WO 36584, WO 2004011410, WO 366672, WO 200607436695.

In one embodiment, a compound of formula I is administered in combination with a protein tyrosine phosphatase 1B (PTP1B) inhibitor, such as the drugs described in: WO 200119830-31, WO 200117516, WO 2004506446, WO 2005012295, WO 2005116003, WO 2005116003, WO 2006007959, DE 102004060542.4, WO 2007009911, WO 2007028145, WO 2007081755.

In one embodiment, a compound of formula I is administered in combination with a sodium-dependent glucose carrier 1 or 2(SGLT1 or SGLT2) modulator, such as KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, sjogren (sergliflozin), or a drug such as those described in: WO 2004007517, WO 200452903, WO 200452902, PCT/EP 2005/005959, WO 2005085237, JP 2004359630, WO 2005121161, WO 2006018150, WO 2006035796, WO2006062224, WO 2006058597, WO 2006073197, WO 2006080577, WO2006087997, WO 2006108842, WO 2007000445, WO 2007014895, WO2007080170 or a.l.handlen in Expert opin.ther patents (2005)15(11), 1531-1540.

In one embodiment, a compound of formula I is administered in combination with a GPR40 modulator, e.g., as described in WO 2007013689, WO 2007033002.

In one embodiment, a compound of formula I is administered in combination with a GPR119b modulator, e.g., as described in WO 2004041274 for example, as a medicament.

In one embodiment, a compound of formula I is administered in combination with a GPR119 modulator, e.g., as described in WO 2005061489(PSN-632408), WO 2004065380, WO 2007003960-62, and WO 2007003964.

In another embodiment, a compound of formula I is administered in combination with a GPR120 modulator.

In one embodiment, the compound of formula I is administered in combination with a Hormone Sensitive Lipase (HSL) and/or phospholipase inhibitor, e.g., as described in WO 2005073199, WO 2006074957, WO 2006087309, WO 2006111321, WO 2007042178.

In one embodiment, the compound of formula I is administered in combination with an acetyl-coa carboxylase (ACC) inhibitor, such as those described in WO 199946262, WO 200372197, WO2003072197, WO 2005044814, WO 2005108370, JP2006131559, WO 2007011809, WO 2007011811, WO 2007013691.

In another embodiment, the compound of formula I is administered in combination with a Xanthine Oxidoreductase (XOR) modulator.

In one embodiment, the compound of formula I is administered in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), such as those described in WO 2004074288.

In one embodiment, a compound of formula I is administered in combination with a glycogen synthase kinase 3 β (GSK-3 β) inhibitor, such as those described in: US 2005222220, WO 2005085230, WO 2005111018, WO2003078403, WO 2004022544, WO 2003106410, WO 2005058908, US2005038023, WO 2005009997, US 2005026984, WO 2005000836, WO2004106343, EP 1460075, WO 2004014910, WO 2003076442, WO2005087727 or WO 2004046117.

In one embodiment, the compound of formula I is administered in combination with a serum/glucocorticoid-regulated kinase (SGK) inhibitor, such as the drugs described in WO 2006072354.

In one embodiment, a compound of formula I is administered in combination with a RUP3 receptor agonist, such as the one described in WO 2007035355.

In one embodiment, a compound of formula I is administered in combination with a protein kinase C β (PKC β) inhibitor, such as ruboxistaurin.

In another embodiment, a compound of formula I is administered in combination with an activator of a gene encoding Ataxia Telangiectasia Mutated (ATM) protein kinase, such as chloroquine.

In one embodiment, a compound of formula I is administered in combination with an endothelin A receptor antagonist, such as avosentan (SPP-301).

In one embodiment, the compound of formula I is administered in combination with an "I- κ B kinase" inhibitor (IKK inhibitor), e.g. a drug as described in WO 2001000610, WO2001030774, WO 2004022553 or WO 2005097129.

In one embodiment, a compound of formula I is administered in combination with a Glucocorticoid Receptor (GR) modulator, e.g., as described in WO 2005090336, WO2006071609, WO 2006135826.

In another embodiment, the compound of formula I is administered in combination with:

CART modulators (see "cocoa-amphetamine-regulated transcription in vitro metabolism, anamorphic and secretory expression in mice," Asakawa, A.et al: Hormone and Metabolic Research (2001), 33(9), 554-);

NPY antagonists such as naphthalene-1-sulfonic acid {4- [ (4-aminoquinazolin-2-ylamino) methyl ] cyclohexylmethyl } amide hydrochloride (CGP 71683A);

NPY-5 receptor antagonists, such as L-152804 or drugs such as those described in WO 2006001318;

NPY-4 receptor antagonists, such as those described in WO 2007038942;

NPY-2 receptor antagonists, such as those described in WO 2007038943;

peptide YY3-36 (PYY3-36) or similar compounds, such as CJC-1682 (PYY3-36 bound to human serum albumin via Cys 34), CJC-1643 (PYY3-36 derivatives bound to serum albumin in vivo) or those drugs described in WO 2005080424, WO 2006095166;

peptide obesity inhibin derivatives, such as the drugs described in WO 2006096847;

CB1R (cannabinoid receptor 1) antagonists, such as rimonabant (rimonabant), SR147778, SLV-319, AVE-1625, MK-0364 or salts thereof or compounds such as those described in the following references: EP, WO-64634, WO-48, WO, US, WO200132663, WO2004058145, WO2004013120, WO2004058255, WO, US20040214855, US, WO2004096794, WO, US, WO2004110453, WO, US20050009870, WO-34, WO-39, WO, US, WO-62, WO-48, WO-20050009, WO 2006087480, WO 2006087476, WO 2006100208, WO 2006106054, WO 2006111849, WO 2006113704, WO 2007009705, WO 2007017124, WO 2007017126, WO 2007018459, WO 2007016460, WO 2007020502, WO 2007026215, WO 2007028849, WO 2007031720, WO 2007031721, WO 2007036945, WO 2007038045, WO 2007039740, US20070015810, WO 2007046548, WO 2007047737, WO 2007084319, WO 2007084450;

cannabinoid receptor 1/cannabinoid receptor 2(CB1/CB2) modulating compounds, such as the drugs described in WO2007001939, WO 2007044215, WO 2007047737;

MC4 agonists, such as 1-amino-1, 2, 3, 4-tetrahydronaphthalene-2-carboxylic acid [2- (3 a-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), LB53280, LB53279, LB53278, THIQ, MB243, RY764, CHIR-785, PT-141 or those drugs described in: WO 2005060985, WO2005009950, WO 2004087159, WO 2004078717, WO 2004078716, WO2004024720, US 20050124652, WO 2005051391, WO 2004112793, WOUS20050222014, US 20050176728, US 20050164914, US 20050124636, US20050130988, US 20040167201, WO 2004005324, WO 2004037797, WO2005042516, WO 2005040109, WO 2005030797, US 20040224901, WO200501921, WO 200509184, WO 2005000339, EP 1460069, WO 2005047253, WO 2005047251, WO 2005118573, EP 1538159, WO 2004072076, WO2004072077, WO 2006021655-57, WO2007009894, WO 2007015162, WO2007041061, WO 2007041052;

orexin receptor antagonists, such as 1- (2-methylbenzoxazol-6-yl) -3- [1, 5] naphthyridin-4-ylurea hydrochloride (SB-334867-A) or drugs such as those described in WO 200196302, WO 200185693, WO2004085403, WO 2005075458 or WO 2006067224;

histamine H3 receptor agonists such as 3-cyclohexyl-1- (4, 4-dimethyl-1, 4, 6, 7-tetrahydroimidazo [4, 5-c ] pyridin-5-yl) propan-1-one oxalate (WO 00/63208) or those drugs described in WO 200064884, WO2005082893, WO 2006107661, WO 2007003804, WO 2007016496, WO 2007020213;

histamine H1/histamine H3 modulators, such as betahistine and its dihydrochloride;

CRF antagonists, such as [ 2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-1, 3, 9-triazafluoren-4-yl ] dipropylamine (WO 00/66585);

CRF BP antagonists, such as urocortin (urocortin);

a urocortin agonist;

beta 3 adrenoceptor agonists such as 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) ethylamino ] ethanol hydrochloride (WO 01/83451), Solabetron (GW-427353), N-5984(KRP-204) or those described in JP 2006111553, WO2002038543, WO 2007048840-843;

MSH (melanocyte stimulating hormone) agonists;

MCH (melanin concentrating hormone) receptor antagonists such as NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or compounds such as those described in the following references: WO 2005085200, WO 2005019240, WO 2004011438, WO2004012648, WO 2003015769, WO 2004072025, WO 2005070898, WO2005070925, WO 2004039780, WO 2004092181, WO 2003033476, WO2002006245, WO 2002089729, WO 2002002744, WO 2003004027, FR2868780, WO 2006010446, WO 2006038680, WO 2006044293, WO2006044174, JP 2006176443, WO 2006018280, WO 2006018279, WO2006118320, WO 2006130075, WO 2007018248, WO 2007012661, WO2007029847, WO 2007024004, WO 2007039462, WO 2007042660, WO 4220070200702007020070668, WO 2007042669, US 2007093508, US 2007093509, WO2007048802, JP 2007091649;

CCK-A agonists, such as {2- [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) thiazol-2-ylcarbamoyl ] -5, 7-dimethylindol-1-yl } acetic acid trifluoroacetate (WO 99/15525), SR-146131(WO 0244150), SSR-125180 or those drugs described in WO 2005116034;

serotonin reuptake inhibitors, such as dexfenfluramine;

a mixed serotonin/dopamine reuptake inhibitor (e.g., bupropion) or a fixed combination of bupropion and naltrexone;

mixed serotonergic and noradrenergic compounds (e.g., WO 00/71549);

5-HT receptor agonists, such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO 01/09111);

mixed dopamine/norepinephrine/acetylcholine reuptake inhibitors, such as tesofensine;

5-HT2C receptor agonists, such as loreaserin hydrochloride (APD-356), BVT-933 or those described in: WO 200077010, WO 20077001-02, WO2005019180, WO 2003064423, WO 200242304, WO 2005035533, WO2005082859, WO 2006077025, WO 2006103511;

5-HT6 receptor antagonists, such as E-6837, BVT-74316 or drugs such as those described in WO 2005058858, WO 2007054257;

bombesin receptor agonists (BRS-3 agonists);

galanin receptor antagonists;

growth hormones, such as human growth hormone or AOD-9604;

growth hormone releasing compounds, such as tert-butyl 6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695);

growth hormone secretagogue receptor antagonists (growth hormone releasing hormone antagonists), such as those described in a-778193 or in WO 2005030734;

TRH agonists (see, e.g., EP 0462884);

uncoupling protein 2 or 3 modulators;

leptin agonists (see, e.g., Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. leptin agonists as a potential improvement pro ach to the treatment of obesity. drugs of the Future (2001), 26(9), 873-);

DA agonists (bromocriptine or Doprexin);

lipase/amylase inhibitors (e.g., WO 00/40569);

diacylglycerol O-acyltransferase (DGAT) inhibitors, such as BAY-74-4113 or medicaments such as those described in: US 2004/0224997, WO 2004094618, WO200058491, WO 2005044250, WO 2005072740, JP 2005206492, WO2005013907, WO 2006004200, WO 2006019020, WO 2006064189, WO2006082952, WO 2006120125, WO 2006113919, WO 2006134317, WO 2007016538;

fatty Acid Synthase (FAS) inhibitors such as C75 or those described in WO 2004005277;

inhibitors of stearoyl-coa δ 9 desaturase (SCD1), such as the drugs described in WO 2007009236, WO 2007044085, WO 2007046867, WO 2007046868, WO 20070501124;

oxyntomodulin;

oleoyl estrone; or

Thyroid hormone receptor agonists or partial agonists, such as KB-2115 or those drugs described in: WO 20058279, WO 200172692, WO 200194293, WO2003084915, WO 2004018421, WO 2005092316, WO 2007003419, WO2007009913, WO 2007039125.

In one embodiment, the other active ingredient is varenicline tartrate (vareniclinetartrate), which is a partial agonist of α 4- β 2 nicotinic acetylcholine receptors.

In one embodiment, the other active ingredient is rodussquesmine.

In one embodiment, the other active ingredient is a SIRT1 enzyme modulator.

In one embodiment of the invention, the other active ingredient is leptin; see, e.g., "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-.

In one embodiment, the other active ingredient is dextroamphetamine or amphetamine.

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

In another embodiment, the other active ingredient is sibutramine.

In one embodiment, the other active ingredient is mazindol or phentermine.

In one embodiment, the compound of formula I is administered in combination with a bulking agent, preferably an insoluble bulking agent (see also forFor example(Zunft H J; et al, Carob pulp prediction for treatment of hypercholesteremia, ADVANCESIN THERAPY (2001 Sep-Oct, 18 (5)), 230-6)). Caromax is a product containing carob bean gum (Nutrinova, Nutrition Specialties)& Food Ingredients GmbH，Industriepark65926 Frankfurt/Main). A compound of the formula I andcan be in one formulation, or a compound of the formula I andthe administration is divided.It may also be administered here in the form of a food product, such as a bakery product or a breakfast bar.

It is to be understood that every suitable combination of a compound of the present invention with one or more of the above compounds and optionally one or more other pharmacologically active substances is within the scope of the present invention.

The activity of the compounds of the invention was tested as follows:

determination of EC50 values for PPAR agonists in cellular PPAR α assays

Principle of

The ability of a substance to bind to human PPAR α and activate it agonistically was analyzed using a stably transfected HEK cell line (HEK ═ human fetal kidney), referred to herein as a PPAR α reporter cell line. It contains two genetic elements, the luciferase reporter element (p. delta. M-GAL4-Luc-Zeo) and the PPAR α fusion protein (GR-GAL 4-human PPAR α -LBD) which mediates expression of the luciferase reporter element dependent on the PPAR α ligand (GR-GAL 4-human PPAR α -LBD). The fusion protein GR-GAL 4-human PPAR α -LBD, stably and constitutively expressed, binds 5' -upstream of the GAL4DNA binding motif in the luciferase reporter element, which is stably integrated in the genome of the PPAR α reporter cell line, via the GAL4 protein moiety in the nucleus of the PPAR α reporter cell line. If fatty acid depleted fetal calf serum (cs-FCS) is used in the assay, the expression of the luciferase reporter is weak in the absence of PPAR α ligand. The PPAR α ligand binds to and activates the PPAR α fusion protein and thus stimulates expression of the luciferase reporter gene. The luciferase formed may be detected by chemiluminescence through a suitable substrate.

Construction of PPAR α reporter cell lines

PPAR α reporter cell lines were prepared in two stages. First, luciferase reporter elements were constructed and stably transfected into HEK cells. For this purpose, 5 binding sites in the yeast transcription factor GAL4 (accession # AF264724) were cloned 5' -upstream in the minimal MMTV promoter (accession # V01175) of 68bp in length. The minimal MMTV promoter fragment contains the CCAAT box and TATA elements, enabling efficient transcription by RNA polymerase II. Cloning and sequencing of the GAL4-MMTV construct was performed in a similar manner as described in Sambrook J. et al (Molecular cloning, Cold spring harbor Laboratory Press, 1989). The entire Photinus pyralis gene (accession # M15077) was then cloned 3' -downstream in the GAL4-MMTV element. After sequencing, the luciferase reporter element containing 5 GAL4 binding sites, MMTV promoter and luciferase gene was again cloned into a plasmid with zeocin resistance, resulting in plasmid p.delta.M-GAL 4-Luc-Zeo. This vector was transfected into HEK cells as described by Ausubel, F.M. et al (Current protocols in molecular biology, Vol.1-3, John Wiley & Sons, Inc., 1995). The zeocin-containing medium (0.5mg/ml) was then used to select suitable stable cell clones that exhibited very low basal expression of luciferase.

In a second step, the PPAR α fusion protein (GR-GAL 4-human PPAR α -LBD) was introduced into the stable cell clone. For this purpose, the cDNA encoding the N-terminal 76 amino acids of the glucocorticoid receptor (accession # P04150) is first ligated to a cDNA fragment encoding amino acids 1-147 of the yeast transcription factor GAL4 (accession # P04386). The cDNA for the ligand binding domain of the human PPAR α receptor (amino acids S167-Y468; accession # S74349) was cloned into the 3' -end of the GR-GAL4 construct. The fusion construct (GR-GAL 4-human PPAR α -LBD) prepared in this way was again cloned into plasmid pcDNA3(Invitrogen) enabling constitutive expression therein by the cytomegalovirus promoter. This plasmid was linearized with restriction endonucleases and stably transfected into the above-described cell clone containing the luciferase reporter element. PPAR α reporter cell lines prepared containing luciferase reporter elements and constitutively expressing PPAR α fusion protein (GR-GAL 4-human PPAR α -LBD) were isolated by selection with zeocin (0.5mg/ml) and G418(0.5 mg/ml).

Measurement method

The activity of PPAR α agonists was determined in a3 day assay as follows:

day 1

The PPAR α reporter cell lines were cultured to 80% fusion in DMEM (#41965-039, Invitrogen) mixed with the following additives: 10% cs-FCS (fetal calf serum; # SH-30068.03, Hyclone), 0.5mg/ml zeocin (# R250-01, Invitrogen), 0.5mg/ml G418(#10131-027, Invitrogen), 1% penicillin-streptomycin solution (#15140-122, Invitrogen) and 2mM L-glutamine (#25030-024, Invitrogen). In a cell culture incubator (37 ℃ and 5% CO)₂) Was cultured in a standard cell culture flask (#353112, Becton Dickinson). Cells with a fusion rate of 80% were washed once with 15ml PBS (#14190-094, Invitrogen), treated with 3ml trypsin solution (#25300-054, Invitrogen) for 2 min at 37 ℃, taken up in 5ml of the DMEM, and counted in a cell counter. After dilution to 500.000 cells/ml, 35,000 cells were seeded into each well of a 96-well microtiter plate (#3610, Corning Costar) with a clear plastic bottom. Plates were placed in a cell culture incubator (37 ℃ C. and 5% CO)₂) And culturing for 24 hours.

Day 2

The PPAR α agonist to be tested was dissolved in DMSO at a concentration of 10 mM. This stock solution was diluted in DMEM (#41965-039, Invitrogen) mixed with 5% cs-FCS (# SH-30068.03, Hyclone), 2mM L-glutamine (#25030-024, Invitrogen) and the above antibiotics (zeocin, G418, penicillin and streptomycin).

The test substances were tested at 11 different concentrations (ranging from 10. mu.M to 100 pM). More potent compounds were tested at concentrations ranging from 1 μ M to 10pM or 100nM to 1 pM.

The medium inoculated with the PPAR α reporter cell line on day 1 was completely removed by aspiration and the test substance diluted in the medium was immediately added to the cells. Dilution and addition of substances is carried out by a robot (Beckman FX). The final volume of test substance diluted in medium was 100 μ l/well per well in a 96-well microtiter plate. The DMSO concentration in the assay was less than 0.1% v/v, thus avoiding the cytotoxic effects of the solvent.

To each plate was added a standard PPAR α agonist diluted in a similar manner at 11 different concentrations to confirm the functionality of the assay for each individual plate. The assay plates were placed in an incubator (37 ℃ C. and 5% CO)₂) And culturing for 24 hours.

Day 3

PPAR α reporter cells treated with test substances were removed from the incubator and the medium was aspirated off. Cells were lysed as follows: to each well of a 96-well microtiter plate, 50. mu.l of Bright Glo reagent (Promega) was pipetted. After incubation for 10 min at room temperature in the dark, the microtiter plates were measured in a luminometer (Trilux from Wallac). The measurement time for each well of the microtiter plate was 1 second.

Evaluation of

The raw data from the photometer was transferred to a Microsoft Excel file. Dose-response curves and EC50 values for PPAR agonists were calculated using the xl. fit program according to the manufacturer's (IDBS) instructions.

The compounds of examples 1 to 24 had PPAR α EC50 values in this assay of 0.2 μ M to 10 μ M. The compounds of formula I of the present invention activate PPAR α receptors.

Principle of

The ability of a substance to bind to human PPAR δ and activate it agonistically was analyzed using a stably transfected HEK cell line (HEK ═ human fetal kidney), referred to herein as a PPAR δ reporter cell line. Similar to the assay described for PPAR α, the PPAR δ reporter cell line also contains two genetic elements, the luciferase reporter element (p δ M-GAL4-Luc-Zeo) and the PPAR δ fusion protein (GR-GAL 4-human PPAR δ -LBD), which mediates expression of the luciferase reporter element dependent on the PPAR δ ligand (GR-GAL 4-human PPAR δ -LBD). The fusion protein GR-GAL 4-human PPAR δ -LBD, stably and constitutively expressed, binds 5' -upstream of the GAL4DNA binding motif in the luciferase reporter element, which is stably integrated in the genome of the PPAR δ reporter cell line, via the GAL4 protein moiety in the nucleus of the PPAR δ reporter cell line. If fatty acid depleted fetal calf serum (cs-FCS) is used in the assay, the expression of the luciferase reporter is minimal in the absence of PPAR delta ligand. The PPAR δ ligand binds to and activates the PPAR δ fusion protein and thus stimulates expression of the luciferase reporter gene. The luciferase formed may be detected by chemiluminescence through a suitable substrate.

Construction of PPAR delta reporter cell lines

The preparation of stable PPAR δ reporter cell lines was based on stable HEK cell clones stably transfected with luciferase reporter elements. This procedure is described above in "construction of PPAR α reporter cell lines". In the second step, the PPAR delta fusion protein (GR-GAL 4-human PPAR delta-LBD) was stably introduced into this cell clone. For this purpose, the cDNA encoding the N-terminal 76 amino acids of the glucocorticoid receptor (accession # P04150) is ligated to a cDNA fragment encoding amino acids 1-147 of the yeast transcription factor GAL4 (accession # P04386). The cDNA for the ligand binding domain of the human PPAR delta receptor (amino acids S139-Y441; accession # L07592) was cloned into the 3' -end of the GR-GAL4 construct. The fusion construct (GR-GAL 4-human PPAR delta-LBD) prepared in this way was again cloned into plasmid pcDNA3(Invitrogen) to enable constitutive expression by the cytomegalovirus promoter. This plasmid was linearized with restriction endonucleases and stably transfected into the above-described cell clone containing the luciferase reporter element. The resulting PPAR delta reporter cell lines containing the luciferase reporter element and constitutively expressing the PPAR delta fusion protein (GR-GAL 4-human PPAR delta-LBD) were isolated by selection with zeocin (0.5mg/ml) and G418(0.5 mg/ml).

Assay methods and evaluation

The activity of PPAR δ agonists was determined in a 3-day assay very similar to the method described for the PPAR α reporter cell line, except that the test efficacy was controlled using a PPAR δ reporter cell line and a specific PPAR δ agonist as standards.

The PPAR agonists of examples 1 to 24 of the present invention were measured to have PPAR Δ EC50 values of 1nM to 10 μ M. The compounds of formula I of the present invention activate the PPAR delta receptor.

The examples given in table 1 are intended to illustrate the invention and not to limit it.

The efficacy of some of the examples is shown in the following table:

examples	PPARδEC50(μM)	PPARαEC50(μM)
			1	0.0023	2.62
3	0.0033	n.a.
			5	0.0019	1.68
8	0.055	1.14
			12	0.53	n.a.
13	0.0004	0.505

Method

The compounds of general formula I of the present invention can be prepared as outlined in the following reaction scheme:

method A

Compounds of the general formula A-1 (wherein n, R3, R4, R5, R6, R7, X4 and X5 are as defined in the specification and Hal represents a halogen such as chlorine, bromine or iodine) are reacted with boronic acids or boronic esters of the general formula A-2 (wherein M1 and M2 may independently be hydrogen or alkyl (when alkyl, M1 and M2 may form a ring system) and R8, R9, X1, X2 and X3 are as defined in the specification) under reaction conditions of the Suzuki type which represent reaction in a solvent (e.g. DMF/water) in a base (e.g. Cs/water)₂CO₃) Using a catalytic amount of a transition metal (e.g., palladium) and a ligand (e.g., triphenylphosphine) in the presence of a catalyst to give a compound of formula a-3, which is then reduced with a reducing agent such as lithium aluminum hydride in a solvent such as tetrahydrofuran to give a compound of formula a-5. Alternatively, the compound of formula A-1 is first reduced under the above reaction conditions to give the compound of formula A-4, which is then reacted with a boronic acid or boronic ester of formula A-2 under the above Suzuki-type reaction conditions to give the compound of formula A-5. The compound of formula A-5 is then reacted with a sulfonyl chloride of formula A-6 (wherein R1 and R2 are as defined herein) in a solvent such as dichloromethane in the presence of a base such as triethylamine or pyridine to provide the compound of formula A-7. The compound of formula a-7 is reacted with hydroxylamine hydrochloride in a solvent such as tetrahydrofuran and methanol in the presence of a base such as triethylamine to provide the compound of formula a-8. The reaction can be promoted by heating the reaction mixture under microwave radiation. The compound of formula A-8 is converted to a product of formula A-9 as follows: the compound of formula A-8 is reacted with phenyl chloroformate in the presence of a base such as pyridine or diisopropylethylamine followed by heating the reaction mixture with microwave radiation to effect cyclization, or the resulting intermediate is isolated and subjected to cyclization with a base such as 1, 8-diazabicyclo [5.4.0 ]]The undec-7-ene is treated in a solvent such as acetonitrile.

Examples 1 to 24 were obtained according to method A.

Other compounds may be obtained accordingly or by known methods.

List of abbreviations:

Ac	acetyl group
		AIBN	2, 2' -azobis (2-methylpropanenitrile)
Bn	Benzyl radical
		iBu	Isobutyl radical
tBu	Tert-butyl radical
		BuLi	N-butyl lithium
Bz	Benzoyl radical
		Cy	Cyclohexyl radical
DBU	1, 8-diazabicyclo [5.4.0 ]]Undec-7-enes
		DCI	Direct chemical ionization (MS)
DCM	Methylene dichloride
		DMAP	N, N-dimethylaminopyridine
DMF	N, N-dimethylformamide
		DMSO	Dimethyl sulfoxide
dba	Dibenzylidene acetone
		dppf	1, 1' -bis (diphenylphosphino) ferrocene

EE	Ethyl acetate
		eq	Equivalent weight
ESI	Electrospray ionization (MS)
		Hal	Halogen element
HPLC	High performance liquid chromatographySpectrum
		LG	Leaving group
LC-MS	Liquid chromatography coupled to mass spectrometry
		Me	Methyl radical
MS	Mass spectrometry
		MsCl	Methanesulfonyl chloride
NBS	N-bromosuccinimide
		NMR	Nuclear magnetic resonance
p	Alignment of
		Pd/C	Palladium/carbon
iPr	Isopropyl group
		nPr	N-propyl radical
Rf	Retention factor (TLC)
		tert	Four stages
TBAF	Tetrabutylammonium fluoride
		TFA	Trifluoroacetic acid

TLC	Thin layer chromatography

Other compounds of formula I may be prepared accordingly or by known methods.

The experimental procedure for preparing the above examples is as follows:

the following examples were prepared according to method a:

example 1

3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-1H-quinolin-2-one

462mg of 4- (trifluoromethyl) phenylboronic acid, 500mg of 6-bromo-3, 4-dihydro-1H-quinolin-2-one and 2.16g of caesium carbonate are dissolved in a mixture of 2ml of water and 8ml of dimethylformamide. The reaction mixture was degassed with argon, then 128mg tetrakis (triphenylphosphine) palladium (0) was added and the mixture was heated to 90 ℃ and held for 2 hours. The cooled reaction mixture was diluted with 100ml of ethyl acetate and washed with 50ml of water and brine. The organic layer was MgSO₄Drying and removing the solvent in vacuum. The resulting crude material was purified by silica gel chromatography to give 637mg of 6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-1H-quinolin-2-one.

C16H12F3NO(291.28)，MS(ESI⁺)：333.21(M+MeCN+H⁺)。

6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline

630mg of 6- (4-trifluoromethyl-phenyl) -3, 4-hydro-1H-quinolin-2-one are dissolved in 10ml of tetrahydrofuran. A solution of lithium aluminum hydride in tetrahydrofuran (1M, 4.76ml) was added and the reaction mixture was stirred at room temperature for 1 hour. Then, 100. mu.l of water and 100. mu.l of 15% sodium hydroxide solution were added to the reaction mixture cooled with ice. The insoluble salts in the reaction mixture were then filtered off and the filtrate was evaporated under reduced pressure to give 485mg of 6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline.

C16H14F3N(277.29)，MS(ESI⁺)：278.1(M+H⁺)。

4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -benzonitrile

582mg of commercially available 4-cyano-benzenesulfonyl chloride was dissolved in 5ml of pyridine. 400mg6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline are then added and the mixture is stirred at room temperature for 30 min. 290mg of commercially available 4-cyano-benzenesulfonyl chloride were then added and the mixture was stirred at room temperature for a further 2 hours. The solvent was then removed in vacuo and the residue was purified by silica gel chromatography to give 307mg of 4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -benzonitrile. C23H17F3N2O2S (442.46).

N-hydroxy-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -benzamidine

305mg of 4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl]-benzonitrile is dissolved in a mixture of 10ml tetrahydrofuran and 10ml methanol. 1.19g hydroxylamine hydrochloride was added followed by 2.42ml triethylamine. The reaction mixture was stirred at 90 ℃ for 4 hours. The solvent is removed in vacuo and the residue obtained is poured into 50ml of water and extracted 5 times with 50ml of ethyl acetate in portions. The combined organic extracts were washed with 100ml brine, MgSO₄Drying and evaporation of the solvent in vacuo gave 355mg of crude N-hydroxy-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl]-benzamidine. This material was used without further purification. C23H20F3N3O3S (475.49), MS (ESI)⁺)：476.14(M+H⁺)，517.2(M+MeCN+H⁺)。

355mg of crude N-hydroxy-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl]-benzamidine is dissolved in 4ml of dichloromethane. Mu.l pyridine and 113. mu.l phenyl chloroformate were added, and the mixture was stirred at room temperature for 10 minutes. The mixture was diluted by adding 4ml acetonitrile, 558. mu.l 1, 8-diazabicyclo [5.4.0 ] was added]Undec-7-ene. The mixture was stirred at room temperature for 15 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reverse phase HPLC to give 209mg of 3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones. C24H18F3N3O4S (501.49), MS (ESI-): 499.9 (M-H)⁺) 545.9(M + formate anion).

Example 2

3- { 2-chloro-4- [6- (6-trifluoromethyl-pyridin-3-yl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

Following the procedure described for 3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one in example 1, 3- { 2-chloro-4- [6- (6-trifluoromethyl-pyridin-3-yl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4 oxadiazol-5-one.

C23H16ClF3N4O4S(536.92)，MS(ESI⁺)：537.1(M+H⁺)。

Example 3

3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline

1.90g of 4- (trifluoromethyl) phenylboronic acid, 2.0g of 6-bromo-4, 4-dimethyl-1, 2, 3, 4-tetrahydro-quinoline (for its synthesis see EP 419132) and 8.14g of cesium carbonate are dissolved in a mixture of 3.5ml of water and 10ml of dimethylformamide. The reaction mixture was degassed with argon, then 480mg tetrakis (triphenylphosphine) palladium (0) was added and the mixture was heated to 100 ℃ and held for 1 hour. The cooled reaction mixture was diluted with 400ml ethyl acetate and washed with 150ml water and brine. The organic layer was MgSO₄Drying and removing the solvent in vacuum. The resulting crude material was purified by silica gel chromatography to give 1.2g 4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline. C18H18F3N (305.35), MS (ESI)⁺)：306.2(M+MeCN+H⁺) Rf (n-heptane: ethyl acetate ═ 2: 1) ═ 0.45.

3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one was obtained from 4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline and 3-chloro-4-cyano-benzenesulfonyl chloride according to the procedure described in example 1 for 3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4 oxadiazol-5-one.

C26H21ClF3N3O4S(563.98)，MS(ESI^-)：562.1(M-H⁺) Rf (ethyl acetate: methanol: 9: 1) is 0.30.

Example 4

3- { 2-chloro-4- [4, 4-dimethyl-6- (6-trifluoromethyl-pyridin-3-yl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

Following the procedure described for 3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one in example 3, 3- { 2-chloro-4- [4, 4-dimethyl-6- (6-trifluoromethyl-pyridin-3-yl) -3 was obtained from 6-bromo-4, 4-dimethyl-1, 2, 3, 4-tetrahydro-quinoline (for its synthesis see EP 419132), 2- (trifluoromethyl) pyridin-5-ylboronic acid and 3-chloro-4-cyano-benzenesulfonyl chloride, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one.

C25H20ClF3N4O4S(564.97)，MS(ESI⁺)：565.1(M+H⁺)，606.1(M+MeCN+H⁺) Rf (ethyl acetate: methanol: 9: 1) 0.28.

Example 5

3- { 2-chloro-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl]-phenyl } -4H- [1, 2, 4]The method described for oxadiazol-5-one gives 3- { 2-chloro-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl from 6-bromo-3, 3-dimethyl-1, 2, 3, 4-tetrahydro-quinoline (for its synthesis see WO 9629327), 4- (trifluoromethyl) phenylboronic acid and 3-chloro-4-cyano-benzenesulfonyl chloride]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones. C26H21ClF3N3O4S (563.99), MS (ESI)^-)：562.0(M-H⁺) 607.9(M + formate).

Example 6

3- {4- [ 4-amino-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -2-chloro-phenyl } -4H- [1, 2, 4] oxadiazol-5-one

(6-iodo-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid tert-butyl ester

884mg of (1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid tert-butyl ester and 1.07g of calcium carbonate are dissolved in 50ml of methanol. 1.3g of benzyltrimethylammoniumdichloroiodate dissolved in 20ml of dichloromethane are added at-78 ℃ over 1.5 hours. The reaction mixture was stirred at-78 ℃ for 2 hours. Then 2ml of saturated NaHSO was added₃The solution was allowed to warm to room temperature. The reaction mixture was diluted with 100ml of ethyl acetate and washed with 50ml of water and brine. The organic layer was MgSO₄Drying and removing the solvent in vacuum. The crude material obtained is purified by chromatography on silica gel to yield 700mg of (6-iodo-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid tert-butyl ester. C14H19IN2O2 (374.22).

[1- [ 3-chloro-4- (5-oxo-4, 5-dihydro- [1, 2, 4] oxadiazol-3-yl) -phenyl ] -6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl ] -carbamic acid tert-butyl ester

According to the method described for 3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one in example 3, [1- [ 3-chloro-4- (5-oxo-4, 5-dihydro- [1, 2, 4] oxadiazol-3-yl) -phenyl ] -6- (4-trifluoromethyl-benzensulfonyl chloride was obtained from (6-iodo-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid tert-butyl ester, 4- (trifluoromethyl) phenylboronic acid and 3-chloro-4-cyano-benzenesulfonyl chloride -phenyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl ] -carbamic acid tert-butyl ester.

C29H26ClF3N4O6S(651.07)。

560mg of [1- [ 3-chloro-4- (5-oxo-4, 5-dihydro- [1, 2, 4] oxadiazol-3-yl) -phenyl ] -6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl ] -carbamic acid tert-butyl ester are dissolved in 7ml of dichloromethane. 1ml of trifluoroacetic acid was added and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was purified by reverse phase chromatography to give 7mg of 3- {4- [ 4-amino-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -2-chloro-phenyl } -4H- [1, 2, 4] oxadiazol-5-one.

C24H18ClF3N4O4S(550.95)，MS(ESI-)：548.9。

Example 7

3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H- [1, 8] naphthyridin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] as in example 1]-phenyl } -4H- [1, 2, 4]The process described for oxadiazole-5-ones from 6-bromo-3, 4-dihydro-1H- [1, 8]Naphthyridin-2-one, 4- (trifluoromethyl) phenylboronic acid and 3-chloro-4-cyano-benzenesulfonyl chloride to give 3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H- [1, 8]Naphthyridin-1-yl]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones. C23H16ClF3N4O4S (536.92), MS (ESI)⁺)：537.1(M+H⁺)。

Example 8

3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [3, 2-b ] [1, 4] oxazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl]-phenyl } -4H- [1, 2, 4]The process described for oxadiazole-5-ones from 7-bromo-3, 4-dihydro-2H-pyrido [3, 2-b][1，4]Oxazine, 4- (trifluoromethyl) phenylboronic acid and 3-chloro-4-cyano-benzenesulfonyl chloride to give 3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [3, 2-b [ ] -3][1，4]Oxazin-4-yl]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones. C22H14ClF3N4O5S (538.89), MS (ESI)⁺)：539.1(M+H⁺) Rf (ethyl acetate) ═ 0.08.

Example 9

3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] thiazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] thiazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one was obtained from 7-bromo-2H- [1, 4] benzothiazin-3 (4H) -one, 4- (trifluoromethyl) phenylboronic acid and 3-chloro-4-cyano-benzenesulfonyl chloride according to the procedure described in example 1 for 3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4 oxadiazol-5-one.

C23H15ClF3N3O4S2(553.97)，MS(ESI-)：551.9(M-H⁺)。

Example 10

3- {2, 3-dichloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] thiazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

When 3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] is used in example 9]Thiazin-4-yl]-phenyl } -4H- [1, 2, 4]Purification of oxadiazol-5-one to isolate 3- {2, 3-dichloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] -a]Thiazin-4-yl]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones. C23H14Cl2F3N3O4S2(588.41), MS (ESI-): 585.9 (M-H)⁺)。

Example 11

3- { 2-chloro-4- [1, 1-dioxo-7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-1H-benzo [1, 4] thiazin-4-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

40mg of 3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] are added]Thiazin-4-yl]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-one is dissolved in 10ml dichloromethane. 35.6mg of m-chloroperoxybenzoic acid were added at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour and then warmed to room temperature. The solvent was removed in vacuo and the residue was purified by reverse phase chromatography to give 19mg of 3- { 2-chloro-4- [1, 1-dioxo-7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-1H-benzo [1, 4]]Thiazin-4-yl]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones. C23H15ClF3N3O6S2(585.97), MS (ESI-): 583.9 (M-H)⁺)。

Example 12

3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3, 4, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-1-sulfonyl group]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones

3- {4- [ 4-amino-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] as in example 6]-2-chloro-phenyl } -4H- [1, 2, 4]The process described for oxadiazol-5-ones from 7-bromo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester, 4- (trifluoromethyl) phenylboronic acid and 3-chloro-4-cyano-benzenesulfonyl chloride to give 3- { 2-chloro-4- [7- (4-trifluoromethyl-phenyl) -2, 3, 4, 5-tetrahydro-benzo [ e ]][1，4]Diaza derivatives-1-sulfonyl group]-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones.

C24H18ClF3N4O4S(550.95)，MS(ESI⁺)：551.2(M+H+)。

Example 13

3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H- [1, 5] naphthyridine-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

5.0g of 5-amino-2-bromopyridine was dissolved in 70ml of ethanol. 9.0g of silver sulfate and 7.33g of iodine were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with 500ml ethyl acetate and filtered through a pad of celite. The filtrate was taken up with 200ml of saturated Na₂S₂O₃The solution was washed with water and MgSO₄Drying, followed by removal of the solvent in vacuo, gave 7.7g of 6-bromo-2-iodo-pyridin-3-ylamine.

C5H4BrIN2(298.91)，MS(ESI⁺): 300.9(M + H +), Rf (ethyl acetate: n-heptane ═ 1: 2) ═ 0.26.

(E) -3- (3-amino-6-bromo-pyridin-2-yl) -acrylic acid ethyl ester

15.5g of 6-bromo-2-iodo-pyridin-3-ylamine, 5.9ml of ethyl acrylate, 2.72g of triphenylphosphine and 28.75ml of triethylamine were dissolved in 90ml of acetonitrile. A stream of argon was bubbled through the reaction mixture for 10 minutes, then 2.33g of palladium (II) diacetate was added and the reaction mixture was stirred at 80 ℃. The reaction mixture was filtered hot through a pad of celite, and the solvent was then removed in vacuo. The residue was purified by chromatography on silica gel to give 10.2g of (E) -3- (3-amino-6-bromo-pyridin-2-yl) -acrylic acid ethyl ester.

C10H11BrN2O2(271.12)，MS(ESI⁺): 273.0, 271.0(M + H +), Rf (ethyl acetate: n-heptane: 1: 2) 0.12.

(E) -3- [ 3-amino-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -acrylic acid ethyl ester

3.0g of (E) -3- (3-amino-6-bromo-pyridin-2-yl) -acrylic acid ethyl ester, 3.05g of 4- (trifluoromethyl) phenylboronic acid and 3.61g of cesium carbonate are dissolved in a mixture of 21ml of dimethylformamide and 7ml of water. A stream of argon was bubbled through the reaction mixture and held for 30 minutes, then 333mg of tetrakis (triphenylphosphine) palladium (0) was added and the reaction mixture was stirred at 110 ℃ for 1.5 hours. The reaction mixture was diluted by adding 50ml of water and extracted 3 times with 80ml of dichloromethane in portions. The combined organic layers were over MgSO₄Dried and then the solvent removed in vacuo. The residue was purified by chromatography on silica gel to give 2.4g of (E) -3- [ 3-amino-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-ethyl acrylate. C17H15F3N2O2(336.32), MS (ESI)⁺): 337.2(M + H +), Rf (ethyl acetate: n-heptane ═ 1: 2) ═ 0.14.

3- [ 3-amino-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -propionic acid ethyl ester

2.4g of (E) -3- [ 3-amino-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -acrylic acid ethyl ester were dissolved in 50ml of tetrahydrofuran. 100mg of palladium on charcoal are added and the reaction mixture is stirred for 4 hours at 40 ℃ under a hydrogen atmosphere. The cooled reaction mixture was filtered and the filtrate evaporated in vacuo to give 2.4g of 3- [ 3-amino-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl ] -propionic acid ethyl ester.

C17H17F3N2O2(338.33)，MS(ESI⁺)：339.2(M+H+)。

6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-1H- [1, 5] naphthyridin-2-one

2.4g of 3- [ 3-amino-6- (4-trifluoromethyl-phenyl) -pyridin-2-yl]-ethyl propionate was dissolved in 200ml ethanol. 2.41g of sodium ethoxide were added and the reaction mixture was stirred at room temperature for 10 minutes and then at 60 ℃ for 1.5 hours. The cooled reaction mixture is evaporated in vacuo, the residue is dissolved in 100ml of ethyl acetate and 200ml of 4M HCl are added. The mixture was stirred vigorously at room temperature. The organic layer was separated and washed with 100ml 4M HCl. The combined aqueous layers were neutralized with NaOH. The precipitate was filtered, washed with water and dried in vacuo to give 1.87g of 6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-1H- [1, 5]Naphthyridin-2-one. C15H11F3N2O (292.26), MS (ESI)⁺): 293.1(M + H +), Rf (ethyl acetate: n-heptane ═ 1: 1) ═ 0.13.

3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] as in example 1]-phenyl } -4H- [1, 2, 4]The process described for oxadiazol-5-ones from 6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-1H- [1, 5]Naphthyridin-2-one and 3-chloro-4-cyano-benzenesulfonyl chloride to give 3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H- [1, 5]Naphthyridine-1-sulfonyl group]-phenyl } -4H- [1, 2，4]Oxadiazol-5-ones. C23H16ClF3N4O4S (536.92), MS (ESI)⁺)：537.0(M+H⁺)。

Example 14

3- { 2-chloro-4- [2, 2-dimethyl-7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] oxazin-4-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

7-bromo-2, 2-dimethyl-4H-benzo [1, 4] oxazin-3-one

5.0g of 2-amino-5-bromophenol was dissolved in 100ml of acetone. Then 11.0g of potassium carbonate and 6.74g of ethyl 2-bromoisobutyrate were added. The reaction mixture was stirred at room temperature overnight and refluxed overnight. The cooled reaction mixture was then filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography to give 4.6g of 7-bromo-2, 2-dimethyl-4H-benzo [1, 4] oxazin-3-one as a yellow solid.

C10H10BrNO₂(256.10)，MS(ESI⁺): 256.0, 258.0(M + H +), Rf (ethyl acetate: n-heptane: 1: 4) 0.11.

3- { 2-chloro-4- [2, 2-dimethyl-7- (4-trifluoromethyl-phenyl) -2, 3-dihydro-benzo [1, 4] oxazin-4-sulfonyl ] -phenyl } -4H- [1, 4] oxa-zin-4-yl ] was obtained from 7-bromo-2, 2-dimethyl-4H-benzo [1, 4] oxazin-3-one, 4- (trifluoromethyl) phenylboronic acid and 3-chloro-4-cyano-benzenesulfonyl chloride according to the procedure described for 3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1 in example 1, 2, 4 oxadiazol-5-one.

C25H19ClF3N3O5S(565.96)，MS(ESI-)：564.3(M-H⁺)。

Example 15

3- { 2-bromo-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

3-bromo-4-cyano-benzenesulfonyl chloride

40mg of CuCl were dissolved in 10ml of water and cooled to 0 ℃ in an ice bath. 1.6ml of thionyl chloride were added dropwise. The reaction solution was allowed to warm to room temperature overnight. 1.0g of 4-amino-2-bromo-benzonitrile are suspended in 12ml of hydrochloric acid and 45ml of water and warmed to 96 ℃ until all 4-amino-2-bromo-benzonitrile has dissolved. The solution was cooled to-5 ℃ and 380mg NaNO was added₂Dissolved in 10ml of water. The thionyl chloride solution was then cooled to-2 ℃ and added dropwise. 3-bromo-4-cyano-benzenesulfonyl chloride precipitated, collected by filtration, washed with ice-cold water, and dried in vacuo to give 956mg of 3-bromo-4-cyano-benzenesulfonyl chloride as a solid. This material was used without further purification. C7H3BrClNO2S (280.53).

Following the procedure described for 3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one in example 3, 3- { 2-bromo-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3 was obtained from 6-bromo-3, 3-dimethyl-1, 2, 3, 4-tetrahydro-quinoline (for its synthesis see WO 9629327), 4- (trifluoromethyl) phenylboronic acid and 3-bromo-4-cyano-benzenesulfonyl chloride, 4-dihydro-2H-quinoline-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one.

C26H21BrF3N3O4S(608.44)，MS(ESI-)：606.4，609.4。

Example 16

3- { 2-cyclopropyl-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

2-cyclopropyl-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -benzonitrile

90mg of 2-bromo-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -benzonitrile (from 6-bromo-3, 3-dimethyl-1, 2, 3, 4-tetrahydro-quinoline (for its synthesis see WO 9629327) as described for 3- { 2-chloro-4- [4, 4-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one in example 3, 4- (trifluoromethyl) phenylboronic acid and 3-bromo-4-cyano-benzenesulfonyl chloride derivative), 153mg potassium phosphate (tripotassium phosphate heptahydrate), 6mg tricyclohexylphosphine, and 42mg cyclopropylboronic acid were dissolved in a mixture of 30ml toluene and 0.6ml water. A stream of argon was bubbled through the reaction mixture and held for 20 minutes. 7.4mg of palladium (II) diacetate were then added and the reaction mixture was stirred at 120 ℃ for 1 hour under microwave irradiation. The cooled reaction mixture was diluted with 50ml ethyl acetate and filtered through a pad of celite. The filtrate was evaporated and purified by silica gel chromatography to give 73mg of 2-cyclopropyl-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -benzonitrile.

C28H25F3N2O2S (510.58), Rf (ethyl acetate: N-heptane 1: 4) 0.27.

3- { 2-cyclopropyl-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one.

C29H26F3N3O48(569.61)，MS(ESI-)：568.4(M-H⁺)。

Example 17

Following the procedure described for 3- { 2-cyclopropyl-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one in example 16, 3- {4- [ 33-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -benzonitrile and (2-methylpropyl) boronic acid gave 3- {4- [ 33-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-isobutyl-phenyl } -4H- [1, 2, 4] oxadiazol-5-one.

C30H30F3N3O4S(585.65)，MS(ESI-)：584.4(M-H⁺)。

Example 18

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2- (furan-3-yl) -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

Following the procedure described for 3- { 2-cyclopropyl-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one in example 16, 3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -benzonitrile and furan-3-boronic acid gave 3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2- (furan-3-yl) -phenyl } -4H- [1, 2, 4] oxadiazol-5-one.

C30H24F3N3O5S(595.60)，MS(ESI-)：594.4(M-H⁺)。

Example 19

3- { 2-chloro-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [2, 3-b ] [1, 4] oxazin-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

2- (6-bromo-3-nitro-pyridin-2-yloxy) -2-methyl-propionic acid methyl ester

330mg of sodium were suspended in 10ml of 1, 4-dioxane. 1.7g of methyl 2-hydroxy-2-methyl-propionate are then added dropwise. The mixture was stirred at 50 ℃ for 30 minutes and then at 70 ℃ for 30 minutes until all the sodium had dissolved. The solution was then added dropwise to a solution of 2.7g of 2, 6-dibromo-3-nitropyridine in 5ml of 1, 4-dioxane at 0 ℃. The cooling bath was removed and the mixture was stirred at room temperature overnight and then at 70 ℃ for 4 hours. The cooled reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give 640mg of 2- (6-bromo-3-nitro-pyridin-2-yloxy) -2-methyl-propionic acid methyl ester as a white solid. C10H11BrN2O5(319.11), MS (ESI)⁺)：319.0，320.0(M+H⁺) Rf (ethyl acetate: n-heptane ═ 1: 4) ═ 0.36.

6-bromo-3, 3-dimethyl-1H-pyrido [2, 3-b ] [1, 4] oxazin-2-one

To a solution of 640mg of 2- (6-bromo-3-nitro-pyridin-2-yloxy) -2-methyl-propionic acid methyl ester and 542mg of tin powder was added dropwise 10ml of concentrated hydrochloric acid while cooling in an ice bath so that the reaction temperature did not exceed 40 ℃. The ice bath was then removed and the reaction mixture was stirred at 85 ℃ for 1 hour. To the cooled reaction mixture was added 100ml of water. The precipitate was collected, dissolved in 300ml ethyl acetate and passed over MgSO₄Drying and then removing the ethyl acetate in vacuo gave 335mg of 6-bromo-3, 3-dimethyl-1H-pyrido [2, 3-b ]][1，4]Oxazin-2-one as a white solid.

C9H9BrN2O2(257.09)，MS(ESI⁺)：257.0，259.0(M+H⁺)。

3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -1H-pyrido [2, 3-b ] [1, 4] oxazin-2-one

443mg of 4- (trifluoromethyl) phenylboronic acid, 300mg of 6-bromo-3, 3-dimethyl-1H-pyrido [2, 3-b ] are added][1，4]Oxazin-2-one, 33mg tricyclohexylphosphine and 1.1g tripotassium phosphate trihydrate were dissolved in a mixture of 0.5ml water and 5ml toluene. The reaction mixture was degassed with argon, then 262mg of palladium (II) diacetate was added and the mixture was heated to 100 ℃ and held for 1 hour. The cooled reaction mixture was diluted with 400ml ethyl acetate and washed with 150ml water and brine. The organic layer was MgSO₄Drying and removing the solvent in vacuum. The resulting crude material was purified by silica gel chromatography to give 184mg of 3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -1H-pyrido [2, 3-b ]][1，4]Oxazin-2-one as a white solid.

C16H13F3N2O2(322.29)，MS(ESI⁺)：323.1(M+H⁺) Rf (n-heptane: ethyl acetate: 1: 2) is 0.44.

3- { 2-chloro-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -2, 3-dihydro-2H-quinolin-1-yl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one was obtained from 3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -1H-pyrido [2, 3-b ] [1, 4] oxazin-2-one and 3-chloro-4-cyano-benzenesulfonyl chloride according to the procedure described for 3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-quinolin-1-yl ] -phenyl } -4H- [1, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [2, 3-b ] [1, 4] oxazine-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one.

C24H18ClF3N4O5S(566.95)，MS(ESI⁺)：567.0(M+H⁺)。

Example 20

3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [2, 3-b ] [1, 4] oxazin-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one

Following the procedure described for 3- { 2-chloro-4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [2, 3-b ] [1, 4] oxazin-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one in example 19, 3- { 2-chloro-4- [6- (4-trifluoromethyl-phenyl) -2, 3-dihydro-pyrido [2, 3-b ] [1, 4] oxazine-1-sulfonyl ] -phenyl } -4H- [1, 2, 4] oxadiazol-5-one.

C22H14ClF3N4O5S(538.89)，MS(ESI⁺)：539.0(M+H⁺)。

Example 21

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-fluoro-phenyl } -4H- [1, 2, 4] oxadiazol-5-one

1- (4-bromo-3-fluoro-benzenesulfonyl) -3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline

500mg of 3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline (just 3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl according to example 1)]-phenyl } -4H- [1, 2, 4]The procedure described for oxadiazol-5-one is derived from 6-bromo-3, 3-dimethyl-1, 2, 3, 4-tetrahydro-quinoline (for its synthesis see WO 9629327) and 4- (trifluoromethyl) phenylboronic acid) and 294mg of 4-dimethylaminopyridine are dissolved in a mixture of 10ml of dichloromethane and 5ml of pyridine. 671mg of 4-bromo-3-fluoro-benzenesulfonyl chloride was then added, and the reaction mixture was stirred at 40 ℃ for 6 hours and at room temperature for 2 days. The reaction mixture was diluted by adding 200ml of dichloromethane and washed with 100ml of water. The organic phase is separated over MgSO₄And (5) drying. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography to give 710mg of 1- (4-bromo-3-fluoro-benzenesulfonyl) -3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline as a white solid. C24H20BrF4NO2S (542.39), Rf (n-heptane: ethyl acetate 4: 1) 0.39.

4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-fluoro-benzonitrile

710mg of 1- (4-bromo-3-fluoro-benzenesulfonyl) -3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline and 123mg of copper (I) cyanide were dissolved in 1.5ml of dimethylformamide, heated to 200 ℃ under microwave irradiation and held for 30 minutes. The cooled reaction mixture was poured into 50ml of 2M hydrochloric acid and extracted 5 times with 20ml of ethyl acetate in portions. The combined organic layers were over MgSO₄And (5) drying. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography to give 481mg of 4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl]-2-fluoro-benzonitrile.

C25H20F4N2O2S (488.51), Rf (N-heptane: ethyl acetate 4: 1) 0.26.

3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] as in example 1]-phenyl } -4H- [1, 2, 4]The process described for oxadiazol-5-ones from 4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl]-2-fluoro-benzonitrile to 3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl]-2-fluoro-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones. C26H21F4N3O4S (547.53), MS (ESI-): 546.1 (M-H)⁺) 592.0(M + formic acid).

Example 22

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-methyl-phenyl } -4H- [1, 2, 4] oxadiazol-5-one

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-fluoro-phenyl } -4H- [1, 2, 4] oxadiazol-5-one was obtained from 3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -1, 2, 3, 4-tetrahydro-quinoline and 4-bromo-3-methyl-benzenesulfonyl chloride according to the procedure described for 3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-methyl-benzene in example 20 -4H- [1, 2, 4] oxadiazol-5-one.

C27H24F3N3O4S(543.57)，MS(ESI-)：542.5(M-H⁺)。

Example 23

3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-ethoxy-phenyl } -4H- [1, 2, 4] oxadiazol-5-one

4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-ethoxy-benzonitrile

165mg of 4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl group]-2-fluoro-benzonitrile and 30ml of ethanol were dissolved in 3ml of dimethylformamide. Then 10mg of sodium hydride was added and the reaction mixture was stirred at room temperature for 4 hours. The mixture is then poured into 20ml of water and extracted 5 times with 20ml of ethyl acetate in portions. The combined organic extracts were over MgSO₄Dried and then evaporated in vacuo, the residue is purified by chromatography on silica gel to give 40mg of 4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl group]-2-ethoxy-benzonitrile.

C27H25F3N2O3S (514.57), Rf (N-heptane: ethyl acetate 4: 1) 0.32.

3- {4- [6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinolin-1-yl ] as in example 1]-phenyl } -4H- [1, 2, 4]The process described for oxadiazol-5-ones from 4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl]-2-ethoxy-benzonitrile to 3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl]-2-ethoxy-phenyl } -4H- [1, 2, 4]Oxadiazol-5-ones. C28H26F3N3O5S (573.60), MS (ESI)⁺)：574.3(M+H⁺)。

Example 24

3- [4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2- (2, 2, 2-trifluoro-ethoxy) -phenyl ] -4H- [1, 2, 4] oxadiazol-5-one

3- [4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-ethoxy-phenyl } -4H- [1, 2, 4] oxadiazol-5-one is obtained from 4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-fluoro-benzonitrile and 2, 2, 2-trifluoroethanol according to the procedure described in example 23 for 3- {4- [3, 3-dimethyl-6- (4-trifluoromethyl-phenyl) -3, 4-dihydro-2H-quinoline-1-sulfonyl ] -2-ethoxy-phenyl } -4H- [1, 2, 4] oxadiazol-5-one, 4-dihydro-2H-quinoline-1-sulfonyl ] -2- (2, 2, 2-trifluoro-ethoxy) -phenyl ] -4H- [1, 2, 4] oxadiazol-5-one.

C28H23F6N3O5S(627.57)，MS(ESI-)：626.4(M-H⁺)。

Claims

1. A compound of formula I:

wherein

Y is O, S, SO₂(C0-C2) alkylene-N (R10), C (R3) (R4);

x1, X2, X3, X4 and X5 are independently N or CH;

2. A compound of formula I according to claim 1, wherein

Y is O, S, SO₂(C0-C2) alkylene-N (R10), C (R3) (R4);

r2 is H, (C1-C8) alkyl, halogen;

r5 is H, (C1-C8) alkyl;

r6 is H, (C1-C8) alkyl;

r7 is H, halogen, (C1-C8) alkyl;

r8 is H, halogen, (C1-C8) alkyl;

r10 is H, (C1-C8) alkyl;

r11 is H, (C1-C8) alkyl;

3. A compound of formula I according to claim 1 or 2, wherein

Y is O, S, C (R3) (R4).

4. A compound of formula I according to claim 1 or 2, wherein

5. A compound of formula I according to claim 1 or 2, wherein

R2 is in the para position relative to R1.

6. A compound of formula I according to claim 1 or 2, wherein

R2 is H, (C1-C3) alkyl, F, Cl.

7. A compound of formula I according to claim 1 or 2, wherein

R3 is H, (C1-C4) alkyl, N (R10) (R11).

8. A compound of formula I according to claim 1 or 2, wherein

R4 is H, (C1-C4) alkyl.

9. A compound of formula I according to claim 1 or 2, wherein

10. A compound of formula I according to claim 1 or 2, wherein

R5 is H, (C1-C4) alkyl.

11. A compound of formula I according to claim 1 or 2, wherein

R6 is H, (C1-C4) alkyl.

12. A compound of formula I according to claim 1 or 2, wherein

13. A compound of formula I according to claim 1 or 2, wherein

R7 is H, F, Cl, (C1-C4) alkyl.

14. A compound of formula I according to claim 1 or 2, wherein

R8 is H, F.

15. A compound of formula I according to claim 1 or 2, wherein

R9 is H, Cl, (C1-C) alkyl, (C1-C4) alkyl-O-, wherein alkyl is unsubstituted or substituted with 1 to 3F.

16. A compound of formula I according to claim 1 or 2, wherein

R10 is H.

17. A compound of formula I according to claim 1 or 2, wherein

R11 is H.

18. A compound of formula I according to claim 1 or 2, wherein

X1, X2, X3 are CH, and one of X4 and X5 is N and the other of X4 and X5 is CH.

19. A compound of formula I according to claim 1 or 2, wherein

X1, X2, X3, X4 are CH, and X5 is N.

20. A compound of formula I according to any one of claims 1 to 19, wherein

Y is O, S, SO₂、CR3R4、CH₂-NR10；

r2 is H, Cl;

r3 is H, (C1-C4) alkyl, NH₂；

R4 is H, (C1-C4) alkyl;

r5 is H, (C1-C4) alkyl;

r6 is H, (C1-C4) alkyl;

r7 is H;

r8 is H;

r9 is CF₃；

R10 is H

X1, X4, X5 are independently CH or N;

x2 and X3 are CH.

21. A medicament containing one or more compounds of the formula I as claimed in one or more of claims 1 to 20.

22. A medicament containing one or more compounds of the formula I as claimed in one or more of claims 1 to 20 and one or more active substances which have a favourable effect on metabolic disorders or diseases which are usually associated with metabolic disorders.

23. A medicament containing one or more compounds of the formula I as claimed in one or more of claims 1 to 20 and one or more antidiabetics.

24. A medicament containing one or more compounds of the formula I as claimed in one or more of claims 1 to 20 and one or more lipid regulators.

25. Compounds of formula I according to one or more of claims 1 to 20 for use in the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders.

26. Compounds of the formula I as claimed in one or more of claims 1 to 20 for the treatment and/or prophylaxis of diseases which are associated with insulin resistance.

27. Compounds of formula I as claimed in one or more of claims 1 to 20 for use in the treatment and/or prevention of diabetes, including the prevention of the sequelae associated with diabetes.

28. Compounds of the formula I as claimed in one or more of claims 1 to 20 for the treatment and/or prophylaxis of dyslipidaemia and their sequelae.

29. A compound of the formula I as claimed in one or more of claims 1 to 20 for use in the treatment and/or prevention of disorders which may be associated with the metabolic syndrome.

30. Compounds of the formula I as claimed in one or more of claims 1 to 20 for use in the treatment and/or prevention of demyelinating and other neurodegenerative diseases in the central and peripheral nervous system.

31. A combination of a compound of the formula I as claimed in one or more of claims 1 to 20 with at least one further active compound for the treatment of disorders of fatty acid metabolism and glucose utilization disorders.

32. A combination of a compound of the formula I as claimed in one or more of claims 1 to 20 with at least one further active compound for the treatment of diseases in which insulin resistance is involved.

33. A process for the preparation of a medicament comprising a compound according to one or more of claims 1 to 20, which comprises mixing the active compound with a pharmaceutically acceptable carrier and bringing this mixture into a form suitable for administration.