WO2007009692A1 - Utilisation de composes de pyrazoline substituee pour le traitement de troubles de l'alimentation dont l'obesite ou le syndrome metabolique chez des patients a diabete developpe. - Google Patents

Utilisation de composes de pyrazoline substituee pour le traitement de troubles de l'alimentation dont l'obesite ou le syndrome metabolique chez des patients a diabete developpe. Download PDF

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WO2007009692A1
WO2007009692A1 PCT/EP2006/006966 EP2006006966W WO2007009692A1 WO 2007009692 A1 WO2007009692 A1 WO 2007009692A1 EP 2006006966 W EP2006006966 W EP 2006006966W WO 2007009692 A1 WO2007009692 A1 WO 2007009692A1
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group
optionally
substituted
mono
branched
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PCT/EP2006/006966
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Helmut H. Buschmann
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Laboratorios Del Dr. Esteve, S.A
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Priority claimed from EP05384016A external-priority patent/EP1743641A1/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
    • A61K31/435—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 or sparfloxacin
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to the use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome, in patients with developed diabetes in humans and animals.
  • Diabetes especially of type II, has - concurrently with obesity and metabolic syndrome - developed into a major health problem. It is a widespread disease or health state involving high risks for a significant part of the population making it interesting to treat diabetes.
  • inventively used substituted pyrazoline compounds of general formula I given below have a high affinity for cannabinoid receptors, particularly for the CBi-receptor, and that they act as modulators e.g. antagonists, inverse agonists or agonists on these receptors.
  • Cannabinoids are compounds, which are derived from the cannabis sativa plant which is commonly known as marijuana.
  • the most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly ⁇ 9 -THC.
  • THC tetrahydrocannabinol
  • cannabinoid-receptors promote their physiological effects via binding to specific G-coupled receptors, the so-called cannabinoid-receptors.
  • CB 1 and CB 2 are involved in a variety of physiological or pathophysiological processes in humans and animals, e.g. processes related to the central nervous system, immune system, cardiovascular system, endocrinous system, respiratory system, the gastrointestinal tract or to reproduction, as described for example, in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug. Res., 36, 71-114, 1991 ; Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRC Press, 1992.
  • the CBrReceptor is involved in many different food-intake related disorders such obesity and thus, compounds suitable for regulating this receptor may be used in the prophylaxis and/or treatment of these disorders.
  • the present invention relates to the use of at least one substituted pyrazoline compound of general formula I,
  • 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,
  • 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,
  • treatment does also include prophylaxis.
  • Diabetes especially type Il diabetes
  • diabetes is a major health problem.
  • diabetes does develop sometimes based on aspects of the metabolic syndrome as well as food disorders like obesity on the other hand diabetes itself being a major risk factor in developing metabolic syndrome in the first place.
  • a big problem for any patient/person having acquired diabetes is losing weight thereafter because diabetes seems to negatively influence loss of weight, including the treatment of food disorders, especially obesity, which on the other hand is very desirable to lower the cardiovascular risk.
  • Being still active under these conditions is one of the major and surprising advantages of the pyrazoline compounds described herein.
  • a mono- or polycyclic ring-system means a mono- or polycyclic hydrocarbon ring-system that may be saturated, unsaturated or aromatic. If the ring system is polycyclic, each of its different rings may show a different degree of saturation, i.e.
  • each of the rings of the mono- or polycyclic ring system may contain one or more, e.g. 1 , 2 or 3, heteroatoms as ring members, which may be identical or different and which can preferably be selected from the group consisting of N, O, S and P, more preferably be selected from the group consisting of N, O and S.
  • the polycyclic ring-system may comprise two rings that are condensed.
  • the rings of the mono- or polycyclic ring-system are preferably 5- or 6-membered.
  • condensed means that a ring or ring- system is attached to another ring or ring-system, whereby the terms “annulated” or “annelated” are also used by those skilled in the art to designate this kind of attachment.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C-i-e-alkoxy, branched or unbranched Ci- 6 -alkyl, branched or unbranched branched or unbranched C 1 - 4 - perfluoroalkyl, oxo, amino, carboxy, amido, cyano, nitro, -SO 2 NH 2 , -CO-Ci- 4 -alkyl, - SO-Ci- 4 -alkyl, -NH-SO 2 -Ci- 4 -alkyl , wherein the Ci- 4 -alkyl may in
  • residues R 3 -R 8 represents or comprises a cycloaliphatic group, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S.
  • a cycloaliphatic group may contain 1 , 2 or 3 heteroatoms independently selected from the group consisting of N, O and S as ring members.
  • Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing, optionally at least mono-substituted cycloaliphatic groups may preferably be selected from the group consisting of Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclooctyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl, Cyclooctenyl, Pyrrolidinyl, Piperidinyl, Piperazinyl, homo-Piperazinyl and Morpholinyl.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched Ci -6 - alkoxy, branched or unbranched Ci- 6 -alkyl, branched or unbranched Ci -4 - perfluoroalkoxy, branched or unbranched Ci- 4 -perfluoroalkyl, amino, carboxy, oxo, amido, cyano, nitro, -SO 2 NH 2 , -CO-C-M-alkyl, -SO-C ⁇ -alkyl, -SO 2 -C 1-4 -alkyl, -NH- SO 2 -Ci- 4 -alkyl , wherein the C- M -alkyl
  • each of the substituents may be independently selected from the group consisting of a halogen atom (e.g. F, Cl, Br, I), a linear or branched C- ⁇ .
  • a halogen atom e.g. F, Cl, Br, I
  • Ci -6 alkoxy group a linear or branched Ci -6 alkoxy group, a formyl group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-Ci-e-alkyl group, a cyano group, a nitro group, a carboxy group, a -CO-O-Ci- 6 -alkyl group, a -CO-
  • NR A R B - moiety a -CO-NH-NR c R D -moiety, an -SH 1 an -S-d- ⁇ -alkyl group, an -SO-d. 6 -alkyl group, an -SO 2 -Ci- 6 -alkyl group, a -Ci- ⁇ -alkylene-S-Ci- ⁇ -alkyl group, a -Ci -6 - alkylene-SO-Ci -6 -alkyl group, a -Ci -6 -alkylene-SO 2 -Ci.
  • R' and R" independently represent a linear or branched Ci- ⁇ -alkyl group, a Ci- 6 -alkyl group substituted by one or more hydroxy groups and a -Ci- 6 -alkylene-NR E R F group,
  • R A , R B identical or different, represent hydrogen or a d- 6 -alkyl group, or R A and R B together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more, identical or different, Ci -6 alkyl groups and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member,
  • R c , R D identical or different, represent a hydrogen atom, a Ci- 6 -alkyl group, a -CO-O-Ci -6 -alkyl group, a C 3-8 -cycloalkyl group, a Ci. 6 -alkylene-C 3 - 8 -cycloalkyl group, Ci- 6 -alkylene-O-C 1-6 -alkyl group or a Ci.
  • R E , R F identical or different, represent hydrogen or a C- ⁇ - 6 -alkyl group, or R E and R F together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more, identical or different Ci_ 6 alkyl groups and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member.
  • Preferred aryl groups which may optionally be at least mono-substituted, are phenyl and naphthyl.
  • each of the substituents may be independently selected from the group consisting of a halogen atom (e.g.
  • a linear or branched C 1-6 -alkyl group a linear or branched Ci -6 alkoxy group, a formyl group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-Ci- ⁇ -alkyl group, a cyano group, a carboxy group, a -CO-O-C 1-6 -alkyl group, a -CO-NR A R B - moiety, a -CO-NH- NR c R D -moiety, an -S-Ci.
  • 6 -alkyl group an -SO-Ci -6 -alkyl group, an -SO 2 -C 1-6 -alkyl group, a -Ci- ⁇ -alkylene-S-Ci- ⁇ -alkyl group, a -Ci- ⁇ -alkylene-SO-Ci- ⁇ -alkyl group, a -C-i. 6 -alkylene-SO 2 -Ci- 6 -alkyl group, a Ci -6 -alkyl group substituted by one or more hydroxy groups and a -Ci -6 -alkylene-NR E R F group,
  • R A , R B identical or different, represent hydrogen or a Ci- 6 -alkyl group, or R A and R B together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more, identical or different, C 1 ⁇ alkyl groups and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member,
  • R c , R D identical or different, represent a hydrogen atom, a Ci- ⁇ -alkyl group, a -CO-O-Ci- 6 -alkyl group, a C 3 . 8 -cycloalkyl group, a Ci- 6 -alkylene-C 3 - 8 -cycloalkyl group, group or a Ci -6 -alkyl group substituted with one or more hydroxy groups, or R c , R D together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more substituents independently selected from the group consisting of C-i-e alkyl group, a -CO-Ci- ⁇ -alkyl group, a -CO-O- Ci- ⁇ -alkyl group, a - CO-NH- group, a -CS-NH- Ci- 6 -alkyl group, an
  • R E , R F identical or different, represent hydrogen or a Ci- 6 -alkyl group, or R E and R F together with the bridging nitrogen atom form a saturated, mono- or bicyclic, 3-10 membered heterocyclic ring system, which may be at least mono-substituted by one or more, identical or different C 1 - 6 alkyl groups and/or which may contain at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur as a ring member,
  • heteroatoms which are present as ring members in the heteroaryl radical, may, unless defined otherwise, independently be selected from the group consisting of nitrogen, oxygen and sulphur.
  • a heteroaryl radical may comprise 1 , 2 or 3 heteroatoms independently selected from the group consisting of N, O and S as ring members.
  • Suitable heteroaryl groups may preferably be selected from the group consisting of thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl, indolyl, chinolinyl, isochinolinyl, benzo[1 ,2,5]- thiodiazolyl, benzo[b]thiophenyl, benzo[b]furanyl, imidazo[2,1-b]thiazolyl, triazolyl, and pyrazolyl, more preferably be selected from the group consisting of thienyl-, benzo[1 ,2,5]-thiodiazolyl, benzo[b]thiophenyl, imidazo[2,1-b]thiazolyl, triazolyl and pyrazolyl.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched Ci- 4 -alkoxy, branched or unbranched Ci- 4 -perfluoroalkoxy, branched or unbranched amino, carboxy, amido, cyano, nitro, -SO 2 NH 2 , -CO-Ci-4-alkyl, -SO-Ci ⁇ -alkyl, -SO 2 -Ci- 4 -alkyl, -NH-SO 2 -Ci- 4 -alkyl , wherein the C- ⁇ - 4 -alkyl may in each case be branched or unbranched, and
  • Preferred linear or branched, saturated or unsaturated aliphatic groups which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl.
  • any of the residues R 4 -R 8 represents or comprises a linear or branched alkylene group
  • said alkylene group may preferably be selected from the group consisting of - methylene -(CH 2 )-, ethylene -(CH 2 -CH 2 )-, n-propylene -(CH 2 -CH 2 -CH 2 )- or iso- propylene -(-C(CH 3 J 2 )-.
  • Preferred is the use of substituted pyrazoline compounds of general formula I given above, wherein
  • 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, R 6 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, a saturated or unsatur
  • 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 3 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3-S 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 3-8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system
  • R 3 represents an -NR 4 R 5 -moiety and R 1 , R 2 and R 4 -R 8 have the meaning given above, 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.
  • 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 d- ⁇ -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 -S ⁇ 2 -R 6 -moiety, or an
  • 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 3-8 cycloaliphatic group, which may be condensed with a 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 a mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH 2 - CH 2 )-group, preferably R 6 represents a Ci -6 -alkyl group, a saturated, optionally at least mono-substituted cycloaliphatic group, which may be condensed with a mono-
  • 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 1-6 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 represent a hydrogen atom or a d- ⁇ alkyl
  • R 1 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
  • 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
  • R 1 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
  • 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
  • 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 Ci- ⁇ -alkyl groups, or R 3 represents an -NR 4 R 5 -moiety, one of the residues R 4 and R 5 represents a hydrogen atom and the other one of these residues R 4 and R 5 represents an optionally at least mono-substituted pyrrolidinyl group; an optionally at least mono-substituted piperidinyl group; an optionally at least mono-substituted piperazinyl group; an optionally at least mono- substituted triazolyl group; an -SO 2 -R 6 -moiety; or an -NR 7 R 8 -moiety, or R 4 and R 5 , identical or different, represent a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-but
  • 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 C- ⁇ - 6 alkyl groups, and
  • R 7 and R 8 identical or different, represent a hydrogen atom or a C-u ⁇ alkyl radical.
  • R 4 represents a hydrogen atom or a linear or branched Ci- 6 -alkyl group
  • 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- 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; a triazolyl group; whereby each of the heterocyclic rings may be substituted with one or more, identical or different, d- 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.
  • 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 -SO 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, Ci -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.
  • At least one pyrazoline compound 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 inventively obtained medicament may be in any form suitable for the application to patients and can be produced by standard procedures known to those skilled in the art.
  • the composition of the medicament may vary depending on the route of administration.
  • Such medicaments 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); ..Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); ..Modern Pharmaceutics", Fourth Edition, Banker G.S. and Rhodes CT. (Eds.) Marcel Dekker, Inc. New York 2002 and n The Theory and Practice of Industrial Pharmacy", Lachman L., Lieberman H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective descriptions are incorporated by reference and form part of the present disclosure.
  • the medicament obtained according to the present invention may, for example, be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical excipients for injection such as stabilising agents, solubilizing agents, and buffers, may be included in such injectable compositions.
  • These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
  • the medicament obtained according to the present invention may also be administered topically, e.g. by means of a transdermal therapeutic system (TTS), or via a suppository.
  • TTS transdermal therapeutic system
  • the medicament is suitable for oral administration.
  • Suitable oral administration forms include tablets, dragees, capsules, syrups, gels, juices (oil- or water-based), chewing gums, sprays, aqueous or oily suspensions, or dry powdered forms, preferably in a sachet, suitable for reconstitution with water or other suitable liquid medium before use.
  • Suitable oral administration forms are multiparticulate formulations, preferably microtablets, microparticles, nanoparticles, 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 inventively obtained medicament may also comprise at least one substituted pyrazoline compound of general formula I given above at least partially in sustained- release form.
  • a sustained-release form By incorporating one or more of the substituted pyrazoline compounds of general formula I given above at least partially or completely into 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 optimal therapeutical plasma or tissue concentrations.
  • 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, MJ. Hadgraft, J. and Roberts, M.S.
  • the medicament obtained according to the present invention comprises at least one of the substituted pyrazoline compounds of general formula I 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(C 1-4 )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-
  • coating materials are commercially available as 30 wt.% aqueous latex dispersions, i.e. as Eudragit RS30D ® , Eudragit NE30D ® or Eudragit RL30D ® , and may also be used as such for coating purposes.
  • 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.
  • 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 C 6 -C 40 aliphatic or aromatic dicarboxylic acid and a CrC 8 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 medicament obtained according to the present invention may also have at least one enteric coating which dissolves as a function of pH. Because of this coating, the medicament can pass through the stomach undissolved and the compounds of general formula I 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 medicament 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.
  • the medicament obtained according to the present invention may contain one or more of the substituted pyrazoline compounds of general formula I 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.
  • the medicament is designed for once daily, twice daily, or three times daily administration. More preferably the medicament is designed for once daily or twice daily administration, most preferably for once daily administration,
  • 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 d- ⁇ 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)
  • 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 hydrazin of general formula (V) is preferably carried out in a suitable reaction medium such as Ci- 4 -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • a suitable reaction medium such as Ci- 4 -alcohols or ethers such as dioxane or tetrahydrofurane 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 C 1 . 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, tetrahydrofurane 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 1 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 fractionalised crystallisation with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.
  • Salts of the inventively used substituted pyrazoline compounds of general formula (I) and stereoisomers thereof may be obtained by a process, wherein at least one compound of general formula (I) 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 substituted pyrazoline compounds of general formula (I) or stereoisomers thereof may also be prepared by a method, wherein at least one compound of general formula (I) 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 R4-n] ⁇ wherein n is 0, 1 , 2, 3 or 4 and R represents a branched or unbranched Ci- 4 -alkyl-radical.
  • 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 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 medicament 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 daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
  • the daily dosage for humans may preferably be in the range fromi to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
  • 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 highly 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 (Harian, Barcelona, Spain) are used in all of the following experiments.
  • mice are acclimatised to the experimental setting. Pre-treatment control values are determined for analgesia hot plate latency (in seconds), rectal temperature, sedation and catalepsy.
  • analgesia hot plate latency in seconds
  • rectal temperature in order to determine the agonistic activity of the substance to be tested
  • 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 minutes 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
  • 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 effects 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 to the following formula:
  • % Catalepsy arithmetic mean / 6 X 100
  • the transgenic RIP/IGF-II mice overexpress Insulin ll-like Growth Factor in beta cells of the pancreatic islets.
  • the production of IGF-II in beta cells of these transgenic mice causes a hyperplasia and disorganisation of the islets, an increase of number and cell mass of beta cells, hyperinsulinemia and resistance to insulin.
  • these mice are slightly hyperglycaemic and show different results in tests such as glucose the tolerance and the insulin sensitivity test. Undergoing a high-lipid diet all of these animals develop obesity a sharp increase in hyperinsulinemia as well as in insulin resistance.
  • mice fed with a high lipid diet develop diabetes with high levels of hyperglycaemia (Devedjian, JC et al. J. Clin. Invest. (2000) 105, 731-740). Therefore, these animals represent a realistic model for diabetes type Il and obesity.
  • the dose was 0.2 ml for each 30 gram of weight.
  • the administration of compounds was done daily using an esophageal tube.
  • Free fatty acids in blood were determined by means of the method of the AcylCoA synthetase (Krebs M, Stingl H, Nowotny P, Weghuber D, Bischof M, Waldhausl W, Roden M., Prevention of in vitro lipolysis by tetrahydrolipstatin Clin Chem. 2000 Jul;46(7):950-4).
  • Figure 1 shows the evolution of free fatty acids (FFA) after one and two months.
  • (A) Vehicle; n 14;
  • (B) N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5- dihydro-I H-pyrazole-3-carboxamide; n 8
  • 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- dichlorophenylH. ⁇ -dihydro-pyrazole-S-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.
  • 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.

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Abstract

L'invention porte sur de composés de pyrazoline substituée utilisés dans la fabrication d'un médicament servant à la prophylaxie et/ou au traitement de l'obésité chez des patients souffrant de diabète de type II.
PCT/EP2006/006966 2005-07-15 2006-07-15 Utilisation de composes de pyrazoline substituee pour le traitement de troubles de l'alimentation dont l'obesite ou le syndrome metabolique chez des patients a diabete developpe. WO2007009692A1 (fr)

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EP05384016.1 2005-07-15
EP05384016A EP1743641A1 (fr) 2005-07-15 2005-07-15 Utilisation de pyrazolines substituées pour le traitement des maladies associées à l'alimentation incluant l'obésité ou le syndrome métabolique chez des diabétiques
US60/705,459 2005-07-15
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Publication number Priority date Publication date Assignee Title
WO2005077911A1 (fr) * 2004-02-17 2005-08-25 Laboratorios Del Dr. Esteve S.A. Composes de pyrazoline substituee, preparation et utilisation de ceux-ci comme medicaments

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ES2137138B1 (es) * 1998-05-29 2000-09-16 Esteve Labor Dr Derivados de pirazolinas, su preparacion y su aplicacion como medicamentos.

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Publication number Priority date Publication date Assignee Title
WO2005077911A1 (fr) * 2004-02-17 2005-08-25 Laboratorios Del Dr. Esteve S.A. Composes de pyrazoline substituee, preparation et utilisation de ceux-ci comme medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SIDDALL R: "RIO-DIABETES: RIMONABANT SHOWS PROMISE IN TYPE 2 DIABETES", BRITISH JOURNAL OF CARDIOLOGY, LONDON, GB, vol. 12, no. 4, July 2005 (2005-07-01), pages 257, XP009053958, ISSN: 0969-6113 *

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