EP1753413A2 - Neue medizinische anwendungen von verbindungen mit cb sb 1 /sb antagonistischer wirkung und kombinationsbehandlung mit diesen verbindungen - Google Patents

Neue medizinische anwendungen von verbindungen mit cb sb 1 /sb antagonistischer wirkung und kombinationsbehandlung mit diesen verbindungen

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Publication number
EP1753413A2
EP1753413A2 EP04817279A EP04817279A EP1753413A2 EP 1753413 A2 EP1753413 A2 EP 1753413A2 EP 04817279 A EP04817279 A EP 04817279A EP 04817279 A EP04817279 A EP 04817279A EP 1753413 A2 EP1753413 A2 EP 1753413A2
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
substituted
compound
cbi
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04817279A
Other languages
English (en)
French (fr)
Inventor
Jochen Antel
Peter-Colin Gregory
Harald Waldeck
Günter Krause
Josephus Hubertus Maria Lange
Chris Kruse
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Products GmbH
Original Assignee
Solvay Pharmaceuticals GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Solvay Pharmaceuticals GmbH filed Critical Solvay Pharmaceuticals GmbH
Priority to EP04817279A priority Critical patent/EP1753413A2/de
Publication of EP1753413A2 publication Critical patent/EP1753413A2/de
Withdrawn legal-status Critical Current

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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Definitions

  • the present invention relates to novel therapeutic and/or prophylactic uses of compounds showing CB antagonistic activity and to pharmaceutical compositions containing one or more of these compounds as an active component for the novel uses.
  • the compounds addressed in this invention show Cannabis-1 (CBi) receptor antagonistic activity and may provide outstanding utility for the novel medical uses provided by the present invention.
  • said compounds with CBi- antagonistic activity may be used in combination with a further active principle, and to pharmaceutical compositions containing at least one of these CB ⁇ antagonistic compounds in combination with said further active principle for the treatment and/or prophylaxis of obesity.
  • the combination provided by the present invention of said compounds having Cannabis-1 (CBi) receptor antagonistic activity with said further active principle are of particular utility for treating of obesity.
  • Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J.J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CBi and CB 2 ) stimulated the search for novel cannabinoid receptor antagonists (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61.
  • Inparticular said compounds with cannabis CBi-receptor activity have been suggested for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers,
  • the international patent application WO 03/026647 describes a group of novel compounds which are 4,5-dihydro-lH-pyrazole derivatives and have the formula (I) defined below.
  • These 4,5-dihydro-lH-pyrazole derivatives are potent cannabinoid (CBi) receptor antagonists with utility for the treatment of diseases connected with disorders of the cannabinoid system.
  • the compounds have the general formula (I) wherein the symbols have the meanings given below in the specification, and show in particular potent CBi antagonistic activity.
  • the international patent application WO 03/027076 describes a group of novel compounds which are 1H-imidazole derivatives and have the formula (II) defined below.
  • These 1H-imidazole derivatives are potent cannabinoid ( CB f ) receptor agonists, partial agonists or antagonists, useful for the treatment of psychiatric and neurological disorders, as well as and other diseases involving cannabinoid neurotransmission.
  • CB f cannabinoid receptor agonists
  • partial agonists or antagonists useful for the treatment of psychiatric and neurological disorders, as well as and other diseases involving cannabinoid neurotransmission.
  • the compounds have the general formula (II) wherein the symbols have the meanings given below in the specification.
  • the international patent application WO 03/026648 describes a group of novel compounds which are also 4,5-dihydro-lH-pyrazole derivatives and have one of the formulas (III) defined below.
  • These 4,5-dihydro-lH-pyrazole derivatives again are potent cannabinoid (CB1) receptor antagonists with utility for the treatment of diseases connected with disorders of the cannabinoid system.
  • CB1 cannabinoid
  • the compounds have the general formula (Ilia) or (1Mb) wherein the symbols have the meanings given in the specification below.
  • the international patent application WO 03/078413 describes a group of novel compounds which are thiazole derivatives and have of the formula (IV) defined below. These thiazole derivatives are potent antagonists, agonists or partial agonists of the cannabinoid CBi-receptor, with utility for the treatment of diseases connected with disorders of the cannabinoid system.
  • the compounds have the general formula (IV) wherein the symbols have the meanings given in the specification below.
  • a further objective is to provide particular beneficial combination treatments and medicaments therefore for the treatment and/or prophylaxis of obesity in patients of any age, e.g. in adolescent as well as in juvenile patients, wherein the compounds with CBi antagonistic activity used according to the present invention are combined with a further active principle for the treatment of obesity.
  • the invention pertains to a combination of a compound with CBi- receptor activity having one of the formulas (I), (II), (III), (IV) or (V) as subsequently defined, or a prodrug, tautomer or salt thereof, preferably of a CBi receptor antagonistic compound or a prodrug, tautomer or salt thereof, with at least one lipase inhibiting compound.
  • the compound with CBi-receptor activity having one of the formulas (I), (II), (III), (IV) or (V) as subsequenzly defined, or a prodrug, tautomer or salt thereof, preferably the CBi receptor antagonistic compound or a prodrug, tautomer or salt thereof, is in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.
  • the CB antagonists of formulas (I), (II), (III), (IV) and/or (V), prodrugs thereof, tautomers thereof and salts thereof show a unique pharmacological profile and therefore are particularly suited for the use in the manufacture of a medicaments for the treatment and/or prophylaxis of obesity patients, in particular of obesity in juvenile patients and/or drug induced obesity in juvenile, as well as adolescent, patients.
  • CBi-antagonistic compounds of formulas (I), (II), (III), (IV) and/or (V), prodrugs thereof, tautomers thereof and salts thereof are highly valuable in providing medicaments for pediatric use on the one hand, and for the general use in drug induced obesity.
  • the compounds used according to the invention are suitable also for use in pediatric treatment and/or prophylaxis of other disorders than juvenile obesity and drug induced obesity in juvenile patients.
  • the other disorders include those known from the literature for the concerned compounds with activity on the cannabis CBi-receptor, and e.g.
  • the pediatric treatment and/or prophylaxis may also pertain to psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, obesity, dis orders, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the pediatric treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the pediatric treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhoea and
  • the CBi antagonistic compounds used in the present the invention can be obtained according to known methods. Suitable ways of synthesis for the compounds used according to the present invention are described in the state of the art, e.g. in the documents cited in the present application and incorporated by reference.
  • CBi antagonistic compounds of the formulas (I), (II), (III), (IV) and/or (V), as well as prodrugs, tautomers and salts thereof, due to their unique pharmacological profile are particularly suited in combination with at least one lipase inhibiting compound
  • lipase inhibitor for the use in the manufacture of a medicaments for the treatment and/or prophylaxis of obesity, including in particular the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.
  • CB antagonistic compound as defined herein with at least one lipase inhibiting compound are highly valuable in providing medicaments for the treatment and/or prophylaxis of obesity in general, e.g. in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and also in drug induced obesity in adolescent and juvenile patients.
  • the present invention is based on the surprising finding that the CBi antagonistic compounds of the formulas (I) being 4,5-dihydro-lH-pyrazole derivatives, (II) being 1H-lmidazole derivatives , (III) being also 4,5-dihydro-lH- pyrazole derivatives, (IV) being thiazole derivatives or (V) being 1 H-1 ,2,4-triazole- 3-carboxamide derivatives, which are antagonists of the cannabis CBi-receptor, prodrugs thereof, tautomers thereof and salts thereof, due to their unique pharmacological profile are particularly suited in combination with at least one lipase inhibiting compound for the use in the manufacture of a medicament for the treatment and/or prophylaxis of obesity in general, e.g.
  • each of the compounds with the formulas (I), (II), III), IV or (V), together with lipase inhibiting compounds are highly valuable in providing medicaments for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug induced obesity.
  • the compounds of the formulas (I), (II), III), (IV) or (V) used in the present the invention can be obtained according to known methods.
  • a suitable synthesis for the compounds of the formulas (I), (II), III), (IV) used according to the present invention is described in the international patent applications WO 03/026647, WO 03/027076, WO 03/078413 or WO 03/078413, which are incorporated by reference into this specification.
  • Compounds of formula (V) can be prepared according to a recently filed international patent application, which is going to be published in March/April 2004 and is based on the European priority application EP 02078966.5 with priority date 19.09.2002, which is also incorporated by reference into the present specification . Preparation of compounds of formula (V) is also described at the end of this specification.
  • the present invention is based on the surprising finding that the 4,5-dihydro-l H-pyrazole derivatives of the formula (I) which are potent and selective antagonists of the cannabis CBi-receptor, prodrugs thereof, tautomers thereof and salts thereof:
  • R and Ri independently represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group d -3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C ⁇ -2 )-amino, mono- or dialkyl (C ⁇ -2 )-amido, (C ⁇ -3 )-alkyl sulfonyl, dimethylsulfamido, C 1-3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or Ri represent naphtyl,
  • R 2 represents hydrogen, hydroxy, C ⁇ -3 -alkoxy, acetyloxy or propionyloxy
  • R 3 represents a hydrogen atom or a branched or unbranched C ⁇ -8 alkyl group or a C 3 - 7 cycloalkyl group which alkyl group or cycloalkyl group may be substituted with a hydroxy group,
  • - t represents a C 2- ⁇ 0 branched or unbranched heteroalkyl group, C ⁇ s non- aromatic heterocycloalkyl group or non -aromatic heterocycloalkyl-alkyl group which groups contain one or more heteroatoms from the group (O, N, S) or a -SO 2 - group, which C 2- ⁇ 0 branched or unbranched heteroalkyl group, C 3 - 8 non-aromatic heterocycloalkyl group or C4-10 non-aromatic heterocycloalkyl-alkyl group may be substituted with a keto group, trifluoromethyl group, C ⁇ -3 alkyl group, hydroxy, amino, monoalkylamino, or dialkylamino group or a fluoro atom, or R 4 represents an amino, hydroxy, phenoxy or benzyloxy group, or R* represents a C ⁇ -8 alkoxy, C 3 - 8 alkenyl, Cs- ⁇ cycloalkenyl
  • R 6 and R 7 are the same or different and represent C 2 ⁇ alkyl , C 2-4 trifluoroalkyl or Re represents a methyl group with the proviso that R represents a C 2 ⁇ alkyl group, or R 6 and R - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated heterocyclic moiety having 4 to 8 ring atoms which heterocyclic moiety may contain an oxygen or sulphur atom or a keto group or -S0 2 - group or an additional nitrogen atom, which saturated or unsaturated heterocyclic moiety may be substituted with a alkyl group, or
  • R 3 and R 4 together with the nitrogen atom to which they are bonded form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic moiety may contain one or more atoms from the group (O, N, S) or a keto group or -SO 2 - group, which moiety may be substituted with a C 1- alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1 H-azepinyl group, - R 5 represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1 , 2, 3 or 4 substituents Y, wherein
  • a lipase inhibiting compound for the use in the manufacture of a medicament for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also for the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.
  • combinations of the compounds of formula (I) together with lipase inhibiting compounds are highly valuable in providing medicaments for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug induced obesity.
  • At least one centre of chirality is present (at the C position of the 4,5-dihydro-lH- pyrazole moiety) in the compounds of the formula (I).
  • the invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (I).
  • Particular compounds of interest of formula (I) have the absolute stereoconfiguration at the C 4 position of the 4,5-dihydro-1 H- pyrazole moiety as represented by formula (1 a ).
  • the invention also relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (I).
  • the present invention is based on the surprising finding that the 1H-imidazole derivatives with CBi antagonistic activity of the formula (II), prodrugs thereof and salts thereof, which are potent antagonists on cannabinoid- CBi receptors:
  • R represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1 , 2, 3 or 4 substituents Y, which can be the same or different, from the group C ⁇ -3 - alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C ⁇ -2 )-amino, mono- or dialkyl (C ⁇ -2 )-amido, (C ⁇ -3 )-alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl, or R represents naphtyl, with the proviso that when R is 4-pyridinyl, R 4 represents a halogen atom or a
  • Ri represents phenyl or pyridinyl, which groups may be substituted with 1 -4 substituents Y, which can be the same or different, wherein Y has the above mentioned meaning, or R represents pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1-2 substituents Y, which can be the same or different or Ri represents a five-membered aromatic heterocyclic ring having one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which five-membered aromatic heterocyclic ring may be substituted with 1 -2 substituents Y, which can be the same or different or Ri represents naphtyl,
  • R 2 represents H, branched or unbranched C ⁇ -8 alkyl, C3-8 cycloalkyl, C3-8 alkenyl, Cs. 8 cycloalkenyl which groups may contain a sulfur, oxygen or nitrogen atom,
  • R 3 represents branched or unbranched C 2 - ⁇ alkyl, C ⁇ -8 alkoxy, cycloalkyloxy, cycloalkyl, Cs-in bicycloalkyl, C ⁇ -io tricycloalkyl, C3- 8 alkenyl, Cs- ⁇ cycloalkenyl, which groups may optionally contain one or more heteroatoms from the group (O, N, S) and which groups may be substituted with a hydroxy group or 1-2 C ⁇ -3 alkyl groups or 1-3 fluoro atoms, or R 3 represents a benzyl or phenethyl group which aromatic rings may be substituted with 1-5 substituents Z, which can be the same or different, from the group C ⁇ -3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C ⁇ -2 )- amino, mono- or dialky
  • R 5 and R 6 are the same or different and represent branched or unbranched C 1- alkyl, or R 5 and R 6 - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms which heterocyclic group contains one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which heterocyclic group may be substituted with a C ⁇ -3 alkyl group or a hydroxy group, or R 2 and R 3 - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated heterocyclic group having 4 to 10 ring atoms which heterocyclic group contains one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which heterocyclic group may be substituted with a C ⁇ -3 alkyl group or a hydroxy group, - R 4 represents a hydrogen or halogen atom
  • a lipase inhibiting compound for the use in the manufacture of a medicament for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also for the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.
  • combinations of the compounds of formula (II) together with lipase inhibiting compounds are highly valuable in providing medicaments for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug induced obesity.
  • the present invention is based on the surprising finding that potent and selective antagonism of cannabinoid-CB receptors is present in the 4,5-dihydro-l H-pyrazole derivatives of the formula (Ilia) or (lllb), prodrugs thereof, tautomers thereof and salts thereof: (Ilia) (lllb)
  • R and Ri independently represent phenyl, thienyl or pyridyl which groups may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, from the group C ⁇ -3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C ⁇ -2 )-amino, mono- or dialkyl (C ⁇ -2 )-amido, (C ⁇ -3 )-alkyl sulfonyl, dimethylsulfamido, C ⁇ -3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or Ri represent naphtyl,
  • R 2 represents hydrogen, hydroxy, C 1-3 -alkoxy, acetyloxy or propionyloxy,
  • - R 3 represents a hydrogen atom or a branched or unbranched d -8 alkyl group or a C 3 . 7 cycloalkyl group which alkyl group or cycloalkyl group may be substituted with a hydroxy group, - R t represents a hydrogen atom or a branched or unbranched Ci -8 alkyl, C3-8 cycloalkyl, C 2- ⁇ 0 heteroalkyl, C3.
  • R 8 alkenyl, Cs- ⁇ cycloalkenyl or C 3 - 9 cycloalkenylalkyl groups may be substituted with a hydroxy group, a trifluoromethyl group, an amino group, a monoalkylamino group or dialkylamino group or a fluoro atom, or R 4 represents a phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl group wherein the aromatic rings may be substituted with 1, 2 or 3 of the substituents Y, wherein Y has the meaning as indicated above, or t represents a group NR 6 R 9 with the proviso that R 3 represents a hydrogen atom or a methyl group and wherein R 8 and R 9 are the same or different and represent C ⁇ _ 4 alkyl or C 2-4 trifluoroalkyl or R 8 and R 9 - together with the nitrogen atom to which they are bonded - form a saturated or un
  • R 5 represents a naphtyl group or a phenyl group which phenyl group may be substituted with 1, 2 or 3 substituents Y wherein Y has the meaning as described hereinabove, with the proviso that R 6 represents a hydrogen atom, or a branched or unbranched alkyl group (C 1 - 5 ) which alkyl group may contain one or more heteroatoms from the group (O, N, S) or the -SO 2 - group and which alkyl group may be substituted with a
  • pyrrolidinyl group or piperidinyl group which monocyclic, bicyclic or tricyclic alkyl or alkenyl group may contain an annelated phenyl group which annelated phenyl group may be substituted with 1 or 2 substituents Y, wherein Y has the meaning as described herein above, - R 7 represents branched or unbranched C ⁇ -3 alkyl,
  • a lipase inhibiting compound for the use in the manufacture of a medicament for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also for the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.
  • combinations of the compounds of formula (Ilia) and/ or (lllb) together with lipase inhibiting compounds are highly valuable in providing medicaments for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug induced obesity.
  • At least one centre of chirality is present (at the C 4 position of the 4,5-dihydro-lH- pyrazole moiety) in the compounds of the formula (Ilia) and (lllb).
  • the invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (Ilia) or (lllb).
  • Particular compounds of interest of formula (Ilia) or (lllb) have the absolute stereoconfiguration at the C 4 position of the 4,5-dihydro-lH-pyrazole moiety as represented by the formulas (Ilia*) and (1Mb*):
  • the invention also relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (Ilia) or (lllb).
  • the present invention is based on the surprising finding that the 4,5-diarylthiazole derivatives with CBi antagonistic activity of the formula (IV), pro-drugs thereof and salts thereof
  • - R represents a hydrogen atom or a substituent X from the group branched or unbranched C ⁇ -3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C ⁇ -2 )- amino, mono- or dialkyl (C ⁇ -2 )-amido, branched or unbranched (C ⁇ -3 )- alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched or unbranched alkyl(C ⁇ -3 )sulfonyl, carboxyl, cyano, carbamoyl, branched or unbranched dialkyl(C ⁇ -3 ) aminosulfonyl, branched or unbranched monoalkyl(C ⁇ -3 )- aminosulfonyl and acetyl,
  • - Ri is a hydrogen atom or represents 1-4 substituents X, wherein X has the abovementioned meaning
  • R 2 represents a phenyl, thienyl, pyridyl or pyrimidinyl group, which groups may be substituted with 1-4 substituents X, wherein X has the abovementioned meaning or R 2 represents naphtyl,
  • R 3 represents a hydrogen atom or a branched or unbranched C MO alkyl or cycloalkyl-alkyl group or a phenyl, benzyl or phenethyl group which aromatic rings may be substituted with 1-5 substituents Z, which can be the same or different, from the group branched or unbranched C ⁇ -3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C ⁇ -2 )-amino, mono- or dialkyl (C ⁇ -2 )-amido, branched or unbranched (C ⁇ -3 )-alkylsulfonyl, dimethylsulfamido, branched or unbranched C ⁇ -3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, s
  • R 4 represents branched or unbranched C ⁇ - ⁇ o alkyl or cycloalkyl-alkyl group, branched or unbranched C MO alkoxy, C 3 . 8 cycloalkyl, bicycloalkyl, C ⁇ -io tricycloalkyl, branched or unbranched C 3 - ⁇ o alkenyl, Cs- ⁇ cycloalkenyl, which groups may contain one or more heteroatoms from the group (O, N, S) and which groups may be substituted with a hydroxy group, 1-3 methyl groups, an ethyl group or 1-3 fluoro atoms, or R 4 represents a phenyl, benzyl or phenethyl group which aromatic rings may be substituted with 1-5 substituents Z, wherein Z has the abovementioned meaning, or R4 represents a pyridyl or thienyl group, or R 4 represents a group NR 5 Rf3 wherein R 5 and R 6 together
  • R 3 and R - together with the nitrogen atom to which they are attached - form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 ring atoms, which heterocyclic group contains one or more heteroatoms from the group (O, N, S) and which heterocyclic group may be substituted with a branched or unbranched C ⁇ -3 alkyl, hydroxy or trifluoromethyl group or a fluoro atom,
  • a lipase inhibiting compound for the use in the manufacture of a medicament for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also for the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.
  • combinations of the compounds of formula (IV) together with lipase inhibiting compounds are highly valuable in providing medicaments for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug induced obesity.
  • the present invention is based on the surprising finding that 1 ,5-diaryl-1H-1,2,4-triazole-3-carboxamide derivatives with CBi antagonistic activity of the formula (V), as well as prodrugs, salts, and stereo-isomers thereof, are potent antagonists, agonists, inverse agonists or partial agonists of the cannabinoid CBi receptor:
  • R and Ri independently represent a phenyl, naphtyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl group, which groups may be substituted with 1-4 substituents X, which can be the same or different, from the group branched or unbranched (C ⁇ -3 )-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C ⁇ -2 )-amino, mono- or dialkyl (C ⁇ -2 )-amido, (C ⁇ -3 )-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, (C ⁇ -3 )-alkylsul- fonyl, carboxyl, cyano, carbamoyl, (C ⁇ ⁇
  • R 2 represents a hydrogen atom or a branched or unbranched C ⁇ -8 alkyl or C 1-8 cycloalkyl -alkyl group or a phenyl, benzyl or phenethyl group which aromatic rings may be substituted with 1 -4 substituents X, wherein X has the meaning as indicated above, or R 2 represents a pyridyl or thienyl group,
  • R 3 represents branched or unbranched C ⁇ -8 alkyl, C ⁇ -8 alkoxy, C3- 8 cycloalkyl, Cs- ⁇ 0 bicycloalkyl, C ⁇ -1 0 tricycloalkyl, C3.
  • R 3 represents a phenyl, benzyl or phenethyl group which aromatic rings may be substituted with 1-4 substituents X, wherein X has the meaning as indicated above, or R 3 represents a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or thienyl group which heteroaromatic rings may be substituted with 1-2 substituents X, wherein X has the meaning as indicated above, or R 3 represents a group NR R 5 wherein R_!
  • a lipase inhibiting compound for the use in the manufacture of a medicament for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also for the treatment and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity in juvenile as well as adolescent patients.
  • combinations of the compounds of formula (V) together with lipase inhibiting compounds are highly valuable in providing medicaments for the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug induced obesity.
  • the compounds of formulas (I), (II), (III), (IV) and/or (V) used according to the invention are suitable also for general use in pediatric treatment and/or prophylaxis of other disorders than juvenile obesity and drug induced obesity in juvenile patients.
  • the other disorders include those known from the literature for the concerned compounds with activity on the cannabis CBi-receptor, and e.g.
  • the pediatric treatment and/or prophylaxis may also pertain to psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodege ⁇ erative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the pediatric treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the pediatric treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrho
  • the affinity of the compounds of the formulas (I), (II), III), (IV) or (V) for cannabinoid CBi receptors can be determined as described in the WO 03/026647, WO 03/027076, WO 03/026648 or WO 03/078413, e.g. it can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabis CBi receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glass fibre filters. Radioactivity on the filter was measured by liquid scintillation counting.
  • the cannabinoid CBi antagonistic activity of compounds of the formulas (I), (II), III), (IV) or (V) is also described in the WO 03/026647, WO 03/027076, WO 03/026648 or WO 03/078413, and was determined by functional studies using CHO cells in which human cannabinoid CB 1 receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CBi receptors by CBi receptor agonists (e.g.
  • CP -55,940 or (R)-WIN-55,212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration-dependent manner.
  • This CBi receptor -mediated response can be antagonized by CBi receptor antagonists such as the compounds used in the present invention.
  • the cannabinoid CBi receptor antagonistic, agonistic or partial agonistic activity of compounds e.g. formula (V) of the invention can be also determined by functional studies using the human CBi receptor cloned in Chinese hamster ovary (CHO) cells according to the following protocol.
  • CHO cells were grown in a DMEM culture medium, supplemented with 10% heat-inactivated fetal calf serum. Medium was aspirated and replaced by DM EM, without fetal calf serum, but containing [ 3 H]-Arachidonic acid and incubated overnight in a cell culture stove (5% CO 2 /95% air; 37 °C; water-saturated atmosphere).
  • Cannabinoid receptor agonistic or partial agonistic activity of compounds of the invention can be determined according to published methods, such as assessment of in vivo cannabimimetic effects (Wiley, J. L. Jefferson et al., J. Pharmacol. Exp. Ther. 2001, 296, 1013).
  • Cannabinoid receptor antagonists may behave as inverse agonists (Landsman, R. S. et al., Eur. J. Pharmacol. 1997, 334, R1-R2).
  • the outstanding unique pharmacological profile of compounds with CBi-receptor activity and the formulas (I), (II), III), (IV) or (V) which are antagonists of the cannabis CBi-receptor, as well as prodrugs, tautomers and salts thereof, includes particularly high safety and tolerability also in combination with other drugs, in particular in combination with lipase inhibiting compounds according to the present invention.
  • the CBi antagonistic compounds of the formulas (I), (II), III), (IV) or (V) in combination with lipase inhibiting compounds are particularly suitable also in patient groups with enhanced need of safety and tolerability, in particular such as juvenile patients and/or patients subject to long term treatment, e.g. in drug induced obesity.
  • CBi antagonistic compounds of the formulas (I), (II), III), (IV) or (V) in combination with lipase inhibiting compounds is advantageous in the treatment and/or prophylaxis of obesity in those patient populations where a single treatment is not sufficiently effective and a combination treatment and/or prophylaxis involving different medical or metabolic mechanisms is desired or required for achieving and stabilizing a defined degree of weight loss.
  • combination of CBi antagonistic compounds of the formulas (I), (II), III), (IV) or (V) in combination with lipase inhibiting compounds according to the present invention is expected to be very is advantageous in the treatment and/or prophylaxis of obesity in general, e.g. of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug induced obesity.
  • the CBi receptor modulating activity of the compounds of the formulas (I), (II), III), (IV) or (V) of the invention makes them particularly useful in the treatment of obesity, juvenile obesity and drug induced obesity, when used in combination with lipase inhibitors.
  • lipase inhibiting compounds which can be used in such combination preparations are (but not restricted to) the synthetic lipase inhibitor oriistat, panclicins, lipase inhibitors isolated from micro organisms such as lipstatin (from Streptomyces toxytricini), ebelactone B (from Streptomyces aburaviensis), synthetic derivatives of these compounds, 2-oxy-4H- 3,1-benzoxazin-4-one derivatives like ATL-962 and structurally related compounds, 2-amino-4H-3,1-benzoxazin-4-one derivatives, as well as extracts of plants known to possess lipase inhibitory activity, for instance extracts of Alpinia officinarum Hance or compounds isolated from such extracts like 3- methylethergalangin (from A. officinarum).
  • the lipase inhibiting compound may also be a lipase inhibiting polymer.
  • Lipase inhibiting compounds used in the combinations according to the present invention may be any lipase inhibiting compound suitable for pharmaceutical use, e.g. in particular inhibitors of pancreatic lipases.
  • Lipases are key enzymes in the digestive system which break down tri- and diglycerides, which are too large to be absorbed by the small intestine into fatty acids which can be absorbed. Since lipases are responsible for the hydrolysis of fat, a consequence of their inhibition is a reduction in fat hydrolysis and absorption. Therefore, inhibition of lipases results in a reduction in the absorption of fat.
  • the lipase inhibiting compound is preferably the synthetic lipase inhibitor oriistat and structurally related compounds, 2-oxy-4H-3,1-benzoxazin-4-one derivatives like ATL-962 and structurally related compounds, 2-amino-4H-3,1-benzoxazin-4-one derivatives, lipase inhibitors isolated from micro organisms such as lipstatin, ebelactone B, or synthetic derivatives of these compounds, however may also be a lipase inhibiting polymer. Most preferred are oriistat, panclicins, ATL-962 and lipstatin.
  • Oriistat tetrahydrolipstatin
  • lipstatin are described in the US-patent US 4,598,089 and its European equivalent EP 0 129 748 B1 in more detail.
  • the compounds are 2-hexyl-3-hydroxy-hexadecanoic acid lactone derivatives with the chemical names (2S,3S,5S,7Z,10Z)-5-((S)-2-formamido-4-methylvaleryloxy)-2- hexyl-3-hydroxy-7,10-hexadecadienoic acid lactone (lipstatin) and (2S,3S,5S)-5- ((S)-2-4-methylvaleryloxy)-2-heyl-3-hydroxy-hexadecanoic acid lactone (tetrahydrolipstatin).
  • the compounds are known to be inhibitors of pancreas lipase which can be used for the prevention of treatment of obesity and hyperiipaemia, for which purpose they can be formulated as medicaments or incorporated into industrially prepared foodstuffs. Inhibition of pancreas lipase prevents the hydrolysis of dietary fats to give absorbable free fatty acids and monoglycerides, so that the fats are excreted unchanged.
  • IC50's for lipstatin and tetrahydrolipstatin for inhibition of hydrolysis of triolein by porcine pancrease lipase are 0.07 and 0.18 mcg/ml, respectively.
  • panclicins are suitable lipase inhibitors which are structurally related to oriistat and/or lipstatin and which are known as panclicins.
  • panclicines are derived from oriistat and contain a 4-ring lactone (Mutoh M; Nakada N; Matsukima S; Ohshima S; Yoshinari K; Watanabe J Location: Kanagawa, Japan Issue Date: 19-JAN-1995 Journal: J.Antibiot., 47, No. 12, 1369-75, 1994).
  • panclicins A, B, C, D and E structural analogs of tetrahydrolipstatin (THL), dose-dependently inhibited hydrolysis of triolein of fatty acids by porcine pancreatic lipase, with IC50 values of 2.9, 2.6, 0.62, 0.66 and 0.89 microM, respectively.
  • the inhibitory activity of panclicins A and B (alanine moiety in place of leucine in THL) was 2-3-fold weaker than that of THL; in contrast, the inhibitory activity of panclicins C, D and E (glycine moiety in place of leucine in THL) was 2-fold stronger than that of THL.
  • Panclicins A, B, C, D and E also potently inhibited plasma lipases with IC50 values of 1.0, 1.2, 0.29, 0.25 and 0,15 microM, respectively.
  • Panclicins A and B inhibited plasma lipases with the same potency as THL, while panclicins C, D and E had a 3-6-fold greater inhibitory activity than THL.
  • Panclicins A, B, C, D and E inhibited bacterial and fungal lipases with profiles similar to those for porcine pancreatic lipase.
  • Panclicins inhibited pancreatic lipase irreversibly, but less irreversibly than THL.
  • Panclicins A, B, C, D and E irreversibly inhibit pancreatic lipase.
  • Ebelactone B is described in the US -patent US 4,358,602 and its German equivalent DE 3 109 335 C1 .
  • Ebelactone A and ebelactone B belong to a group of compounds that exhibit activity to enhance the cell mediated immune response in living animals and they also inhibit inflammations in living animals. Thus they may be used in the immunological treatment of tumours and for enhancing anti- tumour agents such as bleomycins.
  • the compounds have anti-esterase activity and anti-formylmethionine aminopeptidase activity.
  • mice of these compounds at a dosage of 0.781-50 mg/kg (i.p.) or 0.5 mg/kg (per os) enhances the development of DTH response and the compounds show a potentiating effect on cell-mediated immunity.
  • Ebelactone B reduces carragheenin-induced swelling in mice.
  • the lipase inhibitors administered in combination with the CBi antagonistic compounds to a patient for treating obesity may be also a polymer that has been substituted with or comprises one or more groups which can inhibit a lipase.
  • Such lipase inhibiting polymers are described in the US patents US 6572850, US 6558657, US 6352692, US 6267952 and in the international patent application WO 99/34786.
  • the lipase inhibiting group can be a "suicide substrate" which inhibits the activity of the lipase by forming a covalent bond with the enzyme either at the active site or elsewhere.
  • the lipase inhibiting group is an isosteric inhibitor of the enzyme.
  • the lipase inhibiting group inactivates a lipase such as gastric, pancreatic and lingual lipases. Inactivation can result by forming a covalent bond such that the enzyme is inactive.
  • the covalent bond can be formed with an amino acid residue at or near the active site of the enzyme, or at a residue which is distant from the active site provided that the formation of the covalent bond results in inhibition of the enzyme activity.
  • Lipases contain a catalytic triad which is responsible for the hydrolysis of lipids into fatty acids. The catalytic triad consists of a serine, aspartate and histidine amino acid residues.
  • serine protease inhibitors that can be covalently linked to a polymer are preferred lipase inhibiting groups.
  • a covalent bond can be formed between the lipase inhibiting group and a hydroxyl at or the catalytic site of the enzyme.
  • a covalent bond can be formed with serine.
  • Inactivation can also result from a lipase inhibiting group forming a covalent bond with an amino acid, for example cysteine, which is at some distance from the active site.
  • non-covalent interaction between the lipase inhibiting group and the enzyme can also result in inactivation of the enzyme.
  • the lipase inhibiting group can be an isostere of a fatty acid, which can interact non-covalently with the catalytic site of the lipase.
  • the lipase inhibiting group can compete for lipase hydrolysis with natural triglycerides.
  • the polymers can be aliphatic, alicyclic or aromatic or synthetic or naturally occurring. However, aliphatic and alicyclic synthetic polymers are preferred. Furthermore, the polymer can be hydrophobic, hydrophilic or copolymers of hydrophobic and/or hydrophilic monomers. The polymer can be non-ionic (e.g., neutral), anionic or cationic, in whole or in part. Furthermore, the polymers can be manufactured from olefinic or ethylenic monomers (such as vinylalcohol) or condensation polymers.
  • the polymers can be a poly vinylalcohol, polyvinylamine, poly-N-alkylvinylamine, polyallylamine, poly-N-alkylallylamine, polyalkylenimine, polyethylene, polypropylene, polyether, polyethylene oxide, polyamide, polyacrylic acid, polyalkylacrylate, polyacrylamide, polymethacrylic acid, polyalkylmethacrylate, polymethacrylamide, poly-N-alkylacrylamide, poly-N- alkylmethacrylamide, polystyrene, vinylnaphthalene, ethylvinyl benzene, aminostyrene, vinylbi phenyl, vinylanisole, vinylimidazolyl, vinylpyridinyl, dimethylaminomethylstyrene, trimethylammoniumethylmethacrylate, trimethylammoniumethylacrylate, carbohydrate, protein and substituted derivatives of the above (e.g., fluorinated monomers thereof) and copoly
  • R1 may be 7-22C alkyl; 2-4C alkyl substituted by 4-20C alkoxy, 6-10C aryl, 6-10C aryloxy or (4-12C) alkoxy-(2-4C) alkoxy (where aryl can be substituted by one or more of halogen, 1-4C alkyl, 1-4C alkoxy, NO2 or CF3); 7-20C alkenyl; or phenyl substituted by 6-12C alkyl or by phenoxy; and R2 to R5 each may be H, halogen, NO2, 1 -4C alkyl, 1-4C alkoxy, CF3 or OCF3; or (6-10C) aryl-(1-4C) alkoxy, 6-10C aryloxy, 6-10C aryl, 3-8C
  • 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones are described to have pharmacological properties as anorectic, antidiabetic, hypotensive or cardiant, with mechanism of action as pancreatic lipase inhibitors.
  • 5- dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one had IC50 0.03 microM for inhibition of porcine pancreatic lipase.
  • these 5- hydrocarbyloxy-3-phenyl-1 ,3,4-oxadiazol-2-ones may be used as medicaments, especially for the treatment of obesity.
  • the 5- hydrocarbyloxy-3-phenyl-1 ,3,4-oxadiazol-2-ones inhibit the resorption of the fat content of foods and thus reduce fat uptake and body weight (or prevent increase in body weight). Furthermore, the 5-hydrocarbyloxy-3-phenyl-1 ,3,4- oxadiazol-2-ones are reported to also have a beneficial effect in the treatment of metabolic disorders (e.g. diabetes) or cardiovascular disorders (e.g. hypertension and cardiac infarction).
  • metabolic disorders e.g. diabetes
  • cardiovascular disorders e.g. hypertension and cardiac infarction.
  • the lipase inhibiting compounds of formula (A) are described in more detail in the WO 03/072555 and can be obtained according to known methods.
  • R1 may be 1-6C alkyl; 3-9C-cycloalkyl, both groups optionally may be substituted by phenyl, 1-4C alkoxy, S-1-4C alkyl, N(1-4C-alkyl)2; and phenyl optionally may be also substituted by halogen, 1-4C alky, 1-4C-alkyloxy, nitro or CF3; and R2 to R5 each may be independently H, halogen, NO2, 1-4C alkyl, 1-9C alkoxy which is substituted by F, 6-10C-aryl, amino or1-4C alkyl amino; 6-10C-aryl-1 ⁇ C-alkyloxy, 6-10C-aryloxy, 6-10C-aryl, 6-10C-aryloxy-1-4C- alkyl, 3-8C cycloalkyl or 0(3-8 cycloalky), which may optionally be substituted by halogen, CF3, 1-4 alkyloxy or 1-4C alkyl; SO2-NH-(
  • X is O(1 -6C alkyl), NH(1-6C alkyl), NH(3-8C cycloalkyl or N(1-6C alkyl)2 and N(1-6C alkyl)2 may be also pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which optionally substituted by 1 -4C alkyl, benzyl, 6-10C aryl, CO-(1 -4 alkyl), CO-(6-10 aryl), CO-O-(1-4C alkyl), SO2-(1-4C alkyl) or SO2-(6-10C aryl);
  • R6 is H, 1-4C alkyl or 6-10C-aryl-1-4C-alkyl, wherein aryl may be substitutet by halogen, CF3, 1-8C alkyloxy or 1- C alkyl;
  • A is a single bond, COn, SOn or CONH;
  • n is 1 oder2:
  • R7 is H
  • the lipase inhibiting compounds of formula (A) are described in more detail in the WO 03/072098 and can be obtained according to known methods.
  • a suitable synthesis for the lipase inhibiting compounds of formula (A) is described also in the international patent application WO 03/072098.
  • the whole content of the international patent application WO 03/072098 is incorporated by reference into the present application regarding the disclosure of lipase inhibitors of formula (A).
  • R1a is (i) a C10-30 branched or unbranched alkyl , optionally substituted by one or more independently of C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, -C(O)R13, -CO2R13, -SOR13, - SO2R13, -NR13R14, -OR13, -SR13, -C(O)NR13R14, -NR14C(O)R13, halogen, cyano, and nitro and/or optionally interrupted by one or more oxygen atoms with the proviso that any hetero atom in R1a must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms; (ii) C2-25 alkenyl, C2-25 alkynyl, C3-6 cycloalkenyl, aryl-C2-25 alkenyl, heteroaryl-C2-25 alken
  • R8a, R9a, R10a and R11a are each independently hydrogen, halo, hydroxy, amino, nitro, cyano, thiol, C1 -10 alkyl,
  • R15 and R16 each independently represent hydrogen or C1-10 alkyl with the proviso that when R8a, R9a, R10a, and R11a are H, R1a is not CH2CH2CI or
  • ATL-962 has the chemical name 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one. Preclinical studies showed that ATL-962 had similar efficacy to oriistat and no toxicity was observed. Clinical data for these compounds is also available in the public domain, e.g. resulting from clinical studies with ATL-962 in obesity.
  • 55% of subjects who received ATL-962 demonstrated a 3-fold or greater increase in fat excretion and 27% of subjects demonstrated a 7-fold or greater increase.
  • Adverse events and their frequency were similar between ATL-962 and placebo and were mainly gastrointestinal, with the predominant event being oily stool.
  • the lipase inhibiting compounds of formula (B) like ATL-962 and structurally related compounds are described in more detail in the US patent US 6,624,161 and its corresponding international patent application WO 00/040569, and can be obtained according to known methods.
  • a suitable synthesis for the lipase inhibiting compounds of formula (B) is described also in the US 6,624,161 and international patent application WO 00/040569.
  • the whole content of the US 6,624,161 and international patent application WO 00/040569 is incorporated by reference into the present application regarding the disclosure of lipase inhibitors of formula (B).
  • the whole content of the international patent application WO 00/040247 is also incorporated by reference into the present application regarding the disclosure of lipase inhibitors described therein, with related 2- amino-4H-3,1-benzoxazin-4-one compound structure.
  • the CBi antagonistic compound of the formulas (I), (II), III), (IV) or (V), or a prodrug, tautomer or salt thereof, and the lipase inhibiting compound used according to the invention can be brought into forms suitable for pediatric treatment and/or prophylaxis of the diseases indicated above, and in particular of obesity, e.g. for adolescent or pediatric administration, as well as for the administration in treating drug induced obesity by means of usual processes using pharmaceutical excipients, auxiliary substances and/or liquid or solid carrier materials.
  • the CBi antagonistic compound and/or the lipase inhibiting compounds may be contained together with (conventional) pharmaceutical excipients, adjuvants and/or auxiliaries in pharmaceutical preparations such as tablets, capsules, suppositories or solutions.
  • pharmaceutical preparations such as tablets, capsules, suppositories or solutions.
  • These pharmaceutical preparations may be prepared according to known methods, using conventional solid or liquid vehicles such as lactose, starch or talc, or liquid paraffins and/or using (conventional) pharmaceutical excipients, adjuvants and/or auxiliaries, such as tablet disintegrating agents, solubilisers or preservatives.
  • the invention also pertains to a pharmaceutical composition containing at least one compound with CBi-receptor activity of the formulas (I), (II), III), (IV) or (V), or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound.
  • a preferred pharmaceutical composition contains at least one compound of the formulas (I), (II), III), (IV) or (V) as defined above in combination with at least one lipase inhibiting compound as combined active components.
  • a further pharmaceutical composition according to the invention contains as active components at least one compound with CBi-receptor activity having the formula (I), (II), III), (IV) or (V) as defined above, preferably the CB1 antagonistic compound , or a prodrug, tautomer or salt thereof, and at least one lipase inhibiting compound for the treatment and/or prophylaxis of obesity in adolescent or in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients.
  • compositions according to the invention are characterized in that the at least one compound with CBi- receptor activity having the formula (I), (II), III), (IV) or (V) as defined above, preferably the CBi antagonist, or the prodrug, tautomer or salt thereof, and the at least one lipase inhibiting compound each are present in an amount effectively suited for the treatment and/or prophylaxis of obesity in a juvenile patient in need of such treating.
  • the CBi antagonistic compound in particular the CBi antagonistic compound of the formulas (I), (II), III), (IV) or (V), and the lipase inhibiting compound are each present in the pharmaceutical composition in an amount effectively suited for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients in need of such treating.
  • the CBi antagonistic compound preferably the CBi antagonistic having the formula (I), (II), III), (IV) or (V), or the prodrug, tautomer or salt thereof, is used preferably in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, oriistat, panclicins, ATL-962 and lipstatin.
  • the invention also pertains to a pharmaceutical product containing as a medicament a CBi antagonistic compound, preferably the CBi antagonistic compound having one of the formulas (I), (II), III), (IV) or (V) as defined above, or a prodrug, tautomer or salt thereof, and a leaflet indicating that said CBi antagonistic compound may be administered in combination with a lipase inhibiting compound for simultaneous, separate or step-wise administration in the treatment and/or prophylaxis of obesity.
  • a CBi antagonistic compound preferably the CBi antagonistic compound having one of the formulas (I), (II), III), (IV) or (V) as defined above, or a prodrug, tautomer or salt thereof, and a leaflet indicating that said CBi antagonistic compound may be administered in combination with a lipase inhibiting compound for simultaneous, separate or step-wise administration in the treatment and/or prophylaxis of obesity.
  • the invention also includes a method of treatment and/or prophylaxis of obesity, e.g. in adolescent or in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as adolescent patients, characterized in that a CBi antagonistic compound, in particular a compound of the formula (I), (II), III), (IV) or (V), which is an antagonist of the cannabis CBi- receptor, or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibiting compound to a patient in need of such treating.
  • a CBi antagonistic compound in particular a compound of the formula (I), (II), III), (IV) or (V), which is an antagonist of the cannabis CBi- receptor, or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibiting compound to a patient in need of such treating.
  • a CBi antagonistic compound which is a compound of one of the formulas (I), (II), III), (IV) or (V)as defined above, or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibiting compound.
  • the method of treatment and/or prophylaxis of obesity according to the present invention may be directed to obesity in adolescent or in juvenile patients and/or to drug induced obesity in juvenile as well as adolescent patients.
  • the method of treatment and/or prophylaxis is characterized in that the treating is directed to obesity in juvenile patients.
  • the method of treatment and/or prophylaxis is characterized in that the treating is directed to drug induced obesity in juvenile or adolescent patients.
  • the CBi antagonistic compound preferably the CBi antagonistic compound having one of the formulas (I), (II), III), (IV) or (V) as defined above, or a prodrug, tautomer or salt thereof, is administered preferably in combination with at least one lipase inhibiting compound selected from the group of lipase inhibiting polymers, oriistat, panclicins, ATL-962 and lipstatin.
  • the CBi antagonistic compound preferably the CB1 antagonistic compound having one of the formulas (I), (II), III), (IV) or (V) as defined above, or a prodrug, tautomer or salt thereof, is administered in combination with the lipase inhibiting compound by simultaneous, separate or step- wise administration route.
  • the compounds used in the combinations or compositions according to the present invention each are preferably administered to a patient in need thereof and in a quantity sufficient to prevent and/or treat the symptoms of the condition, disorder or disease, e.g. obesity.
  • the administration of a compound or composition has a dosage regime which will ultimately be determined by the attending physician and will take into consideration such factors such as the compound being used, animal type, age, weight, severity of symptoms, method of administration, adverse reactions and/or other contraindications.
  • Specific defined dosage ranges can be determined by standard design clinical trials with patient progress and recovery being fully monitored. Such trials may use an escalating dose design using a low percentage of the maximum tolerated dose in animals as the starting dose in man.
  • the physiologically acceptable compounds used in the combinations or compositions according to the present invention each are will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • a part of the oral dose for an adult patient is administered, e.g. 1 fifth to 1 half of the oral dose described before for an adult patient.
  • the method of treatment and/or prophylaxis is directed to the treating of obesity in juvenile patients.
  • the method of treatment and/or prophylaxis is directed to the treating of drug induced obesity in juvenile or adolescent patients. This drug induced obesity may be in particular caused by drugs like atypical antipsychotics.
  • the method of treatment and/or prophylaxis is directed to the treating of obesity in juvenile patients.
  • Cannabinoid antagonists in combination with lipase inhibitors are particulariy suitable for the treatment of Childhood Obesity and related Comorbidities as for example Type 2 Diabetes.
  • Childhood Obesity and related Comorbidities as for example Type 2 Diabetes.
  • the prevalence of overweight in children grew from 5% to 11% (Sorof and Daniels 2002).
  • childhood obesity has tripled in the past 20 years (Spurgeon 2002).
  • Type 2 diabetes in children is part of the insulin resistance syndrome (Rosenbloom 2002) that includes hypertension, dyslipidemia and other atherosclerosis risk factors, and hyperandrogenism seen as premature adrenarche and polycystic ovary syndrome.
  • Other outcomes related to childhood obesity include left ventricular hypertrophy, nonalcoholic steatohepatitis, obstructive sleep apnea, orthopedic problems, and severe psychosocial problems.
  • CBi antagonists used according to the present invention in combination with lipase inhibitors offer a unique opportunity for the treatment of obesity by interacting with these "driving forces". They are superior to current medical treatments and especially suited for adolescent as well as pediatric treatment because of their outstanding safety profile and/or tolerability and surprisingly beneficial combination effects. Besides efficacy, the treatment of obesity, especially the treatment of childhood obesity, dictated by safety. Obesity in childhood is a medical condition that is likely to require long-term management.
  • CBi antagonists used according to the present invention in combination with lipase inhibitors are suggested to be superior to current standard medications, and these CBi antagonists in combination with lipase inhibitors will be especially suited for the treatment and prevention of obesity in adolescents and in childhood obesity and related co- morbidities.
  • the method of treatment and/or prophylaxis is directed to the treating of drug induced obesity in juvenile or adolescent patients.
  • Drug induced weight gain is also of major concern and subject to high medical need of improved treatments.
  • the CBi antagonists in combination with lipase inhibitors according to the present invention are suggested to be superior to current standard medications, and these CBi antagonists in combination with lipase inhibitors will be especially suited for the treatment and prevention of drug induced obesity in juvenile as well as in adolescent patients.
  • drug induced weight gain it is reported by Zimmermann, U., T. Kraus, et al.
  • the beneficial pharmacological effects of the combination of a CBi antagonist with a lipase inhibitor according to the invention can be shown by standard experimental animal models by measuring the influence of the administered combination of a CBi antagonist with a lipase inhibitor on the driving and characteristic parameters associated with obesity.
  • the rats will have unlimited access to feed for two 2.5h periods per day, during the dark phase of a reversed 12h/12h light cycle, e.g. lights are put on at 21.15h and put off at 09.15h.
  • the rats will be offered a high fat, high sucrose diet (Western diet).
  • the lipase inhibitor will be dosed immediately before the rats are fed.
  • the CBi antagonist will be dosed 1h before the lipase inhibitor is administered.
  • the following daily dosing schedule is applicable for a given period of e.g. days, weeks or months:
  • the CBi antagonist in particular the CBi antagonisic compound of formula (I) as defined above, or a vehicle dose is administered (po) in the morning at ca. 07.45 to 08.00 h.
  • the lipase inhibitor e.g. in particular oriistat, or a vehicle dose is administered (po) ca. 08.45 to 09.00 h.
  • the rats are set to ad- libitum feed from 09.15 to 11.45h, followed by feed removal from about 11.45 to 14.45 h.
  • Another dose of lipase inhibitor e.g.
  • oriistat in particular oriistat, or vehicle (Labrasol) dose is administered (po) in the afternoon at about 14.15 to 14.30h, followed by ad-libitum feed from 14.45 to 17.15 h. Thereafter, the rats are set to feed deprivation from 17.15 - 09.15 h.
  • the experimental protocol results will compare daily food intake and body weight gain as indicators for the effects of the combination treatment on obesity during the experimental phase.
  • biochemical parameters may be measured at slaughter of the rats.
  • Control group The rats receive only vehicle according to the protocol to simulate administration (placebo group).
  • CBi group The rats receive a CBi antagonist in a vehicle.
  • LI group The rats receive as lipase inhibitor ("LI”) e.g. the compound oriistat in a vehicle.
  • CBi+LI group (combination group): The rats receive a CBi antagonist in a vehicle and as lipase inhibitor ("LI”) e.g. the compound oriistat in a vehicle.
  • the 1 H-1 ,2,4-triazole-carboxamide derivatives of formula (V), which are potent cannabinoid-CBi receptor agonists, partial agonists, inverse agonists or antagonists, useful for the treatment of psychiatric and neurological disorders, as well as other diseases involving cannabinoid-CBi neurotransmission, are defined above in the specification.
  • a group of four 1,5-diaryl-1 H-1 ,2,4-triazole-3-carboxamide derivatives in which the amide N-atom is part of an unsubstituted piperidinyl or morpholinyl group is described by D. Clerin and J.P. Fleury in Bull. Soc. Chim. Fr., 1974, 1-2, Pt.2, 211-217.
  • 1-(4-Methylphenyl)-5-phenyl-N-(2-pyridyl)-1 H-1 ,2,4-triazole-3-carboxamide is described by M. H. Elnagdi et al. in Heteroatom Chem., 1995, 6, 589-592.
  • Suitable synthetic routes for the compounds of formula (V) used in the invention are the following:
  • Step 1 Ester hydrolysis of a compound having formula (S-ll) wherein R. 3 represents a branched or unbranched (C ⁇ )-alkyl group or a benzyl group,
  • R and Ri have the meanings as described above.
  • Step 2 Reaction of a compound having formula (S-lll) with a compound having formula R 2 R 3 NH wherein R 2 and R 3 have the meanings as described above via activating and coupling methods such as formation of an active ester, or in the presence of a coupling reagent such as DCC, HBTU, BOP, CIP (2-chloro-1,3- dimethylimidazolinium hexafluorophosphate) or PyAOP (7-azabenzotriazol-1- yloxytris(pyrrolidino)phosphonium hexafluorophosphate).
  • a coupling reagent such as DCC, HBTU, BOP, CIP (2-chloro-1,3- dimethylimidazolinium hexafluorophosphate) or PyAOP (7-azabenzotriazol-1- yloxytris(pyrrolidino)phosphonium hexafluorophosphate.
  • a compound having formula (S-lll) is reacted with a halogenating agent such as thionyl chloride (SOCI 2 ) or oxalyl chloride. This reaction yields the corresponding carbonyl chloride (acid chloride) (S-IV).
  • a halogenating agent such as thionyl chloride (SOCI 2 ) or oxalyl chloride.
  • a compound having formula (S-ll) is reacted in an amidation reaction with a compound having formula R 2 R 3 NH wherein R 2 and R 3 have the meanings as described hereinabove to give a 1H-1 ,2,4-triazole derivative having formula (V).
  • amidation reactions can be promoted by the use of trimethylaluminum AI(CH 3 ) 3 (For more information on aluminum-mediated conversion of esters to amides, see: J. I. Levin, E. Turos, S. M. Weinreb, Synth Commun. (1982), 12, 989-993.)
  • Part B To a stirred suspension of 2,4-dichloroaniline (19.44 gram, 0.12 mol) in concentrated HCI (25 mL) and acetic acid ( 75 mL) at 0 °C is added a solution of NaNO 2 (9.0 gram, 0.13 mol) in water (50 mL) and the resulting solution is stirred for 15 minutes. A solution of dimethyl 2-(4-chlorobenzoylamino)-malonate (28.55 gram, 0.10 mol) in acetone (200 mL) is slowly added while keeping the temperature below 0 °C.
  • Part C To a stirred suspension of methyl 5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-1 H-1,2,4-triazole-3-carboxylate (11.3 gram, 0.0295 mol) in methanol (100 mL) is added KOH (45 % aqueous solution, 7.5 mL) and the resulting mixture is heated at reflux temperature for 4 hours. The mixture is concentrated in vacuo and water (150 mL) and concentrated HCI are added.
  • Part D To a stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H- 1 ,2,4-triazole-3-carboxylic acid (1.48 gram, 4.0 mmol) in acetonitrile (20 mL) is successively added diisopropylethylamine (DIPEA) (1.5 mL, 2.1 molar equivalent), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (1.66 gram, 1.1 molar equivalent) and 1-aminopiperidine (0.44 gram, 1.1 molar equivalent).
  • DIPEA diisopropylethylamine
  • HBTU O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • 1-aminopiperidine (0.44
  • the purified material is treated with ethanolic HCI (1 M solution) to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-1,2,4-triazole-3- carboxamide hydrochloride (1.50 gram, 77 % yield). Melting point: 238-240 °C (decomposition). 1 H-NMR (400 MHz, DMSO-d 6 ): .
  • Part B To a stirred solution of 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1 ,2,4- triazole-3-carboxylic acid (0.37 g, 1.00 mmol) in dichloromethane (10 mL) is added oxalyl chloride (0.254 g, 2.00 mmol). The resulting mixture is concentrated in vacuo to give crude 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1 ,2,4-triazole- 3-carbonyl chloride.
  • Part C The crude 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1 ,2,4-triazole-3- carbonyl chloride is dissolved in tetrahydrofuran (THF) (10 mL). 2,3-Dihydro-1 H- inden-2-ylamine (0.40 g, 3.00 mmol) is added and the resulting solution is stirred for 42 hours at 25 °C.
  • THF tetrahydrofuran
EP04817279A 2003-10-24 2004-10-22 Neue medizinische anwendungen von verbindungen mit cb sb 1 /sb antagonistischer wirkung und kombinationsbehandlung mit diesen verbindungen Withdrawn EP1753413A2 (de)

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EP04817279A EP1753413A2 (de) 2003-10-24 2004-10-22 Neue medizinische anwendungen von verbindungen mit cb sb 1 /sb antagonistischer wirkung und kombinationsbehandlung mit diesen verbindungen

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RU2006117627A (ru) 2007-12-10
WO2005039550A2 (en) 2005-05-06
MXPA06004434A (es) 2006-06-20
BRPI0415851A (pt) 2007-01-02
JP2007513872A (ja) 2007-05-31
WO2005039550A3 (en) 2007-03-22
CA2543338A1 (en) 2005-05-06

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