WO2015155566A1 - Composés pyrazole fusionnés comme antagonistes de cb1r et leurs utilisations - Google Patents

Composés pyrazole fusionnés comme antagonistes de cb1r et leurs utilisations Download PDF

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WO2015155566A1
WO2015155566A1 PCT/IB2014/060518 IB2014060518W WO2015155566A1 WO 2015155566 A1 WO2015155566 A1 WO 2015155566A1 IB 2014060518 W IB2014060518 W IB 2014060518W WO 2015155566 A1 WO2015155566 A1 WO 2015155566A1
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chlorophenyl
methyl
dichlorophenyl
dioxide
alkyl
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Sumit Mukherjee
Rajiv Sharma
Dharnidhar MUNDHE
Nauzer DUBASH
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Piramal Enterprises Limited
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Definitions

  • the present invention relates to fused pyrazole compounds (the compounds of formula I as described herein), processes for their preparation, pharmaceutical compositions containing said compounds, their use as cannabinoid- 1 receptor (CB 1R) antagonists and methods of using said compounds in the treatment of diseases or disorders mediated by CB 1R.
  • CB 1R cannabinoid- 1 receptor
  • Endocannabinoid system is a unique neuromodulatory system in mammalian physiology which is primarily responsible for maintaining homeostasis in all body systems including the central and peripheral nervous systems, all organ systems, somatic tissues, metabolic systems and the immune system (G. Marsicano et al., J. Endocrinol. Invest, 2006, 29, 27-46).
  • the endocannabinoid system consists of transporters, endocannabinoids, enzymes involved in synthesis and degradation of endocannabinoids and G protein-coupled receptors.
  • CB 1R cannabinoid- 1 receptor
  • CB2R cannabinoid-2 receptor
  • CB 1R is prominently expressed in the central nervous system (CNS) and peripheral tissues, including thyroid gland, adrenal gland, reproductive organs, adipose tissue, liver, muscle, pancreas, and gastrointestinal tract.
  • the CB2R is mainly expressed in immune cells and hematopoietic cells and to a lesser extent in myocardium, coronary endothelial cells, and smooth muscle cells.
  • CB 1R plays a pivotal role in regulating energy balance, food intake, and metabolism of lipids and glucose. It has been observed that exogenous cannabinoids and endocannabinoids increase food intake and promote weight gain in animals by activating Cannabinoid- 1 receptor (Stefan Engeli et al., Diabetes, 2005, 54, 2838-2843).
  • CB 1R cannabinoid- 1 receptor
  • Type 2 diabetes is a serious life-threatening disorder with growing prevalence in both adult and childhood populations. According to American Medical Association, Type 2 diabetes is currently the 7 th leading cause of death in the US. It has been reported that endocannabinoid levels are enhanced in the plasma and adipose tissue of type 2 diabetic patients. Studies on CB IR revealed that activation of CB IR with CB IR agonist reduces glucose tolerance and insulin release from pancreatic beta cells, whereas CB IR antagonists reverse this effect by elevating the levels of adiponectin protein. It has further been reported that CB IR undergo increased expression during inflammatory conditions. CB IR antagonist has demonstrated anti-inflammatory effect in rodent models of inflammatory disease.
  • CB IR also plays a pivotal role in cardiovascular regulation. Recently it has been reported that CB IR blockage improves systolic and diastolic heart function, decreases cardiac collagen and hydroxyproline content (Svetlana Slavic et al., J. Mol. Med., 2013, 91, 811-823). Inhibition of CB IR with CB IR antagonist exerts cardio-protective effect in rats with metabolic syndrome. This renders inhibition of CB IR as potential pharmacological tool in the treatment of cardiovascular diseases.
  • CB IR antagonists have been reported to have utility in the treatment of several other diseases and disorders such as cancer, atherosclerosis, psychosis, schizophrenia, epilepsy, Parkinson's disease, amnesia, cognitive disorders, dyslipidemias, dyslipoproteinemia, hepatic lipidosis, liver fibrosis, cirrhosis, fatty liver disease, neuroinflammatory disorders, gastrointestinal disorders, urinary disorders, and infertility disorders.
  • diseases and disorders such as cancer, atherosclerosis, psychosis, schizophrenia, epilepsy, Parkinson's disease, amnesia, cognitive disorders, dyslipidemias, dyslipoproteinemia, hepatic lipidosis, liver fibrosis, cirrhosis, fatty liver disease, neuroinflammatory disorders, gastrointestinal disorders, urinary disorders, and infertility disorders.
  • Rimonabant a central CB IR antagonist, which is selective for CB IR, was the first drug that was developed for therapeutic use. Rimonabant was developed for treating obesity and other related disorders. However, it was withdrawn from the European markets, and was denied FDA approval in the US due to its CNS-related side effects including anxiety, depression and suicidal ideation. Subsequently developed compounds namely ibipinabant, taranabant and otenabant, which belonged to the same class as rimonabant, were also terminated due to similar side effects. Failure with central CB IR antagonists has diverted the attention of researchers towards peripheral CB IR antagonist.
  • peripheral CB IR antagonist In diet-induced obese mice, use of peripheral CB IR antagonist has shown weight loss and significant reduction in insulin and triglyceride level. Studies on peripheral CB IR have led to selection of peripheral CB IR as a promising molecular target for the treatment of diseases or disorders mediated by CB IR.
  • TM38837 (7TM Pharma) a peripheral CB IR antagonist, is in phase I clinical development for the treatment of obesity and type 2 diabetes.
  • CB IR central nervous system related adverse side effects
  • the present invention relates to a compound of formula I (as described herein), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, S-oxide or N-oxide thereof.
  • a pharmaceutical composition comprising one or more of the compounds of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
  • CBD IR cannabinoid-1 receptor
  • a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof for use in the treatment of a disease or a disorder mediated by CB 1R.
  • a method for the treatment of a disease or disorder mediated by CB IR comprising administering to a subject in need thereof; a therapeutically effective amount of the compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
  • a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof for the manufacture of a medicament for the treatment of a disease or a disorder mediated by
  • the present invention relates to use of a compound of formula I or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or a solvate thereof; in combination with at least one further therapeutically active agent for the treatment of a disease or a disorder mediated by CB 1R.
  • the present invention relates to a compound of formula I:
  • n is an integer 0 or 1 ;
  • n is an integer 1 or 2;
  • Ri is hydrogen, (Ci-C 6 )-alkyl, (C3-Ci 2 )-cycloalkyl, halo(Ci-C 6 )alkyl, (C 6 -Ci 4 )-aryl, heterocyclyl, (C 6 -C 14 )ar(C 1 -C 6 )alkyl, heteroaryl, C(0)R a , C(0)OR a , S(0) p -(C 1 -C 6 )-alkyl, S(0) p -(C 3 -C 12 )- cycloalkyl or S(0) p -(C 6 -Ci 4 )-aryl;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, (Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl, halo(Ci-C 6 )alkyl, halo(Ci- C 6 )alkoxy, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl, C(0)R a , C(0)NR a R b , C(0)OR a , S(0) p -(Ci-C 6 )-alkyl, S(0) p -(C 3 - Ci 2 )-cycloalkyl, S(0) p -(C 6 -C
  • R4 and R5 are independently selected from the group consisting of (Ci-C 6 )-alkyl, (C 3 -Ci 2 )- cycloalkyl, (C 6 -Ci 4 )-aryl, heterocyclyl and heteroaryl;
  • R a and R b are independently selected from the group consisting of hydrogen, (Ci-C6)-alkyl, (Ci- C 6 )-alkoxy(Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, halo(Ci-C 6 )alkyl, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )ar(Ci- C 6 )alkyl, heterocyclyl, heteroaryl, C(0)R a, C(0)OR a , S(0) p -(Ci-C 6 )-alkyl, S(0) p -(C 3 -Ci 2 )- cycloalkyl and S(0) p -(C 6 -Ci 4 )-aryl; or
  • R a and R b along with the N to which they are attached, can form a 3-7 membered saturated or unsaturated ring optionally containing one or more additional heteroatoms selected from N, O or S, which ring is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy, (Ci- C 6 )-alkoxy(Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, halo(Ci-C 6 )alkyl, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )ar(Ci- C 6 )alkyl, heterocyclyl, heteroaryl, C(0)R a, C(0)OR a , S(0) p -(Ci-C 6 )-alkyl, S
  • substitution means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
  • (Ci-C6)-alkyl or "alkyl” whether used alone or as part of a substituent group, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups.
  • An alkyl group can have a straight chain or branched chain containing carbon atoms.
  • a straight-chain or branched chain alkyl has six or fewer carbon atoms in its backbone, for instance, Ci-C 6 for straight chain and C3-C6 for branched chain.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec -butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2- hexyl and 3-hexyl.
  • alkyl groups can be unsubstituted or substituted with one or more substituents.
  • a substituted alkyl refers to a (Ci-C6)-alkyl substituted with one or more groups, preferably 1-3 groups, independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a, C(0)OR a , S(0) p -(Ci-C 6 )-alkyl, S(0) p -(C 3 -
  • substituted alkyls include, but are not limited to, benzyl, hydroxymethyl, hydroxyethyl, N-morpholinomethyl, N-indolomethyl, piperidinylmethyl, and aminoethyl.
  • halogen refers to a fluorine, chlorine, bromine, or iodine atom.
  • halo(Ci-C 6 )alkyl When the alkyl group is substituted with one or more halogens, it is specifically referred to as "halo(Ci-C 6 )alkyl" or "haloalkyl".
  • a monohalo(Ci-C 6 )alkyl radical for example, can have a chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhalo(Ci-C 6 )alkyl radicals can have two or more of the same or different halogen atoms.
  • halo(Ci- C 6 )alkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl or the like groups.
  • (C 2 -C 6 )-alkenyl or “alkenyl”, as used herein; alone or as part of a substituent group, refers to a straight or branched chain hydrocarbon radical containing the indicated number of carbon atoms and at least one carbon-carbon double bond (two adjacent sp carbon atoms).
  • (C 2 -C 6 )-alkenyl refers to an alkenyl group having 2 to 6 (both inclusive) carbon atoms.
  • the geometry of the double bond may be
  • alkenyl include, but are not limited to, vinyl, allyl and 2-propenyl.
  • the alkenyl groups can be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci- C 6 )alkyl, halo(d-C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, (C 6 - Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C
  • alkynyl or "(C 2 -C 6 )alkynyl” whether used alone or as part of a substituent group, refers to a straight or branched chain hydrocarbon radical containing the indicated number of carbon atoms and at least one carbon-carbon triple bond (two adjacent sp carbon atoms).
  • the (C 2 -C 6 )alkynyl refers to an alkynyl group having 2 to 6 (both inclusive) carbon atoms.
  • Representative examples of (C 2 -C 6 )alkynyl include, but are not limited to, ethynyl, 1-propynyl, 3-propynyl and 3-butynyl.
  • alkynyl can be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )- alkoxy, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 - Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, (C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a , C(0)OR a , S(0) p -(Ci-C)
  • (Ci-C 6 )alkoxy refers to a (Ci-C 6 )-alkyl having an oxygen radical attached thereto.
  • Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like.
  • An alkoxy group can be unsubstituted or substituted with one or more substituents.
  • a substituted alkoxy refers to an (Ci- C 8 )-alkoxy group in which the alkyl is substituted with one or more groups as explained in the definition of 'substituted alkyl' herein above.
  • substituted (Ci-C 8 )- alkoxy include, but are not limited to, chloromethoxy, 2-cyanoethoxy and benzyloxy group.
  • a benzyloxy group refers to a benzyl having an oxygen radical attached thereto.
  • halo(Ci-C6)alkoxy or “haloalkoxy” refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens.
  • Representative examples of “haloalkoxy” groups include, but are not limited to, difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ) or trifluorethoxy (OCH 2 CF 3 ).
  • (C 3 -Ci 2 )-cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings.
  • the term cycloalkyl includes bridged, fused and spiro ring systems.
  • (C 3 -Ci 2 )-cycloalkyl refers to a cycloalkyl group having 3 to 8 (both inclusive) carbon atoms.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1.0]pentane, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2-ene, spiro[3.3]heptane, 1,2,3, 3a-tetrahydropentalene and the like.
  • the "cycloalkyl” group can be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )- cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 - Ci 4 )ar(Ci-C 6 )alkyl, (C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a, C(0)OR a , S(0) p -(C 1 )
  • (C 3 -Ci 2 )-cycloalkyloxy refers to a (C 3 -Ci 2 )-cycloalkyl having an oxygen radical attached thereto.
  • Representative cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the "cycloalkyloxy" group can be unsubstituted or substituted with one or more groups selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci- C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, (C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a , C(0)OR a , S(0) p -(Ci-C 6 )-
  • (Ci-C 6 )-alkoxy(Ci-C 6 )-alkyl or "alkoxyalkyl” as used herein refers to a (Ci-C 6 )-alkyl group, which is substituted by a (Ci-C 6 )-alkoxy group.
  • (C 6 -Ci 4 )-aryl or "aryl” as used herein refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms (i.e. (C 6 -Cio)-aryl) in which the carbocyclic ring(s) present have a conjugated pi electron system.
  • Examples of (C 6 - Ci 4 )-aryl residues are phenyl, naphthyl, fluorenyl or anthracenyl.
  • Aryl groups can be unsubstituted or substituted by one or more, for example 1, 2, 3, 4 or 5, identical or different substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci- C 6 )alkoxy, (C 6 -C 14 )-aryl, (C 6 -C 14 )aryloxy, (C 6 -C 14 )ar(C 1 -C 6 )alkyl, (C 6 -C 14 )ar(C 1 -C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a, C(0)OR a , S(0) p -(Ci-C 6 )-
  • the substituent can be located in the 2-position, the 3-position or the 4- position. If the phenyl carries two substituents, they can be located in 2, 3-position, 2, 4- position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position.
  • Representative examples of monosubstituted phenyl groups include, but are not limited to 3-trifluoromethylphenyl, 4- chlorophenyl and 4-cyanophenyl.
  • Representative examples of disubstituted phenyl groups include, but are not limited to, 3, 5-difluorophenyl, and 3, 4-dimethoxyphenyl.
  • (C 6 -Ci 4 )-aryloxy refers to an "(C 6 -Ci 4 )-aryl” group having an oxygen radical attached thereto.
  • aryloxy groups include, but are not limited to, phenoxy, 4-chlorophenoxy, and 3, 4-dimethoxyphenoxy.
  • a substituted aryloxy refers to an aryloxy group in which the aryl group is substituted with one or more groups as explained in the definition of aryl herein above.
  • (C 6 -Ci 4 )ar(Ci-C 6 )alkyl refers to (Ci-C 6 )alkyl group substituted with an (C 6 -Ci 4 )-aryl group, wherein the terms alkyl and aryl are as defined above.
  • Exemplary aralkyl groups include (CH 2 ) q -phenyl, wherein q is an integer from 1 to 6, such as benzyl wherein q is 1.
  • the aryl of the (C 6 -Ci 4 )-aralkyl group can be unsubstituted or substituted as explained in the definition of substituted aryl herein above.
  • the term “(C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy” or "aralkyloxy” refers to an aralkyl group having an oxygen radical attached thereto.
  • heteroatom as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
  • heterocyclyl or “heterocyclic” whether used alone or as part of a substituent group, refers to a saturated, partially unsaturated, monocyclic or polycyclic ring system containing 1 to 10 carbon atoms and 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • heterocyclyl primarily refers to a 3 to 10 membered ring system which can be a monocyclic or a bicyclic ring.
  • heterocyclyls include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, pyrazinyl, piperazinyl, oxazolyl, oxadiazolyl, isoxazolyl, triaziolyl, thiazolyl, tetrazolyl, furyl, thienyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, piperidyl, benzoxazolyl, benzothiazolyl, benzofuranyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, isoindolyl, isothiazolyl, isoquinolyl, isoquinolyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-1, 1 -dioxide, quinoxalinyl,
  • heterocyclyl having an aromatic ring containing heteroatom/s are herein referred to by the customary term "heteroaryl".
  • heteroaryl refers to a 5 to 10 membered aromatic monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from the group consisting of nitrogen, sulphur and an oxygen atom.
  • heteroaryls include, but are not limited to, pyrrole, pyrazole, imidazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrine) and tetrazole.
  • heterocyclyl or heteroaryl group can be unsubstituted or substituted.
  • a substituted heterocyclyl or heteroaryl refers to a heterocyclyl or heteroaryl substituted with 1-5 groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Q- C 6 )alkyl, (d-C 6 )-alkoxy, (C 3 -Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(d-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, (C 6 -Ci 4 )ar(Ci- C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a , C(0)OR a , S(0) p -(Ci-C 6 )-alky
  • isotopic forms or “isotopically labeled forms” is a general term used for isotopic forms of compounds of formula I, wherein one or more atoms of compounds of formula I are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention. Examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as H
  • isotopic forms of the compounds of formula I may include, without limitation, deuterated compounds of formula I.
  • deuterated as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom.
  • the compounds of formula I may include in the definitions of one or more of its various variables, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-heterocyclyl, deuterated-aryl, deuterated-heteroaryl and the like.
  • deuterated-alkyl refers to an (Ci- C 6 )-alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bound to a deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.
  • deuterated and the terms deuterated-heterocyclyl, deuterated-heteroaryl, deuterated-cycloalkyl, deuterated-aryl, deuterated-alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.
  • solvate(s) or “pharmaceutically acceptable solvate(s)” as used herein refers to a compound formed by the interaction of a solute (in the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water and the solvates obtained are referred to as hydrates.
  • suitable solvates are the mono- or di-hydrates or alcoholates of the compounds according to the invention.
  • stereoisomer or “stereoisomeric form” is a general term used for all isomers of individual compounds (in the present invention, a compound of formula I) that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • tautomer or “tautomeric form” refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers or amide-imidic acid tautomers.
  • the term "pharmaceutically acceptable” means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • salts of the active compound i.e. the compound of formula I, which retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects; and are prepared with suitable acids or bases, depending on the particular substituents found on the compounds described herein.
  • polymorph(s) or “polymorphic form” refers to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.
  • N-oxide refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle.
  • N-oxide can be formed in the presence of an oxidizing agent such as m-chloro-perbenzoic acid or hydrogen peroxide.
  • N- oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N->0 bond.
  • S-oxide refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S,S -dioxide) of a sulfur-containing heteroaryl or heterocycle.
  • S-oxide and S,S-dioxides can be formed in the presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or oxone (potassium peroxymonosulfate).
  • a prodrug or “prodrugs” refers to any compound, which are derivatives of a parent compound (in the context of the present invention, a compound of formula I), which following administration, release(s) the parent compound in vivo via a chemical or physiological process, e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the parent compound.
  • the term "compound(s) of formula I" or “compounds of the present invention” are used interchangeably and includes all the stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, N-oxides and pharmaceutically acceptable polymorphs thereof.
  • the compound(s) of formula I can also be referred to herein as “the active compound” or “the active ingredient”.
  • the term “CB 1 receptor antagonist” or “CB 1R antagonist” refers to a compound which is capable of binding to the CB 1 receptor, or in its vicinity, and lacks any substantial ability to activate the receptor itself.
  • CB 1R antagonist By binding to the CB 1 receptor, a CB 1R antagonist prevents or reduces the functional activation or occupation of the receptor by a CB 1R agonist such as for example the endogenous agonist, N-Arachidonylethanolamine (anandamide).
  • CB 1 receptor inverse agonist or "CB IR inverse agonist” refers to a compound which binds to the CB IR and exerts the opposite pharmacological effect as a CB IR agonist does upon binding to the CB 1 receptor.
  • disease or disorder mediated by CB IR refers to a disease or condition which is mediated by CB 1R signaling activity.
  • the diseases or disorders mediated by CB IR can be selected from bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; cancer; obesity and metabolic disorders; osteoporosis; nephropathies; glaucoma; psychiatric disorders and neurological disorders; autoimmune hepatitis and encephalitis; pain; reproductive disorders and skin inflammatory or fibrotic diseases.
  • therapeutically effective amount means an amount of a compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; or a composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder mediated by Cannabinoid-1 receptor (CB IR).
  • CBD IR Cannabinoid-1 receptor
  • therapeutically effective amount includes the amount of the compound, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment.
  • the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed and the particular pharmaceutically acceptable carrier utilized.
  • the term "pharmaceutically acceptable carrier” refers to a material that is non- toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type which is compatible with a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warm-blooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
  • subject may be used interchangeably with the term patient.
  • a subject in need thereof means a subject in need of the treatment for the disease or disorder that is mediated by CB 1R.
  • the phrase "a subject in need thereof means a subject (patient) diagnosed having a disease or disorder that is mediated by CB 1R.
  • treatment refers to alleviate, slow the progression, attenuation or cure of existing diseases or condition (e.g. rheumatoid arthritis). Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.
  • the present invention relates to a compound of formula I,
  • R4 and R5 are independently selected from (C6-Ci 4 )-aryl and heteroaryl;
  • the present invention provides a compound of formula I,
  • R 4 is (C 6 -Ci 4 )-aryl
  • the present invention relates to a compound of formula I,
  • R4 is phenyl, which is mono or disubstituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C3- Ci 2 )-cycloalkyl, (C3-Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, (C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a , C(0)OR a , S(0) p -(Ci-C 6 )-alkyl, S(0)
  • the present invention provides a compound of formula I,
  • R 5 is (C 6 -Ci 4 )-aryl
  • the present invention provides a compound of formula I,
  • R5 is phenyl, which is mono or disubstituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 - Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, (C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a , C(0)OR a , S(0) p -(Ci-C 6 )-alkyl, S(0)
  • the present invention provides a compound of formula I,
  • n 0;
  • n i; and Xi, Ri, R 2 , R 4 and R5 are as defined in the first aspect;
  • the present invention provides a compound of formula I,
  • m 1 ;
  • n i ;
  • Xi, Ri and R 2 are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • m 1 ;
  • n 2;
  • Xi, Ri and R 2 are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • R4 is (C 6 -Ci 4 )-aryl
  • n, Xi and Ri are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • R4 is phenyl, which is mono or disubstituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 - Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Ci 4 )-aryl,
  • n, Xi and Ri are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • R5 is (C 6 -Ci 4 )-aryl
  • n, Xi and Ri are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • R5 is phenyl which is substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 -C 12 )- cycloalkyl, (C3-Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 - Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, (C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a, C(0)OR a , S(0) p -(Ci-C 6 )-alkyl, S(0) p -(C 3 -C
  • n, Xi and Ri are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • Xi is CR 2 R 3 ;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, hydroxy and NR a Rb;
  • n, Ri, R a and R are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • n 0 or 1 ;
  • n 1 ;
  • Ri is hydrogen or (Ci-C 6 )-alkyl
  • Xi is CR 2 R 3 ;
  • R 2 is hydrogen
  • R 3 is hydrogen, hydroxy, (Ci-C 6 )-alkoxy, heterocyclyl, heteroaryl or NR a R b ;
  • R4 and R5 are (C 6 -Ci 4 )-aryl
  • the present invention provides a compound of formula I,
  • R4 is (C 6 -Ci 4 )-aryl
  • n, Ri and R 2 are as defined in the first aspect; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof.
  • the present invention provides a compound of formula I,
  • R4 is phenyl which is mono or disubstituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 -
  • n, Ri and R 2 are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • R5 is (C 6 -Ci 4 )-aryl
  • n, Ri and R 2 are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • R5 is phenyl which is mono or disubstituted with one or more groups independently selected from the group consisting of halogen, hydroxy, nitro, cyano, (Ci-C 6 )alkyl, (Ci-C 6 )-alkoxy, (C 3 - Ci 2 )-cycloalkyl, (C 3 -Ci 2 )-cycloalkyloxy, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )aryloxy, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, (C 6 -Ci 4 )ar(Ci-C 6 )alkyloxy, heterocyclyl, heteroaryl, C(0)R a, C(0)OR a , S(0) p -(Ci-C 6 )-alkyl, S(0) p
  • n, Ri and R 2 are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • R 2 is hydrogen, hydroxy or NR a R b ;
  • n, Ri, R a and R b are as defined in the first aspect
  • the present invention provides a compound of formula I,
  • n 0 or 1 ;
  • n 1;
  • Ri is hydrogen or (Ci-C 6 )-alkyl
  • R 2 is heterocyclyl, heteroaryl, or NR a R b ;
  • R a is hydrogen
  • R b is (Ci-C 6 )-alkyl, (C 3 -Ci 2 )-cycloalkyl, halo(Ci-C 6 )alkyl, (C 6 -Ci 4 )-aryl, (C 6 -Ci 4 )ar(Ci-C 6 )alkyl, heterocyclyl, heteroaryl, C(0)R a , or C(0)OR a ; and
  • R4 and R5 are (C 6 -Ci 4 )-aryl
  • Representative compounds of formula I encompassed in accordance with the present invention include:
  • the compounds of the present invention include all isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, N-oxides, S-oxides and polymorphs. According to another aspect of the present invention, there are provided processes for the preparation of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the compound of formula I can be prepared by various methods including using methods well known to the person skilled in the art. Examples of a process for the preparation of the compounds of formula I are described below and illustrated in the following schemes 1 and 2, but are not limited thereto. It will be appreciated by persons skilled in the art that within certain of the processes described herein, the order of the synthetic steps employed can be varied and will depend inter alia on factors such as the nature of functional groups present in a particular substrate and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent such as bases, solvents, coupling agents to be used in the reaction steps.
  • Scheme 1 depicts a process for the preparation of the compounds of formula I, wherein,
  • n i
  • Xi, Ri, R 2 , R 4 and R5 are as defined in the first aspect.
  • A is (i); A is (ii); A is (i);
  • X-i is CR 2 R3;
  • R 2 is hydrogen
  • R 3 is hydroxyl; and R 3 is NR a R b ; m is 0; n is 1.) m is 0; n is 1 ; and
  • R a and R b are as defined in the first aspect.
  • R 2 is NR a R b ;
  • n 0;
  • R a and R b are as
  • R5 is as defined in the first aspect; is reacted with diethyl oxalate [(C0 2 Et)2] in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) in a solvent selected from diethyl ether, tetrahydrofuran (THF), diisopropyl ether, hexane, toluene or ⁇ , ⁇ -dimethylacetamide at a temperature ranging from -90 °C to -50 °C to obtain compound 2 of the following formula;
  • LiHMDS lithium bis(trimethylsilyl)amide
  • step (la) The compound of formula 2 as obtained in step (la) is reacted with a compound 3 of the following formula:
  • R 4 is as defined in the first aspect
  • R 4 and R5 are as defined in the first aspect.
  • step (lb) Reducing the compound of formula 4 as obtained in step (lb) by reaction with a reducing agent such as sodium dithionite (Na 2 S 2 0 4 ) in a solvent selected from ethyl acetate, dimethylformamide (DMF), tetrahydrofuran (THF) or water to obtain a compound 5 of the following formula;
  • a reducing agent such as sodium dithionite (Na 2 S 2 0 4 ) in a solvent selected from ethyl acetate, dimethylformamide (DMF), tetrahydrofuran (THF) or water
  • step (lc) The compound of formula 5 as obtained in step (lc) is reacted with methanesulfonyl chloride (MeS0 2 Cl) in the presence of a base selected from triethylamine (TEA), sodium hydride (NaH), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO) or N,N- diisopropylethylamine at a temperature ranging from 0 °C to 30 °C to obtain a mixture of compounds 6 and 7 of the following formulae;
  • a base selected from triethylamine (TEA), sodium hydride (NaH), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO) or N,N- diisopropy
  • R 4 and R5 are as defined in the first aspect.
  • step (Id) The mixture of compounds of formula 6 and 7 as obtained in step (Id) is reacted with a compound 8 of the following formula
  • Ri is as defined in the first aspect
  • a base selected from potassium carbonate (K 2 C0 3 ), triethylamine (TEA), N,N- diisopropylethylamine, pyridine, caesium carbonate (Cs 2 C0 3 ), l,8-Diazabicyclo[5.4.0]undec-7- ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), sodium hydride (NaH) or lithium diisopropylamide (LDA) in a solvent selected from dimethylformamide (DMF), tetrahydrofuran (THF) or acetonitrile at a temperature ranging from 80 °C to 100 °C to obtain a compound 9 of the following formula;
  • a base selected from potassium carbonate (K 2 C0 3 ), triethylamine (TEA), N,N- diisopropylethylamine, pyridine, caesium carbonate (Cs 2 C0 3
  • step (le) The compound of formula 9 as obtained in step (le) is reacted with lithium bis(trimethylsilyl)amide (LiHMDS) in a solvent selected from N,N-dimethylacetamide, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, hexane or toluene at a temperature ranging from -5 °C to 5 °C to obtain a compound of formula I;
  • a solvent selected from N,N-dimethylacetamide, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, hexane or toluene
  • n 0;
  • n i ;
  • Ri, R4 and R5 are as defined in the first aspect.
  • step (If) The compound of formula I as obtained in step (If) is reacted with an amine represented by the following formula;
  • R a and R b are as defined in the first aspect; in the presence of a reagent titanium(IV)isopropoxide in a solvent selected from 1,2-dichloroethane, dichloromethane, toluene, diethyl ether, cyclohexane or acetonitrile at a temperature ranging from 80 °C to 100 °C to obtain a compound of formula I;
  • R 2 is NR a R b ; m is 0;
  • n i
  • R a , Rb, Ri, R 4 and R5 are as defined in the first aspect.
  • step (If) The compound of formula I as obtained in step (If) is reacted with a reducing agent selected from sodium borohydride (NaBH 4 ), lithium borohydride or diisobutylaluminium hydride (DIBAL-H) in a solvent such as methanol or tetrahydrofuran (THF) at a temperature ranging from -5 °C to 5 °C to obtain a compound of formula I
  • a reducing agent selected from sodium borohydride (NaBH 4 ), lithium borohydride or diisobutylaluminium hydride (DIBAL-H) in a solvent such as methanol or tetrahydrofuran (THF)
  • Xi is CR 2 R 3 ;
  • R 2 is hydrogen
  • R 3 is hydroxy
  • n 0;
  • n i
  • Ri, R4 and R5 are as defined in the first aspect.
  • step (lh) The compound of formula I as obtained in step (lh) is reacted with methanesulfonyl chloride in the presence of a base selected from triethylamine (TEA), ⁇ , ⁇ -diisopropylethylamine, sodium hydride (NaH), l,4-diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), Pyridine or s-Collidine in a solvent selected from dichloromethane (MDC), tetrahydrofuran (THF), acetonitrile or toluene at a temperature ranging from -5 °C to 5 °C to obtain a compound of formula I; wherein,
  • R 2 is hydrogen
  • n 0;
  • n i
  • Ri, R4 and R5 are as defined in the first aspect.
  • step (li) The compound of formula I as obtained in step (li) is reacted with an amine represented by the formula
  • Ra and Rb are as defined in the first aspect; in the presence of a catalyst such as 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in a solvent selected from ethanol, methanol, tetrahydrofuran (THF), acetonitrile or dioxane at a temperature ranging from 90 °C to 110 °C to obtain a compound of formula I
  • Xi is CR 2 R 3 ;
  • R 2 is hydrogen
  • R 3 is NR a R b ;
  • n 0;
  • n i
  • Scheme 2 depicts a process for the preparation of the compounds of formula I, wherein
  • m 1 ;
  • n i ;
  • Xi, Ri, R 2 , R 4 and R5 are as defined in the first aspect.
  • A is (i); A is (ii);
  • n 1;
  • R a and R b are as
  • R5 is as defined in the first aspect
  • LiHMDS lithium bis(trimethylsilyl)amide
  • a solvent selected from diisopropyl ether, tetrahydrofuran (THF), diethyl ether, hexane, toluene or N,N- dimethylacetamide at a temperature ranging from -80 °C to -50 °C.
  • the resulting reaction mixture is reacted with diethyl oxalate at a temperature ranging from 25 °C to 30 °C to obtain an intermediate compound 11 of the following formula:
  • R 4 wherein, R 4 is as defined in the first aspect
  • R 4 and R5 are as defined in the first aspect.
  • step (2a) The compound of formula 12 as obtained in step (2a) is reacted with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a solvent such as carbon tetrachloride at a temperature ranging from 60 °C to 100 °C to obtain compound 13 of following formula:
  • R 4 and R5 are as defined in the first aspect.
  • step (2b) The compound of formula 13 as obtained in step (2b) is reacted with silver nitrate (AgN0 3 ) in a solvent selected from mixture of acetonitrile and water, tetrahydrofuran (THF) or N,N- dimethylformamide at a temperature ranging from 60 °C to 80 °C to obtain compound 14 of following formula:
  • step (2c) The compound of formula 14 as obtained in step (2c) is reacted with methanamine hydrochloride (MeNH 2 HCl) in a solvent such as N-methylpyrrolidine.
  • the resulting reaction mixture is reacted with sodium triacetoxyborohydride (STAB) at a temperature ranging from 20 °C to 30 °C to obtain compound 15 of the following formula:
  • R 4 and R5 are as defined in the first aspect.
  • step (2d) The compound of formula 15 as obtained in step (2d) is reacted with methanesulfonyl chloride in the presence of a base selected from triethylamine (TEA), ⁇ , ⁇ -diisopropylethylamine, sodium hydride (NaH), l,4-diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine or s-collidine in a solvent selected from dichloromethane (MDC), tetrahydrofuran (THF), acetonitrile, ⁇ , ⁇ -dimethylformamide or dioxane at a temperature ranging from -5 °C to 5 °C to obtain a compound 16 of the following formula:
  • a base selected from triethylamine (TEA), ⁇ , ⁇ -diisopropylethylamine, sodium hydride
  • step (2e) The compound of formula 15 as obtained in step (2e) is reacted with lithium bis(trimethylsilyl)amide (LiHMDS) in a solvent selected from N,N-dimethylacetamide, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, hexane or toluene at a temperature ranging from -5 °C to 5 °C to obtain a compound of formula I
  • a solvent selected from N,N-dimethylacetamide, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, hexane or toluene
  • n 1;
  • n 1;
  • step (2h) The compound of formula I as obtained in step (2h) is reacted with an amine represented by the formula;
  • Ra and Rb are as defined in the first aspect; in presence of a reagent titanium(IV)isopropoxide in a solvent selected from 1,2-dichloroethane, dichloromethane, toluene, diethyl ether, cyclohexane or acetonitrile at a temperature ranging from 80 °C to 100 °C to obtain a compound of formula I
  • n 1 ;
  • R 2 is NR a Rb > ;
  • R a , R b , Ri, R 4 and R5 are as defined in the first aspect.
  • the compound of formula I, as obtained in Scheme 1 or Scheme 2 may be optionally converted into its corresponding pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts refers to organic and inorganic salts of a compound of the invention, depending on the particular group (acidic or basic group) present in the compounds of formula I described herein.
  • base addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, magnesium, calcium, ammonium, zinc or organic base salt.
  • pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine, choline, guanidine, diethanolamine, tromethamine, metformin and the like.
  • acid addition salts can be obtained by contacting the compounds of formula I with a sufficient amount of an appropriate acid, either neat or in a suitable inert solvent.
  • suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, mono-hydrogensulfuric or hydriodic acids and the like, as well as the salts derived from organic acids such as acetic, ascorbic, isobutyric, benzoic, citric, oxalic, succinic, suberic, fumaric, propionic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, lactic, maleic, malonic, mandelic, tartaric, methanesulfonic, ethanesulfonic, glucuronic or galacturonic
  • the pharmaceutically acceptable salts of the compounds of formula I can be synthesized from the compound of formula I, which contains a basic or an acidic group, by using conventional chemical methods. Generally, the salts are prepared by treating the compound of formula I which may be a free base or an acid with a suitable salt-forming inorganic or an organic acid or a base in a suitable solvent or dispersant or from another salt by cation or anion exchange.
  • suitable solvents that can be used for the preparation of pharmaceutically acceptable salts include, but are not limited to, ethyl acetate, diethyl ether, methanol, ethanol, acetone, tetrahydrofuran, dioxane or mixtures of these solvents.
  • the compounds of formula I can be regenerated from their corresponding salts by contacting the salt with an appropriate base or acid depending on the type of salt and isolating the parent compound in the conventional manner.
  • the compound differs from the various salt forms in certain physical properties.
  • An example of physical properties that may differ is solubility in polar solvents.
  • the present invention also encompasses within its scope the solvates of the compounds of formula I.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • polymorphs of compounds of formula I can be prepared by crystallization of the compounds under different conditions.
  • the different conditions are, for example, using different solvents or their mixtures for crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs can also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs can be determined by IR (infra-red) spectroscopy, solid probe NMR (nuclear magnetic resonance) spectroscopy, differential scanning calorimetry, powder x-ray diffraction or such other techniques.
  • the present invention includes all possible stereoisomers and geometric isomers of formula I and includes not only racemic compounds but also the optically active isomers as well.
  • a compound of formula I When a compound of formula I is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or an appropriate intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example, Chiral reagents for asymmetric synthesis by Leo A. Paquette; John Wiley & Sons Ltd (2003). Additionally, in situations wherein tautomers of the compounds of formula I are possible, the present invention is intended to include all tautomeric forms of the compounds.
  • prodrugs of the compound of formula I are those compounds that are converted to their parent compound intracellularly, where the cellular converting location is the site of therapeutic action.
  • the prodrugs of the compounds of the present invention are derivatives, particularly simple derivatives of the said compounds which upon administration to a subject in need thereof undergoes conversion by metabolic or chemical processes to release the parent drug (e.g. the compound of formula I) in vivo from which the prodrug is derived.
  • preferred produgs are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substituted alkyl esters such as the pivaloyloxymethyl ester and the like conventionally used in the art (An introduction to Medicinal Chemistry, Graham. L. Patrick, Second Edition, Oxford University Press, pg 239-248; Prodrugs: Challenges and Rewards, Part 1 and Part 2, AAPS Press, Edited by Valentino J. Stella, Renald T. Borchardt, Michael J. Hagemon, Reza Oliyai, Hans Maag, Jefferson W. Tilley).
  • alkyl esters e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substituted alkyl esters
  • the present invention relates to a method for the treatment of a disease or a disorder mediated by CB 1R, comprising administering to a subject in need thereof; a therapeutically effective amount of a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.
  • the present invention provides a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; for use as a CB 1R antagonist.
  • the compound of formula I of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof; can be used as CB 1R inverse agonist.
  • the present invention provides use of a compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a disease or a disorder mediated by CB 1R.
  • the present invention encompasses within its scope all the diseases or disorders wherein CB 1R is implicated.
  • the disease or disorder mediated by CB 1R is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder (e.g. obesity); osteoporosis; nephropathy; glaucoma; psychiatric disorder; neurological disorder; autoimmune hepatitis and encephalitis; pain; reproductive disorder and skin inflammatory or fibrotic disease.
  • the disease or disorder mediated by CB 1R is gastrointestinal disorder; inflammatory disease or disorder; cardiovascular disease; cancer; metabolic disorder (e.g. obesity); psychiatric or neurological disorder.
  • the disease or disorder mediated by CB 1R is gastrointestinal disorder.
  • the gastrointestinal disorder that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is selected from functional bowel disease, gastro- esophagael reflux condition, secretory diarrhea, gastric ulcer, paralytic ileus, cholelithiasis or hernia.
  • the disease or disorder mediated by CB 1R is an inflammatory disease or disorder.
  • the inflammatory disease or disorder that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is selected from arthritis, hepatitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease or congestive obstructive pulmonary disorder.
  • the disease or disorder mediated by CB 1R is a cardiovascular disease.
  • the cardiovascular disease that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds; is selected from aneurysm, angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease, coronary artery disease, dilated cardiomyopathy, diastolic dysfunction, endocarditis, high blood pressure (hypertension), hypertrophic cardiomyopathy and its associated arrhythmias and dizziness, mitral valve prolapse, myocardial infarction (heart attack), venous thromboembolism, varicose veins or pulmonary embolism.
  • aneurysm angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve
  • the disease or disorder mediated by CB 1R is cancer.
  • Cancer can include metastatic or malignant tumors.
  • the cancer that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is selected from thyroid carcinoma, cardiac sarcoma, lung carcinoma, gastrointestinal carcinoma, genitourinary tract carcinoma, liver carcinoma, mantle cell lymphoma, bone sarcoma, sarcoma of the nervous system, gynaecological carcinoma, haematological cancer, adrenal gland neuroblastoma, skin cancer, astrocytic cancer, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer or oral cancer.
  • cancer examples include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, blood cancer, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • the disease or disorder mediated by CB 1R is a metabolic disorder.
  • the metabolic disorder that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is selected from obesity, dyslipidemia, hyperlipidemia, low HDL cholesterol level, high LDL cholesterol level, hypertriglyceridemia, low adiponectin level, dyslipoproteinemia, impaired glucose tolerance, insulin resistance, increase in HbAlc (glycosylated haemoglobin) level, type 2 diabetes, reduced metabolic activity, hypertension or non-alcoholic fatty liver disease.
  • the metabolic disorder that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is selected from obesity, low HDL cholesterol level, high LDL cholesterol level, impaired glucose tolerance, insulin resistance, type 2 diabetes or hypertension.
  • the metabolic disorder that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is obesity.
  • the metabolic disorder that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is type 2 diabetes, insulin resistance, impaired glucose or reduced metabolic activity.
  • the metabolic disorder that can be treated by the compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or pharmaceutical compositions containing the said compounds is type 2 diabetes.
  • the disease or disorder mediated by CB 1R is a psychiatric disorder or a neurological disorder.
  • the psychiatric disorder or neurological disorder that can be treated by the compound of formula I of the invention or pharmaceutical compositions containing the said compounds is selected from: psychosis, anxiety, depression, attention deficits, dementia, distonia, Parkinson's disease, Alzheimer's disease, schizophrenia, epilepsy, Huntington's disease, Tourette's syndrome or cerebral ischaemia.
  • the present invention also encompasses within its scope the use of a compound of formula I or its pharmaceutically acceptable salt or a solvate in combination, with other therapeutically active agents; wherein the compound of formula I and the further therapeutic agent are administered either simultaneously or sequentially.
  • the present invention relates to pharmaceutical composition(s) containing a therapeutically effective amount of at least one compound of formula I or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate thereof and a conventional pharmaceutically acceptable carrier.
  • the present invention also relates to a process for the production of a pharmaceutical composition, which includes bringing at least one compound of formula I, into a suitable administration form using a pharmaceutically acceptable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries can be added.
  • composition(s) of the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
  • composition(s) according to the invention is/are prepared in a manner known and familiar to one skilled in the art.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compound(s) of formula I, and/or its (their) pharmaceutically acceptable salt(s).
  • Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
  • Suitable carriers for the production of solutions are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
  • the pharmaceutical compositions normally contain from about 1 % to 99 %, for example, from about 5 % to 70 %, or from about 10 % to 30 % by weight of the compound of formula I or its pharmaceutically acceptable salt.
  • the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical compositions normally ranges from about 0.01 mg to 1000 mg, preferably 0.5 mg to 500 mg.
  • the dose of the compounds of formula I of the present invention can cover a wide range depending on the type of disease or disorder to be treated.
  • the dose to be administered daily is to be selected to suit the desired effect.
  • a suitable dosage can be from about 0.01 mg/kg to 100 mg/kg of the compound of formula I or its pharmaceutically acceptable salt depending on the body weight of the recipient (subject) per day, for example, from about 0.1 mg/kg to 50 mg/kg/day of a compound of formula I or its pharmaceutically acceptable salt. If required, higher or lower daily doses can also be administered.
  • the selected dosage level will depend upon a variety of factors including the activity of a compound of the present invention employed, or the pharmaceutically acceptable salt thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compounds employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the pharmaceutical compositions can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain two or more compounds of formula I or their pharmaceutically acceptable salts. Furthermore, in addition to at least one compound of formula I or its pharmaceutically acceptable salt, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active agents.
  • the present invention also encompasses within its scope use of a compound of formula I or its pharmaceutically acceptable salt or a solvate in combination with other therapeutically active agents.
  • the compound of formula I or its pharmaceutically acceptable salt can be administered either simultaneously or sequentially in combination with the further therapeutically active agents.
  • the therapeutically active agents that can be used in combination with one or more compounds of formula I or its pharmaceutically acceptable salt can be selected from: CB 1R antagonists such as AM-6545 (National Inst. Alcohol Abuse Alcoholism, Northeastern University) LY-320135 (Lilly), Otenabant (Pfizer) and Rosonabant (Esteve); anti-inflammatory agents such as COX-2 inhibitors (e.g., VioxxTM, CelebrexTM and BextraTM); non-selective anti-inflammatory agents (ibuprofen, naproxen), acetaminophen, and steroids such as prednisolone, and budesonide; serotonin reuptake inhibitors (SSRls, also known as serotonin boosters), such as CipramilTM or CelexaTM (citalopram), EffexorTM (venlafaxine HCI), ElavilTM (amitriptyline), fluvoxamine maleate, Lexapro ® (escitalopram
  • LiHMDS Lithium bis(trimethylsilyl)amide; MeNH 2 HCl Methanamine hydrochloride;
  • the compound of example 8 was prepared analogous to the procedure described in example 7 by reaction of compound of example 6 with cyclopropanamine.
  • the compound of example 9 was prepared analogous to the procedure described in example 7 by reaction of the compound of example 6 with cyclohexanamine.
  • the compound of example 10 was prepared analogous to the procedure described in the example 7 by reaction of the compound of example 6 with adamantan-1 -amine.
  • the compound of example 12 was prepared analogous to the procedure described in the example 7 by reaction of the compound of example 6 with phenylmethanamine.
  • the compound of example 13 was prepared analogous to the procedure described in the example 7 by reaction of the compound of example 6 with morpholine.
  • the compound of example 14 was prepared analogous to the procedure described in the example 7 by reaction of the compound of example 6 with thiomorpholine 1,1 -dioxide.
  • the compound of example 15 was prepared analogous to the procedure described in the example 7 by reaction of the compound of example 6 with 4-aminothiomorpholine- 1, 1 -dioxide.
  • the compound of example 16 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with 1-methylpiperazine.
  • the compound of example 17 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with l-(piperazin-l-yl)ethanone.
  • the compound of example 19 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with oxetan-3-amine.
  • the compound of example 20 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with l-(oxetan-3-yl)piperidin-4-amine.
  • the compound of example 22 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with (S)-ethyl 2-amino-3-methylbutanoate.
  • the compound of example 23 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with (S)-2-amino-3-methylbutanoic acid.
  • the compound of example 24 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with 2-amino-2-methylpropanamide.
  • the compound of example 25 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with 1-aminocyclopropanecarboxamide.
  • the compound of example 26 was prepared analogous to the procedure described in the example 7 by reaction of compound of the example 6 with tert-butyl piperidin-4-ylcarbamate.
  • the compound of example 27 was prepared analogous to the procedure described in the examples 5-7, by using chloroacetamide instead of iodomethane in the example 5 and by reaction of compound corresponding to that of example 6 with adamantan- 1 -amine analogous to the reaction in the example 7.
  • the compound of example 28 was prepared analogous to the procedure described in the examples 5-7, by using chloroacetamide instead of iodomethane in the example 5 and by reaction of compound corresponding to that of example 6 with adamantan-2-amine analogous to the reaction in the example 7.
  • the compound of example 29 was prepared analogous to the procedure described in the examples 5-7, by using chloroacetamide instead of iodomethane in the example 5 and by reaction of compound corresponding to that of example 6 with thiomorpholine 1,1 -dioxide analogous to the reaction in the example 7.
  • the compound of example 30 was prepared analogous to the procedure described in the examples 5-7, by using chloroacetamide instead of iodomethane in the example 5 and by reaction of compound corresponding to that of example 6 with 4-aminothiomorpholine 1, 1- dioxide analogous to the reaction in the example 7.
  • the compound of example 31 was prepared analogous to the procedure described in the examples 2-7, by using (4-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with cyclohexanamine analogous to the reaction in the example 7.
  • the compound of example 32 was prepared analogous to the procedure described in the examples 2-7, by using (4-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with thiomorpholine 1,1 -dioxide analogous to the reaction in the example 7.
  • the compound of example 34 was prepared analogous to the procedure described in the examples 2-7, by using (2-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with cyclopropanamine analogous to the reaction in the example 7.
  • the compound of example 35 was prepared analogous to the procedure described in the examples 2-7, by using (2-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with adamantan-1 -amine analogous to the reaction in the example 7.
  • the compound of example 36 was prepared analogous to the procedure described in the examples 2-7, by using (2-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with adamantan-2- amine analogous to the reaction in the example 7.
  • the compound of example 37 was prepared analogous to the procedure described in the examples 2-7, by using (2-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with oxetan-3-amine analogous to the reaction in the example 7.
  • the compound of example 38 was prepared analogous to the procedure described in the examples 2-7, by using (2-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with phenylmethanamine analogous to the reaction in the example 7.
  • the compound of example 39 was prepared analogous to the procedure described in the examples 2-7, by using (2-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with thiomorpholine 1,1 -dioxide analogous to the reaction in the example 7.
  • the compound of example 40 was prepared analogous to the procedure described in the examples 2-7, by using (2-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with (S)-methyl 2-amino-3-methylbutanoate analogous to the reaction in the example 7.
  • the compound of example 41 was prepared analogous to the procedure described in the examples 1-7, by using acetophenone instead of l-(4-chlorophenyl)ethanone in the example 1 and by reaction of compound corresponding to that of example 6 with adamantan- 1 -amine analogous to the reaction in the example 7.
  • the compound of example 42 was prepared analogous to the procedure described in the examples 1-7, by using acetophenone instead of l-(4-chlorophenyl)ethanone in the example 1 and by reaction of compound corresponding to that of example 6 with thiomorpholine 1,1- dioxide analogous to the reaction in the example 7.
  • the compound of example 43 was prepared analogous to the procedure described in the examples 1-7, by using acetophenone instead of l-(4-chlorophenyl)ethanone in the example 1 and by reaction of compound corresponding to that of example 6 with 4-aminothiomorpholine 1,1 -dioxide analogous to the reaction in the example 7.
  • the compound of example 44 was prepared analogous to the procedure described in the examples 1-7, by using l-(2,4-dichlorophenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example 1, (4-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with adamantan-1 -amine analogous to the reaction in the example 7.
  • the compound of example 45 was prepared analogous to the procedure described in the examples 1-7, by using l-(2,4-dichlorophenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example 1, (4-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with thiomorpholine 1,1 -dioxide analogous to the reaction in the example 7.
  • the compound of example 46 was prepared analogous to the procedure described in the examples 1-7, by using l-(2,4-dichlorophenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example 1, (4-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2 and by reaction of compound corresponding to that of example 6 with 4-aminothiomorpholine 1, 1 -dioxide analogous to the reaction in the example 7.
  • the compound of example 47 was prepared analogous to the procedure described in the examples 1-7, by using l-(4-methoxyphenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example land reaction of compound corresponding to that of example 6 with adamantan-1- amine analogous to the reaction in the example 7.
  • the compound of example 48 was prepared analogous to the procedure described in the examples 1-7, by using l-(4-methoxyphenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example 1 and by reaction of compound corresponding to that of example 6 with thiomorpholine 1,1 -dioxide analogous to the reaction in the example 7.
  • the compound of example 49 was prepared analogous to the procedure described in the examples 1-7, by using l-(4-methoxyphenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example 1 and by reaction of compound corresponding to that of example 6 with 4- aminothiomorpholine 1,1 -dioxide analogous to the reaction in the example 7.
  • the compound of example 53 was prepared analogous to the procedure described in the example 52 by reaction of compound of the example 51 with phenylmethanamine.
  • the compound of example 54 was prepared analogous to the procedure described in the example 52 by reaction of compound of the example 51 with (4-methoxyphenyl)methanamine.
  • the compound of example 55 was prepared analogous to the procedure described in the example 52 by reaction of compound of the example 51 with morpholine.
  • the compound of example 56 was prepared analogous to the procedure described in the example 52 by reaction of compound of the example 51 with l-(piperazin-l-yl)ethanone.
  • Example 59 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 52, by using (4- chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2.
  • the compound of example 60 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 53, by using (4- chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2.
  • the compound of example 62 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 53, by using (2- chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2.
  • Example 62 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 54, by using (2- chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in the example 2.
  • the compound of example 64 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 52, by using acetophenone instead of l-(4-chlorophenyl)ethanone in the example 1.
  • the compound of example 65 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 54, by using acetophenone instead of l-(4-chlorophenyl)ethanone in the example 1.
  • the compound of example 66 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 56, by using acetophenone instead of l-(4-chlorophenyl)ethanone in the example 1.
  • the compound of example 67 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 52, by using l-(4- methoxyphenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example 1.
  • the compound of example 66 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 54, by using l-(4- methoxyphenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example 1.
  • the compound of example 66 was prepared analogous to the procedure described in the examples 1-6 followed by the procedures of examples 50, 51 and 56, by using l-(4- methoxyphenyl)ethanone instead of l-(4-chlorophenyl)ethanone in the example 1.
  • N-Bromosuccinimide N-Bromosuccinimide
  • AIBN azobisisobutyronitrile
  • reaction mixture was partitioned between water and ethyl acetate; the organic layer was separated, washed with water and brine, dried with sodium sulphate (Na 2 S0 4 ), concentrated and purified by column chromatography (silica gel, 0-20 % ethyl acetate in petroleum ether) to afford the title compound.
  • the resulting reaction mixture was stirred at 90 °C for 15 h and cooled to a room temperature. On completion of the reaction, the reaction mixture was quenched with 10 % aqueous K 2 CO 3 solution. The aqueous layer was separated and extracted in dichloromethane, dried with sodium sulphate (Na 2 S0 4 ), concentrated and purified by column chromatography (silica gel) to afford the title compound.
  • the compound of example 77 was prepared analogous to the procedure described in example 76 by reaction of compound of example 75 with 4-aminothiomorpholine 1,1 -dioxide.
  • the compound of example 78 was prepared analogous to the procedure described in examples 70-75 and 77, by using (2-chlorophenyl)hydrazine hydrochloride instead of (2,4- dichlorophenyl)hydrazine hydrochloride in example 70.
  • the biological activity of the compounds as CB IR antagonist can be confirmed by a number of biological assays known in the art.
  • the exemplified biological assay, given below, has been carried out with certain representative compounds of the formula I (referred to as the test compounds) synthesized in the above examples.
  • CBIR Radioligand Binding Assay at Cannabinoid-1 Receptors
  • Radioligand CP55,940 [ 3 H](-)-cis-3-[2-hydroxy-4-(l,l-dimethylheptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol (final concentration 0.1 nM);
  • Human cannabinoid-1 receptors (CB IR) source membrane preparations of Chinese hamster ovary (CHO) cells stably expressing the CB IR subtype (50 ⁇ g of protein/vial); Assay buffer (composition: 50 mM TRIS, 3 mM MgCl 2 , 0.1% BSA, pH 7.4); washing buffer (composition: 50 mM TRIS, 0.1% BSA, pH 7.4); Micro scint 0 (Perkin Elmer); Topcount NXT (Packard).
  • the binding reaction was terminated by rapid filtration through GF/B glass fiber filters pre-soaked for 0.5 h with 0.3 % aqueous polyethyleneimine solution, using a Brandel 48- channel cell harvester (Brandel, Gaithersburg, MD). The filters were washed four times with ice- cold washing buffer (50 mM TRIS, 0.1 % BSA, pH 7.4) to remove free [ 3 H]CP55,940 and dried for 1.5 h at 50 °C. 50 ⁇ ⁇ Microscint 0 (Perkin Elmer) was added per well, and the amount of bound radioactivity was determined with a Topcount NXT (Packard). IC 50 values (the concentration of the test compound required to inhibit 50 % of the binding of [ H]CP55,940 to the receptor) were calculated. The IC 50 values for test compounds are given in table I.
  • IC 50 values determined for the test compounds by the radioligand binding Assay indicative of CB IR antagonist activity of th compounds of the invention.

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Abstract

La présente invention concerne des composés de formule I, ou leurs formes isotopiques, des stéréoisomères, tautomères, sels, solvates, polymorphes, promédicaments, S-oxydes ou N-oxydes pharmaceutiquement acceptables de ces derniers, et leurs procédés de préparation. L'invention concerne en outre des compositions pharmaceutiques contenant les composés ; et l'utilisation des composés de formule I et les compositions pharmaceutiques comprenant les composés dans le traitement de maladies ou de troubles à médiation par le récepteur aux cannabinoïdes 1 (CB1R).
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WO2021067834A1 (fr) * 2019-10-03 2021-04-08 Corbus Pharmaceuticals, Inc. Cannabinoïdes et utilisations associées

Citations (1)

* Cited by examiner, † Cited by third party
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US20120058893A1 (en) * 2010-09-01 2012-03-08 Bayer Cropscience Ag Herbicidally active ketosultams and diketopyridines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120058893A1 (en) * 2010-09-01 2012-03-08 Bayer Cropscience Ag Herbicidally active ketosultams and diketopyridines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MALINKA, W. ET AL.: "Antitumour In Vitro Evaluation of Certain Derivatives of Pyrido- 1,2-thiazines", ACTA POLONIAE PHARMACEUTICA, vol. 61, 2004, pages 100 - 102 *
MANFRONI, G. ET AL.: "New Pyrazolobenzothiazine Derivatives as Hepatitis C Virus NS5B Polymerase Palm Site I Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, no. 8, 2014, pages 3247 - 3262, XP055229470 *
SABATINI, S. ET AL.: "Pyrazolo[4,3-c][1,2]benzothiazines 5,5-Dioxide: A Promising New Class of Staphylococcus aureus NorA Efflux Pump Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 7, 2012, pages 3568 - 3572, XP055229472 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021067834A1 (fr) * 2019-10-03 2021-04-08 Corbus Pharmaceuticals, Inc. Cannabinoïdes et utilisations associées

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