US 20120022039A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0022039 A1 Schwink et al. (43) Pub. Date: Jan. 26, 2012 (54) NOVEL SUBSTITUTED INDANES, METHOD Publication Classification FOR THE PRODUCTION THEREOF, AND USE (51) Int. Cl. THEREOF AS DRUGS A 6LX 3L/397 (2006.01) C07D 207/06 (2006.01) C07D 2L/22 (2006.01) C07D 22.3/04 (2006.01) (75) Inventors: Lothar Schwink, Frankfurt am C07D 22L/22 (2006.01) Main (DE); Siegfried Stengelin, C07C 235/54 (2006.01) Frankfurt am Main (DE); Matthias C07D 307/14 (2006.01) Gossel, Frankfurt am Main (DE); A63L/35 (2006.01) Klaus Wirth, Frankfurt am Main A6II 3/40 (2006.01) (DE) A6II 3/445 (2006.01) A6II 3/55 (2006.01) A63L/439 (2006.01) A6II 3/66 (2006.01) (73) Assignee: SANOFI, Paris (FR) A6II 3/34 (2006.01) A6IP3/10 (2006.01) A6IP3/04 (2006.01) A6IP3/06 (2006.01) (21) Appl. No.: 13/201410 A6IPL/I6 (2006.01) A6IP3/00 (2006.01) C07D 309/04 (2006.01) (52) U.S. Cl. .................... 514/210.01; 549/426: 548/578; (22) PCT Filed: Feb. 12, 2010 546/205; 540/484; 546/112:564/176; 549/494; 514/459:514/408: 514/319; 514/212.01; 514/299; 514/622:514/471 (86). PCT No.: PCT/EP2010/051796 (57) ABSTRACT The invention relates to substituted indanes and derivatives S371 (c)(1), thereof, to physiologically acceptable salts and physiologi (2), (4) Date: Oct. 4, 2011 cally functional derivatives thereof, to the production thereof, to drugs containing at least one substituted indane according (30) Foreign Application Priority Data to the invention or derivative thereof, and to the use of the Substituted indanes according to the invention and to deriva Feb. 13, 2009 (EP) .................................. O929O109.9 tives thereofas MCH antagonists. US 2012/0022039 A1 Jan. 26, 2012 NOVEL SUBSTITUTED INDANES, METHOD include 0 to 3 additional heteroatoms selected from the FOR THE PRODUCTION THEREOF, AND USE group of oxygen, nitrogen and Sulfur, where the heterocy THEREOF AS DRUGS clic ring system may additionally be substituted by F, Cl, Br, CF, CN, (C-C)-alkyl, (C-C)-cycloalkyl, O—(C- Cs)-alkyl, (C-C)-alkoxy-(C-C)-alkyl, hydroxy-(C- 0001. The invention relates to substituted indanes and C)-alkyl, oxo, CO(R18), CONOR 19)(R20), hydroxyl, derivatives thereof, and the physiologically compatible salts COO(R21), N(R22)CO(C-C)-alkyl, N(R23)(R24) or and physiologically functional derivatives thereof, to the SO(C-C)-alkyl: preparation thereof, to medicaments comprising at least one O011 R10, R11 substituted indane or derivative thereof, and to the use of the 0012 are each independently H, (C-C)-alkyl, inventive substituted indanes and derivatives thereofas medi hydroxy-(C-C)-alkyl, F, OH: Caments. 0002 Compounds which have a different pharmacologi 0013 R9, R13, R14, R16, R17, R18, R19, R20, R21, R22, cal action but whose overall structure is similar to that of the R23, R24, substituted indanes and derivatives thereof described in the 0.014) are each independently H, (C-C)-alkyl: present application have already been described in the prior O art, for example stimulants of endothelial NO synthase for 0.015 R16 and R17, R23 and R24 treatment of cardiovascular disorders in WO2002/064565, 0016 optionally form, together with the nitrogen atom antagonists of the dopamine D2 receptor or of the serotonin to which they are bonded, a 5-6-membered ring which, 2A (5HT2A) receptor for treatment of schizophrenia in apart from the nitrogen atom, may also include 0-1 fur WO2005056540, and PPAR agonists in WO2007039174. ther heteroatom from the group of NH, N—(C-C)- 0003. Further compounds with MCH-antagonistic action alkyl, oxygen and Sulfur, for treatment of obesity are described in the prior art (ex 0017 q, r are each independently 0, 1, 2, 3, 4, 5, 6; amples: WO2005047293, WO2004.092181, 0018. R12, R15 WO2005103039, WO2004024702, WO2001021577, 0.019 are each independently H, OH. F. O—(C-C)- WO2003035624, WO2002089729, WO2002006245, alkyl, S (C-C)-alkyl, CN, COO(R25), N(R26)CO WO2002002744. WO2002057233, WO2003045313, (C-C)-alkyl, N(R27)(R28), CONCR29)(R30), SO WO2003097047, WO20020101.46, WO 2003087044, (C-C)-alkyl, a 3-12-membered mono-, bi- or WO2003/087046, WO2001/021577, WO2007018248, spirocyclic ring which may contain one to four heteroa WO2008022979, US2008058423, WO2008/002575, toms from the group of N, O and S and the 3-12-mem WO2008/001160, WO2006/044293, WO2005/033063, bered ring may contain further Substituents such as F, Cl, US2005/0075324, US 2006/0247239). Reviews are given in Br, OH, CF, NO, CN, OCF, oxo, O (C-C)-alkyl, Rokosz, L.L., Expert Opin. Drug Discov, 2007, 2, 1301-1327 (C-C)-alkoxy-(C-C)-alkyl, S (C-C)-alkyl, (C- and Curr. Med. Chem. 2008, 15, 1025-1043. 0004. It was an object of the invention to provide novel C)-alkyl, (C-C)-alkenyl, (C-C)-cycloalkyl, compounds which bring about a reduction in weight in mam O—(C-C)-cycloalkyl, (C-C)-cycloalkenyl, mals and which are suitable for prevention of obesity and O—(C-C)-cycloalkenyl, (C-C)-alkynyl, N(R31) diabetes, and the various sequelae thereof. (R32), COO(R33), SO(C-C)-alkyl and COOH: 0005. A series of compounds which modulate the activity 0020 R25, R26, R27, R28, R29, R30, R31, R32, R33 of MCH receptors has been found. More particularly, the 0021 are each independently H, (C-C)-alkyl: compounds are notable for antagonism of MCH R1. The O invention therefore relates to compounds of the formula I 0022 R27 and R28, R29 and R30, R31 and R32 0023 each independently optionally form, together R3 R1 with the nitrogen atom to which they are bonded, a R7' M 5-6-membered ring which, apart from the nitrogenatom, R7 L1-N may also include 0-1 further heteroatom from the group O V of NH, N—(C-C)-alkyl, oxygen and sulfur, us R2 0024 L1 is C(R34)(R35), C(R36)(R37)C(R38)(R39), B-L2-A R4 (C-C)-cycloalkyl: 0.025 R2 may optionally be joined to one of the R34, R35, R36, R37, R38 or R39 radicals so as to form an in which optionally (C1-C6)-alkyl-substituted 5-6-membered 0006 R1 r1ng, 0007 is H. (C-C)-alkyl, (C-C)-alkoxy-(C-C)- 0026 R34, R35, R36, R37, R38, R39 alkyl, (C-C)-alkenyl, (C-C)-alkynyl, CO(R9). 0027 are each independently H, (C-C)-alkyl, (C(R10)(R11))-R12, CO(C(R13)(R14)),-R15, CO-O 0028 R3, R4, R5 (C-C)-alkyl, CO(C(R13)(R14))-N(R16)(R17); 0029) are each independently H, F, Cl, Br, I, OH, CF, 0008 R2 NO, CN, OCF. O—(C-C)-alkyl, S (C-C)-alkyl, 0009 is H. (C-C)-alkyl, (C-C)-alkoxy-(C-C)- O—(C-C)-alkoxy-(C-C)-alkyl, (C-C)-alkyl, CON alkyl, (C-C)-alkenyl, (C-Cs)-alkynyl, CO(R9), (R40)(R41), CO(R42): (C(R10)(R11))-R12, CO(C(R13)(R14)), R15, CO-O 0030 R40, R41, R42 (C-C)-alkyl, CO(C(R13)(R14))-N(R16)(R17); 0031) are each independently H, (C-C)-alkyl: O O 0010 R1 and R2 form, together with the nitrogen atom to 0032 R40 and R41 which they are bonded, a 4- to 10-membered mono-, bi- or 0033 each independently optionally form, together spirocyclic ring which, apart from the nitrogenatom, may with the nitrogen atom to which they are bonded, a US 2012/0022039 A1 Jan. 26, 2012 5-6-membered ring which, apart from the nitrogenatom, rine, chlorine, bromine and iodine, preferably fluorine, chlo may also include 0-1 further heteroatom from the group rine and bromine, particularly preferably fluorine. of NH, N—(C-C)-alkyl, oxygen and sulfur, 0049. Examples of alkyl groups are: methyl, ethyl, propyl, 0034 R6, R6', R7, R7 butyl, pentyl, hexyl, heptyl and octyl. Included therein are 0035) are each independently H. F. (C-C)-alkyl, OH, both the n-isomers of these radicals and branched isomers O—(C-C)-alkyl: Such as isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, 0036 R8 is H., (C-C)-alkyl: neopentyl, 3.3-dimethylbutyl, etc. Unless stated otherwise, 0037 A is a 5-6-membered aromatic ring which may the term alkyl additionally also includes alkyl radicals which include up to 2 heteroatoms selected from the group of are unsubstituted or optionally substituted by one or more nitrogen, oxygen and Sulfur, and may be substituted by one (e.g. 1, 2, 3 or 4) further radicals from the group consisting of (C-C)-alkoxy or halogen. Examples of alkyl groups substi or more of the substituents H, F, Cl, Br, I, OH, CF, NO, tuted by halogen are fluorinated alkyl groups such as CF, CN, OCF. O—(C-C)-alkyl, O (C-C)-alkoxy-(C- CHF CHF, 3-fluoroprop-1-yl, 2.2,1,1-tetrafluoroethyl. The C.)-alkyl, (C-C)-alkyl, N(R43)(R44), SO CH, CON additional Substituents may appear in any desired position of (R45)(R46), N(R47)CO(R48), CO(R49): the alkyl radical. Unless defined otherwise, the alkyl radicals 0038 optionally, C(O)NR8 may be joined to an ortho sub are preferably unsubstituted. stituent of A via a bridge comprising one or two elements 0050 Cycloalkyl means in the context of the present appli from the group of carbon and nitrogen so as to form, cation cycloalkyl and cycloalkylalkyl (alkyl which is in turn overall, a 9- to 10-membered bicyclic ring: substituted by cycloalkyl), where cycloalkyl has at least 3 0039 R43, R44, R45, R46, R47, R48, R49 carbonatoms.