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    Benzodioxole Derivatives - US2005143373A1 - CB1 Agonists (Antiobesity)

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    muopioidreceptor

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    US 2000501433731 (NINA nit «) United States (2) Patent Application Publication (1) Pub. No.: US 2005/0143373 Al Alanine et al, (3) Pub. Dat Jun. 30, 2005 (54) BENZODIOXOLE DERIVATIVES Publication Classification (76) Inventors: Alevander Alanine, Schlierbach (FR); (51) Int. CL? AGIK 31/851; AGIK 31/5377 Konrad Bleicher, Freiburg (DE); Wolfgang Guba, Muellheim (DE); Wolfgang Haap, Locrrach (DE), (2) US.C Dagmar Kube, Rochester, MN (US); Thomas Luebbers, Loecrach (DE); 540575; 544/148; 544.375, Jean-Mare Plancher, Knceringue (FR); 546/14 8/526 Olivier Roche, Folgeashourg (FR); “Mark Rogers-Evans, Binningen (CH); Gishert Schneider, Oberuse! (DE); oy ABSTRACT Jochen Zuegge, Frankfurt (DE) The present iaveation relates to compounds of the - frau PATENT LAW DEPARTMENT M0 KINGSLAND STREET NUTLEY, Niro e (21) Appl. Nos 11/062,973, a P xe (©) Fike: Feb. 22,2005 & Y . Related U.S. Application Data (62) Division of application No, 1/626,681, filed on Ju 24, 20m. and pharmaceutically acceptable salts thereof. The com= ‘pounds are useful forthe teatment andor prophylaxis of diseases such as abesity by selective modulation of CBL Jul, 29, 2002 (EP). 02016831.6 receptors a) US 2005/0143373 AL BENZODIOXOLE DERIVATIVES PRIORITY TO RELATED APPLICATIONS. [0001] This application isa Division of Serial No. 10626, 681, filed Ju. 24, 2003, which is now pending BACKGROUND OF THE INVENTION (0002) The present invention relates to he use of anlago- nisi of the CB, eannabinnoid receptor. Two diferent sub- types of cannabinoid receptors (CB, and CB) have been Isolated and both belong to G protein coupled reeptor superfamily. An allerative spliced form of CB, CB bus kobeen described, but didnot exhibit diferent properties in terms of ligand binding and eecoploe activation than CB, (Die, C. Caio, M- Kapha B. Calandra, M. Rina Carmoas,G.Le Fu,D. Cap, Fer, J. Biok. Chem, 270 (8) (1995) 372631) The CB, receptor is mainly loeaed in te brain, whereas the CB receptor is predominately dis tchuted inthe pecphery primarily lealized in spleen and cells ofthe immune sytem (S. Mune, K.L. Thomas, M ‘Abu-Shaar, Nature 365 (1993) 6-61, 0003} Therefore ia onder to avoil side effects « CB, selective compound is desirable. 4°-cirhydrocannabinol (8°-THO) is the principal psychoactive compound inthe Todian hemp CY. Gaoni,R. Mechoulam, 1. Am. Chem, Soe, 86 (1964) 1646), canabis savia (marijuana, whichis used in medicine since ages (R. Mechoulam (Ed) in “Cannab ins as therapewtc Agents”, 1986, pp. 1-20, CRC Press). A°-THC is a nonselective CB,/, reeptor agonist and is, available in the USA as dronabinol (marinol) for the alleviation of cancer chemotherapy-indueed emesis (CIE) andthe reversal of boy weight Iss experienced by AIDS patents through appetite stimulation, tothe UK Nabolinone (L¥-100514, Cesamet®), a synthetic analogue of CP-THC, is used for CIE (R. G, Pertwee, Pharmaccut. Sci. 3 (11) (1997) 539-545, E. M. Williamson, FJ. Evans, Drags 60 (6) (2000) 1303-1314). [0008] | Anandamie (arachidonylethanolamide) was iden lied as the endogenous ligand (agonist) for CB, (R. G. Pertwee, Cur. Med. Chem., 6 (8) (1999) 635.668,W. A. Devane, L. Hanus, A. Breuer, R.G. Pertwee, L.A. Steven- son, G. Grillin, D. Gibson, A. Mandelbaum, A. Etnger,R ‘Mechoulam, Science 258 (1992) 1946-9), Anandamide and 2arachidonoylglyeerol (2-AG) modulate a the presynaptic perve teminal negatively adenylate eyelas: and volage- sensitive Ca channels and activates the inwandly rectifying K channel (V. Di Marzo, D. Melek, T. Bisogno, L. De Petrcelis, Trends in Neuroscience 21 (12) (1998) 521-8), thereby affecting neurotransmitter release and/or action, Which decreases the release of neurotansmitter (A. C. Porter, C.C. Felder, Pharmacol. Ther. 50 (1) (2001) 45-60). 0005} Anandamide as A°-THC also increases feeding through CB, receptor-medited mechanism. CB, selective antagonists block the increase in feeding associated with aaiministation of anandamide (C. M. Willams, T. C. Kirkham, Psychopharmacology 143 (3) (1999) 315-3175 C , Felder, E. M. Briley, J. Axelrod, J.T. Simpson, K. Mackie, W. A. Devane, Proc. Natl. Acad. Sei. U.S. A. 90, (16) (1993) 7656-60) and caused appetite suppression and ‘weight oss (G, Colombo, R. Agabio, G. Diz, C. Lobin, R. Reali, G. L. Gessa, Life Sei. 63 (8) (1998) L113-PL.117). Jun, 30, 2005 [0006] Leptin is the primary signal through which the Fbypothalamus senses nutritional slate and modulates food inake and energy balance. Following temporary food restriction, CBI receptor knockout mice eat less than their wild-ype litermates, and the CBI antagonist SRISITI6A reduces food intake in wikl-type but not knockout mice. Furthermore, defective leptin signaling is associated with elevated hypothalamic, ut not cereellr, Ievelsof endocan- rabinoids in obese dbdb and obi mice and Zucker rats. Acute leptin treatment of aormal sats and objob mice reduces inandamide and 2arachidonoy! glycerol in the hypothalamus. These findings indicate that endocaamab- inoids in the hypothalamus may tonially activate CBL receptors to maintain food intake and form part of the neural circuitry regulated by leptin (V. Di Marzo, . K. Geparaj, Wang, J. Liu, 8. Bika, Z Jara, F Feaza, G. 1 Miura, R D. Palmiter, T. Sugiura, G. Kunes, Nature 410 (6830) 822-825). [0007] SR-141716A, a CBI selective antagonisjinverse agonist is curently undergoing phase IM clinical trials for the treatment of obesity. In a double blind placebo-con- trolled study, at the doses of 5, 10 and 20 mg daily, SR 141716 significantly reduced body weight when compared to placebo (F. Barth, M, Rinslt-Carmona, M. Arnone, H Heshmati, G. Le For, “Canaabinoid antagonists: From research tool to potential new drugs.” Abstracts of Papers, 22nd ACS National Meeting, Chicago, TI, United States, ‘Aug. 26-30, 2001). {08} Otter compounds which ave been proposed as CCL receptor antagonisis are aminosligtndols (AK, Mt Pacheco, 8 R. Childers, R Arma, F. Caso, 8. Wad, 1. Pharmacol. Exp. Thr. 257 (1) (1991) 190183), lke SromoxWINSHS61; FM. Cosimo, R. Aro D. Hay cok, J Kus, S.J Wad, NIDA Res Monoge 1051981) 285.6 oe Gsiodoprauaoline (AMES, K. Heo, R. ML ‘Quack, R. Mi Hosoi, TH. Burkey, A. Makiyani,P CCnsto, WR. Roesky HI Yamamurt Lie S61 (1997) US-118/R Pewee, Git, S. Femando, X.1i,A. Hill ‘A. Makrivanns, Lie Sei $6 (2524) (1998) 104085). ‘Aylbennfb] thiophene sod benzo jfvan (LYS20135,C. (Felder KE Joye, EM. Briley, M. Glas K.P. Mac, K J. Fey, .. Colinan, D.C. Henden,D. W. Jonson, MO. Chane, G.A. Koppel, Mi Browasn, J Pharmacol Exp. The, 284 (1 (1998) 291-7 dscosed in WO9602248, US. Pat, No. 5,596,106, 3-alkyl-(5,5-diphenyl)jimidazo- lisietioes (M. Kanyooyo, S.J. Gove, E Hermans, , Poupoe,D.M. Lamber, Bioorg, Med, Chem. Lat 9 (15) (1999) 2258-2236) os wll as Salky-Saylimidaro- Tisinetones (F. Ooms, 1, Wouter, O. Oscar. Happaes, G. Bouchard, P-A, Capt, B. Test, D.M. Lambe, 3. Med. Chem. 45 @) (2002) 1748-1756 are known to satago- nize the CB, receptor respectively act aan inverse agonist Gn the HB, receptor, WODDLSGOD (FROTS324-AD, ‘Woot6463# (HRENISSI7-A1), WON22346, WOO64532 (FR2805818-A1), WO0L64633 (FR2805810-A1) disclosed Subsitued L-bigaryDmeybazsilines derivatives 3s fnlagoists of CR, In WOOL T0700 4.- ave independently unsubstituted phenyl, or phenyl which is mono-, dor trisubs tuted, independently, by hydroxy lower alkyl, lower alkoxy, perluoo-lower alkyl, perluoro-iower alkox,alkanoyl, eyan, nitro or halogen; ot Rand together wih the carbon atom to which they are attached form a 10,1'-inydro-25-{SH1pibenz0fa, ‘eyclobeptene residue; [0014] _R? and R* are independently hydrogen, halo- en, hydroxy, lower alkyl, kower alkoxy, peruoro- lower alkyl, slkanoyl or ejan0; [01S] R* is hydeogen, lower alkyl, lower akylsul- foayl, cycloalkyl lower alkyl oF hydroxylower alkyl [0016] R* is YR’, lower alkyl, lower alkoxy hydoxy-lower alkyl, lower alkoxy-lower alkyl Tower akylaminocarbonyl-lower alkyl, heerocyely, ‘eycoalky phenyl or phenyl lower alkyl, wherein the phenyl moiety may optionally be mono, di- or Jun, 30, 2005 tessubstitutd, independently, by lower alkyl, lower alkoxy, halogen, perfuoro-lower alkyl, hydroxy, allanoyl or eyano; oF [0017] R° is hydrogen when X is —C(O}— or 80. oF [0018] R* and R® together wit he nitrogen stom to whith they ace atched form a4 bered momeydie ora 8,9 10 bicjlic, saturated or unsaturated heterocyelic rng which may optionally contain one or two faher heterosis independently selected from 0, N and S, said heterayele rng being optionally mouo- di ‘or Wisubwttuled, independenly, by lower alk lower akoxyearbony, hydroxy lower ally, lover alkoxy-lower alkyl, dower allgleatbamoyl, eae hanes, lower akyleabonyl amino, ox, dioxo, alkanoyl, amino lower alk ydoxy ower alkoxy, halogen, peuor-lower all cyano, beteroary, of by phenyl or pny] ower alkyl, wherein the phenyl moiety may optionally be mom, di- or t-substi tuted, independent, by lower ali, lower alkoxy, halogen, perftor-lower alkyl hyckoxy alkanoy or eyan0; [0019] _R ishydogea, halogen, lower alkyl or cyano; [0020] _R° is phenyl, eycloalky, heterocyclyl or het- ‘eroaryl, [o02t] x is a single bond, —CHL—, —C(0)—, —S0_— or —S0,NH—; [0022] Y is —CH.—, —C(0)—, —NH— or —S0, [0023] and pharmaceutically acceptable als thereof [0024] Unless otherwise indicated, the following defini- tions are sot forth to define the meaning and scope of the various terms used to describe the invention herein [0025] In this specification the term “lower” is used to ‘mean a group consisting of one to six, preferably of one to Tour carbon atom), [0026] The term “halogen” refers to urine, eblorine, bromine and iodine, preferably to chlorine, fuorine and bromine, most preferably o chlorine and huoine. [0027] The term “alkyl”, alone or in combination with ‘ther groups, ler to a branched o staight-chain monova- leat saturated aliphatic bydrocarboa radical of one to twenty cathon atoms, preferably one to sixteen carbon aloms, more preferably one to ten carbon atoms. [0028] The term “lower alkyl, alone or in combination With other groups, refers to a branched or straight-chain ‘monovalent alkyl radical of one to six carbon atoms, pref cnibly one to four carbon atoms. This team is funher exemplified by radicals such as methyl, etbyl, n-propyl, isopropyl, butyl, sbuty, isobutyl uty, pentyl, me tylbuyl, achexyl, 2-morpholin-t- ybmethanone, [0193] _(6-Methyl-2.2-diphenyl-beazo{,3Hioxol-5- yD-piperiin-I-yl-methanone, [0194] [6-Fluoro-2,2-bis(-fuoro-pheny)-benz0f1, 3]lioxol-5y1}-morpholin-+-yl-methanone, Jun, 30, 2005 [0198] (6-Bromo-2,2-tphenyl-benzI,3}liovol-5- y)-iperiin-I-yl-methanone, [0196] (+){2-(,4-Diehloro-phenyl)-6-uoro2-(4 fluoto-pheay!)-benzo[1,$}lioxol-S-yl}mompbolin-f- ybmethanone, [0197] (-}{242,4-Dichloro-pheay!)-6-fhio-2-(4- fluoro-pheay!)-benzo[1,3]lioxo-5-y]-moxpbolin-t ybmethanone, [0199] (204-0). pee ‘ayl}-benzof 1,3 ioxol-5-yl]-piperidin-1-ylmetha- [820]. (6-Ciow-22mettanone, [0283]. [22-Bis-2,4fluoro-pheny!).6-uoro- benzoft 3 oxol5-yl}-(-iluoromethyl-pipei- din-L-y)}-methanone, [0294] [22-Ris-2,4ifluoro-pheny!).6-luoro- enrol 3 oxol S-v1}(4-hydroxy-piperidin-I-y)- imethanone, [0295]. (22-Bis(2,4-bena sono -Sy1}(r-pi- peridia-L-ypmettanone, [371] 2-G-Chior-phenyd opt ter sethanone, [0372] (244-Chor- phen) 22 techlomahe- nyDpGaluro-benaf 13 Mix mmetanone, (0373) (2-4-Chioro-phensd2 nyDp6sluro-benaf 13 Hox ykmethanone, (0374) (22-Bis(2-tifuoro-pheny))-6-Muoro- benz 3 }ix015-y}mxpbolin-4-y-methanone, [0378] [2-(4-Diehlorosheny)-6-uoro-2-(4- fiuoro-phenyly-benel,3}ioxol-S-} 444i Iuoro-pipeidin-L-y)setbanone, [0376] [2.2-Bis(4-chloro.pheny! 6-voro-henfl, Aichloro-phe- -l}-orpholine 3ioxol5-y1}-piperidin--yl-methanone, [0377]. [2.2-Bis44-ciloro-pheny))-6-tloro-benzofl, 3]lioxol5-y1}pyrmlidia-1-yL-metbanone, [0378] [22-Rie(4bromo-2-oce-phen!)-6-ure- ‘benzo[1,3Mioxel-5-yl}-morpholin-4-yl-methanone, [0379] [22-Bis(2-tiuoropheny)-6-luoco- henzoiS oxo 5-y}(4tifluorepipeidin-l- yimettianone, {0380} [22-1i(2-tuoropheny)-6-luor0- benzo ioxol5-y} (hy droxy-piper. mmetbanon, {0381} (2.2-Bie(24-100°C) to yield product I. Alternatively, a compound of formals (0) ray be prepared by reacting the eatecho intermediate of foanla Awith& ketone of formula C at elevated tempera ture (ea >150° C,) neat or nan ine solvent (eg, tluene) With o without the removal of water hy disilation,32e0- twopic disillation or sdlition of drying agents (e.g. molecu- lar sieves or 22imethoxypropane) by methods known ia the a (see eg. TR. Kelly, A. Szabados, Yel. Lee, J. Org. Chem, 62 () (1997) 428). [0386] Attrmatively, a compound of formula (1) may be ‘prepared by reacting the catechol intermediate of formula A ‘With a thioketone of formula (C) neat oi an inert solvent (€g. acetonitrile) with or without the presence of a base (e. ‘wiethylamine) with metal sat (e.g, Cut) by methods known inthe at (se eg. Shibuya, E. Kat, ¥. Gama, A. Oishi, . Taguchi and: Tsuchiya, Heterocycles, 43 (1996) £851), Compounds of formula (I) wherein X is —CH,— can also be obiained by eduction of a coresponding compound ‘of formula (2) wherein X is —CO—by means known ia the an. scontiaued UY [0387] The bis-subsiuted dichloromethane derivatives of Tormula B can be easly prepared by methods known inthe at from the corresponding ketone by reaction with thionyl chloride in the presence of DMF or another N-foemylated agent, by reaction with phosplionss pentachlorid at elevated temperature (e.g, >100° C) with or without the presence of 4 suitable solvent (eg. phosphomis oxide chloride), by clecteophilic aromatic substitution of the tiuoromethyl US 2005/0143373 AL erivative E with a benzene derivative of formula in the presenoc of a Lewis acid (¢. aluminium trichloride) in an inert solvent (¢. 12-ichloroethane) (eg. R.K. Ramchan- dani, R. D. Wakharkar, A Sudali, Tetrahedron Lett.37 023) (1996) 4063), by ciorination of bsarylmethane derivative (eg US. Pat, No, 5,578,737 o¢ W, Deusehel, Helv, Chim, ‘Acta 34 (1951) 2413) or in case of symmetrically bis- substituted dichloromethane derivatives of formula B by clectrophilic aromatic substitution of « benzene derivative ‘with trachloromethane in the presence ofa Lewis acid (e- AICl,) in an inert solvent (eg 12-dichloroethane) (see e-8 LLP Picard, C. Keamns, Can. J. Res. 28 (1950) 56). Scheme 3 ® e wo, rs — w ¥ [0388] _Catechols of formula Acan be easily prepared from the corresponding diphenylmethylene protected ketals of formula (Ia) by treatment with an acid (eg, tritworoacetic ci) in a suitable inet solvent (e.g, methylene chloride) of by treatment with an acid (eg, trifluoroacetic acd) in the presence of a suitable reducing agent (e.,trethysilane), ‘eat or witha suitable inext solvent (eg. methylene cblo- tide). Alternatively, a catechol of formula A can be easily prepared from a corresponding bis-ben7y] protected cat- chal of formula (A) by eduction (eg bylrogenation inthe presence of suitable catalyst (e.g palladium on carbon) by ‘means known inthe at). Alternatively a catechol derivative of fonmula F can be coupled with an appropriate amine in 3 suitable inert solvent (¢.g. DME, methylene chloride, pyri> Jun, 30, 2005 dine or THE) in the presence ofa base (eg. triethyl amine). Eiter the corresponding acid chlorides (X=CO, Z=C)) respectively the corresponding sulfonyl chlorides (X=S0, ZAC) oF the corresponding carboxylic acids (X= CO, ZAOH) after stivation with an appropriate coupling agent (€g. eatbonyldimidezole) are used for the preparation of catechols of formula A by methods known in the art ‘Compounds of formula (A) wherein X is —CH,— can be obtained by reduction of a corresponding compound of Formula (A) wherein X is —CO—by means known in the a, Kew . i & x“ qe eos ¥ ¥ F : xt 1 * x I seen ' 2 e 4 _ ° sv 7 I US 2005/0143373 AL [0389] Compounds of formula G can be coupled with an appropriate amine in a suitable inert salveat (¢g, DME, snthylene chloride, pyridine or THF) i the presence of & base (eg. triethyl amine) to yield henzodioxole of formula (D, Either the conresponding acid chlorides (X=CO, Z=Cl) respectively the coerespoadling sulfons chlorides (X- ZaC)) oF the corresponding carboxylic acids (X=CO, ZeON) after activation with an appropriate coupling agent (€g. caboayldiimidazole) ste used forthe prepacation of bbenzadioxoles of formula () by methods known in the art ° 4 : — Ss — xO [0390] Beozndioxoles of formula (in whieh X is single bond may also be prepared according to Scheme 5 above by ‘coupling an aniline of formula J witha compounelof formula, K ina suitable inet solvent (-g, DME, methylene chloride, pyridine or THF) in the presence ofa base (eg tnthyl amine) to yield benzodioxole of formula (Ia). Beazoiox- ‘les of formula (la) may thea be futher coupled with a compound of formula K' in a suitable inert solvent (e- DME, methylene chloride, pyridine oe THE) inthe presence ‘of a base (eg. triethyl amine) to yield benzodioxoles of {ormula (1). Compounds of formulae K and K’ may be either the corresponding acid chlorides, respectively the corresponding sulfonyl chlorides, respectively the corre sponding carbamoyl chlorides, respectively the eomtespond- ing sulfamoyl chlorides or the comesponding carboxylic acids of Rand R°, respectively, afte setvation with an appropriate coupling agent (eg, earbonyldimidazoe), [0391] The invention further relates to compounds of Tormula (1) 3s defined above, when manufactured according to a process as defined shove, [0392] Some compounds of formula (0) may possess asymmetric centres and are therefore capable of existing in ‘more than one stereoisomerie form, The iaveation thus also Jun, 30, 2005 relates to compounds in substantially pure isomeric form at ‘one oF more asymmetric centres as well s mixtures, includ ing racemic mixtures, thereof. Such isomers may be pre~ pared by asymmeiri synthesis, for example using chiral intermediate, or mixtures may be resolved by conventional methods, eg, chromatography (chromatography with a chiral adsorbent or eluant), or use of a resolving agent [0393] Ie vill be appreciated, thatthe compounds of gen- ral formula (I) in this invention may be derivatised at Tunctioal groups to provide derivatives which are capable ‘of eonversion bck 0 the parent compound in vivo, [0394] As described above, the compounds of formula (1) ‘or pharmaceutically acceptable salts thereof can be used as medicaments forthe treatment andior prophylaxis of dis- ceases which are associated withthe modulation ofthe CBI receptors [0395] The invention therefore also relates to pharmacen tical compositions comprising a compound as defined above and a pharmaceutically acceptable curser andor adjuvant [0396] Farber, the invention relates to compounds as efined above for use as therapeutic active substances, particularly as therapeutic active substances forthe teat- ‘ment andlor prophylaxis of diseases which are associated with the modulation of CBL receptors. [0397] In another embodiment, the invention relates to a ‘method for the testment andor prophylaxis of diseases ‘which are associated with the modulation of CBI receptors, which metbod comprises. administering 2 compound 3s defined above to human being or animal [0398] The invention further relates tothe use of com- pounds as defined above for the treatment andor prophy laxisof diseases which are associated withthe modulation of CBI receptors. [0399] In addition, the inveotion relates to the use of ‘compounds as defined above forthe preparation of medica- ‘ments forthe treatment andor prophylaxis of diseases which fate associated with the modulation of CB receptors. Such ‘medicaments comprise a compound as defined above. [0400] In this context, the expression “diseases associated With modulation of CBL receptors’ means diseases which cean be treated andlor prevented by modulation of CBI receptors. Such diseases encompass Dut are not limited to, psychic disorders, especially anxiety and anxiety disorders, psyebosis, schizophrenia, depression, substance abuse dis- ‘orders including sbuse of psychotropes, for example forthe shuse andior dependence of substances, including alcohol dependency and nicotine dependency, neuropathies, ‘migraine, sites, epilepsy, dyskinesia, Parkinson's disease, amnesia, memory and cognitive disorders, senile dementia, Alcimer's disease, eating disorders, obesity, diabetes type 1 or non insalin dependent diabetes (NIDD), gastointesi nal diseases, vomiting, diartea, urinary disorder, cardio- vascular disorders, inferilty disorders, inflammations, infections, cancer, demyelinsation related disorders, new ‘inflammation, in particular in atherosclerosis, or the Guil- Iain-Bareé syndrome, viral enephliis, cerebral vascular incidents and cranial trauma, [0401] In a preferable aspect, the expression ‘diseases associated with modulation of CBI receptors’ relates 10 cating disorders, obesity, diabetes type Tl of non insulin US 2005/0143373 AL pendent diabetes (NIDD), neuroinflammation, diseres, abuse andlor dependence of a substances, including alcohol ‘dependency and nicotine dependency. In a more preferable aspect, the suid term related to eating disorders, obesity, Liubetes type Il or non insulin dependent cisbetes (NID), abuse andlor dependence of a substances, including alcohol dependency and nicotine dependency, with obesity being especially protece. [0402] Isa further prefered object to provide a method ff treatment of prevention of Type I diabetes (noa-iasuin dependent diabetes mellitus (NIDDM) in a human which comprises administration of a therapeutically lfective amount of compound according t formula () ia com nation or association with a therapeutically effective amount ‘of lipase inhibitor, particulary, wherein the lipase inbibitor is orlistat. Also an object of the invention isthe method as described above for the simultaneous, separate or sequential dmiaistation of a compound socording to formula (1) and lipase inhibitor, particularly etrahydolipstati, [0403] 1 isa further preferred object to provide a method Tor the treatment or prevention of obesity al esi elated disorders which comprises administration of a therapeu cally effective amount of a compounc accoeding to formula (Din combination or association with a therapeutically elective amount of other drugs forthe treatment of obesity ‘oreating disorders so that together they give effective rele. Suitable other drugs include but are ot limited to anorectic. agents, lipase inhibitors and selective serotonin reuptake {nhbitors (SSRI, Combinations or associations ofthe above agents may be encompassing separate, sequential or imul- tancous administration, [0404] Preferable lipase inhibitor is tetrahydrolipstatn [0405] Suitable anorectic agents of use in combination ‘ith 4 compound of the present invention include, but are ‘ot limited to, aminorex, amphechloral, amphetamine, ben- ‘phetamine, chlorphentermine, lobenzorex, cloforex, clo- rminorex, clortemine, eyelexedrine, dexfenfluramine, dex- froamphetamine, —diethylpopion, — diphemethoxidine, [N-cthylamphetamine,fenbutrazate,fenturamine, fenisorex, enproporex, Hudorex, Auminorex, furfurylmethylamph amine, levamfetamine, Jevophacetoperane, - mazindol, rmefenorex, metamfepramone, methamphetamine, nonpseu- oephedrne, pentorex, phendimetrazine, phenmetrazine, phentermine, pheaylpropanolamine, piclorex and sibut ‘mine, and pharmaceutically acceptable salts thereof [0406] Most preferable anorectic agents are sibutramine ‘and phentermine. [0407] Suitable selective serotonin reuptake inhibitors of ‘use in combination with 2 compound of the preseat inven tion include: fluoxetine, fovoxamine, paroxetine and sertra- line, and pharmaceutically acceptable salt thereof, [0408] | Demonstration of adional biological activities of the compounds of the present invention may be aocom- plished through ia vito, ex vivo, aad in vivo assays that are well known in the art. For example, to demonstrate the clicey of a pharmaceutical agent for the treatment of obesity-related disorders such as diabetes, Syndrome X, o atherosclerotic disease and related disorders such as hyper leigyeeridemia and hypercbolesteremia, the following assays may be used, Jun, 30, 2005 [0409] Method for Measuring Blood Glucose Levels [0410] abidy mice (obtained from Jackson Laboratories, Bar Harbor, Me) are bled (by either eye or tail vein) and _rouped acconding fo cquivalent mean blood glucose level ‘They are dosed erally (by gavage in a pharmaceutically scceptable vehicle) wit the test compound once daily for 7 to 14 days, At tis point, the animals re bled again by eye ‘or tall vein and blood glucose levels are determined, [0411] Method for Measuring Triglyceride Levels [0412] bApoAL mice (obtained from Jackson Laborato- ries, Bar Harbor, Me.) ate bled (by cither eye or tail vein) and grouped according to equivalent mean serum trglycer- ide levels. They are dosed orally (by gavage ina pharma- ceutically acceptable vehicle) wit the test compound once daily foe to 14 days, The animals are then bled again by eye or tail vein, and serum triglyceride levels are determined [0413] Method for Messuring HDL-Cholesterol Levels [0414] To determine plasma HDL-cholesterol levels, FApoAl mice are bled and grouped with equivalent mean plasma HDL-cholesterol levels. The mice ate orally dosed ‘once daily with vehicle or test compound for 7 to 14 days, ‘and then bled on the following day. Plasma is analyzed for HDL-cholesterol [0415] In addition, to demonstrate CNS activites of the ‘compounds of the present invention, the following in vivo assays may be used [0416] Method for Testing Task Leaming. and. Spatial Memory [0417] The Moris Water Maze is routinely used 0 asses task learning and spatial memory (Jaspers etal, Neurosci Latt_ 117-149-153, 1990, Moris, J. Neurosci Methods 11-47-60, 1984). In tis assay, animals are placed in a water pool which is divided into quadrants. One platform ishidden in one ofthe quadants. The animal is placed inthe water pool and is expected to locate the hidden platform within a predetermined time. During a umber of training trial, the ‘animal learns the location of the platform and escape from the pool. The animal receives multiple trials inthis task. ‘Toal distance traveled, number of trials to locate platform, latency to find platform, ad the swimming path is recorded for each animal. The animal's learning ability is measured by the length of time or number of trials required to find the hidden platform. Memory deficit or improvemeat is deter- ‘mined by the aumber of trials or the Istency to find the platform at predetermined delay time after acquisition. Leaning and memory may be measured by the gumber of times tht the animal crosses the quadrant where the plat- form was located during the acquisition phase [0418] | Method for Testing Drug Dependence [0419] Seit-adminisiration in animals i8 2 predictor of a compound's abuse potential in humans. Modifications to this procedure may also be used to identify compounds that prevent or block the reinforcing properties of drugs that have abuse potential. A compound that extinguishes the sell- administration ofa drug may prevent that drug's abuse or its, dependence. (Ranaldi et al, Psychopharmacol. 161:442- 4448, 2002; Campbell etal, Exp. Clin, Psychopharmacol 8312-25, 2000), In a selfadministation test, animals are placed ia the operant chambers containing both an active US 2005/0143373 AL and inactive lever. Each response on the active lever pro- duces an infusion of either the test compound or & drug knowa tobe sel-administered, Presses on the inetive lover have no elect, hut are also recorded. Animals are then trad to selfadminiser compoundidrug over a set period of time by having dug access during each daly session, umination ofthe chamber houselight signals the beg ting of the session and the availsblity ofthe compound! dug. When the session ends, the house light is tured off Initially, 2 drug infusion oocurs with every press of the active lever Once lever-pressing behavior has been estab- lished, the number of presses to produce a drug infusion is. jncreated, Alter stable compound drug sll-administetion is oblained, the effeet of a second compound! on the drug reinforced behavior may be evaluated, Administration of {his second compound prior wo the session eaa ether poten tine, extinguish, or produce ao change tothe self-adminis- wating behavior [0420] The following tests were catied out in ox to Setermine the activity of the compounds of formula (D, [0421] |The affinity of the compounds of the invention for cannabinoid CBI receptors was determined using mem- brane preparations of human embryonic kidney (HEK) cells in which the buman cannabis CBL receptor is transiently transfected using the Semliki Forest Virus system in con- junction wilh [BH}-CP-5540 as radioligand. After incuba- tion of a freshly prepased cell membrane preparation with the [3HHigand, with or without addition of compounds of the invention, Separation of bound and free ligand was performed by ftration over glassfiber files. Radioactivity fn the filler was measored by liquid scintillation counting [0422] The affinity of the compounds of the invention for ‘cannabinoid CB2 receptors was determined using mem- borane preparations of human embryonic kidney (HEK) cells in which the human cannabis CB2 receptor is transiently transfected using the Semliki Forest virus system in con= {junction with [3H}-CP-55.940 as radioligand. After incuba- tion of a freshly prepared cell membrane preparation with the (3H]ligand, with or without addition of compounds of the invention, sparaton of bound of bound and fre ligand was performed by filtration over glassier filters. Radioac- tivity on the filer was measured by liquid scintillation ‘outing [0423] The cannabinoid CBL antagonistic activity of com- pounds of the invention was determined by functional sies using CHO cells in which human cannabinoid CBE receptors are stably expressed (see M. Rinaldi-Carmona et. al, 1 Pharmacol, Exp. Ther. 278 (1996) 871). The stable expression ofthe human cannabinoid receptor in cell sy ‘ems was first described in Nature 1990, 346, 561-564 (CBI) and Nature 1993, 365, 61-65 (CH2) respectively. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Con- omitant activation of CBL receptors by CBL reoeptor agonists (cg. CP.55,940 or (R)-WIN-55212-2) can alten ae the forskoln-indvoed accumulation of GAMBP in a con- centration dependent manner. This CBL receptor mediated response can be antagonised by CBI receptor antagoniss, such as the compounds ofthe iveation, [0424] The compounds of formula (I) show an excellent alliny forthe CBL receptor, determined with the experi> ‘mental conditions described in Devane etal. Mol. Pharma Jun, 30, 2005 col. 34 (1988) 615-613. The compounds of the present invention or their pharmaceutically aoceplable salts are antagonists and scletve for the CBI receptor with alinites, below ICx,=2 pM, preferably | aM to 100M. They exhibit atleast «10 fold selectivity against the CB2 receptor Cony af ample > za [0425] Elect of CB1 Receptor Antagonist/Iaverse Agonist. 60n CP 55,940-Induced Hypothermia in NMRI Mice (0426) Animals [0427] Male NMIRI mice were used in tis study and were ‘obtained from Research Consulting Company Ltd (RCC) of Fllindort (Switzriand). Mice, weighing 3031 g were used in this dy. Ambient temperature is approximately 20-21% C. and relative humidity 35-65%. A.12 hour light- dark eyele is msiatsined inthe rooms with al ess being performed during the light phase. Acoess to tap Water and Tod are ad libitum, [0428] Method [0429] All measurements were made between 12:00 3 and 5:00 pm, Mice were brought in this environment an habituated for atleast evo hours before the stut of the ‘experiment. They had always free access to food and water For each dose, 8 mioe were used, Rectal boxy temperature measurements were recorded by mean of 4 rectal probe (RET? of Phystemp) and digital thermometer (Digi-sease 'n°8528-20 of Cole Parmer, Chicago USA). The probe was, inserted about 3.5 em ia each mouse [0430] The body temperature was taken 15 min before administration of ether Vehicle or CBI receptor antagonist inverse agonist, 300 90 min slerip. orp. administration ofthis compound, respectively etal body temperature was, recorded inorder to evaluate any influence ofthe compound itself The CB receptor agonist CP 5,940 (03 mika) was, immediately administered intravenously, thes 20 min ater ix administation of CP $5940, boxy temperature was again measured. [0431] The in vivo atvty of compounds of formula (1) was assessed for ther ability to regulate feeding behaviour by recording foo consumption in food! deprived animals. {0432} Rats were trained to have accesso fod for 2h per day and were food deprived for 22h. When they were trained under this schedule, the amount of food taken every day during these 2h food intake session was consistent day afer day. [0433] To test the ability of compounds of formula (1) © decrease fond intake, 8 animals were used in a crossover US 2005/0143373 AL study. Rats were individually housed in Plexiglas boxes with «grid on the oor and a paper was placed below the cage ‘Noor to collect aay spillage. food dispenser (bec) filled with a presweighed amount of food was presented to them for 2b, AL the end ofthe food intake session, rats returned to teie home cage. Each rat was weighed before te start of the experiment and the amount of food consumed during this, 2b food intake session was eeoorded. Either various doses, ‘of test compound or vehicle was administered orally 60 min, before the 2h food intake session. positive control Rimonabant (SR141716) was included inthe experiment ‘Aa Anova analysis with repeated measures was used fol- Towed by a posthoc test Student Neumana-Keuls. * P <0.05 ‘compared t0 Saline-treated ras, [0434] Puribemore the utility of compounds of formula (1) in seas or disorders may be demonstrated in animal clisease model that have been epoted in the ierture. The following are examples of such animal disease models a) reduction of sweet food intake in marmoses (Behavioural Pharm, 1998, 9179-181); b) reduction of sucrose and thar 10 intake in mice (Psychopharm, 1997, 132, 104-106); &) increased motor activity and place conditioning in rls (Psychophiem. 1998, 135, 324-22; Psychopharmacol 2000, 15 25-3} ¢)spontancous locomotor activity in mie harm. Exp. Ther. 19%, 277, 586-594); e) reduction in opiate sel-administeation in mie (Si. 199,283, 401-408), [0435] The compounds of formula (0) andor their phar- ‘maceuically acceptable salts can be used as medicaments, eg. in the form of pharmaceutical preparation for enteral, parenteral or Lopial administration. They ca be adminis: fered, for example, peroraly, ¢. in the form of tablets, coated tablets, dragées, ard and soft gelatine capsules, Solutions, emulsions or suspensions, retally eg. inthe form of suppositories, parenterary, eg, inthe form of injection solutions or infusion solutions, or topically, eg. in the form of ointments, creams or oils. Oral administration is pre- ferred [0436] The production ofthe pharmaceutics] preparations ‘canbe effected in manner which willbe familiar to aay person skilled ia the art by bringing the described com- ‘pounds of formula (} andor thee pharmaceutically acee able salts, optionally ia combination with otber thecapen cally valuable substances, into a gilenical adainistation form together with suitable, non-toxic, ines, terapeatically compatible soli or liquid carrier materials and, if desired, ‘usual pharmaceutical adjuvans [0437] Suitable case materials are not oaly inorganic ‘atriet materials, but also onganic carrier materials. Thus, for example, lacose, corn starch or derivatives thereo, tale, Steari acid or is salis cam be used a carrier materials. for tables, coated tables, dragées and hard gelatine capsules. Suitable eattioe materials for soft gelatine capsules ar, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature ofthe active ingre= dient no caries might, however, be roquited in the case of soft gelatine capsules). Suitable cucier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar andthe lke. Suitable cartier ‘malerals for ijection solutions ar, for example, water, leobols, polyols, elveerol and vegetable cis. Suitable car- ‘er materials for suppositories ae, for example, natural or Dbardened oils, waxes, fats and sem-iguid or liquid polyols. Jun, 30, 2005 Suitable cartier materials for topical preparations are glye~ crides, semi-synthetic and synthetic glycerides, hydroge= nated oils liquid waxes, liquid paralfins, liquid Tally aleo- bls sterols, polyethylene glycols and cellulose derivatives. (0438) Usual stabilizers, preservatives, weting and emul sifyng agents, eonssency-improving ageats, Ravoursim- roving agents, sls for varying he osmotic pressure, buler Substances, sober, colorants and masking agents and antioxidants come into consideration as pharmaceutical sgjvants, [0439] The dosage ofthe compounds of formula (1) an vary with wide limits depeading on the disease to be controled, he age andthe iviual condition of the patent Sd the made of administration, ad wil, ofcourse be fied to the individual eequrements in each particular ease. For aul patents dally dosage of about 1 10 1000 mg, especially ahout 1 10 100 mg, comes into consideration Depending on severity ofthe disease and the precise phar ‘macokiactic profile the compound could be administered with one or several daily dosage units, ein to 3 dosage ats, 0440) ‘The pharmaceutical preparations conveniently contaia about 1-500 mg, preferably 1-100 mg, of & com- pound of formula (Dy {O441] The following Examples serve to ilusete the prseat invention in more dei. They are, bawever, aot Intended to Limit its scope in any manner. EXAMPLES [042] MS=mass spectromety, ISPxion spray (positive fon), mp.amelting point, g.-aqueous, DMSO=dimetl- sulfoxide, NMRenuclear magnetic resonance spectosc0py, EDCI=N-(-dimethylaminopropy))-Nthylearbodiimide hydrochloride, HPLC=high pertormance liquid chromatog ‘apy. Example 1 Preparation of 142,2elipenyL-benzo 1,3 }lioxole-5-sulfony-piperidine (0443) pheayl-beam{L,3foxole-S-lfonyl_chlo~ Fide (336 g, 9 mmol) was dissolved in methylene chloride (135 m). Pperidine (133 ml, 135 mmol) and ethyiso- propyl amine (233 ml, 135 mmol) were added at room temperature. The reaction Was sired st room temperature overnight and washed twice with IN agueous HCl solution, twice with IN aqueous NaOH solution and once with brine US 2005/0143373 AL ‘The organic layer was dried over sodium sulfate and filtered ‘The solvent was evaporated and the residue was purified by column chromatography (4/1 hexane/ethyl acetate eluant), ‘The product was suspended in diethylether and filtered to yell a white crystalline solid (1.98 g, 52 4), mp: 163-168" © Preparation of 22-diphenyl-benzo[t,3ioxole5- Sulfoyl ebloride [O45] The sulfonyl chloride derivative was. prepared according to literature procedures (WO9218490, EPS44166), [046] Mettod A [0447] Method A is general method forthe preparation ‘of 22-tiphenyl-benzo{1,3}dioxole-S-sulfonamides starting from commercially available amines: [048] 22-Diphenyl-benzo{1.3}lioxoleS-sulfonylchlo- tide (93 mg, 0.25 mmol) was dissolved in pyridine (1a). ‘The appropriate amine (0.25 mmol) was added snd the reaction was heated to 60° C. overnight, Water was added and solids respectively oils separated. The aqueous phase ‘was decanted and te residue was sted with acetonitrile. A solid precipitated, which was filtered off and washed with a litle acetonitile to yield after deying at high vacuum the product [0449] The following examples were prepared using the general method A: Example 2 Prspration of 144-shlom-pheny)-+(2,2phenyt ‘ena 3loxolesulfonyD piperazine [o4s0) [0451] Using 4.(4-chloropheny)piperazine (49.2 mg, 0.25, ‘iml) as an amine, the tlle compound was obianed as a white solid (27 mg, 20%. [0452] MS (ISP): 533.2 (M+H", 100). NMR (300 MHz, DDMSO-<,) ppm: 744-756 (m, 10H), 71 (5, 1), 7.37 (, 1H), 7.32 (d, 1H), 7.26 (d, 2H), 6.90 (a, 2H), 3.16-3.19 (m, 419, 298-802 (om, 4H) Jun, 30, 2005 Example 3 Preparation of L(2,3dimethyl-phenyl)-4-(2,2

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