US0078.97616B2

(12) United States Patent (10) Patent No.: US 7,897,616 B2 Zoller et al. (45) Date of Patent: Mar. 1, 2011

(54) IMIDAZOPYRIDIN-2-ONE DERIVATIVES AS (56) References Cited INHIBITORS OF LIPASES AND U.S. PATENT DOCUMENTS PHOSPHOLPASES 4,144,341 A 3, 1979 Clark et al. (75) Inventors: Gerhard Zoller, Frankfurt am Main FOREIGN PATENT DOCUMENTS (DE); Stefan Petry, Frankfurt am Main WO WO O2/3O886 4/2002 (DE); Markus Follmann, Wülfrath WO WO 2005, O73199 8, 2005 (DE); Gunter Muller, Frankfurt am WO WO 2006/022954 3, 2006 Main (DE); Norbert Tennagels, WO WO 2006/097808 9, 2006 Frankfurt am Main (DE) WO WO 2006,131231 12/2006 OTHER PUBLICATIONS (73) Assignee: Sanofi-Aventis, Paris (FR) Hcaplus 1979: 145541 abstract, “Synthesis and analgesic activity of (*) Notice: Subject to any disclaimer, the term of this 1,3-dihydro-3-(substituted phenyl)imidazo[4,5-b]pyridines”. Clark patent is extended or adjusted under 35 et al., 1978.* U.S.C. 154(b) by 234 days. * cited by examiner Primary Examiner Zinna N Davis (21) Appl. No.: 12/235,053 (74) Attorney, Agent, or Firm Scully, Scott, Murphy & (22) Filed: Sep. 22, 2008 Presser, P.C. (57) ABSTRACT (65) Prior Publication Data The present invention relates to imidazopyridin-2-one deriva tives of the formula I with the definitions specified in the US 2009/0076068 A1 Mar. 19, 2009 description, to their pharmaceutically usable salts and to their Related U.S. Application Data use as medicaments. (63) Continuation of application No. PCT/EP2007/ 002637, filed on Mar. 26, 2007. (I) 4 ,6 (30) Foreign Application Priority Data X 3 Mar. 28, 2006 (DE) ...... 10 2006 O14685 O 6X CO Yx2 N (51) Int. Cl. 7 R2 CO7D 47L/04 (2006.01) WNN A6 IK 3/437 (2006.01) V (52) U.S. Cl...... 514/303:546/118 R1 (58) Field of Classification Search ...... 546/118: 514/303 See application file for complete search history. 9 Claims, No Drawings US 7,897,616 B2 1. 2 MIDAZOPYRIDIN-2-ONE DERVATIVES AS be mono- or polysubstituted preferably by halogen, (C- INHIBITORS OF LIPASES AND C)-alkyl, (C-C)-alkyloxy, hydroxyl, (C-C)-alkylmer PHOSPHOLIPASES capto, amino, (C-C)-alkylamino, di-(C-C)-alky lamino, mono-(C-C)-alkylaminocarbonyl, di-(C-Cs)- This application is a Continuation of International Appli 5 alkylaminocarbonyl, (C-C)-alkyloxycarbonyl, (C-C)- cation No. PCT/EP2007/002637, filed Mar. 26, 2007, which alkylcarbonyl, cyano, nitro, trifluoromethyl, is incorporated herein by reference in its entirety. trifluoromethyloxy, pentafluorosulfanyl, (C-C)-alkylsul fonyl, aminosulfonyl: FIELD OF THE INVENTION R1" is (C-C)-alkyl, (C-C)-cycloalkyl, (C-C)-alkyle 10 nearyl, (C-C)-alkyleneheteroaryl, (C-C)-alkylene The present invention relates to imidazopyridin-2-one (C-C)-cycloalkyl, bicycle, where aryl, heteroaryl, derivatives of the formula I, to their pharmaceutically usable cycloalkyl or bicycle may be mono- or polysubstituted salts and to their use as medicaments. preferably by halogen, (C-C)-alkyl, (C-C)-alkyloxy, hydroxyl, (C-C)-alkylmercapto, amino, (C-C)-alky BACKGROUND OF THE INVENTION 15 lamino, di-(C-C)-alkylamino, mono-(C-C)-alkylami nocarbonyl, di-(C-Cs)-alkylaminocarbonyl, (C-C)- In addition to the imidazopyridin-2-one derivatives alkyloxycarbonyl, (C-C)-alkylcarbonyl, cyano, nitro, described in the present application, structurally similar com trifluoromethyl, trifluoromethyloxy, (C-C)-alkylsulfo pounds with pharmacological action have already been nyl, aminosulfonyl: described in the prior art. For instance, U.S. Pat. No. 4,144, R2 is hydrogen; 341 describes imidazopyridin-2-one derivatives for the treat R3 is the same or different and is hydrogen, (C-C)-alkyl, ment of fever and pain. WO02/30886 describes angiogenesis benzyl: inhibitors which have animidazopyridin-2-one base structure R4, R5 are the same or different and are each hydrogen, among other compounds. (C-C)-alkyl, aryl, (C-C)-cycloalkyl, (C-C)-alkyle Compounds with inhibitory action on endothelial lipase 25 nearyl, (C-C)-alkylene-(C-C)-cycloalkyl; are described in the prior art, for example in WO2004/ R6 is hydrogen, (C-C)-alkyl, (C-C)-alkylenearyl, (C- 094394, WO2004/094393 or WO2004/093872. Cl)-alkylene-heterocycle, (C-C)-alkylene-(C-C)-cy It is an object of the present invention to provide alternative cloalkyl, bicycle, where aryl, heterocycle, cycloalkyl or compounds which bring about inhibition of endothelial bicycle may be mono- or polysubstituted preferably by lipase. 30 halogen, (C-C)-alkyl, (C-C)-alkyloxy, hydroxy, (C- C)-alkylmercapto, amino, (C-C)-alkylamino, di-(C- SUMMARY OF THE INVENTION C)-alkylamino, mono-(C-C)-alkylaminocarbonyl, di (C-C)-alkylaminocarbonyl, (C-C)-alkoxycarbonyl, The invention provides imidazopyridin-2-one derivatives (C-C)-alkylcarbonyl, trifluoromethyl, trifluoromethy of the formula I 35 loxy, cyano, (C-C)-alkylsulfonyl, aminosulfonyl: O (I) -(C=O) NR1'R2: 4 R6 O X 3\ -(C=O) O R1": x1 N 2 40 O with the proviso that, when R1 is (C-C)-alkyl, R6 is not 6.Nx NX (C-C)-alkylenearyl, (C-C)-alkylene-heterocycle, (C- 7 V R2 Cl)-alkylene-(C-C)-cycloalkyl or bicycle; / WNN the tautomeric forms of the compounds and their physiologi V 45 R1 cally compatible salts. DETAILED DESCRIPTION OF THE INVENTION where: Preference is given to compounds of the formula I in which X is the same or different and is —C(—R)—or—N—, where 50 at least one X and at most two X are —N—; W is —(C=O)-. W is —(C=O)— —(S—O)— —(SO)—: Preference is equally given to compounds of the formula I R is the same or different and is hydrogen, halogen, (C-C)- in which alkyl, (C-C)-haloalkyl, (C-C)-alkyloxy-(C-C)-alky X is the same or different and is —C(—R)—or—N , where one X is —N—. lene, aryl, heterocycle, hydroxyl, (C-C)-alkyloxy, (C- 55 Cs)-haloalkyloxy, aryloxy, cyano, nitro, -S(O) (C- Preference is also given to compounds of the formula I in C)-alkyl, where p=0, 1 or 2, aminosulfonyl, which pentafluorosulfanyl, amino, (C-C)-alkylamino, di-(C- X is the same or different and is —C(—R)—or—N , where C)-alkylamino, (C-C)-alkylcarbonyl, COOR3, one X is —N—; CO NR4R5, O CO. NR4R5, O CO (C-C)- 60 W is —(C=O)–: alkylene-CO-O (C-C)-alkyl, O CO (C-C)- R is the same or different and is hydrogen, halogen, (C-C)- alkylene-CO-OH, O CO (C-C)-alkylene-CO— alkyl, hydroxyl, phenoxy, trifluoromethyl, COOR3, pen NR4R5; tafluorosulfanyl, amino, (C-C)-alkylamino, di-(C-C)- R1, R1" are the same or different and are each (C-C)-alkyl, alkylamino, (C-C)-alkylsulfonyl, aminosulfonyl, (C-C)-cycloalkyl, (C-C)-alkylenearyl, (C-C)-alky 65 phenyl, (C-C)-heterocycle, (C-C)-alkylcarbonyl, leneheteroaryl, (C-C)-alkylene-(C-C)-cycloalkyl, CO NR4R5, O CO. NR4R5, O CO (C-C)- bicycle, where aryl, heteroaryl, cycloalkyl or bicycle may alkylene-CO O (C-C)-alkyl, O—CO (C-C)- US 7,897,616 B2 3 4 alkylene-CO NR4R5 or unsubstituted or mono- or poly alkoxycarbonyl, (C-C)-alkylcarbonyl, cyano, trifluo F-substituted (C-C)-alkyloxy; romethyl, trifluoromethyloxy; R1, R1" are the same or different and are each (C-C)-alkyl, R1" is (C-Co)-alkyl, —CH2-phenyl, (C-C)-alkylenehet (C-C)-alkylenearyl, (C-C)-alkylene-heterocycle, (C- eroaryl or bicycle of the formula Ic Cl)-alkylene-(C-C)-cycloalkyl, (C-C)-bicycle, 5 Ic where aryl, heterocycle, cycloalkyl or bicycle may be mono- or poly Substituted preferably by halogen, (C-C)- alkyl, (C-C)-alkyloxy, hydroxyl, amino, (C-C)-alky lamino, (C-C)-alkyloxycarbonyl, (C-C)-alkylcarbo Yg nyl, cyano, trifluoromethyl, trifluoromethyloxy; R1" is (C-C)-alkyl, (C-C)-alkylenearyl, (C-C)-alky 10 ( lene-heterocycle, (C-C)-alkylene-(C-C)-cycloalkyl, (C-C)-bicycle, where aryl, heterocycle, cycloalkyl or bicycle may be mono- or polysubstituted preferably by where q1 or 2, halogen, (C-C)-alkyl, (C-C)-alkyloxy, hydroxyl, where phenyl, heteroaryl or bicycle of the formula Ic may amino, (C-C)-alkylamino, (C-C)-alkyloxycarbonyl, 15 be mono- to disubstituted preferably by halogen, (C- (C-C)-alkylcarbonyl, cyano, trifluoromethyl, trifluorom C)-alkyl, (C-C)-alkyloxy, hydroxyl, amino, (C-C)- ethyloxy; alkoxycarbonyl, (C-C)-alkylcarbonyl, cyano, trifluo R2 is hydrogen; romethyl, trifluoromethyloxy; R3 is hydrogen, (C-C)-alkyl, benzyl, R2 is hydrogen; R4, R5 are the same or different and are each hydrogen, R3 is hydrogen, (C-C)-alkyl, (C-C)-alkyl, (C-C)-cycloalkyl, phenyl, (C-C)-alky R6 is hydrogen, (C-C)-alkyl, (C-C)-alkylene-phenyl, lenephenyl, (C-C)-alkylene-(C-C)-cycloalkyl: (C-C)-alkylene-heteroaryl, where phenyl or heteroaryl R6 is hydrogen, (C-C)-alkyl, (C-C)-alkylene-phenyl, may be mono- or polysubstituted by halogen, (C-C)- (C-C)-alkylene-heterocycle, (C-C)-alkylene-(C- alkyl, (C-C)-alkyloxy, hydroxyl, (C-C)-alkoxycarbo C)-cycloalkyl, where phenyl, heterocycle, cycloalkyl 25 nyl, (C-C)-alkylcarbonyl, trifluoromethyl; may be mono- or poly Substituted preferably by halogen, O (C-C)-alkyl, (C-C)-alkyloxy, hydroxyl, (C-C)- -(C=O) NR1'R2 alkoxycarbonyl, (C-C)-alkylcarbonyl, cyano, trifluo O romethyl, trifluoromethyloxy, (C-C)-alkylsulfonyl: -(C=O) O R1": O 30 the tautomeric forms of the compounds and their physiologi O cally compatible salts. (C=O) O R1": Very particular preference is given to the compounds of the formula I in which the tautomeric forms of the compounds and their physiologi cally compatible salts. 35 X is the same or different and is —C(—R)—or—N , where Preference is also given to the compounds of the formula I one X is —N—; in which W is —(C=O)–: X in positions 5 and 6 are identical or different and are each R is the same or different and is hydrogen, halogen, hydroxyl, =C(—R)—, and in position 7 or 4 is =N-. (C-C)-alkyloxy, trifluoromethyl, (C-C)-alkylcarbonyl Further preferred compounds are those of the formula I in 40 or (C-C)-alkyl; which R1, R1" are the same or different and are each (C-C)-alkyl, X in positions 4, 5 and 6 are identical or different and are each —CH-phenyl or bicycle of the formula Ic =C(—R)—, and in position 7 is =N-. Ic Particular preference is given to the compounds of the formula I in which 45 X is the same or different and is —C(—R)—or—N—, where Yg one X is —N—; W is —(C=O)–: ( ). R is the same or different and is hydrogen, halogen, (C-C)- alkyl, trifluoromethyl, hydroxyl, amino, (C-C)-alkylcar 50 bonyl, COOR3, (C-C)-alkylsulfonyl, pentafluorosulfa where q1 or 2, where phenyl or bicycle may be mono nyl, or unsubstituted or mono- or poly-F-substituted (C- to disubstituted by halogen, (C-C)-alkyl, (C-C)- Cl)-alkyloxy, alkyloxy, (C-C)-alkylcarbonyl, trifluoromethyl; R1, R1' are the same or different and are each (C-C)-alkyl, R1 is (C-C)-alkyl, —CH-phenyl orbicycle of the formula —CH2-phenyl, (C-C)-alkyleneheteroaryl or bicycle of 55 Ic the formula Ic Ic Ic Y. 60 ( (-), where q1 or 2, where phenyl, heteroaryl or bicycle of the formula Ic may 65 where q1 or 2, where phenyl or bicycle may be mono be mono- to disubstituted preferably by halogen, (C- to disubstituted by halogen, (C-C)-alkyl, (C-C)- C)-alkyl, (C-C)-alkyloxy, hydroxyl, amino, (C-C)- alkyloxy, (C-C)-alkylcarbonyl, trifluoromethyl; US 7,897,616 B2 5 6 R2 is hydrogen; The alkyl or alkylene radicals in the substituents R, R1, R6 is hydrogen, (C-C)-alkyl, CH-phenyl, where phenyl R1, R1", R2, R3, R4, R5 and R6 may be either straight-chain may be mono- or poly Substituted by halogen, (C-C)- or branched. Halogen is fluorine, chlorine, bromine or iodine, alkyl, (C-C)-alkyloxy, hydroxyl, (C-C)-alkylcarbonyl, particularly fluorine or chlorine. trifluoromethyl; Haloalkyl is an alkyl substituted singly, multiply or fully by O halogen. Preferred halogens are fluorine and chlorine. (C=O) NR1'R2 A cycloalkyl radical is understood to mean a ring system O which comprises one or more rings and is Saturated or par (C=O) O R"; tially unsaturated (with one or two double bonds), which is the tautomeric forms of the compounds and their physiologi 10 composed exclusively of carbon atoms, for example cyclo cally compatible salts. propyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl. A particular preference is given to the compounds of the The cycloalkyl radicals may be mono- or polysubstituted formula I in which by suitable groups, for example F, Cl, Br, I, CF, NO, N, X is the same or different and is —C(—R)—or—N—, where 15 CN, COOH, COO(C-C)alkyl, CONH CONH(C-C) one X is —N—; alkyl, CONCC-C)alkyl, cycloalkyl, (C-C)-alkyl, (C- W is —(C=O)–: C)-alkenyl, (C-C)-alkynyl, O—(C-C)-alkyl, O—CO— R is the same or different and is hydrogen, methyl; (C-C)-alkyl, O—CO—(C-C)-aryl, O—CO—(C-C)- R1, R1' are the same or different and are each (C-C)-alkyl, heterocycle; POH, SOH, SO. NH, SONHCC-C)- —CH2-phenyl or bicycle of the formula Id alkyl, SONI(C-C)-alkyl S-(C-C)-alkyl, S (CH)- Id aryl, S (CH)-heterocycle, SO (C-C)-alkyl, SO— (CH2)-aryl, SO-(CH2)-heterocycle, SO (C-C)-alkyl, SO (CH)-aryl, SO (CH)-heterocycle, SO. NH (CH)-aryl, SO. NH(CH)-heterocycle, SO N((C- 25 C)-alkyl)(CH), aryl, SO NC(C-C)-alkyl)(CH)-het erocycle, SO, N(CH2)-aryl), SO, N(CH)- heterocycle), where n may be 0-6 and the aryl radical or heterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF, NO, CN, OCF. O—(C-C)-alkyl, (C-C)-alkyl, 30 NH: C(NH)(NH), NH, NH-(C-C)-alkyl, N(C-C)- where q=1, where phenyl or bicycle may be substituted alkyl). NH(C-C,)-acyl, NH CO (C-C)-alkyl, by methyl: NH COO (C-C)-alkyl, NH CO-aryl, NH CO-het R2 is hydrogen; erocycle, NH COO-aryl, NH COO-heterocycle, R6 is hydrogen, methyl, or NH CO. NH (C-C)-alkyl, NH CO. NH-aryl, (C=O) NR1'R2: 35 NH CO. NH-heterocycle, N(C-C)-alkyl —CO—(C- the tautomeric forms of the compound and its physiologically C)-alkyl, N(C-C)-alkyl —COO (C-C)-alkyl, N(C- compatible salts. C)-alkyl —CO-aryl, N(C-C)-alkyl —CO-heterocycle, In a further preferred embodiment of the compounds of the N(C-C)-alkyl —COO-aryl, N(C-C)-alkyl —COO-het formula I, erocycle, N(C-C)-alkyl —CO. NH-(C-C)-alkyl, W is —(SO)—. 40 N(C-C)-alkyl —CO. NH-aryl, N(C-C)-alkyl —CO— In a further preferred embodiment of the compounds of the NH-heterocycle, N((C-C)-alkyl)-CO N-((C-C)- formula I, alkyl). N((C-C)-alkyl)-CO N((C-C)-alkyl)-aryl, R6 is hydrogen, (C-C)-alkyl, (C-C)-alkylenearyl, prefer N((C-C)-alkyl)-CO—N((C-C)-alkyl)-heterocycle, ably hydrogen or (C-C)-alkyl, more preferably hydro N((C-C)-alkyl)-CO N-(aryl), N(C-C)-alkyl)-CO— gen, methyl, ethyl, n-propyl or n-butyl, most preferably 45 N-(heterocycle), N(aryl)-CO (C-C)-alkyl, N(hetero hydrogen or methyl; cycle)-CO—(C-C)-alkyl, N(aryl)-COO (C-C)-alkyl, where aryl may be mono- or polysubstituted preferably by N(heterocycle)-COO (C-C)-alkyl, N(aryl)-CO-aryl, halogen, (C-C)-alkyl, (C-C)-alkyloxy, hydroxyl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl, N(heterocycle)- (C-C)-alkylmercapto, amino, (C-C)-alkylamino, di COO-aryl, N(aryl)-CO. NH (C-C)-alkyl, N(hetero (C-C)-alkylamino, mono-(C-C)-alkylaminocarbo 50 cycle)-CO. NH (C-C)-alkyl, N(aryl)-CO. NH-aryl, nyl, di-(C-Cs)-alkylaminocarbonyl, (C-C)-alkoxy N(heterocycle)-CO. NH-aryl, N(aryl)-CO N-((C-C)- carbonyl, (C-C)-alkylcarbonyl, trifluoromethyl, alkyl), N(heterocycle)-CO N ((C-C)-alkyl), N(aryl)- trifluoromethyloxy, cyano, (C-C)-alkylsulfonyl, ami CO N((C-C)-alkyl)-aryl, N(heterocycle)-CO N((C- nosulfonyl: C)-alkyl)-aryl, N(aryl)-CO N-(aryl), N(heterocycle)- 55 CO-N-(aryl), aryl, O-(CH2)-aryl, O—(CH2)- with the proviso that, when R1 is (C-C)-alkyl, R6 is not heterocycle, where n may be 0-6, where the aryl radical or (C-C)-alkylenearyl. heterocyclic radical may be mono- to trisubstituted by F, Cl, In a further preferred embodiment of the compounds of the Br, I, OH, CF, NO, CN, OCF. O (C-C)-alkyl, (C-C)- formula I, alkyl, NH, NH(C-C)-alkyl, N(C-C)-alkyl), SO = R6 is (C=O) NR1'R2. 60 CH, COOH, COO (C-C)-alkyl, CONH. In another preferred embodiment of the compounds of the Bicycle is a partly unsaturated bicyclic ring system which formula I, has from 8 to 14 ring members and has exclusively carbon R6 is —(C=O) O R1". atoms as ring members. Ring systems which contain a fused The invention relates to compounds of the formula I in the benzene ring are included in this definition. Mention is made form of their salts, racemates, racemic mixtures and pure 65 by way of example of the tetrahydronaphthyl, alpha- or beta enantiomers, and also to their diastereomers and mixtures tetralonyl, indanyl or indan-1-onyl radical. Preferred bicycle thereof. radicals are tetrahydronaphthyl and indanyl.

US 7,897,616 B2 9 10 The heterocyclic rings or heterocyclic radicals may be alkali metal salts (such as Sodium and potassium salts) and mono- or poly Substituted by Suitable groups, for example: F, alkaline earth metal salts (such as magnesium and calcium Cl, Br, I, CF, NO, N, CN, COOH, COO(C-C)alkyl, salts) and salts of trometamol (2-amino-2-hydroxymethyl-1, CONH2, CONHCC-C)alkyl, CONI(C-C)alkyl (C- 3-propanediol), diethanolamine, lysine or ethylenediamine. C)-alkyl, (C-C)-alkenyl, (C-C)-alkynyl, O—(C-C)- Salts with a pharmaceutically unacceptable anion, for alkyl, where one, more than one orall hydrogen(s) in the alkyl example trifluoroacetate, are likewise included in the scope of radicals may be replaced by fluorine; POH, SOH, SO = the invention as useful intermediates for the preparation or NH, SONHCC-C)-alkyl, SONI(C-C)-alkyl, S (C- purification of pharmaceutically acceptable salts and/or for C)-alkyl, S-(CH)-phenyl, SO—(C-C)-alkyl, SO— the use in non-therapeutic, for example in vitro, applications. (CH2)-phenyl, SO (C-C)-alkyl, SO-(CH2),-phenyl, 10 The term "physiologically functional derivative' used here where n may be 0-6 and the phenyl radical may be up to refers to any physiologically compatible derivative of an disubstituted by F, Cl, Br, OH, CF, NO, CN, OCF, inventive compound of the formula I, for example an ester O—(C-C)-alkyl, (C-C)-alkyl, NH, C(NH)(NH), NH, which, on administration to a mammal, for example the NH-(C-C)-alkyl, N(C-C)-alkyl). NH(C-C)-acyl, human, is capable (directly or indirectly) of forming a com phenyl, O (CH)-phenyl where n may be 0-6, where the 15 pound of the formula I or an active metabolite thereof. phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, The physiologically functional derivatives also include CF, NO, CN, OCF. O—(C-C)-alkyl, (C-C)-alkyl, prodrugs of the inventive compounds, as described, for NH, NH(C-C)-alkyl, N((C-C)-alkyl), SO CH, example, in H. Okada et al., Chem. Pharm. Bull., 1994, 42, COOH, COO (C-C)-alkyl, CONH2. 57-61. Such prodrugs can be metabolized in vivo to give an Heteroaryl is a mono- or bicyclic aromatic ring system inventive compound. These prodrugs may themselves be having from 5 to 12 ring members, in which at least one atom active or not. in the ring system is a heteroatom selected from the group The inventive compounds may also be present in various consisting of N, O and S. This definition also includes ring polymorphic forms, for example as amorphous and crystal systems in which the heteroaryl is fused to a benzene ring. line polymorphic forms. All polymorphic forms of the inven Suitable'heteroaryl rings” or "heteroaryl radicals” are, for 25 tive compounds are included within the scope of the invention example, benzimidazolyl, benzofuranyl, benzothiophenyl, and are a further aspect of the invention. benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, Hereinafter, all references to “compound(s) of the formula benzisoxazolyl, benzisothiazolyl, quinolinyl, furyl, furaza Irelate to compound(s) of the formula I as described above, nyl, imidazolyl, 1H-indazolyl, indolyl, 1.2.3-oxadiazolyl, and also their salts, Solvates and physiologically functional 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1.3,4-oxadiazolyl, 30 derivatives as described herein. pyrimidinyl, pyrazinyl, pyrazolyl pyridyl, pyrrolyl, thiaz olyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiaz Use olyl, 1,3,4-thiadiazolyl, thiophenyl. Preferred heteroaryl The compounds of the formula I in which radicals are benzothiophenyl and thiophenyl. X is the same or different and is —C(—R)—or—N , where The heteroaryl rings or heteroaryl radicals may be mono 35 at least one X and at most two X are —N—; or polysubstituted by suitable groups, for example: F, Cl, Br, W is —(C=O)— —(S—O)— —(SO)—: I, CF, NO, N, CN, COOH, COO(C-C)alkyl, CONH2, R is the same or different and is hydrogen, halogen, (C-C)- CONHCC-C)alkyl, CONI(C-C)alkyl, (C-C)-alkyl, alkyl, (C-C)-haloalkyl, (C-C)-alkyloxy-(C-C)-alky (C-C)-alkenyl, (C-C)-alkynyl, O—(C-C)-alkyl, where lene, aryl, heterocycle, hydroxyl, (C-C)-alkyloxy, (C- one, more than one or all hydrogen(s) in the alkyl radicals 40 Cs)-haloalkyloxy, aryloxy, cyano, nitro, -S(O) (C- may be replaced by fluorine; POH, SOH, SO. NH2, C)-alkyl, where p=0, 1 or 2, aminosulfonyl, SONHCC-C)-alkyl, SONI(C-C)-alkyl, S (C-C)- pentafluorosulfanyl, amino, (C-C)-alkylamino, di-(C- alkyl, S-(CH2)-phenyl, SO—(C-C)-alkyl, SO-(CH2)- C)-alkylamino, (C-C)-alkylcarbonyl, COOR3, phenyl, SO (C-C)-alkyl, SO -(CH2)-phenyl where n CO NR4R5, O CO. NR4R5, O CO (C-C)- may be 0-6 and the phenyl radical may be up to disubstituted 45 alkylene-CO O (C-C)-alkyl, O—CO (C-C)- by F, Cl, Br, OH, CF, NO, CN, OCF O-(C-C)-alkyl, alkylene-CO OH, O CO (C-C)-alkylene-CO— (C-C)-alkyl, NH, C(NH)(NH), NH, NH (C-C)- NR4R5; alkyl, N(C-C)-alkyl). NH(C-C)-acyl, phenyl, R1, R1" are the same or different and are each (C-C)-alkyl, O—(CH)-phenyl, where n may be 0-6, where the phenyl (C-C)-cycloalkyl, (C-C)-alkylenearyl, (C-C)-alky ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF, 50 leneheteroaryl, (C-C)-alkylene-(C-C)-cycloalkyl, NO, CN, OCF. O (C-C)-alkyl, (C-C)-alkyl, NH, bicycle, where aryl, heteroaryl, cycloalkyl or bicycle may NH(C-C)-alkyl, N(C-C)-alkyl), SO CH, COOH, be mono- or polysubstituted preferably by halogen, (C- COO (C-C)-alkyl, CONH2. C)-alkyl, (C-C)-alkyloxy, hydroxyl, (C-C)-alkylmer Owing to their higher water solubility, pharmaceutically capto, amino, (C-C)-alkylamino, di-(C-C)-alky acceptable salts are particularly Suitable for medical applica 55 lamino, mono-(C-C)-alkylaminocarbonyl, di-(C-Cs)- tions compared to the starting or base compounds. These salts alkylaminocarbonyl, (C-C)-alkyloxycarbonyl, (C-C)- must have a pharmaceutically acceptable anion or cation. alkylcarbonyl, cyano, nitro, trifluoromethyl, Suitable pharmaceutically acceptable acid addition salts of trifluoromethyloxy, pentafluorosulfanyl, (C-C)-alkylsul the inventive compounds are salts of inorganic acids such as fonyl, aminosulfonyl: hydrochloric acid, hydrobromic acid, phosphoric acid, meta 60 R1" is (C-C)-alkyl, (C-C)-cycloalkyl, (C-C)-alkyle phosphoric acid, nitric acid and Sulfuric acid, and organic nearyl, (C-C)-alkyleneheteroaryl, (C-C)-alkylene acids, for example acetic acid, benzenesulfonic acid, benzoic (C-C)-cycloalkyl, bicycle, where aryl, heteroaryl, acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic cycloalkyl or bicycle may be mono- or polysubstituted acid, glycolic acid, isethionic acid, lactic acid, lactobionic preferably by halogen, (C-C)-alkyl, (C-C)-alkyloxy, acid, maleic acid, malic acid, methanesulfonic acid. Succinic 65 hydroxyl, (C-C)-alkylmercapto, amino, (C-C)-alky acid, p-toluenesulfonic acid and tartaric acid. Suitable phar lamino, di-(C-C)-alkylamino, mono-(C-C)-alkylami maceutically acceptable basic salts are ammonium salts, nocarbonyl, di-(C-Cs)-alkylaminocarbonyl, (C-C)- US 7,897,616 B2 11 12 alkyloxycarbonyl, (C-C)-alkylcarbonyl, cyano, nitro, high blood pressure trifluoromethyl, trifluoromethyloxy, (C-C)-alkylsulfo heart failure, for example (but not restricted thereto) fol nyl, aminosulfonyl: lowing myocardial infarction, hypertensive heart dis R2 is hydrogen; ease or cardiomyopathy R3 is the same or different and is hydrogen, (C-C)-alkyl, diabetes mellitus, in particular type 2 diabetes, including benzyl: the prevention of the sequelae associated therewith (hy R4, R5 are the same or different and are each hydrogen, perglycemia, glucose intolerance, loss of pancreatic B (C-C)-alkyl, aryl, (C-C)-cycloalkyl, (C-C)-alkyle cells, macro- and microvascular disorders nearyl, (C-C)-alkylene-(C-C)-cycloalkyl; . Other disorders or conditions in which inflammatory reac R6 is hydrogen, (C-C)-alkyl, (C-C)-alkylenearyl, (C- 10 tions or cell differentiation, for example, are involved are: Cl)-alkylene-heterocycle, (C-C)-alkylene-(C-C)-cy atherosclerosis, for example (but not restricted thereto) cloalkyl, (C-C)-bicycle, where aryl, heterocycle, coronary Sclerosis, including angina pectoris or myocar cycloalkyl or bicycle may be mono- or polysubstituted dial infarction, stroke preferably by halogen, (C-C)-alkyl, (C-C)-alkyloxy, vascular restenosis or reocclusion hydroxyl, (C-C)-alkylmercapto, amino, (C-C)-alky chronic inflammatory bowel diseases, for example Crohn's lamino, di-(C-C)-alkylamino, mono-(C-C)-alkylami 15 disease and ulcerative colitis nocarbonyl, di-(C-C)-alkylaminocarbonyl, (C-C)- pancreatitis alkoxycarbonyl, (C-C)-alkylcarbonyl, trifluoromethyl, other inflammatory states trifluoromethyloxy, cyano, (C-C)-alkylsulfonyl, amino retinopathy sulfonyl: adipose cell tumors adipose cell carcinomas, for example liposarcomas O Solid tumors and neoplasms, for example (but not restricted (C=O) NR1'R2: thereto) carcinomas of the gastrointestinal tract, of the O liver, of the biliary tract and of the pancreas, endocrine O tumors, carcinomas of the lungs, of the kidney and the 25 urinary tract, of the genital tract, prostate carcinomas, (C=O) O R1": etc. and the tautomeric forms of the compounds and also their acute and chronic myeloproliferative disorders and lym physiologically compatible salts have a surprising inhibitory phomas effect on endothelial lipase (EL). HDL, which has antiathero angiogenesis sclerotic action, is the preferred substrate for EL. A lowering 30 neurodegenerative disorders of the HDL level leads to the progression of atherosclerosis Alzheimer's disease and its sequelae such as coronary heart disease and addition multiple sclerosis ally promotes the development of metabolic syndrome and its Parkinson's disease sequela of diabetes. An inhibition of the EL should thus lead erythemato-squamous dermatoses, for example psoriasis generally to the prevention of atherosclerotic disorders and 35 acne Vulgaris indirectly reduce the probability of illness in persons with an other skin disorders and dermatological conditions which increased risk of diabetes. are modulated by PPAR It has also been found that the inhibitory effect of the eczemas and neurodermatitis inventive compounds of the formula I is selective compared to other lipases. dermatitis for example seborrheic dermatitis or photoder 40 matitis The compounds of the formula I are notable for exhibiting keratitis and keratoses, for example seborrheic keratoses, an improved solubility compared with compounds of similar senile keratoses, actinic keratosis, photo-induced kera structure in aqueous media with at least the same time high toses or keratosis follicularis activity. Preferred compounds of the invention further exhibit keloids and keloid prophylaxis an improved metabolic Stability compared with compounds warts, including condylomata or condylomata acuminata of the prior art. 45 human papilloma viral (HPV) infections, for example Furthermore the compounds of the invention show advan Venereal papillomata, viral warts, for example mollus tages in terms of serum stability. cum contagiosum, leukoplakia Such compounds are particularly suitable for the treatment papular dermatoses, for example lichen planus and/or prevention of skin cancer, for example basal-cell carcinomas, melano 1. Dyslipidemias and general impairments of lipid metabo 50 mas or cutaneous T-cell lymphomas lism and their sequelae, for example atherosclerosis, coro localized benign epidermal tumors, for example kerato nary heart disease, cerebrovascular disorders etc., espe derma, epidermal naevi cially those (but not restricted thereto) which are chilblains characterized by one or more of the following factors: high blood pressure high plasma triglyceride concentrations, high postprandial 55 syndrome X plasma triglyceride concentrations, polycystic ovary syndrome (PCOS) low HDL cholesterol concentration asthma low ApoA lipoprotein concentrations osteoarthritis high LDL cholesterol concentrations 60 lupus erythematosus (LE) or inflammatory rheumatic dis small dense LDL cholesterol particles orders, for example rheumatoid arthritis high ApoB lipoprotein concentrations vasculitis 2. Various other conditions which may be associated with the wasting (cachexia) metabolic syndrome, Such as: gout obesity (excess weight), including central obesity 65 ischemia/reperfusion syndrome thromboses, hypercoagulable and prothrombotic stages acute respiratory distress syndrome (ARDS) (“shock (arterial and venous) lung). US 7,897,616 B2 13 14 Formulation prepared by shaping the pulverulent compound moistened The amount of an inventive compound which is required in with an inert liquid diluent in a Suitable machine. order to achieve the desired biological effect is dependent Pharmaceutical compositions which are suitable for per upon a series of factors, for example the specific compound oral (Sublingual) administration include lozenges which con selected, the intended use, the mode of administration and the tain a compound of formula I with a flavoring, customarily clinical condition of the patient. The daily dose is generally in Sucrose, and gum arabic or tragacanth, and pastilles which the range from 0.3 mg to 100 mg (typically from 3 mg to 50 include the compound in an inert base, such as gelatin and mg) per day per kilogram of bodyweight, for example 3-10 glycerol or Sucrose and gum arabic. mg/kg/day. An intravenous dose may, for example, be in the Suitable pharmaceutical compositions for parenteral range from 0.3 mg to 1.0 mg/kg and may suitably be admin administration include preferably sterile aqueous prepara istered as an infusion of from 10ng to 100ng per kilogram per 10 tions of a compound of the formula I which are preferably minute. Suitable infusion Solutions for these purposes may, isotonic with the blood of the intended recipient. These prepa for example, contain from 0.1 ng to 10 mg. typically from 1 ng rations are preferably administered intravenously, although to 10 mg, per milliliter. Single doses may contain, for the administration may also be subcutaneous, intramuscular example, from 1 mg to 10 g of the active ingredient. or intradermal as an injection. These preparations can prefer Ampoules for injections may therefore contain, for example, 15 ably be produced by mixing the compound with water and from 1 mg to 100 mg, and single dose formulations which can making the Solution obtained Sterile and isotonic with the be administered orally, for example tablets or capsules, may blood. Injectable compositions according to the invention contain, for example, from 0.05 to 1000 mg. typically from generally contain from 0.1 to 5% by weight of the active 0.5 to 600 mg. The compounds of the formula I may be used compound. for therapy of the abovementioned conditions as the com Suitable pharmaceutical compositions for rectal adminis pounds themselves, although they are preferably in the form tration are preferably in the form of single dose Suppositories. of a pharmaceutical composition with an acceptable carrier. These can be prepared by mixing a compound of the formula The carrier of course has to be acceptable, in the sense that it I with one or more conventional Solid carriers, for example is compatible with the other constituents of the composition cocoa butter, and shaping the resulting mixture. and is not damaging to the health of the patient. The carrier 25 Suitable pharmaceutical compositions for topical applica may be a solid or a liquid or both and is preferably formulated tion on the skin are preferably in the form of an ointment, with the compound as a single dose, for example as a tablet, cream, lotion, paste, spray, aerosol or oil. Useful carriers which may contain from 0.05 to 95% by weight of the active include petroleum jelly, lanolin, polyethylene glycols, alco ingredient. Further pharmaceutically active Substances may hols and combinations of two or more of these Substances. likewise be present, including further inventive compounds. The active ingredient is generally present in a concentration The inventive pharmaceutical compositions may be produced 30 of from 0.1 to 15% by weight of the composition, preferably by one of the known pharmaceutical methods which consist from 0.5 to 2%. essentially in mixing the constituents with pharmacologically Transdermal administration is also possible. Suitable phar acceptable carriers and/or excipients. maceutical compositions for transdermal applications may be Inventive pharmaceutical compositions are those which in the form of single plasters which are suitable for long-term are suitable for oral, rectal, topical, peroral (for example 35 close contact with the epidermis of the patient. Such plasters Sublingual) and parenteral (for example Subcutaneous, intra Suitably contain the active ingredient in an optionally buff muscular, intradermal or intravenous) administration, ered aqueous Solution, dissolved and/or dispersed in an adhe although the most Suitable mode of administration depends in sive or dispersed in a polymer. A Suitable active ingredient each individual case on the nature and severity of the condi concentration is from approx. 1% to 35%, preferably from tion to be treated and on the type of the compound of formula 40 approx. 3% to 15%. A particular means of releasing the active I used in each case. Coated formulations and coated slow ingredient may be by electrotransport or iontophoresis, as release formulations are also encompassed by the scope of the described, for example, in Pharmaceutical Research, 206): invention. Preference is given to acid- and gastric fluid-resis 318 (1986). tant formulations. Suitable gastric fluid-resistant coatings The compounds of the formula I are notable for favorable include cellulose acetate phthalate, polyvinyl acetate phtha 45 effects on disorders of lipid metabolism. They positively late, hydroxypropylmethylcellulose phthalate and anionic influence the HDL to LDL ratio and increase in particular the polymers of methacrylic acid and methyl methacrylate. HDL leveland are suitable for the prevention and treatment of Suitable pharmaceutical preparations for oral administra dyslipidemias and metabolic syndrome and their diverse tion may be in the form of separate units, for example cap sequelae Such as atherosclerosis, coronary heart disease, Sules, cachets, lozenges or tablets, each of which contains a 50 heart failure, obesity and diabetes. certain amount of the compound of the formula I; as powder Combinations with Other Medicaments or granules; as solution or Suspension in an aqueous or non The compounds of the invention can be administered alone aqueous liquid; or as an oil-in-water or water-in-oil emulsion. or in combination with one or more further pharmacologi These compositions may, as already mentioned, be prepared cally active ingredients. In particular, the compounds of the by any suitable pharmaceutical method which includes a step 55 invention can be administered with active ingredients which in which the active ingredient and the carrier (which may have a similar pharmacological effect to themselves. For consist of one or more additional constituents) are brought example, they can be administered in combination with active into contact. In general, the compositions are prepared by ingredients which have favorable effects on metabolic distur uniform and homogeneous mixing of the active ingredient bances or disorders frequently associated therewith. with a liquid carrier and/or finely divided solid carrier, after which the product is shaped if necessary. For example, a 60 Examples of such medicaments are tablet can thus be produced by compressing or shaping a 1. medicaments which lower blood glucose, antidiabetics, powder or granules of the compound, optionally with one or ... active ingredients for the treatment of dyslipidemias, more additional constituents. Compressed tablets can be pre ... antiatherosclerotic medicaments, pared by tableting the compound in free-flowing form, for ... antiobesity agents, example a powder or granules, optionally mixed with a 65 ... antiinflammatory active ingredients binder, lubricant, inert diluent and/or one (or more) surfac ... active ingredients for the treatment of malignant tumors tants/dispersants in a Suitable machine. Shaped tablets can be ... antithrombotic active ingredients US 7,897,616 B2 15 16 8. active ingredients for the treatment of high blood pres inhibitors of liver enzymes involved in Stimulating gluconeo SU genesis and/or glycogenolysis, 9. active ingredients for the treatment of heart failure and modulators of glucose uptake, of glucose transport and of 10. active ingredients for the treatment and/or prevention glucose reabsorption, inhibitors of 113-HSD1, of complications caused by diabetes or associated with 5 inhibitors of protein tyrosine phosphatase 1B (PTP1B), diabetes modulators of the Sodium-dependent glucose transporter 1 11. active ingredients for the treatment of neurodegenera or 2 (SGLT1, SGLT2), tive diseases compounds which alter lipid metabolism such as antihyper 12. active ingredients for the treatment of diseases of the lipidemic active ingredients and antilipidemic active ingre central nervous system 10 dients, 13. active ingredients for the treatment of dependence on compounds which reduce food intake, drugs, nicotine and alcohol compounds which increase thermogenesis, 14. analgesics PPAR and RXR modulators and They can be combined with the compounds of the inven active ingredients which act on the ATP-dependent potassium tion of the formula I in particular for a synergistic improve 15 channel of the beta cells. ment in the effect. Administration of the active ingredient In one embodiment of the invention, the compound of the combination can take place either by separate administration formula I is administered in combination with an HMGCoA of the active ingredients to the patient or in the form of reductase inhibitor Such as simvastatin, fluvastatin, pravasta combination products in which a plurality of active ingredi tin, lovastatin, atorvastatin, cerivastatin, rosuvastatin or ents are present in one pharmaceutical preparation. L-659699. Further active ingredients particularly suitable for the com In one embodiment of the invention, the compound of the bination products are: formula I is administered in combination with a cholesterol All antidiabetics which are mentioned in the Rote Liste absorption inhibitor Such as, for example, eZetimibe, tique 2006, chapter 12; all weight-reducing agents/appetite Sup side, pamaqueside, FM-VP4 (sitostanol/campesterol ascor pressants which are mentioned in the Rote Liste 2006, chapter 25 byl phosphate: Forbes Medi-Tech, WO 2005/042692), 1; all lipid-lowering agents which are mentioned in the Rote MD-0727 (Microbia Inc., WO 2005/021497) or with com Liste 2006, chapter 58. They can be combined with the com pounds as described in WO 2002/0664.64 (Kotobuki Pharma pound of the invention of the formula I in particular for a ceutical Co. Ltd.), WO 2005/062824 (Merck & Co.) or WO synergistic improvement in the effect. Administration of the 2005/061451 and WO 2005/061452 (AstraZeneca AB). active ingredient combination can take place either by sepa 30 In one embodiment of the invention, the compound of the rate administration of the active ingredients to the patientorin formula I is administered in combination with a PPAR the form of combination products in which a plurality of gamma agonist Such as, for example, rosiglitaZone, pioglita active ingredients are present in one pharmaceutical prepara Zone, JTT-501, GI 262570, R-483 or CS-011 (rivoglitazone). tion. Most of the active ingredients mentioned hereinafter are In one embodiment of the invention, the compound of the disclosed in the USP Dictionary of USAN and International 35 formula I is administered in combination with a PPAR alpha Drug Names, US Pharmacopeia, Rockville 2001. agonist such as, for example, GW'9578, GW-590735, K-1 11, Antidiabetics include insulin and insulin derivatives such LY-674, KRP-101 or DRF-10945. as, for example, Lantus(R (see www.lantus.com) or HMR In one embodiment of the invention, the compound of the 1964 or those described in WO 2005/005477 (Novo Nordisk), formula I is administered in combination with a mixed PPAR fast-acting insulins (see U.S. Pat. No. 6,221,633), inhalable 40 alpha/gamma agonist Such as, for example, muraglitazar, insulins such as, for example, Exubera R or oral insulins such tesaglitazar, naveglitazar, LY-510929, ONO-5129, E-3030 or as, for example, IN-105 (Nobex) or Oral-lynTM (Generex as described in WO 00/64888, WO 00/64876, WO Biotechnology), GLP-1-derivatives such as, for example, 03/020269, WO 2004/075891, WO 2004/076402, WO 2004/ exenatide, liraglutide or those which have been disclosed in 075815, WO 2004/076447, WO 2004/076428, WO 2004/ WO 98/08871 or WO 2005/027978 of Novo Nordisk A/S, in 45 076401, WO 2004/076426, WO 2004/076427, WO 2006/ WO 01/04156 of Zealand or in WOOO/34331 of Beaufour O18118, WO 2006/0181 15, and WO 2006/018116 or in J. P. Ipsen, Pramlintide Acetate (Symlin; Amylin Pharmaceuti Berger et al., TRENDS in Pharmacological Sciences 28(5), cals), and orally effective hypoglycemic active ingredients. 244-251, 2005. The active ingredients include preferably In one embodiment of the invention, the compound of the Sulfonylureas, 50 formula I is administered in combination with a PPAR delta biguanidines, agonist such as, for example, GW-501516, or as described in meglitinides, WO 2005/097762, WO 2005/097786, WO2005/097763, WO oxadiazolidinediones, 2006/O29699. thiazolidinediones, In one embodiment of the invention, the compound of the glucosidase inhibitors, 55 formula I is administered in combination with metaglidasen inhibitors of glycogen phosphorylase, or with MBX-2044 or other partial PPARgamma agonists/ glucagon antagonists, antagonists. glucokinase activators, In one embodiment of the invention, the compound of the inhibitors of fructose-1,6-bisphosphatase, formula I is administered in combination with a fibrate such modulators of glucose transporter 4 (GLUT4), 60 as, for example, fenofibrate, clofibrate or bezafibrate. inhibitors of glutamine-fructose-6-phosphate amidotrans In one embodiment of the invention, the compound of the ferase (GFAT), GLP-1 agonists, formula I is administered incombination with an MTP inhibi potassium channel openers such as, for example, those which tor such as, for example, implitapide, BMS-201038, have been disclosed in R-103757 or those described in WO 2005/085226. WO 97/26265 and WO99/03861 of Novo Nordisk A/S, 65 In one embodiment of the invention, the compound of the inhibitors of dipeptidylpeptidase IV (DPP-IV), formula I is administered in combination with a CETP inhibi insulin sensitizers, tor such as, for example, torcetrapib or JTT-705. US 7,897,616 B2 17 18 In one embodiment of the invention, the compound of the In one embodiment of the invention, the compound of the formula I is administered in combination with a bile acid formula I is administered in combination with an O-glucosi absorption inhibitor (see, for example, U.S. Pat. Nos. 6.245, dase inhibitor Such as, for example, miglitol or acarbose. 744, 6,221,897 or WO 00/61568), such as, for example, HMR In one embodiment of the invention, the compound of the 1741 or those as described in DE 10 2005 033099.1 and DE formula I is administered in combination with an active ingre 10 2005 O331 OO.9. dient which acts on the ATP-dependent potassium channel of In one embodiment of the invention, the compound of the the beta cells, such as, for example, tolbutamide, glibencla formula I is administered in combination with a polymeric mide, glipizide, glimepiride or repaglinide. bile acid adsorbent such as, for example, cholestyramine or In one embodiment of the invention, the compound of the colesevelam. 10 formula I is administered in combination with more than one In one embodiment of the invention, the compound of the of the aforementioned compounds, e.g. in combination with a formula I is administered in combination with an LDL recep Sulfonylurea and metformin, a Sulfonylurea and acarbose, tor inducer (see U.S. Pat. No. 6,342.512), such as, for repaglinide and metformin, insulin and a Sulfonylurea, insu example, HMR1171, HMR1586 or those as described in WO lin and metformin, insulin and troglitaZone, insulin and lov 2005/097738. 15 astatin, etc. In one embodiment, the compound of the formula I is In one embodiment of the invention, the compound of the administered in combination with Omacor(R) (Omega-3 fatty formula I is administered in combination with an inhibitor of acids; highly concentrated ethyl esters of eicosapentaenoic glycogen phosphorylase, such as, for example, PSN-357 or acid and of docosahexaenoic acid). FR-258900 or those as described in WO 2003/084922, WO In one embodiment of the invention, the compound of the 2004/007455, WO 2005/073229-31 or WO 2005/067932. formula I is administered in combination with an ACAT In one embodiment of the invention, the compound of the inhibitor Such as, for example, avasimilbe. formula I is administered in combination with glucagon In one embodiment of the invention, the compound of the receptor antagonists such as, for example, A-770077, NNC formula I is administered in combination with an antioxidant 25-2504 or as described in WO 2004/100875 or WO 2005/ such as, for example, OPC-14117, probucol, tocopherol, 25 O6568O. ascorbic acid, B-carotene or selenium. In one embodiment of the invention, the compound of the In one embodiment of the invention, the compound of the formula I is administered in combination with activators of formula I is administered in combination with a vitamin Such glucokinase, such as, for example, RO-4389620, as, for example, vitamin B6 or vitamin B12. LY-2121260 (WO 2004/063179), PSN-105, PSN-110, GKA In one embodiment of the invention, the compound of the 30 50 or those as are described for example by Prosidion in WO formula I is administered in combination with a lipoprotein 2004/072031, WO 2004/072066, WO 05/103021 or WO lipase modulator such as, for example, ibrolipim (NO-1886). 06/016178, by Rochein WO00/058293, WO00/183465, WO In one embodiment of the invention, the compound of the 00/183478, WO 00/185706, WO 00/185707, WO 01/044216, formula I is administered in combination with an ATP citrate GB 02385328, WO 02/008209, WO 02/014312, WO lyase inhibitor such as, for example, SB-204990. 35 02/.46173, WO 02/48106, DE 10259786, WO 03/095438, US In one embodiment of the invention, the compound of the 04067939 or WO 04/052869, by Novo Nordisk in EP formula I is administered in combination with a squalene 1532980, WO 03/055482, WO 04/002481, WO 05/049019, synthetase inhibitor such as, for example, BMS-188494 or as WO 05/066145 or WO 05/123132, by Merck/Banyu in WO described in WO 2005/077907. 03/080585, WO 03/097824, WO 04/081001, WO 05/063738 In one embodiment of the invention, the compound of the 40 or WO 05/090332, by Eli Lilly in WO 04/063194, or by Astra formula I is administered in combination with a lipoprotein Zeneca in WO 01/020327, WO 03/000262, WO 03/000267, (a) antagonist Such as, for example, gemcabene (CI-1027). WO 03/015774, WO 04/045614, WO 04/046139, WO In one embodiment of the invention, the compound of the 05/044801, WO 05/054200, WO 05/054233, WO 05/056530, formula I is administered in combination with an HM74A WO 05/080359, WO 05/080360 or WO 05/121110. receptor agonist Such as, for example, nicotinic acid. 45 In one embodiment of the invention, the compound of the In one embodiment of the invention, the compound of the formula I is administered in combination with an inhibitor of formula I is administered in combination with a lipase inhibi gluconeogenesis, such as, for example, FR-225654. tor such as, for example, orlistat or cetilistat (ATL-962). In one embodiment of the invention, the compound of the In one embodiment of the invention, the compound of the formula I is administered in combination with inhibitors of formula I is administered in combination with insulin. 50 fructose-1,6-bisphosphatase (FBPase), such as, for example, In one embodiment of the invention, the compound of the CS-917. formula I is administered in combination with a sulfonylurea In one embodiment of the invention, the compound of the Such as, for example, tolbutamide, glibenclamide, glipizide formula I is administered in combination with modulators of or glimepiride. glucose transporter 4 (GLUT4), such as, for example, KST-48 In one embodiment of the invention, the compound of the 55 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 formula I is administered in combination with a biguanide (2004)). Such as, for example, metformin. In one embodiment of the invention, the compound of the In another embodiment of the invention, the compound of formula I is administered in combination with inhibitors of the formula I is administered in combination with a megli glutamine-fructose-6-phosphate amidotransferase (GFAT), tinide Such as, for example, repaglinide or nateglinide. 60 as are described for example in WO 2004/101528. In one embodiment of the invention, the compound of the In one embodiment of the invention, the compound of the formula I is administered in combination with a thiazo formula I is administered in combination with inhibitors of lidinedione Such as, for example, troglitaZone, ciglitaZone, dipeptidylpeptidase IV (DPP-IV), such as, for example, pioglitaZone, rosiglitaZone or the compounds disclosed in vildagliptin (LAF-237), sitagliptin (MK-0431), saxagliptin WO 97/41097 of Dr. Reddy's Research Foundation, in par 65 (BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR ticular 5-4-(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl 619, TA-6666, TS-021, GRC-8200, GW-825964x or as are methoxyphenylmethyl-2,4-thiazolidinedione. described in WO 2003/074500, WO 2003/106456, WO 2004/ US 7,897,616 B2 19 20 50658, WO 2005/058901, WO 2005/012312, WO 2005/ “I-kappaB kinase” (IKK inhibitors), as are described for 0.12308, PCT/EP2005/007821, PCT/EP2005/008005, PCT/ example in WO 2001/000610, WO 2001/030774, WO 2004/ EP2005/008002, PCT/EP2005/008004, PCT/EP2005/ O22553 or WO 2005/097 129. 008283, DE 10 2005 012874.2 or DE 10 2005 012873.4. In one embodiment of the invention, the compound of the In one embodiment of the invention, the compound of the 5 formula I is administered in combination with modulators of formula I is administered in combination with inhibitors of the glucocorticoid receptor, like those described for example 11-beta-hydroxysteroid dehydrogenase 1 (113-HSD1), such in WO 2005/090336. as, for example, BVT-2733 or those as are described for In a further embodiment of the invention, the compound of example in WO 2001/90090-94, WO 2003/43999, WO 2004/ the formula I is administered in combination with CART 112782, WO 2003/44000, WO 2003/44009, WO 2004/ 10 modulators (see "Cocaine-amphetamine-regulated transcript 112779, WO 2004/113310, WO 2004/103980, WO 2004/ influences energy metabolism, anxiety and gastric emptying 112784, WO 2003/065983, WO 2003/104207, WO 2003/ in mice' Asakawa, A. et al.: Hormone and Metabolic 104208, WO 2004/106294, WO 2004/011410, WO 2004/ Research (2001), 33(9), 554-558); NPY antagonists such as, 033427, WO 2004/041264, WO 2004/037251, WO 2004/ for example, naphthalene-1-sulfonic acid {4-(4-amino 056744, WO 2004/065351, WO 2004/089367, WO 2004/ 15 quinazolin-2-ylamino)methylcyclohexylmethylamide 089380, WO 2004/089470-71, WO 2004/089896, WO 2005/ hydrochloride (CGP 71683A); peptide YY 3-36 (PYY3-36) O16877 or WO 2005/097759. or analogous compounds, such as, for example, CJC-1682 In one embodiment of the invention, the compound of the (PYY3-36 conjugated with human serum albumin via formula I is administered in combination with inhibitors of Cys34), CJC-1643 (derivative of PYY3-36 which conjugates protein tyrosine phosphatase 1B (PTP1 B), as are described in vivo to serum albumin) or those as are described in WO for example in WO 2001/19830-31, WO 2001/17516, WO 2005/080424; 2004/506446, WO 2005/012295, PCT/EP2005/005311, cannabinoid receptor 1 antagonists Such as, for example, PCT/EP2005/005321, PCT/EP2005/007 151, PCT/EP2005/ O1294 or DE 10 2004 O605424. rimonabant, SR147778 or those as are described for 25 example in EP 0656354, WO 00/15609, WO 02/076949, In one embodiment of the invention, the compound of the WO 2005/080345, WO 2005/080328, WO 2005/080343, formula I is administered in combination with modulators of WO 2005/075450, WO 2005/080357, WO 2001/70700, the sodium-dependent glucose transporter 1 or 2 (SGLT1, WO 2003/026647-48, WO 2003/02776, WO 2003/ SGLT2), such as, for example, KGA-2727, T-1095 and SGL 04.01.07, WO 2003/007887, WO 2003/027069, U.S. Pat. 0010 or as are described for example in WO 2004/007517, 30 No. 6,509,367, WO 2001/32663, WO 2003/086288, WO WO 2004/52903, WO 2004/52902, WO 2005/121161, WO 2003/087037, WO 2004/048317, WO 2004/058145, WO 2005/085237, JP2004359630 or by A. L. Handlon in Expert 2003/084930, WO 2003/084943, WO 2004/058744, WO Opin. Ther. Patents (2005) 15(11), 1531-1540. 2004/013 120, WO 2004/029204, WO 2004/035566, WO In one embodiment of the invention, the compound of the 2004/058249, WO 2004/058255, WO 2004/058727, WO formula I is administered in combination with inhibitors of 35 2004/069838, US20040214837, US20040214855, hormone-sensitive lipase (HSL) as described for example in US20040214856, WO 2004/096209, WO 2004/096763, WO 01/17981, WO 01/66531, WO 2004/035550, WO 2005/ WO 2004/096794, WO 2005/000809, WO 2004/099157, O73199 or WO O3/051842. US20040266845, WO 2004/110453, WO 2004/108728, In one embodiment of the invention, the compound of the WO 2004/000817, WO 2005/000820, US20050009870, formula I is administered in combination with inhibitors of 40 WO 2005/00974, WO 2004/111033-34, WO 2004/11038 acetyl-CoA carboxylase (ACC). Such as, for example, those 39, WO 2005/016286, WO 2005/007111, WO 2005/ as described in WO 1999/46262, WO 2003/72197, WO 2003/ 007628, US2005.0054679, WO 2005/027837, WO 2005/ O72197 or WO 2005/044814. 028456, WO 2005/063761-62, WO 2005/061509 or WO In one embodiment of the invention, the compound of the 2005/077897; formula I is administered in combination with an inhibitor of 45 MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene phosphoenolpyruvate carboxykinase (PEPCK), such as, for 2-carboxylic acid 2-(3a-benzyl-2-methyl-3-oxo-2.3.3a.4, example, those as described in WO 2004/074288. 6,7-hexahydropyrazolo 4.3-cpyridin-5-yl)-1-(4-chlo In one embodiment of the invention, the compound of the rophenyl)-2-oxoethylamide: (WO 01/91752)) or formula I is administered in combination with an inhibitor of LB53280, LB53279, LB53278 or THIQ, MB243, RY764, glycogen synthase kinase 3 beta (GSK-3beta), as described 50 CHIR-785, PT-141 or those as are described in WO 2005/ for example in US2005222220, WO 2004/046117, WO 2005/ 060985, WO 2005/009950, WO 2004/087.159, WO 2004/ 085230, WO 2005/111018, WO 2003/078403, WO 2004/ 078717, WO 2004/078716, WO 2004/024720, 022544, WO 2003/106410, WO 2005/058908, US20050124652, WO 2005/051391, WO 2004/112793, US2005038023, WO 2005/009997, US2005026984, WO WOUS20050222014, US20050176728, 2005/000836, WO 2004/106343, EP1460075, WO 2004/ 55 US20050164914, US20050124636, US20050130988, 014910, WO 2003/076442, WO 2005/087727 or WO 2004/ US2004.0167201, WO 2004/005324, WO 2004/037797, O46117. WO 2005/042516, WO 2005/040109, WO 2005/030797, In one embodiment of the invention, the compound of the US20040224901, WO 2005/01921, WO 2005/09184, WO formula I is administered in combination with an inhibitor of 2005/000339, EP1460069, WO 2005/047253, WO 2005/ protein kinase C beta (PKC beta), such as, for example, 60 047251, EP1538159, WO 2004/072076, WO 2004/072077 ruboxistaurin. or WO 2006/024390; In one embodiment of the invention, the compound of the orexin receptor antagonists (e.g. 1-(2-methylbenzoxazol-6- formula I is administered in combination with an endothelin yl)-3-1.5 naphthyridin-4-ylurea hydrochloride (SB A receptor antagonist Such as, for example, avosentan (SPP 334867-A) or those as are described for example in WO 301). 65 2001/96302, WO 2001/85693, WO 2004/085403 or WO In one embodiment of the invention, the compound of the 2005/075458); histamine H3 receptor agonists (e.g. 3-cy formula I is administered in combination with inhibitors of clohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydro-imidazo[4, US 7,897,616 B2 21 22 5-cpyridin-5-yl)propan-1-one oxalic acid salt (WO In one embodiment of the invention, the further active 00/63208) or those as are described in WO 2000/64884, ingredient is leptin; see, for example, “Perspectives in the WO 2005/082893); therapeutic use of leptin', Salvador, Javier; Gomez-Ambrosi, CRF antagonists (e.g. 2-methyl-9-(2,4,6-trimethylphenyl)- Javier; Fruhbeck, Gema, Expert Opinion on Pharmaco 9H-1,3,9-triazafluoroen-4-yldipropylamine (WO therapy (2001), 2(10), 1615-1622. 00/66585)); In one embodiment of the invention, the further active CRF BP antagonists (e.g. urocortin); urocortin agonists; ingredient is dexamphetamine or amphetamine. 33 agonists (such as, for example, 1-(4-chloro-3-methane sulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6- In one embodiment of the invention, the further active ingredient is fenfluramine or dexfenfluramine. yloxy)ethylaminoethanol hydrochloride (WO 10 01/83451)); In another embodiment of the invention, the further active MSH (melanocyte-stimulating hormone) agonists; ingredient is sibutramine. In one embodiment of the inven MCH (melanin-concentrating hormone) receptor antagonists tion, the further active ingredient is mazindole or phenter (such as, for example, NBI-845, A-761, A-665798, A-798, mine. ATC-0175, T-226296, T-71, GW-803430 or compounds 15 In one embodiment of the invention, the compound of the such as are described in WO 2003/15769, WO 2005/ formula I is administered in combination with bulking agents, 085200, WO 2005/019240, WO 2004/011438, WO 2004/ preferably insoluble bulking agents (see, for example, Carob/ 012648, WO 2003/015769, WO 2004/072025, WO 2005/ Caromax(R) (Zunft H J; et al., Carob pulp preparation for 070898, WO 2005/070925, WO 2006/018280, WO 2006/ treatment of hypercholesterolemia, ADVANCES IN 018279, WO 2004/03 9780, WO 2003/033476, WO 2002/ THERAPY (2001 Sep.-Oct.), 18(5), 230-6)). Caromax is a 006245, WO 2002/002744, WO 2003/004027 or carob-containing product from Nutrinova, Nutrition Special FR2868780); ties & Food Ingredients GmbH, Industriepark Hoechst, CCK-A agonists (such as, for example, {2-4-(4-chloro-2,5- 65926 Frankfurt/Main. Combination with Caromax(R) is pos dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcar sible in one preparation or by separate administration of com bamoyl-5,7-dimethylindol-1-yl)acetic acid trifluoroace pounds of the formula I and Caromax(R). Caromax(R) can in tic acid salt (WO 99/15525), SR-146131 (WO 0244150) or 25 this connection also be administered in the form of food SSR-125180); products Such as, for example, in bakery products or muesli serotonin reuptake inhibitors (e.g. dexfenfluramine); bars. mixed serotoninergic and noradrenergic compounds (e.g. In one embodiment of the invention, the compound of the WO 00/71549): formula I is administered in combination with PDE inhibitors 5-HT receptor agonists, e.g. 1-(3-ethylbenzofuran-7-yl)pip 30 (phosphodiesterase), like those described for example in WO erazine oxalic acid salt (WO 01/09111): 2003/O77949 or WO 2005/O12485. 5-HT2C receptor agonists (such as, for example, APD-356, In one embodiment of the invention, the compound of the BVT-933 or those as are described in WO 2000/77010, WO formula I is administered in combination with NAR-1 (nico 2007/7001-02, WO 2005/019180, WO 2003/064423, WO tinic acid receptor) agonists like those described for example 2002/42304 or WO 2005/082859); 35 in WO 2004/094429. 5-HT6 receptor antagonists as are described for example in In one embodiment of the invention, the compound of the WO 2005/058858; formula I is administered in combination with CB2 (cannab bombesin receptor agonists (BRS-3 agonists); inoid receptor) agonists like those described for example in galanin receptor antagonists; US2005/143448. growth hormone (e.g. human growth hormone or AOD 40 In one embodiment of the invention, the compound of the 9604): formula I is administered in combination with histamine 1 growth hormone releasing compounds (tertiary butyl 6-ben agonists like those described for example in WO 2005/ Zyloxy-1-(2-diisopropyl-aminoethylcarbamoyl)-3,4-dihy 101979. dro-1H-isoquinoline-2-carboxylate (WO 01/85695)); In one embodiment of the invention, the compound of the growth hormone secretagogue receptor antagonists (ghrelin 45 formula I is administered in combination with bupropion as antagonists) such as, for example, A-778193 or those as are described in WO 2006/017504. described in WO 2005/030734; TRH agonists (see, for example, EP 0462.884); uncoupling In one embodiment of the invention, the compound of the protein 2 or 3 modulators; formula I is administered in combination with opioid antago leptin agonists (see, for example, Lee, Daniel W.; Leinung, nists like those described for example in WO 2005/107806 or Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patri 50 WO 2004/0944.29. cia. Leptinagonists as a potential approach to the treatment In one embodiment of the invention, the compound of the of obesity. Drugs of the Future (2001), 26(9), 873-881); formula I is administered in combination with neutral DA agonists (bromocriptine or Doprexin); endopeptidase inhibitors like those described for example in lipase/amylase inhibitors (like those described for example in WO 2002/02513, WO 2002/06492, WO 2002/040008, WO WO 00/40569); 55 2002/04.0022 or WO 2002/04767O. inhibitors of diacylglycerol O-acyltransferases (DGATs) as In one embodiment of the invention, the compound of the described for example in US2004/0224997, WO 2004/ formula I is administered incombination with NPY inhibitors 094618, WO 2000/58491, WO 2005/044250, WO 2005/ (neuropeptide Y) like those described for example in WO 072740, JP2005206492 or WO 2005/013907; 2002/04767O. inhibitors of fatty acid synthase (FAS) such as, for example, 60 In one embodiment of the invention, the compound of the C75 or those as described in WO 2004/005277: formula I is administered in combination with sodium/hydro oxyntomodulin; gen exchange inhibitors like those described for example in oleoyl-estrone WO 2003/092694. or thyroid hormone receptor agonists such as, for example: In one embodiment of the invention, the compound of the KB-2115 or those as described in WO 2005/8279, WO 65 formula I is administered in combination with modulators of 2001/72692, WO 2001/94293, WO 2003/084915, WO the glucocorticoid receptor like those described for example 2004/O18421 or WO 2005/0923.16. in WO 2005/090336. US 7,897,616 B2 23 24 In one embodiment of the invention, the compound of the In one embodiment of the invention, the compound of the formula I is administered in combination with nicotine recep- formula I is administered in combination with antithrombotic sists like those described for example in WO 2004/ active ingredients such as, for example, clopidogrel. In one embodiment of the invention, the compound of the s It will be appreciated that every suitable combination of the formula I is administered in combination with NRIs (norepi- compounds of the invention with one or more of the afore nephrine reuptake inhibitors) like those described for mentioned compounds and optionally one or more other example in WO 2002/053140. pharmacologically active Substances is regarded as falling In one embodiment of the invention, the compound of the formula I is administered in combination with MOA (E-beta within the protection conferred by the present invention. methoxyacrylate) Such as, for example, Segeline or like those 10 Some of the formulae for the development codes men described for example in WO 2002/053140. tioned above are detailed hereinafter.

HO O

le HO O Na"

FM-VP4. O

O CH OH N O O O n N

O ar NH N O O HN O

JTT-5O1

GI262570 O

S N / HO O O f O H O N N N N a H O S

CS-011 RivoglitaZone

GW-9578 C Cl OH

O C

K-1 11 US 7,897,616 B2 25 26

-continued N

HO N X. h O O

LY-674

O

H O CCOH 1. O F

KRP-101

LY-510929

BMS-201038

US 7,897,616 B2 29 30

-continued N O

O OH O OH roc "Yuu- O-x" O HC CH

CI-1027 ATL-962

HO HO Na O o

O E OH OH

O

FR-258900

HO 2 N

NH 22 O

NNC-25-2504

O O 21 OH leo 1. JX C l ro's s N-n-

GKA-50 LY-21.21260

US 7,897,616 B2 33 34

-continued

N MeO O SN N N

CHIR-785

RYT64 COr O.

COUO O O F C N

A-761 A-66.5798

H N N O n O N CO H F N N 21 H

F 1. Nn F O

ATC-0175 T-226296

O

S N o1 O C \le CCO roHO O

US 7,897,616 B2 37 38 The activity of the compounds of the invention of the determined by various methods. Suitable examples of solu formula I was tested in the following enzyme assay System: tion precipitation methods (“kinetic solubility”) and methods EL Inhibition Assay: which investigate the dissolution of a solid sample until an EL is released as secretory protein in high concentration equilibrium is set up (“thermodynamic solubility'). into cell culture medium (conditioned medium) by recombi nant cell lines (CHO, HEK293). This is employed as an a) Kinetic Solubility enzyme solution after concentration. A DMSO solution of the test compound (2.5 mM, 0.5 LL) is pipetted into 200LL of an aqueous test solution (e.g. phos EL Activity Assay phate-buffered saline, 10x. 1M, Sigma, adjusted to 10 mM, The phospholipase-specific substrate 1.2-bis(4,4-difluoro 10 5,7-dimethyl-4-bora-3a,4a-diaza-S-indacene-3-unde pH 7.4) in a 96-well microtiter plate, and the turbidity is canoyl)-sn-glycero-3-phosphocholine (manufacturer measured at the resulting theoretical concentration for the test Molecular Probes) is used to characterize the enzymatic compound of 6.25 uM using a nephelometer (e.g. activity of endothelial lipase and the effect of inhibitors. Nephelostar Galaxy, BMG Labtech). The concentration of Hydrolysis of the A1 ester linkage of this phospholipid by the the test compound in the aqueous test Solution is then raised to enzyme liberates a fatty acid labeled with the fluorescent dye 15 a theoretical 12.5M by adding further DMSO solution (2.5 Bodipy which can be detected after separation by thin-layer mM: 0.5 LL), and the turbidity measurement is repeated. chromatography on an HPTLC plate (silica gel 60, Merck) or Further additions of DMSO solutions (1 uL., 2.5 mM, 0.5uL. directly in the reaction vessel by measuring the fluorescence. The substrate solution is prepared by dissolving 100 ug of 10 mM; then 9x1 uL. 10 mM resulting in theoretical concen 1.2-bis(4,4-difluoro-5,7-dimethyl-4-bora-3a.4a-diaza-s-in trations of 25uM, 50 uM, 100 uM, 150 uM,200 uM,250 uM, dacene-3-undecanoyl)-sn-glycero-3-phospho-choline 300 uM,350 uM,400 uM,450 uMand500 uM) with turbidity (manufacturer Molecular Probes) in 100 ul of DMSO and measurement in between complete the measurement process. taking up in 2.4 mg of tripalmitin (Sigma) in 393 ul of chlo Evaluation: The turbidity values from the nephelometer are roform which comprises 20 mg/ml of DOP-choline (1.2- plotted against the theoretical concentration of the test com dioleoyl-sn-glycero-3-phosphocholine). 39.3 ul of this lipid 25 pound in the aqueous test Solution. As soon as a significant mixture are transferred into a fresh reaction vessel, and the turbidity is detected (e.g. 5 times above the control value of solvent is evaporated off. The lipid mixture is dissolved in 4 the aqueous test solution) at a theoretical concentration, the ml of 200 mMTRIS-HCl, 150 mM sodium chloride, pH=74, level of concentration below this is stated to be the solubility by Sonicating twice. The Subsequent enzymic reaction takes limit of the test compound in the test solution. Thus, the place at 37°C. for 90 minutes. For this purpose, 20 ul of the 30 substrate solution are incubated with 2 ul of inhibitor of maximum possible measurement range emerges as values appropriate concentration (dissolved in 10% DMSO, using <6.25 uM, 6.25-500 uM and >500 uM. 10% strength DMSO solution for control) and 2 ul of enzyme Preferred compounds of the invention show a kinetic solu Solution (conditioned medium). Subsequently, 4 Jul of the bility in phosphate buffer (pH 7.4) of at least 12.5 uM; more assay mixture are loaded onto an HPTLC plate (silica gel 60, preferably of at least 50 M and even more preferably of at Merck), and the liberated fluorescent dye is separated for 35 least 250 uM. detection with a mobile phase (diethyl etherpetroleum spirit: acetic acid 78:22:1). After evaporation of the mobile phase, b) Thermodynamic Solubility the plate is read in a fluorescence scanner. An increased The integrated UV absorption from HPLC UV measure liberation of the fluorescent dye in the uninhibited reaction is ment of serial dilutions of the test compound in DMSO (500 observed as a measure of the enzyme activity. 40 uM, 100 uM, 50 uM, 10 uM and 1 uM) shows a linear The enzymatic activity is reduced as a function of the correlation with the concentration in a calibration line. The inhibitor concentration used, and the inhibitor concentration test compound (500 ug) is shaken together with the aqueous at which a half-maximum enzymatic activity is observed is test solution (250 uL) in a closed vessel (capacity: 1.5 mL) for called ICso. 16 hours (Eppendorf thermoshaker, 1400 rpm, 25°C., cover In these assays, the compounds of the examples exhibited 45 ing to protect from light). The sample is then centrifuged at the following ICso values: maximum rotational speed, and the Supernatant is finally filtered. A sample of the filtered supernatant is analyzed directly by HPLC UV measurement (see above). A further sample is analyzed after dilution (1 part by Volume of Super ICso I.M 50 Example EL natant, 39 parts by volume of test solution). 1 O.O6 Evaluation: The concentration of the test compound in the 2 O.24 undiluted Supernatant is calculated from the resulting inte 7 O.146 grated UV absorptions of the Supernatant samples on the 8 O.226 basis of the constructed calibration lines and stated as solu 9 O.232 55 bility of the test compound in the respective aqueous test Solution. Other Test Models Examples of aqueous test solutions are deionized water or Suitability of the compounds of the invention as active aqueous phosphate buffer with various pH values (e.g. pH 60 1.2; pH 4.0; pH 6.8; pH 7.4; pH 9.0) which can be prepared pharmaceutical ingredient can be tested by means of various from the commercial solution (phosphate buffered saline, test models. Descriptions are given of Such test models by 10X, Sigma) by dilution and adjustment with phosphoric acid way of example below. or sodium hydroxide solution by standard methods. Solubility in Aqueous Systems Preferred compounds of the invention show a solubility in Adequate solubility of a Substance in aqueous solvent sys 65 phosphate buffer (pH 7.4) of at least 12.5 uM; more prefer tems is an important prerequisite for a (reproducible) phar ably of at least 50 uMand even more preferably of at least 250 macological effect. Solubilities in aqueous systems can be uM. US 7,897,616 B2 39 40 Metabolic Stability The metabolic stability is determined by incubating the test -continued compound (5uM) with microsomal liver fractions (1 mg/mL protein with 0.1% w/v. BSA; 1 mMNADPH, 0.5% DMSO) at 5 37° C. Analysis at an incubation time of 0 and 20 minutes takes place by means of LCMS/MS. Further descriptions of R1 X R2 / the test system and references for the experimental procedure N are to be found in Plant, N.; Drug Discovery Today 2004, 10 IV O k 9(7), 328-336 and Lau, Y.Y. et al.: Pharmaceutical Res. 2002, 19(11), 1606-1610. I Process for Preparation ,6 C The inventive compounds of the formula I are prepared by 15 X methods known perse, for example by acylating Substituted X| X=o O y - or unsubstituted imidazopyridin-2-one derivatives II with né N R1 carbamoyl chlorides III (method A) or in two stages by react ing imidazopyridin-2-one derivatives II with phosgene or II III equivalents, such as trichloromethyl chlorocarbonate, di(trichloromethyl) carbonate or 4-nitrophenyl chlorofor X ,6 mate, and further reacting the resulting imidazopyridin-2-one x1 n N carboxylic acid derivatives with amines IV (method B). It is 25 | X=0 likewise also possible to react the imidazopyridin-2-one Xaa-N derivatives II with the corresponding isocyanates V / - N R2 R1-N=C=O (method C). O W R1 The R6 radicals may also be introduced subsequently by 30 alkylating the compounds I (where R6–hydrogen) by litera I ture methods.

R6 radicals of the —(C=O) NR1'R2 type can be intro X ,6 duced by the above-mentioned methods A, B or C. This can be 35 x1's-N O done by using components IV and phosgene, or III or V in a | X=o -- N -- more than 2-fold excess relative to the starting compounds II. X Nx2 N s The R6 radicals may also be introduced subsequently by R1 the abovementioned methods A, B or C, especially when R1 40 II V and R1" are different. R6 R6 radicals of the —(C=O) O—R1" type can be intro X M duced by literature methods, either by reaction of unsubsti tuted imidazopyridin-2-ones with the corresponding chloro 45 formates in order to arrive at the compounds of the formula II, which are reacted further as described above for A, B or C, or by Subsequently reacting of compounds of the formula I where R6=H with the corresponding chloroformates. 50 The compounds of the formula I obtained by above-de scribed processes can be separated by known separation pro cesses, for example chromatographic processes, in order to Since acids are generally released in these reactions, it is isolate, for example, monosubstituted from disubstituted imi 55 advisable to add bases such as pyridine, triethylamine, dazopyridin-2-ones. sodium hydroxide solution or alkali metal carbonates for acceleration. The reactions may be performed within wide temperature ranges. In general, it has been found to be advan tageous to work at from 0°C. up to the boiling point of the 60 Solvent used. The solvents used include, for example, meth ylene chloride, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, diethyl ether or pyridine. When anhydrous condi tions are employed, strong bases such as lithium hydride, Sodium hydride or potassium tert-butoxide in aprotic solvents 65 such as THF or DMF have also been found to be useful. II The imidazopyridin-2-one derivatives used are starting compounds II are commercially available or can be prepared US 7,897,616 B2 41 42 by literature processes (for example, G. P. Zecchini, I. Torrini Example 6 and M. P. Paradisi, J. Het. Chem. (1985) 22, 313-318; G. P. Zecchini, I. Torrini and M. P. Paradisi, J. Het. Chem. (1985) N-Hexyl-7-methyl-2-oxo-1,2-dihydroimidazo[4,5-c. 22, 1061-1064). pyridine-3-carboxamide The examples adduced below serve to illustrate the inven- 5 tion but without restricting it. The identity of the compounds was checked by mass spec Analogously to Example 1, 2 g (14.8 mmol) of 1,3-dihy trometry. droimidazo 4.5-cpyridin-2-one and 1-isocyanatohexane (2.26 g. 17.76 mmol) were reacted in toluene. Yield: 43 mg EXAMPLES 10 (1%), M+H+: 263.19. Example 1 Example 7 N-Hexyl-1-methyl-2-oxo-1,2-dihydroimidazo[4,5-b] tert-Butyl 3-hexylcarbamoyl-7-methyl-2-oxo-2,3- pyridine-3-carboxamide 15 dihydroimidazo[4,5-b]pyridine-1-carboxylate 1-Methyl-1,3-dihydroimidazo[4,5-b]pyridin-2-one (75 Analogously to Example 1, tert-butyl 7-methyl-2-oxo-2,3- mg, 0.5 mmol) and 1-isocyanatohexane (64 mg., 0.5 mmol) dihydroimidazo[4,5-b]pyridine-1-carboxylate (200 mg. 0.8 were stirred at 80°C. in 3.5 ml of dioxane for 4h. The reaction mixture was concentrated and purified by means of prepara- 20 mmol) and 1-isocyanatohexane (113 mg, 0.88 mmol) were tive HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 40 reacted in dioxane. Yield: 5 mg (2%), M+H+: 377.20. mg (29%), M+H+: 277.16. Example 8 Example 2 25 N,N'-Bishexyl-2-oxoimidazo[4,5-cpyridine-1,3-dicar N-(2-Methylbenzyl)-1-methyl-2-oxo-1,2-dihy boxamide droimidazo[4,5-b]pyridine-3-carboxamide As a further compound, N,N'-bishexyl-2-oxoimidazo[4,5- cpyridine-1,3-dicarboxamide was isolated from the mixture Analogously to Example 1, 75 mg (0.5 mmol) of 1-methyl in Example 6. Yield: 16 mg (1%), M+H+: 390.28. 1,3-dihydroimidazo[4,5-b]pyridin-2-one were reacted with 30 74 mg (0.5 mmol) of 1-isocyanatomethyl-2-methylbenzene Example 9 in dioxane at 80° C. Yield: 11 mg (7%), M+H+: 297.05. 1-Methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyri Example 3 dine-3-carboxylic acid-(R)-indan-1-ylamide 35 As a further example 1-Methyl-2-oxo-1,2-dihydro-imi N-Hexyl-2-oxo-2,3-dihydroimidazo[4,5-b]pyridine dazo[4,5-b]pyridine-3-carboxylic acid-(R)-indan-1-ylamide 1-carboxamide was prepared analogously: M+H+: 309.21. Analogously to Example 1,1,3-dihydroimidazo 4,5-b]py We claim: ridin-2-one (100 mg, 0.74 mmol) and 1-isocyanatohexane 40 1. A compound of formula (I) (113 mg, 0.89 mmol) were reacted in dioxane. Yield: 75 mg (I) (39%), M+H+: 263.15. 4 X 3 ,6 Example 4 x1 n N 2 O 45 N-Hexyl-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-b] 6 Yx NX pyridine-1-carboxamide 7 WNN R2 In 2.5 ml of DMF, N-hexyl-2-oxo-2,3-dihydroimidazo[4, V 5-b]pyridine-1-carboxamide (65 mg, 0.248 mmol), 50 R1 iodomethane (70 mg. 0.5 mmol) and cesium carbonate (80 wherein: mg, 0.25 mmol) were stirred at RT for 5 h. After concentra X is —N— at one of the 4,5,6 and 7-positions, and is tion, the mixture was admixed with water and ethyl acetate, =C(—R)—at the other positions; and the organic phase was removed, concentrated and puri W is —(C=O)— —(S=O)—, or —(SO) II; fied by means of preparative HPLC (PR18, acetonitrile/water 55 R is the same or different and is hydrogen, halogen, (C- 0.1% TFA). Yield: 16 mg (23%), M+H+: 277.17. C)-alkyl, (C-C)-haloalkyl, (C-C)-alkoxy-(C-C)- alkylene, aryl, heterocyclyl, hydroxyl, (C-C)-alkoxy, Example 5 (C-C)-haloalkoxy, aryloxy, cyano, nitro, -S(O) - (C-C)-alkyl, where p=0, 1 or 2, aminosulfonyl, pen N-Hexyl-7-methyl-2-oxo-1,2-dihydroimidazo[4,5-b] 60 tafluorosulfanyl, amino, (C-C)-alkylamino, di-(C- pyridine-3-carboxamide C)-alkylamino, (C-C)-alkylcarbonyl, COOR3, CO NR4R5.O CO. NR4R5, O CO (C-C)- Analogously to Example 1, tert-butyl 7-methyl-2-oxo-2,3- alkylene-CO-O (C-C)-alkyl, O CO (C-C)- dihydroimidazo[4,5-b]pyridine-1-carboxylate (300 mg, 1.2 alkylene-CO-OH, or O CO (C-C)-alkylene mmol), 1-isocyanatohexane (183.8 mg, 1.44 mmol) and 65 CO NR4R5; 4-dimethylaminopyridine (14.7 mg, 0.12 mmol) were reacted R1 is (C-C)-alkyl, (C-C)-alkylenearyl, or indanyl. in toluene. Yield: 8 mg (2%), M+H+: 277.16. wherein the aryl, indanyl moiety is optionally mono- or US 7,897,616 B2 43 44 poly Substituted by halogen, (C-C)-alkyl, (C-C)- R1 is (C-C)-alkyl, -CH2-phenyl or indanyl, and the alkoxy, hydroxyl, (C-C)-alkylmercapto, amino, (C- phenylorindanyl is optionally mono- to disubstituted by C)-alkylamino, di-(C-C)-alkylamino, mono-(C- halogen, (C-C)-alkyl, (C-C)-alkyloxy, (C-C)- C)-alkylaminocarbonyl, di-(C-C)- alkylcarbonyl, or trifluoromethyl: alkylaminocarbonyl, (C-C)-alkyloxycarbonyl, (C- 5 R1 is (C-Co)-alkyl; C)-alkylcarbonyl, cyano, nitro, trifluoromethyl, R1" is (C-C)-alkyl; and trifluoromethyloxy, pentafluorosulfanyl, (C-C)-alkyl Sulfonyl, or aminosulfonyl: R6 is hydrogen, (C-C)-alkyl, R1 is (C-C)-alkyl; (C=O) O R1": R1" is (C-C)-alkyl, 10 or a tautomeric form thereof, or a physiologically compat R2 is hydrogen; ible salt thereof. R3 is hydrogen, (C-C)-alkyl, or benzyl, 6. The compound according to claim 1, wherein R4 and R5 are each independently hydrogen, (C-C)- R is the same or different and is hydrogen, or methyl; alkyl, aryl, (C-C)-cycloalkyl, (C-C)-alkylenearyl, R1 is (C-C)-alkyl, —CH2-phenyl or bicycle of formula or (C-C)-alkylene-(C-C)-cycloalkyl; and Id R6 is hydrogen, (C-C)-alkyl, 15 (C=O) NR1'R2, or Id (C=O) O R1": or a tautomeric form thereof, or a physiologically compat ible salt thereof. 2. The compound according to claim 1, wherein R is the same or different and is hydrogen, halogen, (C- C)-alkyl, hydroxyl, phenoxy, trifluoromethyl, COOR3, pentafluorosulfanyl, amino, (C-C)-alkylamino, di wherein q is 1, and the phenyl or bicycle moiety of (C-Cs)-alkylamino, (C-C)-alkylsulfonyl, aminosul formula Id is optionally substituted by methyl: fonyl, phenyl (C5-C7)-heterocycle, (C-C)-alkylcar 25 R1 is (C-Co)-alkyl; and bonyl, CO NR4R5, O CO. NR4R5, O CO (C- R6 is hydrogen, methyl, or —(C=O) NR1'R2: C)-alkylene-CO O—(C-C)-alkyl, O CO (C- or a tautomeric form thereof, or a physiologically compat C)-alkylene-CO NR4R5 or unsubstituted or mono or poly-F-substituted (C-C)-alkyloxy; ible salt thereof. R1 is (C-C)-alkyl, (C-C)-alkylenearyl, or indanyl, 7. A pharmaceutical composition comprising the com wherein the aryl, or indanyl moiety is optionally mono 30 pound according to claim 1, or a tautomeric form thereof, or or polysubstituted by halogen, (C-C)-alkyl, (C-C)- a physiologically compatible salt thereof, and a pharmaceu alkyloxy, hydroxyl, amino, (C-C)-alkylamino, (C- tically acceptable carrier. C)-alkyloxycarbonyl, (C-C)-alkylcarbonyl, cyano, 8. The pharmaceutical composition according to claim 7. trifluoromethyl, or trifluoromethyloxy; further comprising at least one additional active ingredient R1 is (C-C)-alkyl; 35 selected from the group consisting of antidiabetics, active R1" is (C-C)-alkyl; and hypoglycemic ingredients, HMG-CoA reductase inhibitors, R4 and R5 are each independently hydrogen, (C-C)- cholesterol absorption inhibitors, PPARgamma agonists, alkyl, (C-C)-cycloalkyl, phenyl, (C-C)-alkyle PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, nephenyl, or (C-C)-alkylene-(C-C)-cycloalkyl; MTP inhibitors, bile acid absorption inhibitors, CETP inhibi or a tautomeric form thereof, or a physiologically compat 40 tors, polymeric bile acid adsorbents, LDL receptor inducers, ible salt thereof. ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, 3. The compound according to claim 1, wherein ATP citrate lyase inhibitors, squalene synthetase inhibitors, X in positions 4, 5 and 6 are identical or different and are lipoprotein(a) antagonists, lipase inhibitors, insulins, Sulfo each =C(—R)—, and in position 7 is =N-; or a tautomeric form thereof, or a physiologically compat nylureas, biguanides, meglitinides, thiazolidinediones, ible salt thereof. 45 C-glucosidase inhibitors, active ingredients which act on the 4. The compound according to claim 1, wherein ATP-dependent potassium channel of the beta cells, CART R is the same or different and is hydrogen, halogen, (C- agonists, NPY agonists, MC4 agonists, orexin antagonists, C)-alkyl, trifluoromethyl, hydroxyl, amino, (C-C)- H3 agonists, TNF agonists, CRF antagonists, CRF BP alkylcarbonyl, COOR3, (C-C)-alkylsulfonyl, pen antagonists, urocortin agonists, B3 agonists, MSH (melano tafluorosulfanyl, or unsubstituted or mono- or poly-F- 50 cyte-stimulating hormone) agonists, CCKagonists, serotonin Substituted (C-C)-alkyloxy; reuptake inhibitors, mixed serotoninergic and noradrenergic R1 is (C-C)-alkyl, —CH2-phenyl, or, and the phenyl or compounds, 5HT agonists, bombesin agonists, galanin indanyl moiety is optionally mono- to disubstituted by antagonists, growth hormones, growth hormone-releasing halogen, (C-C)-alkyl, (C-)-alkyloxy, hydroxyl, compounds, TRHagonists, uncoupling protein 2 or 3 modu amino, (C-C)-alkoxycarbonyl, (C-C)-alkylcarbo 55 lators, leptinagonists, DA agonists, bromocriptine, doprexin, nyl, cyano, trifluoromethyl, or trifluoromethyloxy; lipase inhibitors, amylase inhibitors, PPAR modulators, RXR R1' is (C-C)-alkyl; modulators, TR-Bagonists and amphetamines. R1" is (C-C)-alkyl; 9. A process for preparing a pharmaceutical composition R3 is hydrogen, or (C-C)-alkyl, and R6 is hydrogen, (C-C)-alkyl, comprising at least one compound according to claim 1, or a (C=O) NR1'R2, or 60 tautomeric form thereof, or a physiologically compatible salt (C=O) O R1": thereof, which comprises mixing the compound according to or a tautomeric form thereof, or a physiologically compat claim 1, or the tautomeric form thereof, or the physiologically ible salt thereof. tolerated salt thereof, with a pharmaceutically suitable carrier 5. The compound according to claim 1, wherein and converting this mixture into a form suitable for adminis R is the same or different and is hydrogen, halogen, 65 tration. hydroxyl, (C-C)-alkyloxy, trifluoromethyl, (C-C)- alkylcarbonyl or (C-C)-alkyl;