WO2007009693A1 - Combinaison d'un compose pyrazolinique substitue et medicament utilise pour des troubles en lien avec les aliments - Google Patents

Combinaison d'un compose pyrazolinique substitue et medicament utilise pour des troubles en lien avec les aliments Download PDF

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Publication number
WO2007009693A1
WO2007009693A1 PCT/EP2006/006967 EP2006006967W WO2007009693A1 WO 2007009693 A1 WO2007009693 A1 WO 2007009693A1 EP 2006006967 W EP2006006967 W EP 2006006967W WO 2007009693 A1 WO2007009693 A1 WO 2007009693A1
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group
optionally
mono
substituted
branched
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PCT/EP2006/006967
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Helmut H. Buschmann
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Laboratorios Del Dr.Esteve, S.A
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Priority claimed from EP05384012A external-priority patent/EP1743636A1/fr
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Publication of WO2007009693A1 publication Critical patent/WO2007009693A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

Definitions

  • the present invention relates to an active substance combination comprising at least one substituted pyrazoline compound and at least one compound used in food- related disorders, a medicament comprising said active substance combination, a pharmaceutical formulation comprising said active substance combination and the use of said active substance combination for the manufacture of a medicament.
  • the present invention relates to an active substance combination comprising
  • R 1 represents an optionally at least mono-substituted phenyl group
  • R 2 represents an optionally at least mono-substituted phenyl group
  • R 3 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, or R 3 represents an -NR 4 R 5 -moiety,
  • R 4 and R 5 identical or different, represent a hydrogen atom; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group; an -SO 2 -R 6 - moiety; or an -NR 7 R 8 -moiety, with the proviso that R 4 and R 5 do not identically represent hydrogen;
  • R 6 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with a mono- or polycyclic ring- system; or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group;
  • R 7 and R 8 identical or different, represent a hydrogen atom; an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system; or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group;
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof,
  • R 1 represents hydrogen or a linear or branched Ci- 4 -alkyl group
  • R ⁇ 2' , t R-,3 1 and R i4' independently of each other represent hydrogen, a linear or branched Ci- 6 -alkyl group, a linear or branched C- ⁇ - 6 -alkoxy group, a halogen atom, CH 2 F,
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • (B) at least one drug used in food-related disorders.
  • an active substance combination comprising as component (B) at least one lipase inhibitor may be excluded.
  • lipase inhibitors are the synthetic lipase inhibitor oriistat, lipase inhibitors isolated from micro organisms such as lipstatin (from Streptomyces toxytricini), ebelactone B (from Streptomyces eburaviensis), synthetic derivatives of these compounds, as well as extracts of plants known to possess lipase inhibitory activity, for instance extracts of Alpinia officinarum or compounds isolated from such extracts like 3-methylethergalangin (from A. officinarum).
  • R 1 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear or
  • R 1 represents a phenyl group, which is optionally substituted by one or more substituents selected from the group consisting of methyl, ethyl, F, Cl, Br and CF 3 , more preferably R 1 represents a phenyl group, which is mono-substituted with a chlorine atom in the 4-position.
  • R' and optionally R" for each substituent independently represent linear or branched Ci -6 alkyl, preferably R 2 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, ethyl, F, Cl, Br and CF 3 , more preferably R 2 represents a phenyl group, which is di-substituted with two chlorine atoms in its 2- and 4-position.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I given above, wherein R 3 represents a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C 3-8 cycloaliphatic group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, or R 3 represents an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an -NR 4 R 5 -moiety, preferably R 3 represents a saturated, optionally at least mono-substituted, optionally one or more nitrogen-atoms as ring member containing C 3- ⁇ cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I given above, wherein R 4 and R 5 , identical or different, represent a hydrogen atom; an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C ⁇ -aliphatic radical; a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C 3 - 8 - cycloaliphatic group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system; or an optionally at least mono- substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH 2 -CH 2 )-group; an -SO 2 -R 6 -moiety
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I given above, wherein R 6 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted Ci -6 aliphatic group; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 .
  • R 6 represents a Ci -6 -alkyl group; a saturated, optionally at least mono-substituted cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system; or a phenyl group, which is optionally substituted with one or more Ci_ 6 alkyl groups.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I given above, wherein R 7 and R 8 , identical or different, represent a hydrogen atom; an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted C- I-6 aliphatic radical; a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing C 3-8 cycloaliphatic group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system; or an optionally at least mono- substituted, 5- or 6 membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH 2 -CH 2 )-group, preferably R 7 and R 8 , identical or different, represent a hydrogen atom
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I given above, wherein
  • R 1 represents a phenyl group, which is optionally substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl, ethyl, F 1 Cl, Br and CF 3 ,
  • R 2 represents a phenyl group, which is optionally substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl, ethyl, F, Cl, Br and CF 3
  • R 3 represents a pyrrolidinyl group, a piperidinyl group or a piperazinyl group, whereby each of these groups may be substituted with one or more of C 1-6 -alkyl groups, or R 3 represents an -NR 4 R 5 -moiety
  • R 4 represents a hydrogen atom or a linear or branched Ci- 6 -alkyl group
  • R 5 represents a linear or branched Ci -6 alkyl group; an -SO 2 -R 6 -moiety; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; a homo-piperazinyl group; a morpholinyl group; a triazolyl group; whereby each of the heterocyclic rings may be substituted with one or more, identical or different, Ci. 6 -alkyl groups, and
  • R 6 represents a phenyl group, which is optionally substituted with one or more Ci- ⁇ alkyl groups, which may be identical or different.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I given above, wherein
  • R 1 represents a phenyl ring, which is mono-substituted with a halogen atom, preferably a chlorine atom, in its 4-position,
  • R 2 represents a phenyl ring, which is di-substituted with two halogen atoms, preferably chlorine atoms, in its 2- and 4-position,
  • R 3 represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo- piperazinyl group, a morpholinyl group, or an -NR 4 R 5 -moiety,
  • R 4 represents a hydrogen atom or a linear or branched Ci- 6 -alkyl group
  • R 5 represents a linear or branched Ci- 6 alkyl group; an -S ⁇ 2 -R 6 -moiety; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; a homo-piperazinyl group; a morpholinyl group; or a triazolyl group whereby each of the heterocyclic rings may be substituted with one or more, identical or different, C ⁇ -alky! groups, and R 6 represents a phenyl group, which is optionally substituted with one or more Ci -6 alkyl groups, which may be identical or different.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I given above selected from the group consisting of
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the active substance combination according to the present invention may as the pyrazoline compound of general formula I comprise one of the following compounds
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein at least one of R 2 , R 3 or R 4 represents hydrogen, while at least one of R 2 , R 3 or R 4 is different from hydrogen.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein R 7 represents hydrogen.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein R 2 , R 3 and R 4 independently of each other represent hydrogen, a linear or branched Ci -6 -alkyl group, a halogen atom, or CF 3 , preferably R 2 , R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein R 5 and R 6 independently of each other represent a linear or branched Ci- 6 -alkyl group, a halogen atom, or CF 3 , preferably R 5 and R 6 independently of each other represent methyl, ethyl, F, Cl, Br and CF 3 .
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein R 2 represents a chlorine atom in the 4-position of the phenyl ring, while R 3 and R 4 represent hydrogen.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein R 5 and R 6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R T represents hydrogen.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I 1 given above, wherein the compounds of general formula I' are represented by the following structure II:
  • R 1 represents hydrogen or a linear or branched Ci -4-alkyl group
  • R 12 or R 13 independently of each other represent a linear or branched d -6 -alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, NO 2 , SH, NH 2 , hydrogen, methyl, ethyl, F 1 Cl, Br and CF 3 ,
  • R 14 or R 15 independently of each other represent a linear or branched Ci. 6 -alkyl group, a linear or branched C-
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein in general structure Il R 12 and R 13 independently of each other represent hydrogen, a linear or branched Ci- ⁇ -alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein in general structure Il R 14 and R 15 independently of each other represent a linear or branched Ci- ⁇ -alkyl group, a halogen atom, or CF 3 , preferably R 14 and R 15 independently of each other represent methyl, ethyl, F, Cl, Br and CF 3 .
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein in general structure Il R 13 represents Cl and R 12 represents hydrogen.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I' given above, wherein in general structure Il R 14 and R 15 each represent Cl.
  • the active substance combination according to the present invention comprises one or more substituted pyrazoline compounds of general formula I 1 given above, wherein in general structure Il R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.
  • the active substance combination according to the present invention comprises the compound
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof as compound of general formula I'.
  • the active substance combination according to the present invention may as the pyrazoline compound of general formula I' comprise one of the following compounds
  • the other active component of the inventive active substance combination, component (B), is a drug used in a food-related disorder.
  • Suitable drugs used in a food-related disorder, their modes of action and dosages to be administered are well known to those skilled in the art.
  • the drug used in a food-related disorder of component (B) is selected from the group consisting of drugs influencing digestive metabolism, food intake regulating drugs, Lipase inhibitors, Energy expenditure modulators, Central anorexigenic compounds and Peripheral anorexigenic compounds.
  • the drug used in food-related disorders of component (B) is selected from the group consisting of Rimonabant, Orlistat, Sibutramine, Diethylpropion, Mazindol, Phentermine, Phenylpropanolamine, Xamoterol, Fluoxetine and Topiramate, optionally in form of an stereoisomer, preferably enantiomer or diastereomer, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • inventive active substance combination comprising
  • R 1 represents a phenyl group, which is optionally substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl, ethyl, F, Cl, Br and CF 3 ,
  • R 2 represents a phenyl group, which is optionally substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl, ethyl, F, Cl, Br and CF 3 ,
  • R 3 represents a pyrrolidinyl group, a piperidinyl group or a piperazinyl group, whereby each of these groups may be substituted with one or more of Ci -6 -alkyl groups, or R 3 represents an -NR 4 R 5 -moiety,
  • R 4 represents a hydrogen atom or a linear or branched Ci- 6 -alkyl group
  • R 5 represents a linear or branched Ci- ⁇ alkyl group; an -S ⁇ 2-R 6 -moiety; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; a homo-piperazinyl group; a morpholinyl group; a triazolyl group; whereby each of the heterocyclic rings may be substituted with one or more, identical or different, C- ⁇ - 6 -alkyl groups, and
  • R 6 represents a phenyl group, which is optionally substituted with one or more Ci -6 alkyl groups, which may be identical or different.
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof,
  • R represents hydrogen or a linear or branched Ci-4-alkyl group
  • R 12 or R 13 independently of each other represent a linear or branched Ci -6 -alkyl group, a linear or branched group, a halogen atom, CH 2 F, CHF2, CF 3 , CN, OH, NO 2 , SH, NH 2 , hydrogen, methyl, ethyl, F, Cl, Br and CF 3 ,
  • R 14 or R 15 independently of each other represent a linear or branched Ci -6 -alkyl group, a linear or branched Ci_ 6 -alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, NO 2 , SH, NH 2 , methyl, ethyl, F, Cl 1 Br and CF 3 ,
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • a drug used in food-related disorders selected from the group consisting of Rimonabant, Orlistat, Sibutramine, Diethylpropion, Mazindol, Phentermine, Phenylpropanolamine, Xamoterol, Fluoxetine and Topiramate, optional
  • inventive active substance combination comprising
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof,
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof,
  • a drug used in food-related disorders selected from the group consisting of Rimonabant, Orlistat, Sibutramine, Diethylpropion, Mazindol, Phentermine, Phenylpropanolamine, Xamoterol, Fluoxetine and Topiramate,
  • inventively used substituted pyrazoline compounds may, for example, be obtained by the following process, according to which at least one benzaldehyde compound of general formula Il
  • G represents an OR group with R being a branched or unbranched C 1-6 alkyl radical, preferably an ethyl radical, or G represents an O " K group with K being a cation, preferably a monovalent cation, more preferably an alkali metal cation, even more preferably a sodium cation, to yield a compound of general formula (IV)
  • R 1 has the meaning given above, which is optionally isolated and/or optionally purified, and which is reacted with an optionally substituted phenyl hydrazine of general formula (V)
  • substituents R 1 and R 2 have the meaning given above and A represents a leaving group, via the reaction with an activating agent, said compound being optionally isolated and/or optionally purified, and at least one compound of general formula (Vl) is reacted with a compound of general formula R 3 H, wherein R 3 represents an -NR 4 R 5 -moiety, wherein R 4 and R 5 have the meaning given above, to yield a substituted pyrazoline compound of general formula I, wherein R 3 represents an -NR 4 R 5 -moiety,
  • the reaction of the benzaldehyde compound of general formula Il with a pyruvate compound of general formula III is preferably carried out in the presence of at least one base, more preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic communications, 26(11), 2229-33, (1996).
  • an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide
  • an alkali metal methoxide such as sodium methoxide
  • sodium pyruvate may be used as the pyruvate compound.
  • said reaction is carried out in a protic reaction medium such as a Ci -4 alkyl alcohol or mixtures of these.
  • reaction temperature as well as the duration of the reaction may vary over a broad range. Preferred reaction temperatures range from -10 0 C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • reaction of the benzaldehyde compound of general formula Il with a pyruvate compound of general formula III is carried out under acid catalysed conditions, more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1 ), 147-149, 2001.
  • acid catalysed conditions more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1 ), 147-149, 2001.
  • the respective description is hereby incorporated by reference and forms part of the disclosure.
  • reaction of the compound of general formula (IV) with an optionally substituted phenyl hydrazine of general formula (V) is preferably carried out in a suitable reaction medium such as Ci ⁇ -alcohols or ethers such as dioxane or tetrahydrofuran or mixtures of at least two of these afore mentioned compounds.
  • a suitable reaction medium such as Ci ⁇ -alcohols or ethers such as dioxane or tetrahydrofuran or mixtures of at least two of these afore mentioned compounds.
  • said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid.
  • reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 0 C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • the carboxylic group of the compound of general formula (Vl) may be activated for further reactions by the introduction of a suitable leaving group according to conventional methods well known to those skilled in the art.
  • the compounds of general formula (Vl) are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a Ci -4 alkyl ester, an activated ester such as p- nitrophenylester.
  • Other well known methods for the activation of acids include the activation with N,N-dicyclohexylcarbodiimide or benzotriazol-N- oxotris(dimethylamino) phosphonium hexafluorophosphate (BOP)).
  • said activated compound of general formula (VII) is an acid chloride
  • it is preferably prepared by reaction of the corresponding acid of general formula (Vl) with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the solvent.
  • an additional solvent may be used.
  • Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane. Mixtures of two or more solvents from one class or two or more solvents from different classes may also be used.
  • Preferred reaction temperature range from 0° C to the boiling point of the solvent and reaction times from several minutes to several hours.
  • said activated compound of general formula (VII) is a mixed anhydride
  • said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula (Vl) with ethyl chloroformiate in the presence of a base such as triethylamine or pyridine, in a suitable solvent.
  • reaction of general formula (VII) with a compound of general formula HR 3 to yield compounds of general formula I, wherein R 3 represents an -NR 4 R 5 moiety is preferably carried out in presence of a base such as triethylamine in a reaction medium such as methylenchloride.
  • a base such as triethylamine
  • a reaction medium such as methylenchloride.
  • the temperature is preferably in the range from O 0 C to the boiling point of the reaction medium.
  • the reaction time may vary over a broad range, e.g. from several hours to several days.
  • reaction is carried out in the presence of a Lewis acid, which is preferably selected from the group consisting of FeCb, ZnCb and AICb, in a suitable reaction medium such as toluene, benzene, tetrahydrofurane or similar.
  • a Lewis acid which is preferably selected from the group consisting of FeCb, ZnCb and AICb
  • the temperature is preferably in the range from O 0 C to the boiling point of the reaction medium, more preferably from 15 to 25 0 C.
  • the reaction time may vary over a broad range, e.g. from several minutes to several hours.
  • substituted pyrazoline compounds of general formula (I) themselves are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or fractionalized crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.
  • Salts of the inventively used active compounds may be obtained by a process, wherein at least one of the compounds having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium.
  • Suitable reaction media include, for example, any of the ones given above.
  • Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid
  • suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
  • Salts of the inventively used active compounds may also be prepared by a method, wherein at least one of the compounds having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium.
  • suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NH n R- ⁇ n] + . wherein n is 0, 1 , 2, 3 or 4 and R represents a branched or unbranched Suitable reaction media are, for example, any of the ones given above.
  • Solvates, preferably hydrates, of the inventively used substituted pyrazoline compounds of general formula (I), of corresponding stereoisomers, of corresponding N-oxides or of corresponding salts thereof may also be obtained by standard procedures known to those skilled in the art.
  • Substituted pyrazoline compounds of general formula I 1 which comprise nitrogen- atom containing saturated, unsaturated or aromatic rings may also be obtained in the form of their N-oxides by methods well known to those skilled in the art and used in the active substance combination of the present invention.
  • substituted pyrazoline compounds as used herein is to be understood as encompassing derivatives such as ethers, esters and complexes of these compounds as well.
  • derivatives as used in this application is defined here as meaning a chemical compound having undergone a chemical derivation starting from an acting (active) compound to change (ameliorate for pharmaceutical use) any of its physico-chemical properties, especially a so-called prodrug, e.g. their esters and ethers. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002). The respective description is hereby incorporated by reference and forms part of the disclosure.
  • the inventive active substance combination may comprise the components (A) and (B) in a molar ratio of component (A) to component (B) in the range of 1 :10 to 10:1 , preferably 1 :5 to 5:1.
  • the inventive active substance combination is suitable for the administration to humans, including infants, children and grown-ups, as well as animals.
  • Medicaments on the basis of the inventive active substance combination may preferably be administered once daily, twice daily or three times daily, more preferably once daily or twice daily, most preferably once daily.
  • the present invention relates to a medicament comprising an inventive active substance combination and optionally at least one further active substance and/or optionally at least one auxiliary substance.
  • the inventive medicament is suitable for the modulation of cannabinoid- receptors, preferably cannabinoid 1 (CBi) receptors; for influencing digestive metabolism, for regulating food intake, for inhibiting a lipase, for modulating energy expenditure, for reducing central anorexigenic effects and/or for reducing peripheral anorexigenic effects.
  • cannabinoid- receptors preferably cannabinoid 1 (CBi) receptors
  • the inventive medicament is suitable for the prophylaxis and/or treatment of a food related disorder, preferably a food related disorder selected from the group consisting of bulimia, anorexia, cachexia, obesity, drug-induced obesity, metabolic syndrome, appetence disorder, appetite disorders, eating disorders associated with excessive food intake and type Il diabetus mellitus (non-insuline dependent diabetes mellitus).
  • a food related disorder selected from the group consisting of bulimia, anorexia, cachexia, obesity, drug-induced obesity, metabolic syndrome, appetence disorder, appetite disorders, eating disorders associated with excessive food intake and type Il diabetus mellitus (non-insuline dependent diabetes mellitus).
  • Another aspect of the present invention is the use of at least one active substance combination according to the present invention and optionally at least one further active substance and/or optionally at least one auxiliary substance for the manufacture of a medicament for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors; for influencing digestive metabolism, for regulating food intake, for inhibiting a lipase, for modulating energy expenditure, for reducing central anorexigenic effects and/or for reducing peripheral anorexigenic effects.
  • cannabinoid-receptors preferably cannabinoid 1 (CBi) receptors
  • Another aspect of the present invention is the use of at least one active substance combination according to the present invention and optionally at least one further active substance and/or optionally at least one auxiliary substance for the manufacture of a medicament for the prophylaxis and/or treatment of a food related disorder, preferably a food related disorder selected from the group consisting of bulimia, anorexia, cachexia, obesity, drug-induced obesity, metabolic syndrome, appetence disorder, appetite disorders, eating disorders associated with excessive food intake and type Il diabetus mellitus (non-insuline dependent diabetes mellitus). Also particularly preferred is the use of at least one of the pyrazoline compounds as defined herein and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the treatment of metabolic syndrome.
  • the metabolic syndrome and definitions thereof are described in detail by Eckel et al., The Lancet, Vol. 365 (2005), 1415-1428, included herewith by reference.
  • One of the respective definitions was established by the WHO in 1998 (as described in Alberti et al., Diabet. Med. 1998, 15, pages 539-53, the respective description thereof is herewith incorporated by reference and forms part of the present disclosure).
  • the other, more widely accepted, definition of the metabolic syndrome was established by the Adult Treatment Panel (ATP III) of the US National Cholesterol Education Program (NCEP) in 2001 , as described in JAMA 2001 ; 285; 2486-97, the respective description thereof is herewith incorporated by reference and forms part of the present disclosure.
  • the metabolic syndrome is characterized by an interaction of several physiological parameters such as triglycerides, lipids, blood pressure, glucose levels and insuline levels.
  • Another aspect of the invention is the use of one or more pyrazoline compounds as defined herein for the manufacture of a medicament for improvement of cardiovascular and/or metabolic risk factors, such as one or more of the following factors:
  • Elevated triglycerides whereby elevated levels of triglycerides are preferably understood as being > 150 mg/dl,
  • Low HDL cholesterol whereby low levels of HDL cholesterol are preferably understood as being ⁇ 40 mg/dl in men and ⁇ 50 mg/dl in women,
  • Hypertension whereby hypertension is preferably understood as being > 130/85 mmHg,
  • Impaired fasting glucose whereby impaired fasting glucose levels are preferably understood as being > 110 mg/dl,
  • Another aspect of the invention is the use of one or more pyrazoline compounds as defined herein for the manufacture of a medicament for the treatment of the weight independent aspects of metabolic syndrome.
  • Another aspect of the invention is a method for improving cardiovascular and/or metabolic risk factors, such as one or more of the following factors:
  • Elevated triglycerides whereby elevated levels of triglycerides are preferably understood as being > 150 mg/dl,
  • Low HDL cholesterol whereby low levels of HDL cholesterol are preferably understood as being ⁇ 40 mg/dl in men and ⁇ 50 mg/dl in women,
  • Hypertension whereby hypertension is preferably understood as being > 130/85 mmHg,
  • Impaired fasting glucose whereby impaired fasting glucose levels are preferably understood as being > 110 mg/dl,
  • a subject preferably a human.
  • Another aspect of the invention is a method for treating of the weight independent aspects of metabolic syndrome.
  • the pyrazoline compounds as defined herein also have a beneficial effect on the ratio of low density lipoprotein (LDL) to high density lipoprotein (HDL), i.e. they lower the LDL-levels and/or elevate the HDL levels; they are also useful as coating material or co-coating material in stents in order to prevent restenosis.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • the inventive medicament is also suitable for the prophylaxis and/or - treatment of one or more of the following disorders: food intake disorders, preferably selected from the group consisting of bulimia; anorexia; cachexia; obesity and type Il diabetes mellitus (non-insuline dependent diabetes mellitus), more preferably obesity; psychosis; alcohol abuse and/or addiction; nicotine abuse and/or addiction; drug abuse and/or addiction; medicament abuse and/or addiction; schizophrenia; anxiety; depression; epilepsy; neurodegenerative disorders, preferably Morbus Parkinson; Morbus Huntington; Morbus Alzheimer and/or Multiple Sclerosis; cerebellar disorders; spinocerebellar disorders; cognitive disorders; cranial trauma; panic attacks; peripheric neuropathy; glaucoma; migraine; Raynaud's disease; tremblement disorders; compulsive disorders; senile dementia; thymic disorders; tardive dyskinesia; bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer,
  • the inventive medicament is also suitable for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of dementia and related disorders, preferably for the prophylaxis and/or treatment of one or more types of dementia selected from the group consisting of memory loss, vascular dementia, mild cognitive impairment, frontotemporal dementia and Pick's disease; binge eating disorders; juvenile obesity; drug induced obesity; atypical depression; behavioural addictions; attention deficit disorders; Tourette's syndrome; suppression of reward- related behaviours; e. g.
  • conditioned place avoidance such as suppression of cocaine- and morphine induced conditioned place preference; impulsivity; sexual dysfunction; preferably for the prophylaxis and/or treatment of one or more types of sexual dysfunction selected from the group consisting of erectile difficulty and female sexual dysfunction; seizure disorders; nausea; emesis; neuroinflammatory disease, preferably for the prophylaxis and/or treatment of one or more types of neuroinflammatory diseases selected from the group consisting of multiple sclerosis, demyelinisation related disorders, Guillan-Barre syndrome, viral encephalitis and cerebrovascular accidents; neurological disorders; muscle spasticity; traumatic brain injury; spinal cord injury; inflammation and immunomodulatory disorders, preferably for the treatment and/or prophylaxis of one or more types of inflammation and immunomodulatory disorders selected from the group consisting of cutaneous T-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, sepsis, sarcoidosis, idiopathic pulmonary
  • components (A) and (B) of the active substance combination as well as the different components of components (A) may be administered simultaneously or sequentially to one another, whereby in each case components (A) (including one or both of substituted pyrazoline compounds of general formula I and I') and (B) may be administerd via the same or different administration pathways, e.g. orally or parenterally. preferably both components (A) and (B) are administered simultaneously in one and the same administration form.
  • food intake disorders preferably selected from the group consisting of bulimia; anorexia; cachexia; obesity and type Il diabetes mellitus (non-insuline dependent diabetes mellitus), more preferably obesity; psychosis; alcohol abuse and/or addiction; nicotine abuse and/or addiction; drug abuse and/or addiction; medicament abuse and/or addiction; schizophrenia; anxiety; depression; epilepsy; neurodegenerative disorders, preferably Morbus Parkinson; Morbus Huntington; Morbus Alzheimer and/or Multiple Sclerosis; cerebellar disorders; spinocerebellar disorders; cognitive disorders; cranial trauma; panic attacks; peripheric neuropathy; glaucoma; migraine; Raynaud's disease; tremblement disorders; compulsive disorders; senile dementia; thymic disorders; tardive dyskinesia; bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer; bone
  • a further aspect of the present invention relates to pharmaceutical formulations in different pharmaceutical forms comprising an inventive active substance combination and optionally at least one further active substance and/or optionally at least one auxiliary substance.
  • inventive pharmaceutical formulation is suitable for oral or parenteral administration, more preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathekal, rectal, transdermal, transmucosal or nasal administration.
  • inventive pharmaceutical formulation for oral administration are preferably selected from the group consisting of tablets, dragees, capsules, powders, drops, gels, juices, sirups, solutions and suspensions.
  • the pharmaceutical formulation of the present invention for oral administration may also be in the form of multiparticulates, preferably microparticles, microtablets, pellets or granules, optionally compressed into a tablet, filled into a capsule or suspended in a suitable liquid. Suitable liquids are known to those skilled in the art.
  • the respective pharmaceutical formulations may - depending on their route of administration - also contain one or more auxiliary substances known to those skilled in the art.
  • the pharmaceutical formulations according to the present invention may be produced according to standard procedures known to those skilled in the art, e.g. from the tables of contents from ..Pharmaceutics: the Science of Dosage Forms", Second Edition, Aulton, M. E. (Ed.) Churchill Livingstone, Edinburgh (2002);
  • the pharmaceutical formulation comprises one or both of the components (A) and (B) at least partially in a sustained- release form.
  • the inventive pharmaceutical formulation comprises component (B) at least partially in a sustained-release form.
  • sustained-release form By incorporating one or both of these components at least partially or completely in a sustained-release form it is possible to extend the duration of their effect, allowing for the beneficial effects of such a sustained release form, e.g. the maintenance of even concentrations in the blood.
  • Suitable sustained-release forms as well as materials and methods for their preparation are known to those skilled in the art, e.g. from the tables of contents from ,,Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); ,,Handbook of Pharmaceutical Controlled Release Technology", Wise, D.L. (Ed.), Marcel Dekker, Inc. New York, (2000);”Controlled Drug Delivery", Vol. I, Basic Concepts, Bruck, S.D. (Ed.), CRC Press Inc., Boca Raton (1983) and from Takada, K.
  • the pharmaceutical formulation according to the present invention comprises at least one of the components (A) and (B) at least partially in a sustained-release form
  • said sustained release may preferably be achieved by the application of at least one coating or provision of a matrix comprising at least one sustained-release material.
  • the sustained-release material is preferably based on an optionally modified, water- insoluble, natural, semisynthetic or synthetic polymer, or a natural, semisynthetic or synthetic wax or fat or fatty alcohol or fatty acid, or on a mixture of at least two of these afore mentioned components.
  • the water-insoluble polymers used to produce a sustained-release material are preferably based on an acrylic resin, which is preferably selected from the group of poly(meth)acrylates, particularly preferably poly(Ci- 4 )alkyl (meth)acrylates, poly(Ci- 4 )dialkylamino(Ci- 4 )alkyl (meth)acrylates and/or copolymers or mixtures thereof, and very particularly preferably copolymers of ethyl acrylate and methyl methacrylate with a monomer molar ratio of 2:1 (Eudragit NE30D ® ), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate- chloride with a monomer molar ratio of 1 :2:0.1 (Eudragit RS ® ), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate
  • the sustained-release material is based on water-insoluble cellulose derivatives, preferably alkyl celluloses, particularly preferably ethyl cellulose, or cellulose esters, e.g. cellulose acetate.
  • Aqueous ethyl cellulose dispersions are commercially available, for example, under the trademarks Aquacoat ® or Surelease ® .
  • the sustained- release material may be based on carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol ditripalmitostearate, microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a mixture of at least two of these components.
  • the afore mentioned polymers of the sustained-release material may also comprise a conventional, physiologically acceptable plasticizer in amounts known to those skilled in the art.
  • plasticizers are lipophilic diesters of a Ce-C 40 aliphatic or aromatic dicarboxylic acid and a CrCs aliphatic alcohol, e.g. dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic citric acid esters, e.g. triethyl citrate, tributyl citrate, acetyltributyl citrate or acetyltriethyl citrate, polyethylene glycols, propylene glycol, glycerol esters, e.g.
  • Aqueous dispersions of Eudragit RS ® and optionally Eudragit RL ® preferably contain triethyl citrate.
  • the sustained-release material may comprise one or more plasticisers in amounts of, for example, 5 to 50 wt.% based on the amount of polymer(s) used.
  • the sustained-release material may also contain other conventional auxiliary substances known to those skilled in the art, e.g. lubricants, coloured pigments or surfactants.
  • the pharmaceutical formulation of the present invention may also comprise at least one of the components (A) and (B) covered by an enteric coating form which dissolves as a function of pH. Because of this coating, part or all of the pharmaceutical formulation can pass through the stomach undissolved and the components (A) and/or (B) are only released in the intestinal tract.
  • the enteric coating preferably dissolves at a pH of between 5 and 7.5.
  • the enteric coating may be based on any enteric material known to those skilled in the art, e.g. on methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1 :1 (Eudragit L ® ), methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1 :2 (Eudragit S ® ), methacrylic acid/ethyl acrylate copolymers with a monomer molar ratio of 1 :1 (Eudragit L30D-55 ® ), methacrylic acid/methyl acrylate/methyl methacrylate copolymers with a monomer molar ratio of 7:3:1 (Eudragit FS ® ), shellac, hydroxypropyl methyl cellulose acetate-succinates, cellulose acetate-phthalates or a mixture of at least two of these components, which can optionally also be used in combination with the above-mentione
  • the coatings of the pharmaceutical formulations of the present invention may be applied by the conventional processes known to those skilled in the art, e.g. from Johnson, J. L., ..Pharmaceutical tablet coating", Coatings Technology Handbook (Second Edition), Satas, D. and Tracton, A.A. (Eds), Marcel Dekker, Inc. New York, (2001), 863-866; Carstensen, T., ..Coating Tablets in Advanced Pharmaceutical Solids", Swarbrick, J. (Ed.), Marcel Dekker, Inc. New York (2001 ), 455-468; Leopold, CS.
  • the pharmaceutical formulation of the present invention contains one or both of components (A) and (B) not only in sustained-release form, but also in non-retarded form.
  • a high initial dose can be achieved for the rapid onset of the beneficial effect.
  • the slow release from the sustained release form then prevents the beneficial effect from diminishing.
  • Such a pharmaceutical formulation is particularly useful for the treatment of acute health problems.
  • a pharmaceutical formulation having at least one immediate-release coating comprising at least one of the components (A) and (B) to provide for rapid onset of the beneficial effect after administration to the patient.
  • Substances with affinity for cannabinoid receptors are known to produce a wide range of pharmacological effects. It is also known that intravenous administration of a substance with affinity for cannabinoid receptors in mice produces analgesia , hypothermia, sedation and catalepsy. Individually, none of these effects can be considered as proof that a tested substance has affinity for cannabinoid-receptors, since all of these effects are common for various classes of centrally active agents. However, substances, which show all of these effects, i.e. substances that are active in this so-called tetrad model are considered to have affinity for the cannabinoid receptors. It has further been shown that cannabinoid receptor antagonists are higly effective in blocking the effects of a cannabinoid agonist in the mouse tetrad model.
  • mice with a weight of 20-30 g Male NMRI mice with a weight of 20-30 g (Harlan, Barcelona, Spain) are used in all of the following experiments.
  • mice are acclimatized to the experimental setting.
  • Pre-Treatment control values are determined for analgesia hot plate latency (in seconds), rectal temperature, sedation and catalepsy.
  • the mice are injected intravenously with the substance to be tested or the vehicle alone. 15 minutes after injection, latency in hot plate analgesia is measured. Rectal temperature, sedation and catalepsy are measured 20 minutes after injection.
  • the hot plate analgesia is determined according to the method described in Woolfe D. et al. ,,The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307,1944. The respective description is hereby incorporated by reference and forms part of the present disclosure.
  • mice are placed on a hot plate (Harvard Analgesimeter) at 55 ⁇ 0.5 0 C until they show a painful sensation by licking their paws or jumping and the time for these sensations to occur is recorded. This reading is considered the basal value (B).
  • B basal value
  • PC cut-off time
  • mice Fifteen minuts after the administration of the substance to be tested, the mice are again placed on the hot plate and the afore described procedure is repeated. This period is called the post-treatment reading (PT).
  • PT post-treatment reading
  • the degree of analgesia is calculated from the formula :
  • % MPE of Analgesia ( PT- B) / (PC-B) x 100
  • Sedation and ataxia is determined according to the method described in Desmet L. K. C. et al. ..Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975.
  • the respective description is hereby incorporated by reference and forms part of the present disclosure.
  • the chosen scoring system is
  • the percentage of sedation is determined according to the formula:
  • % of sedation arithmetic mean / 3 X 100
  • hypothermia is determined according to the method described in David R. Compton et al. ,,ln-vivo Characterization of a Specific Cannabinoid Receptor Antagonist (SR141716A) Inhibition of Tetrahydrocannbinol- induced Responses and Apparent Agonist Activity", J. Pharmacol Exp Ther. 277 , 2, 586-594, 1996. The respective description is hereby incorporated by reference and forms part of the present disclosure.
  • the base-line rectal temperatures are determined with a thermometer (YeIIo Springs Instruments Co., Panlabs) and a thermistor probe inserted to 25mm before the administration of the substance to be tested. Rectal temperature is again measured 20 minutes after the administration of the substances to be tested. The temperature difference is calculated for each animal, whereby differences of ⁇ -2 0 C are considered to represent activity.
  • Catalepsy is determined according to the method described in Alpermann H. G. et al. ..Pharmacological effets of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992. The respective description is hereby incorporated by reference and forms part of the present disclosure.
  • the cataleptic effect of the substance to be tested is evaluated according to the duration of catalepsy, whereby the animals are placed head downwards with their kinlegs upon the top of the wooden block.
  • the chosen scoring system is:
  • the percentage of catalepsy is determined according ot the following formula:
  • % Catalepsy arithmetic mean / 6 X 100
  • step a) 4-(4-chlorophenyl)-2-oxo-3-butenoic acid obtained according to step a) (12.6 g, 60 mmoles), 2,4-dichlorophenylhydrazine hydrochloride (12.8 g, 60 mmoles) and glacial acetic acid (200 ml_) were mixed under a nitrogen atmosphere and heated to reflux for 4 hours, cooled down to room temperature (approximately 25 0 C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield).
  • N-aminopiperidine (0.6 ml_, 5.6 mmoles) and triethylamine (4 ml_) were dissolved in methylene chloride (25 ml_).
  • methylene chloride 25 ml_.
  • the resulting mixture was ice-cooled down to 0 0 C and a solution of 5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride obtained in step (c) in methylene chloride (15 ml_) was added dropwise.
  • the resulting reaction mixture was stirred at room temperature (approximately 25 0 C) overnight.
  • This compound was obtained in form of an oil.
  • IR(KBr, cm 1 ) 2934, 1622, 1470, 1446, 1266, 1010, 817.
  • N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0,15 g, 332 mmoles) was dissolved in 7 ml of dichloromethane. The resulting solution was ice-cooled to 0 0 C and m-chloroperbenzoic acid (0,204 g, 0,83 mmoles) added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was remaining. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered.
  • inventive pyrazoline compounds are particularly suitable for regulating the CBi-Receptor.
  • inventive pyrazoline compounds show an antagonistic effect.

Abstract

La présente invention concerne une combinaison de principes actifs comprenant au moins un composé pyrazolinique substitué, et au moins un composé s'utilisant dans les troubles en liens avec les aliments. L'invention concerne également un médicament contenant cette combinaison de principes actifs, une formulation pharmaceutique comprenant cette combinaison, et l'utilisation de cette combinaison de principes actifs pour la confection d'un médicament.
PCT/EP2006/006967 2005-07-15 2006-07-15 Combinaison d'un compose pyrazolinique substitue et medicament utilise pour des troubles en lien avec les aliments WO2007009693A1 (fr)

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