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(12) Patent Application Publication (10) Pub. No.: US 2011/0178134 A1 JAEHINE Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0178134 A1 JAEHINE Et Al US 2011 0178134A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0178134 A1 JAEHINE et al. (43) Pub. Date: Jul. 21, 2011 (54) NOVEL PHENYL-SUBSTITUTED (30) Foreign Application Priority Data IMIDAZOLIDINES, PROCESS FOR PREPARATION THEREOF, MEDICAMENTS Feb. 7, 2008 (EP) .................................. O829O133.1 COMPRISING SAID COMPOUNDS AND USE Publication Classification THEREOF (51) Int. Cl. (75) Inventors: Gerhard JAEHNE, Frankfurt A6II 3/4439 (2006.01) (DE); Siegfried STENGELIN, C07D 233/02 (2006.01) Eppstein-Bremthal (DE); Matthias C07D 40/06 (2006.01) GOSSEL, Hofheim (DE); Thomas A63L/466 (2006.01) KLABUNDE, Frankfurt (DE): A6IP3/04 (2006.01) Irvin WINKLER, Liederbach A6IP3/10 (2006.01) (DE); Antony BIGOT, Massy A6IP 25/00 (2006.01) (FR); Anita DIU-HERCEND, A6IP 25/28 (2006.01) Charenton Le Pont (FR); Gilles A6IP 25/32 (2006.01) TIRABOSCHI, Montgeron (FR) A6IP 25/34 (2006.01) A6IP 25/18 (2006.01) (73) Assignee: SANOFI-AVENTIS, Paris (FR) (52) U.S. Cl. ................... 514/341; 548/321.1; 546/274.4: 514/391 (21) Appl. No.: 12/852,038 (57) ABSTRACT (22) Filed: Aug. 6, 2010 The invention relates to compounds of formula (I) wherein Related U.S. ApplicationO O Data theE. groups have salts. stated Said meanings,E. and a to theirE. physiologicall CNE (63) Continuation of application No. PCT/EP2009/ as anti-obesity drugs and for treating cardiometabolic Syn 000588, filed on Jan. 30, 2009. drome. US 2011/0178134 A1 Jul. 21, 2011 (C-C2)-aryl, O—(C-C)-aryl, O—(C-C)-alkylene I0081. The invention further provides both stereoisomer (C-C2)-aryl, S(O), (C-C2)-aryl; mixtures of the formula I and the pure stereoisomers of the 0053 R6, R7 are each independently H, halogen, CF, formula I, and also diastereoisomer mixtures of the formula I SFs. OCF, S(O), (C-C)-alkyl), (C-C)-alkyl, OH, and the pure diastereoisomers. The mixtures are separated, COOH, for example, by a chromatographic route. 0054 NH, -NH CO. NH (C-C)-alkyl-CO I0082. The invention relates to compounds of the formula I O (C-C)-alkyl). - NH SO. NH, -NH in the form of their tautomers, racemates, racemic mixtures, SO. NH CO O(C-C)-alkyl, (C-C)-aryl, Stereoisomer mixtures, pure stereoisomers, diastereoisomer O—(C-C)-aryl, O—(C-C)-alkylene-(C-C)- mixtures, pure diastereoisomers. The mixtures are separated, aryl, S(O), (C-C2)-aryl; for example, by a chromatographic route. 0055 and the physiologically compatible salts thereof. I0083. Owing to their high water solubility, pharmaceuti 0056 Very particular preference is further given to com cally acceptable salts are particularly suitable for medical pounds of the formula I in which one or more radicals are applications compared to the starting or base compounds. defined as follows: These salts must have a pharmaceutically acceptable anion or 0057 R1 is CN or halogen: cation. Suitable pharmaceutically acceptable acid addition 0058 R2 is CF, or halogen: salts of the inventive compounds are salts of inorganic acids, 0059 A is CH: Such as hydrochloric acid, hydrobromic acid, phosphoric 0060 B is CH, N: acid, metaphosphoric acid, nitric acid and Sulfuric acid, and 0061 R3, R4 are each independently hydrogen, (C-C)- also organic acids, for example acetic acid, benzenesulfonic alkylene-(C-C)-aryl; acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric 0062 R5 is SFs, OCF, S(O), (C-C)-alkyl, -NH acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, CO. NH (C-C)-alkyl-CO-O (C-C)-alkyl). lactobionic acid, maleic acid, malic acid, methanesulfonic NH SO, NH, NH-SO. NH CO. O(C- acid, Succinic acid, p-toluenesulfonic acid and tartaric acid. C)-alkyl, O—(C-C)-alkylene-(C-C)-aryl; Suitable pharmaceutically acceptable basic salts are ammo 0063 R6, R7 are each independently H, halogen, CF, nium salts, alkali metal salts (such as sodium and potassium SFs. OCF, S(O)(C-C)-alkyl, (C-C)-alkyl, OH, salts), alkaline earth metal salts (such as magnesium and COOH, calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3- 0064 NH, -NH CO. NH (C-C)-alkyl-CO propanediol), diethanolamine, lysine or ethylenediamine. O (C-C)-alkyl, - NH SO. NH —NH I0084 Salts with a pharmaceutically unacceptable anion, SO. NH CO-O(C-C)-alkyl, (C-C)-aryl, for example trifluoroacetate, are also included within the Scope of the invention as useful intermediates for the prepa O—(C-C2)-aryl, O—(C-C)-alkylene-(C-C)- ration or purification of pharmaceutically acceptable salts aryl, S(O), (C-C)-aryl; and/or for use in non-therapeutic applications, for example in 0065 and the physiologically compatible salts thereof. vitro applications. 0066. In one embodiment, preference is given to com I0085. The inventive compounds may also be present in pounds of the formula I in which R1 is CN. different polymorphic forms, for example as amorphousand 0067. In one embodiment, preference is given to com crystalline polymorphic forms. All polymorphic forms of the pounds of the formula I in which R1 is NO. inventive compounds are included within the scope of the 0068. In one embodiment, preference is given to com invention and are a further aspect of the invention. pounds of the formula I in which R1 is halogen. I0086. Hereinafter, all references to “compound(s) of the 0069. In one embodiment, preference is given to com formula Irelate to compound(s) of the formula I as described pounds of the formula I in which R2 is CF. above, and to their salts and solvates as described herein. 0070. In one embodiment, preference is given to com I0087 (C-C-Alkyl) is understood to mean a straight pounds of the formula I in which R1 is halogen. chain or branched hydrocarbon chain having from one to 0071. In one embodiment, preference is given to com twelve carbons, for example methyl, ethyl, isopropyl, tert pounds of the formula I in which A is CH. butyl, hexyl, dodecyl. 0072. In one embodiment, preference is given to com I0088 Halogen is understood to mean F. C1 or Br. pounds of the formula I in which A is N. I0089. An aryl radical is understood to mean a phenyl, 0073. In one embodiment, preference is given to com naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-te pounds of the formula I in which B is CH. tralonyl, indanyl or indan-1-onyl radical. 0074. In one embodiment, preference is given to com 0090 The aryl radicals may be mono- or polysubstituted pounds of the formula I in which B is N. by Suitable groups as described above. 0075. In one embodiment, preference is given to com 0091. A heteroaryl radical is understood to mean aromatic pounds of the formula I in which A and B are each CH. rings and ring systems which, apart from carbon, also contain 0076. In one embodiment, preference is given to com heteroatoms, for example nitrogen, oxygen or Sulfur. This pounds of the formula I in which A is N and B is CH. definition also includes ring systems in which the heteroaryl 0077. In one embodiment, preference is given to com radical is fused to benzene rings. This likewise includes sys pounds of the formula I in which R5 is not H. tems in which one or more CH group(s) has/have been 0078. In one embodiment, preference is given to com replaced by CO—O or C—S, preferably CO—O. pounds of the formula I in which R5 and R6 are not H. 0092 Suitable heteroaryl radicals are, for example, furyl, 0079. In one embodiment, preference is given to com imidazolyl, benzimidazolyl, indolyl, indolinyl, pyrimidinyl, pounds of the formula I in which R5 is OCF. pyridyl, pyrazinyl, pyrrolyl, thiazolyl, oxazolyl, thienyl, 1.2, 0080. In one embodiment, preference is given to com 3-triazolyl, 1,2,4-triazolyl, tetrazolyl, isoxazolyl pyridazi pounds of the formula I in which R5 is SFs. nyl, 1,3,5-triazinyl, 1,2,4-triazinyl; the 2H-pyridazin-3-one, US 2011/0178134 A1 Jul. 21, 2011 dihydropyridazine-3,6-dione, imidazolidin-2-one, 1,3-dihy 0104. The inventive compounds of the formula I are par droimidazol-2-one, imidazolidin-2,5-dione, quinoline, iso ticularly suitable for the treatment of obesity or of bulimia, quinoline, quinoxaline, quinazoline system. and for the treatment of type II diabetes and also for the 0093. The linkage to the heteroaryl radicals may be at any treatment of dyslipidemias and of metabolic syndrome. The of the possible atoms; for example, pyridyl may be 2-, 3- or inventive compounds of the formula I are therefore useful for 4-pyridyll; thienyl may be 2- or 3-thienyl; furyl may be 2- or the treatment of obesity and of the risks associated with 3-furyl. obesity, especially the cardiovascular risks. 0094. Also included are the corresponding N-oxides of 0105 Moreover, the inventive compounds of the formula I these compounds, i.e., for example, 1-oxy-2-, -3- or -4-py may be used as medicaments for the treatment of gastrointes ridyl. tinal disorders, for the treatment of diarrhea, of gastric and 0095. The heteroaryl radicals may be mono- or polysub intestinal ulcers, of vomiting, of bladder trouble and disorders of urination, of disorders of endocrine origin, of cardiovas stituted by suitable groups as described above. cular problems, of low blood pressure, of hemorrhagic shock, 0096. The invention also encompasses Solvates or of Septic shock, chronic liver cirrhosis, liver Steatosis, of hydrates of the compounds of the formula I. nonalcoholic steatohepatitis, of asthma, of Raynaud's Syn 0097. The compounds of the formula I are cannabinoid 1 drome, of glaucoma, of fertility problems, termination of receptor (CB1R) modulators and are, as such, suitable in pregnancy, early birth, inflammatory symptoms, disorders of humans and in animals for the treatment or for the prevention the immune system, especially autoimmune and neuroin of diseases which are based on disruption of the endocannab flammatory disorders, for example rheumatic inflammation inoid system.
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