WO2007009697A1 - Sels d'ammonium quaternaire de composes pyrazoliniques substitues, elaboration, utilisation medicamenteuse - Google Patents

Sels d'ammonium quaternaire de composes pyrazoliniques substitues, elaboration, utilisation medicamenteuse Download PDF

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Publication number
WO2007009697A1
WO2007009697A1 PCT/EP2006/006971 EP2006006971W WO2007009697A1 WO 2007009697 A1 WO2007009697 A1 WO 2007009697A1 EP 2006006971 W EP2006006971 W EP 2006006971W WO 2007009697 A1 WO2007009697 A1 WO 2007009697A1
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substituted
mono
group
unsubstituted
methyl
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PCT/EP2006/006971
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English (en)
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Antonio Torrens Jover
Jose Mas Prio
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Laboratorios Del Dr. Esteve, S.A.
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Priority claimed from EP05384026A external-priority patent/EP1749821A1/fr
Priority claimed from EP05384025A external-priority patent/EP1749820A1/fr
Application filed by Laboratorios Del Dr. Esteve, S.A. filed Critical Laboratorios Del Dr. Esteve, S.A.
Publication of WO2007009697A1 publication Critical patent/WO2007009697A1/fr

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    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Quaternary ammonium salts of substituted pyrazoline compounds their preparation and use as medicaments
  • the present invention relates to quaternary ammonium salts of substituted pyrazoline compounds, methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals.
  • 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.
  • cannabinoids as well as their synthetic analogues promote their physiological effects via binding to specific G-coupled receptors, the so-called cannabinoid-receptors.
  • CBi 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 CB r receptor is involved in many different food-intake related disorders such as bulimia or obesity, including obesity associated with type Il diabetes (non-insulin-dependent diabetes) and thus, compounds suitable for regulating this receptor may be used in the prophylaxis and/or treatment of these disorders.
  • these compounds have a high affinity for cannabinoid receptors, particularly for the CB r receptor, and that they act as modulators e. g. antagonists, inverse agonists or agonists on these receptors. They are therefore suitable for the prophylaxis and/or treatment of various disorders related to the central nervous system, the immune system, the cardiovascular system, the endocrinous system, the respiratory system, the gastrointestinal tract or reproduction in humans and/or animals, preferably humans including infants, children and grown- ups.
  • the present invention relates to quaternary ammonium salts of substituted pyrazoline compounds of general formula I,
  • X is O or S
  • A represents a hydrogen atom or an unsubstituted or at least mono-substituted alkyl radical
  • R 1 and R 2 independently of one another, in each case represent an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an optionally at least mono-substituted alkylene group, alkenylene group or alkinylene group; a -O-R 7 moiety; a -S-R 8 moiety; a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 5 and R 6 independently of one another, in each case represent a hydrogen atom
  • R 5 and R 6 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated heterocyclic ring which may contain at least one further heteroatom as a ring member and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of one another, in each case represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
  • an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group;
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
  • R 12 and R 13 independently of one another, in each case, represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • residues R 1 to R 13 and B represents or comprises an aryl, heteroaryl, benzoate or naphthoate radical, which may be substituted, unless defined otherwise, preferably said aryl, heteroaryl, benzoate or naphthoate radical may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -Ci- 6 -perfluoralkyl, -d- 6 -alkyl substituted with one or more methoxy and/or ethoxy groups, -Ci.
  • cyclic moieties cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl can optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -OH, -CF 3 , -CN, -NO 2 , -d. 6 -alkyl, -0-Ci -6 - alkyl, -O-CF 3 and -S-CF 3 and
  • R A , R B , R E and R F independently of one another, represent hydrogen or -Ci- 6 -alkyl or R A and R B in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different C h alky! radicals
  • said aryl and heteroaryl radicals may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF 3 , - C 2 F 5 , -C 3 F 7 , -C 4 F 9 , -CH 2 CI, -CHCI 2 , -C 2 H 4 CI, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -CH 2 -CH 2 -OH, -0-CH 2 -O-CH 3 , -0-CH 2 -CH 2 -O-CH 3 , -0-CH 2 -O-C 2 H 5 , - C(OCH 3 )(
  • Preferred aryl radicals which are optionally at least mono-substituted are phenyl and naphthyl (1- and 2-naphthyl).
  • 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 sulfur. More preferably a heteroaryl radical is 5- to 14-membered and may comprise 1 , 2, 3 or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • Preferred heteroaryl radicals which are unsubstituted or at least mono-substituted are pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzox
  • Preferred aryl and heteroaryl radicals which are condensed with a mono- or polycyclic ring system are [1 ,3]-benzodioxolyl, [1 ,4]-benzodioxanyl, [1 ,2,3,4]- tetrahydronaphthyl, (2,3)-dihydro-1 H-cyclopenta[b]indolyl, [1 ,2,3,4]- tetrahydroquinolinyl, [1 ,2,3,4]-tetrahydroisoquinolinyl, [1 ,2,3,4]-tetrahydroquinazolinyl and [3,4]-dihydro-2H-benzo[1 ,4]oxazinyl.
  • residues R 1 to R 13 and B represents or comprises a saturated or unsaturated, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, preferably a C3.-i 8 cycloaliphat.ic radical, a heterocyclic ring, preferably a 4- to 10-membered heterocyclic ring, a C 3- i 6 cycloalkyl radical, a C 4-16 cycloalkenyl radical, a C 4-I6 heterocycloalkyl radical, or a C 5- - I6 heterocycloalkenyl radical, which may be substituted, unless defined otherwise, preferably said cycloaliphatic radical, heterocyclic ring, C 3 -i 6 cycloalkyl radical, C 4-I6 cycloalkenyl radical, C 4-I6 heterocycloalkyl radical, or C 5-I6 heterocycloalkenyl radical, may in each case optionally be substituted with 1 , 2, 3, 4 or 5 substituent(
  • 6 -alkyl substituted with one or more chlorine atoms -Ci. 6 -alkyl substituted with one or more methoxy and/or ethoxy groups, -O-Ci. 6 -alkyl, -O-Ci.
  • R A , R B , R E and R F independently of one another, represent hydrogen or -Ci- 6 -alkyl or R A and R B in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different C- ⁇ - 6 alkyl radicals
  • residues R 1 to R 13 and B represents or comprises a cycloaliphatic radical, preferably a C 3 .i 6 cycloaliphatic radical, 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 nitrogen, oxygen and sulfur. More preferably a cycloaliphatic group may optionally contain 1 , 2, 3 or 4 heteroatom(s) 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 cycloaliphatic radicals may preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl
  • Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals which are condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system may preferably be selected from the group consisting of indolinyl, isoindolinyl, decahydronaphthyl, (1 ,2,3,4)- tetrahydroquinolinyl, (1 ,2,3,4)-tetrahydroisoquinolinyl, (1 ,2,3,4)-tetrahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)-hexahydro-2H-quinolizinyl, (1 ,2,3,5,6,8a)-hexahydro-indolizinyl, decahydroquinolinyl, dodecahydro-carbazolyl, 9H-carbazolyl
  • a cycloaliphatic radical, a C 3 -i 6 cycloalkyl radical, a C/ M ⁇ cycloalkenyl radical, a C-ne heterocycloalkyl radical or a C 5-I6 heterocycloalkenyl radical may be bridged by 1 , 2 or 3 unsubstituted or at least mono-substituted alkylene group(s).
  • Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals which are bridged by at least one unsubstituted or at least mono-substituted alkylene group may preferably be selected from the group consisting of adamantyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, norbornenyl and 8- aza-bicyclo[3.2.1]octyl.
  • a mono- or polycyclic ring system according to the present invention - if not defined otherwise - means a mono- or polycyclic hydrocarbon ring system, preferably a mono- or bicyclic ring system, that may be saturated, unsaturated or aromatic. Each of its different rings may show a different degree of saturation, i.e. they may be saturated, unsaturated or aromatic.
  • each of the rings of the mono- or bicyclic ring system may contain one or more, preferably 1 , 2 or 3, heteroatom(s) as ring member(s), which may be identical or different and which can preferably be selected from the group consisting of nitrogen, oxygen and sulfur.
  • the rings of the mono- or bicyclic ring system are preferably 5-, 6- or 7-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.
  • cyclic moieties cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl can optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -OH, -CF 3 , -CN, -NO 2 , -d -6 -alkyl, -0-Ci -6 - alkyl, -0-CF 3 and -S-CF 3 and
  • R A , R B , R E and R F independently of one another, represent hydrogen or -Ci- 6 -alkyl or R A and R B in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different d- ⁇ alkyl radicals
  • residues R 3 to R 13 , A and B represent or comprise a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical, preferably a Ci- 16 aliphatic radical, said aliphatic radical may be linear or branched.
  • Ci-i 6 alkyl radicals, C 2 -i 6 alkenyl radical and C 2 .i 6 alkinyl radicals may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of -OH, F, Cl, Br, I, -O-Ci- 6 -alkyl, -OCF 3 , -0-C 2 F 5 , -0-C 3 F 7 , -0-C 4 F 9 , -CF 3 , -C 2 F 5 , -C 3 F 7 , -C 4 F 9 , - NH 2 , -NH-d- ⁇ -alkyl, -N(Ci.
  • Suitable alkyl radicals are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)- heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl, 2-(6-methyl)-octyl, 2-(6-methyl)-oc
  • Suitable at least mono-substituted alkyl radicals are selected from the group consisting of -CF 3 , -CH 2 F, -CF 2 H, -CH 2 -O-CH 3 , -C 2 F 5 , -CH 2 -CH 2 -F, -CH 2 -CN, -CH 2 - OH, -CH 2 -CH 2 -CN, -CH 2 -CH 2 -OH, -CH 2 -CH 2 -OCH 3 , -CH 2 -CH 2 -CH 2 -CN, -CH 2 -CH 2 - CH 2 -OH, -CH 2 -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -CH 2 -CH 2 -O-CH 31 -CH 2 -NH 2 , -CH 2 - N(CH 3 ) 2 , -CH 2 -N(C 2 Hs) 2 , -CH 2 -CH-NH
  • An alkenyl radical according to the present invention comprises at least one carbon- carbon double bond.
  • Suitable alkenyl radicals preferably C 2- i 6 alkenyl radicals, are selected from the group consisting of vinyl, n-propenyl, n-butenyl, n-pentenyl, n- hexenyl, n-heptenyl, n-octenyl, n-nonenyl, n-decenyl, n-undecenyl, n-dodecenyl, n- tridecenyl, n-tetradecenyl, n-pentadecenyl and n-hexadecenyl.
  • An alkinyl radical comprises at least one carbon-carbon triple bond.
  • Suitable alkinyl radicals preferably C 2- -I 6 alkinyl radicals, are selected from the group consisting of ethinyl, propinyl, n-butinyl, n-pentinyl, n-hexinyl, n-octinyl, n-noninyl, n-decinyl, n- undecinyl, n-dodecinyl, n-tridecinyl, n-tetradecinyl, n-pentadecinyl and n-hexadecinyl.
  • any of the substituents represents an alkylene group, an alkenylene group or an alkinylene group, which may be substituted, said alkylene group, alkenylene group or alkinylene group may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably unsubstituted or substituted with 1 , 2 or 3 substituent(s).
  • Said substituent(s) may preferably be selected independently from the group consisting of -O-Ci-e-alkyl, -S-Ci -6 -alkyl, -F, Cl, Br, I 1 -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -SO 3 H, -NH 2 , -NH(C 1-6 -alkyl), -N(C 1-6 -alkyl) 2 and phenyl.
  • said substituent(s) may be selected from the group consisting of -F, Cl, Br, I, -CN, - CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -SO 3 H, -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -0-CH 3 and -O- C 2 H 5 .
  • An alkenylene group comprises at least one carbon-carbon double bond
  • an alkinylene group comprises at least one carbon-carbon triple bond.
  • X is O or S
  • A represents a hydrogen atom or an unsubstituted or at least mono-substituted Ci-- I0 alkyl radical
  • R 1 and R 2 independently of one another, in each case represent an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted C 3-I e cycloalkyl radical or C 4- - I6 cycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • an unsubstituted or at least mono-substituted C 3- I 6 cycloalkyl radical or C4- 16 cycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1 . 5 alkylene group, C 2 - 5 alkenylene group or C 2 - 5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • an unsubstituted or at least mono-substituted C4-1 6 heterocycloalkyl radical or C 5- i 6 heterocycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1 - 5 alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci- 5 alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group;
  • a -O-R 7 moiety a -S-R 8 moiety; a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 5 and R 6 independently of one another, in each case represent a hydrogen atom
  • Ci -16 alkyl radical an unsubstituted or at least mono-substituted Ci -16 alkyl radical, C 2 -i 6 alkenyl radical or C 2 -i ⁇ alkinyl radical;
  • R 5 and R 6 together with the bridging nitrogen form an unsubstituted or at least mono- substituted, saturated or unsaturated 4- to 10-membered heterocyclic ring which may optionally contain 1 , 2 or 3 additional heteroatom(s) selected from the group consisting of sulfur, nitrogen and oxygen as ring member(s) and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of one another, in each case represent
  • cycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C 2 - 5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • an unsubstituted or at least mono-substituted C 4-16 heterocycloalkyl radical or C 5-I6 heterocycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1 .
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C 2 - 5 alkenylene group or C 2-5 alkinylene group;
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
  • Ci-i 6 alkyl radical an unsubstituted or at least mono-substituted Ci-i 6 alkyl radical, C 2 -i 6 alkenyl radical or C 2- i 6 alkinyl radical;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C2- 5 alkenylene group or C2 -5 alkinylene group; an unsubstituted or at least mono-substituted C 3 -i 6 cycloalkyl radical or C 4- i 6 cycloalkenyl radical, which in each case may be bonded via an unsubstituted or at least mono-substituted C-1. 5 alkylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • the rings of the aforementioned ring system are in each case independently of one another 5- 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
  • heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
  • heterocycloalkyl radicals and heterocycloalkenyl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -0-CH 3 , -0-C 2 H 5 , -0-CH 2
  • R 1 to R 13 , X and B 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 solvate thereof.
  • R 1 and R 2 independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]- benzothiadia
  • R 3 to R 13 , X, A and B 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 solvate thereof.
  • R 3 and R 4 independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO 2 ; -NC; -OH; -NH 2 ; -SH; -C(O)-H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- oc
  • a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH 2 )-, -(CH 2 HCH 2 )-, -(CH 2 )-(CH 2 )-(CH 2 )- or -CH CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF 3 , methyl, ethyl, n-propyl, isopropyl, n-but
  • a -O-R 7 moiety a -S-R 8 moiety, a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 1 , R 2 , R 5 to R 13 , X, A and B 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 solvate thereof.
  • quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above wherein R 5 and R 6 , independently of one another, in each case represent a hydrogen atom;
  • R 1 to R 4 , R 7 to R 13 , X, A and B 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 solvate thereof.
  • R 1 to R 4 , R 7 to R 13 , X, A and B 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 solvate thereof.
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4- heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5- methyl)-he
  • a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH 2 )-, -(CH 2 HCH 2 )-, -(CH 2 )-(CH 2 )-(CH 2 )- or -CH CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF 3 , methyl, ethyl, n-propyl, isopropyl, n-CF
  • R 1 to R 6 , R 12 , R 13 , X, A and B 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 solvate thereof.
  • quaternary ammonium salts of substituted pyrazoline compounds of general formula I wherein B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -0-CH 3 and -0-C 2 H 5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
  • R 1 to R 13 , X and A 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 solvate thereof.
  • R 12 and R 13 independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2- octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2- (4-methyl)-hex
  • R 1 to R 11 , X 1 B and A 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 solvate thereof.
  • X is O or S:
  • A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4- heptyl, n-octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -O- CH 3 , -0-C 2 H 5 , -0-CH 2 -CH 2 -CH 3 , -O-CH(CH 3 ) 2 , -0-CH 2
  • R 1 and R 2 independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, diazepanyl, azocan
  • a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH 2 )-, -(CH 2 HCH 2 )-, -(CH 2 )-(CH 2 )-(CH 2 )- or -CH CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF 3 , methyl, ethyl, n-propyl, isopropyl, n-but
  • a -O-R 7 moiety a -S-R 8 moiety, a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 5 and R 6 independently of one another, in each case represent a hydrogen atom
  • R 5 and R 6 together with the bridging nitrogen atom form a moiety selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, azepanyl, diazepanyl, azocanyl, (2,5)-dihydro-1 H-pyrrolyl, (2,3)-dihydro-1 H-pyrrolyl, (1 ,2,3,6)- tetrahydropyridinyl, (1 ,2,3,4)-tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]- oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-d
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7- methyl)-octyl;
  • a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH 2 )-, -(CH 2 )-(CH 2 )-, -(CH 2 )-(CH 2 )-(CH 2 )- or -CH CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF 3 , methyl, ethyl, n-propyl, isopropyl,
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -0-CH 3 and -0-C 2 H 5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate, R i2 -sor and R 13 -NH-S ⁇ 3 ;
  • R 12 and R 13 independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n- heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)- heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • X is O or S
  • A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl;
  • R 1 and R 2 independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]- be
  • a -O-R 7 moiety a -S-R 8 moiety, a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 4 represents H or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl;
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl; R 5 and R 6 together with the bridging nitrogen atom form a moiety selected from the group consisting of
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -O- CH 3 and -0-C 2 H 5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
  • R 12 and R 13 independently of one another, in each case represent a radical selected from the group consisting Of -CF 3 , -C 2 F 5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7- methyl )-oct
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl and n-propyl;
  • R 1 represents a radical selected from the group consisting of phenyl and thienyl (thiophenyl), which may optionally be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -0-CH 3 and -O-C 2 H 5 ;
  • R 2 represents a phenyl radical, which may be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br and I;
  • R 4 represents H or a radical selected from the group consisting of methyl, ethyl, n- propyl, iso-propyl and n-butyl;
  • R 5 and R 6 together with the bridging nitrogen atom form a moiety selected from the group consisting of
  • R 7 represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, (2,5)-dihydroxy-benzenesulfonate, naphthalene-2-sulfonate, 5- sulfo-napthalene-1 -sulfonate, cyclamate, dodecane-1 -sulfonate and (7,7)-dimethyl-2- oxo-bicyclo[2.2.1]-hept-1-yl-methanesulfonate;
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • trans-1 [27] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [28] trans-1 -[[5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [29] trans-1 -[[5-(4-Fluoro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [30] c
  • trans-1 [32] trans-1 -[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [33] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [34] cis-2-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-2-methyl-octahydrocyclopenta[c]pyrrolium iodide [
  • 4,5-dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • the present invention provides a N-oxide of general formula Ia,
  • X a is O or S
  • R 1a and R 2a independently of one another, in each case represent an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an optionally at least mono-substituted alkylene group, alkenylene group or alkinylene group;
  • R 5a and R 6 * 1 independently of one another, in each case represent a hydrogen atom
  • R 5a and R 68 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated heterocyclic ring which may contain at least one further heteroatom as a ring member and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
  • R 7a , R 8a , R 9a , R 1Oa and R 11a independently of one another, in each case represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
  • an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group;
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • X a is O or S
  • R 1a and R 2a independently of one another, in each case represent an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • Ci-i 6 alkyl radical C 2-16 alkenyl radical or C 2-16 alkinyl radical;
  • an unsubstituted or at least mono-substituted C 3-16 cycloalkyl radical or C- M6 cycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1 - S alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted C 1-5 alkylene group;
  • an unsubstituted or at least mono-substituted C-J -16 heterocycloalkyl radical or C 5 .i 6 heterocycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1-5 alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted C 1-5 alkylene group;
  • an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci- 5 alkylene group, C 2-5 alkenylene group or C 2 .
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C 2 . 5 alkenylene group or C 2 - 5 alkinylene group;
  • a -O-R 7a moiety a moiety; a -S-R 83 moiety; a -NH-R 9a moiety or a -NR 1Oa R 11a moiety;
  • R 5a and R 68 independently of one another, in each case represent a hydrogen atom
  • Ci.i 6 alkyl radical an unsubstituted or at least mono-substituted Ci.i 6 alkyl radical, C 2- i 6 alkenyl radical or C 2 -i 6 alkinyl radical;
  • R 5a and R 68 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated 4- to 10-membered heterocyclic ring which may optionally contain 1 , 2 or 3 additional heteroatom(s) selected from the group consisting of sulfur, nitrogen and oxygen as ring member(s) and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
  • R 7a , R 83 , R 9a , R 1Oa and R 11a independently of one another, in each case represent
  • an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted C1-5 alkylene group, C2- 5 alkenylene group or C 2-5 alkinylene group;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C 2 - 5 alkenylene group or C 2-S alkinylene group;
  • the rings of the aforementioned ring system are in each case independently of one another 5- 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
  • heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
  • heterocycloalkyl radicals and heterocycloalkenyl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s); optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • N-oxides of general formula Ia given above More particularly preferred are N-oxides of general formula Ia given above, wherein
  • X a is O or S
  • R 1a and R 2a independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]
  • R 4a represents H or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl;
  • R 7a , R 8a , R 9a , R 1Oa and R 11a independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
  • R 5a and R 68 together with the bridging nitrogen atom form a moiety selected from the group consisting of
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • X a is O
  • R 1a represents a radical selected from the group consisting of phenyl and thienyl (thiophenyl), which may optionally be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -0-CH 3 and -0-C 2 H 5 ;
  • R 2a represents a phenyl radical, which may be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br and I;
  • R 4a represents H or a radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl and n-butyl;
  • R 5a and R 68 together with the bridging nitrogen atom form a moiety selected from the group consisting of
  • R 7a represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • R 3 and X have the meaning given above and R' represents a linear or branched Ci -6 -alkyl radical, a potassium cation or a sodium cation, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one base, to yield at least one compound of general formula IV,
  • R 1 , X and R 3 have the meaning given above, which is optionally purified and/or isolated,
  • R 1 , X, R 2 and R 3 have the meaning given above, which is optionally isolated and/or purified,
  • R 1 , X, R 2 and R 3 have the meaning given above and LG represents a leaving group, which is optionally purified and/or isolated, and at least one compound of general formula VII is reacted with at least one compound of general formula NH 2 -NR 5 R 6 , wherein R 5 and R 6 have the meaning given above, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one base selected from the group consisting of diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine and N- methylmorpholine, to yield at least one compound of general formula VIII,
  • R 1 , R 2 , R 3 , X, R 5 and R 6 have the meaning given above, which is optionally purified and/or isolated;
  • At least one compound of general formula Vl is reacted with at least one compound of general formula NH 2 -NR 5 R 6 , wherein R 5 and R 6 have the meaning given above, in a reaction medium, in the presence of at least one coupling agent, optionally in the presence of at least one base, to yield at least one compound of general VIII, which is optionally purified and/or isolated;
  • R 4 represents hydrogen, which is optionally purified and/or isolated.
  • a compound of general formula Il is reacted with a compound of general formula III in a protic reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, water and mixtures thereof, in the presence of at least one base, 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).
  • 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 between a compound of general formula Il and a compound of general formula III can also be carried out under acid catalysed conditions, more preferably by refluxing the above mentioned compounds 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 above mentioned compounds 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.
  • step 2 a compound of general formula IV is reacted with a compound of general formula V in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, dieethylether, tert-butyl-methylether, dioxane, tetrahydrofuran or mixtures of at least two of these afore mentioned reaction media.
  • 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 mixtures of at least two of these bases.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide or mixtures of at least two of these bases.
  • 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.
  • a suitable leaving group Preferably the compounds of general formula Vl are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a Ci- 4 alkyl ester or an activated ester such as p- nitrophenylester.
  • Suitable activating agent therefore are selected from the group consisting of thionyl chloride, oxalyl chloride and ethylchloroformiate.
  • said activated compound of general formula VII is an acid chloride, wherein LG represents a chlorine atom
  • that compound is preferably prepared by the reaction of the corresponding acid of general formula Vl with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the reaction medium, in the presence of at least one base, preferably in the presence of a base selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, dimethylaminopyridine and diisopropylethylamine.
  • a base selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, dimethylaminopyridine and diisopropylethylamine.
  • an additional reaction medium may be used.
  • Suitable reaction media 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 or dimethylformamide and mixtures thereof. More preferably toluene in the presence of a catalytic amount of dimethylformamide is used as reaction medium.
  • Preferred reaction temperature range from 0° C to the boiling point of the solvent and reaction times vary from several minutes to several hours.
  • said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula Vl with ethylchloroformiate in the presence of a base such as triethylamine, pyridine or diisopropylethylamine, in a suitable solvent such as dichloromethane, optionally in an inert atmosphere, at a temperature between -50 0 C and 50 0 C.
  • step 4 the reaction between a compound of general formula VII with a compound of general formula NHb-NR 5 R 6 to yield a compound of general formula VIII is preferably carried out in the 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 0 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.
  • a compound of general formula Vl is reacted with a compound of general formula NHk-NR 5 R 6 in a reaction medium, preferably in a reaction medium selected from the group consisting of diethylether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1 ,2)-dichlorethane, dimethylformamide, dichlormethane and mixtures thereof, in the presence of at least one coupling agent, preferably in the presence of at least one coupling agent selected from the group consisting of 1 -benzotriazolyloxy- tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI) 1 diisoproylcarbodiimide, 1 ,1'-carbonyl-diimidazole (CDI
  • reaction is carried out in the presence of EDCI and HOBt, optionally in the presence of N-methylmorpholine or triethylamine, in an aprotic reaction medium such as dimethylformamide or tetrahydrofuran, at a temperature between 20 °C and 30 0 C for 15 to 24 hours as described in Tetrahedron Lett. 2004, 45, 4977.
  • aprotic reaction medium such as dimethylformamide or tetrahydrofuran
  • reaction can be carried out by using HBTU in the presence of a base such as diisopropylethylamine in an aprotic solvent, such as acetonitrile, preferably at a temperature between 20 and 30 0 C for 15 to 24 hours.
  • a base such as diisopropylethylamine
  • an aprotic solvent such as acetonitrile
  • A represents an unsubstituted or at least mono-substituted alkyl radical, preferably an unsubstituted C 1-I0 alkyl radical and B represents an anion selected from the group consisting of fluoride, chloride, bromide and iodide, in a reaction medium, preferably in a reaction medium selected from the group consisting of chloroform, acetone, acetonitrile, dichloromethane, carbon tetrachloride, toluene and mixtures of the afore mentioned reaction media, at a temperature between 0 0 C to 120 °C, preferably at a temperature between 20 0 C to 100 0 C, to afford a salt of general formula I.
  • the duration of the reaction may vary over a broad range. Suitable reaction times may vary for example
  • A represents a hydrogen atom
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate, R 1 -SO-f and R 1 -NH-SO 3 ; wherein R 12 and R 13 have the meaning given above; in a reaction medium, preferably in a reaction medium selected from the group consisting of
  • Suitable acids include hydrochloric, hydrofluoric, hydroiodic or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; thiocyanic acid; cyanic acid; cyclamic acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g.
  • Suitable acids also include 3-amino-1-propanesulfonic acid, aniline-2-sulfonic acid, 3- pyridinesulfonic acid, 4-amino-3-hydroxy-1 -naphthalenesulfonic acid, 2-amino-1 ,5- naphthalenedisulfonic acid, aminomethanesulfonic acid, 2-mesitylenesulfonic acid, 7- amino-1 ,3-naphthalenedisulfonic acid, (2,5)-diaminobenzenesulfonic acid, trifluormethanesulfonic acid, 1 -naphthalenesulfonic acid, 6-amino-m-toluenesulfonic acid, 2-phenylbenzimidazole-5-sulfonic acid, 1-amino-benzimidazole-2-sulfonic acid, I H-benzimidazole-2-sulfonic acid, 1-methylbenzimidazole-2-sulfonic acid, 5- isoquinolinesulfonic
  • Hydrochloric acid is preferably used as a methanolic, ethanolic, ethereal or aqueous solution.
  • hydrogen chloride gas can be used for the preparation of the salts of general formula I given above.
  • a compound of general formula IMb is reacted with a compound of general formula Il in a reaction medium , preferably in a protic reaction medium, more preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, water and mixtures thereof, in the presence of at least one base, 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 or in the presence of lithium diisopropylamide in an aprotic solvent, preferably in tetrahydrofuran.
  • a reaction medium preferably in a protic reaction medium, more preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, water and mixtures thereof, in the presence of at least one base, preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or
  • step 2 a compound of general formula Xl is transformed into a compound of general formula XII which contains a good living group LG, preferably a leaving group selected from the group consisting of mesyl and tosyl, using conventional methods known to those skilled in the art.
  • LG preferably a leaving group selected from the group consisting of mesyl and tosyl
  • step 3 a compound of general formula XII is reacted with a compound of general formula V in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, dieethylether, tert-butyl-methylether, dioxane, tetrahydrofuran or mixtures of at least two of these afore mentioned reaction media.
  • 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 mixtures of at least two of these bases.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide or mixtures of at least two of these bases.
  • 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.
  • Step 4 can be carried out as described for step 3, scheme I; step 5 can be carried out as described for step 5, scheme I, step 6 can be carried out as described for step 4, scheme 1 and step 7 can be carried out as described for step 6, scheme I.
  • the afore mentioned reactions involving the synthesis of the 4,5-dihydro-pyrazole ring or the reaction of a compound comprising said ring are preferably carried out under an inert atmosphere, preferably under a nitrogen or argon atmosphere, to avoid oxidation of the ring-system.
  • an inert atmosphere preferably under a nitrogen or argon atmosphere
  • the protection of sensitive or reactive groups may be necessary and/or desirable. This can be performed by using conventional protective groups like those described in Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T.W. Greene & P.G.M. Wuts and Protective Groups in Organic Chemistry, John Wiley & sons, 1991.
  • the respective parts of the description is hereby incorporated by reference and forms part of the disclosure.
  • the protective groups may be eliminated when convenient by means well-known to those skilled in the art.
  • substituted pyrazoline compounds and/or the quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above 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 crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.
  • Solvates preferably hydrates, of the quaternary ammonium salts of substituted pyrazoline compounds, of corresponding stereoisomers or of corresponding diastereomers thereof may also be obtained by standard procedures known to those skilled in the art.
  • the purification and isolation of the substituted pyrazoline compounds and/or of quaternary ammonium salts of substituted pyrazoline compounds, of a corresponding stereoisomer, or diastereomer or solvate or any intermediate thereof may, if required, be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.
  • the quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above may also act as prodrugs, i.e. they represent a drug precursor, which following administration to a patient releases a drug in vivo via some kind of chemical and/or physiological process (e.g., a prodrug on being brought to a physiological pH and/or through an enzyme action is converted to a desired drug form; see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8).
  • the compounds of general formula I give rise to a compound of general formula XIII,
  • Prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics for a particular compound.
  • a hydroxyl group can be esterified, e.g., with a carboxylic acid group to yield an ester.
  • the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal the hydroxyl group.
  • quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above have a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CBi)-receptors, i.e. they are selective ligands for the (CBi)-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors.
  • cannabinoid 1 (CBi)-receptors particularly cannabinoid 1 (CBi)-receptors, i.e. they are selective ligands for the (CBi)-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors.
  • these quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above show little or no development of tolerance during treatment, particularly with respect to food intake, i.e.
  • the inventively used quaternary ammonium salts of substituted pyrazoline compounds will again show the desired effect.
  • the positive influence on the body weight is found to continue.
  • inventively used quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above are distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively little undesired effects, i.e. effects which do not positively contribute to or even interfere with the well being of the patient.
  • an other aspect of the present invention relates to a medicament comprising at least quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally at least one physiologically acceptable auxiliary agent.
  • said medicament is suitable for the modulation (regulation) of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • cannabinoid-receptors preferably cannabinoid 1 (CBi) receptors
  • Particularly preferably said medicament is suitable for the prophylaxis and/or treatment of psychosis.
  • said medicament is suitable for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity and/or type Il diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
  • the inventive medicament also seems to be active in the prophylaxis and/or treatment of appetency disorders, e.g. the quaternary ammonium salts of substituted pyrazoline compounds also reduce the desire for sweets.
  • 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 mm Hg,
  • 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 mm Hg, 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.
  • said medicament is suitable for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
  • cancer preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
  • Particularly preferably said medicament is suitable for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
  • the inventive medicament is active in the treatment of abstinence, craving reduction and relapse prevention of alcohol intake.
  • the inventive medicament can also be used in the prophylaxis and/or treatment of smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking.
  • Medicaments and/or drugs, which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
  • the medicament is also suitable for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g. osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer-associated bone disease or Paget's disease of bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebella disorders, spinocerebella disorders, cognitive disorders, cranial trauma, head trauma, stroke, panic attacks, peripheric neuropathy, inflammation, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, medicament-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrho
  • the 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
  • Another aspect of the present invention is the use of at least one quaternary ammonium salt of general formula I given above as suitable active substances, 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 solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • cannabinoid-receptors preferably cannabinoid 1 (CBi) receptors
  • At least one of the respective quaternary ammonium salts of general formula I 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 solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of psychosis.
  • a medicament for the prophylaxis and/or treatment of food intake disorders preferably bulimia, anorexia, cachexia, obesity and/or type Il diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
  • a medicament for the prophylaxis and/or treatment of cancer preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected
  • At least one quaternary ammonium salt of substituted pyrazoline compounds of general formula I 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 solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
  • Medicaments/drugs which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
  • At least one of the respective quaternary ammonium salts of substituted pyrazoline compounds of general formula I 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 solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g.
  • At least one of the respective quaternary ammonium salts of substituted pyrazoline compounds of general formula I 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 solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament 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
  • 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
  • Dementia is a disease characterized by the progressive deterioration in cognitive and social adaptive functions that can eventually interfere with the patient's ability to live independently. Dementia also constitutes of impairment in short- and long-term memory plus additional symptoms, such as problems with abstract thinking, judgment, or personality. An estimated 18 million patients suffer from dementia worldwide. The most common forms of dementia include Alzheimer's disease and vascular dementia. Other forms are frontotemporal dementia and Pick's disease.
  • Vascular dementia is considered to be the second most common dementia of late life, affecting approximately 10-15% of all cases. AD and vascular dementia can exist in isolation or together (mixed dementia). In vascular dementia, atherosclerotic changes in cerebral vessels can lead to reduced local blood flow that results in multiple small strokes (multi-infarct dementia). Vascular dementia is pharmacologically treated by stroke prophylaxis, and by treatment of the cognitive deficit.
  • AD Alzheimer's disease
  • AD the most common and important form of dementia
  • cognitive functions such as abstract reasoning and memory.
  • AD is a neurodegenerative disorder that is characterized by progressive impairment of cognitive functions, such as abstract reasoning and memory.
  • AD is one of the most prevalent illnesses in the elderly.
  • the majority of AD patients are in their sixties or older. More than 5% of all persons over the age of 70 have significant memory loss due to AD.
  • AD is mainly characterized through a gradual development of forgetfulness. In further advanced disease stages, other failures in cerebral function become increasingly apparent. This includes impairment of speech, writing, and arithmetic skills.
  • Visiospacial orientation such as parking the car, dressing properly, and giving and understanding directions to a location, can become defective or impaired.
  • patients forget how to use common objects and tools while retaining necessary motor power and co-ordination for these activities.
  • Schizophrenia is characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, perception, affect, and sense of self.
  • Positive symptoms include psychotic manifestations, such as hearing internal voices or experiencing other sensations not connected to an obvious source (hallucinations) and assigning unusual significance or meaning to normal events or holding fixed false personal beliefs (delusions).
  • Negative symptoms are characterized by affective flattening and lack of initiative or goals (avolition), loss of usual interests or pleasures (anhedonia), disturbances of sleep and eating, dysphoric mood (depressed, anxious, irritable, or angry mood) and difficulty concentrating or focusing attention.
  • Major depression is a multifaceted disorder characterized by primarily by dysphoric mood and loss of interest or pleasure in activities that were once enjoyable. Other physical and psychological symptoms include inability to concentrate, motor disturbances (psychomotor retardation or agitation), feelings of worthlessness, inappropriate guilt, thoughts of suicide, and disturbances in appetite and sleep.
  • Anxiety disorders are a group of syndromes that include generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, and post traumatic stress disorder. Although each disorder has its own distinct features, all share common symptoms of excessive worrying, intense fears and dread, hypervigilance and/or somatic symptoms, in the absence of a dangerous situation.
  • Normal sexual function requires, among others, the ability to achieve and maintain penile erection.
  • Major anatomic structures of the penis that are involved in erectile function include the corpus cavernosum, corpus spinosum, and the tunica albuginea (a collagenous sheath that surrounds each corpus).
  • Thecorpora are composed of a mass of smooth muscle (trabecule) which contains a network of endothelial-lined vessels (lacunar spaces). Penile tumescence and erection is caused by relaxation of the arteries and corporal smooth muscles, while closing emissary veins, leading to increased blood flow into the lacunar network. Central and peripheral innervation contributes to regulation of the erectile response.
  • Erectile dysfunction may result from failure to initiate, fill, or store adequate blood volume within the lacunar network of the penis.
  • ED may be vasculogenic, neurogenic, endocrinologic, diabetic, psychogenic, or medication-related.
  • ED affects 10-25% of middle-aged and elderly men, and has a profound impact on the well-being of affected men. It is currently treated using PDE5 inhibitors such as vardenafil, tadalifil, and sildenafil, lntraurethral alpostadil (prostaglandin El) may be used in patients that fail on oral agents.
  • PDE5 inhibitors such as vardenafil, tadalifil, and sildenafil, lntraurethral alpostadil (prostaglandin El) may be used in patients that fail on oral agents.
  • VCD vacuum constriction devices
  • FSD Female sexual dysfunction
  • FSD denotes a range of medical problems and is categorized according to disorders of (1) desire, (2) arousal, (3) orgasm and (4) sexual pain, and symptoms include diminished vaginal lubrication, pain and discomfort with intercourse, decreased arousal, and difficulty achieveing orgasm.
  • VIP vasoactive intestinal peptide
  • NO nitic oxide
  • sex hormones such as estrogens and androgens
  • Current treatment approaches include estrogen replacement therapy, methyl testosterone, PDE5 inhibitors such as sildenafil, the NO-donor L- arginine, prostaglandin El, phentolamine, and the dopamine agonists apomorphine.
  • the medicament according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.
  • the medicament can be produced by standard procedures known to those skilled in the art, e.g. from the table of contents of "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.
  • composition of the medicament may vary depending on the route of administration.
  • the medicament of 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.
  • Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form.
  • These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the compositions may take any convenient form, such as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
  • the multiparticulate forms, such as pellets or granules may e.g. be filled into a capsule, compressed into tablets or suspended in a suitable liquid.
  • Suitable controlled release formulations, materials and methods for their preparation are known from the prior art, e.g. from the table of contents of "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);
  • Medicaments according to the present invention may also comprise an enteric coating, so that their dissolution is dependent on pH-value. Due to said coating the medicament can pass the stomach undissolved and the respective quaternary ammonium salt of general formula I is liberated in the intestinal tract.
  • the enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials and methods for the preparation are known from the prior art.
  • the medicaments according to the present invention may contain 1-60 % by weight of one or more quaternary ammonium salts of substituted pyrazoline compounds as defined herein and 40-99 % by weight of one or more auxiliary substances (additives).
  • liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
  • Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
  • compositions of the present invention may also be administered topically or via a suppository.
  • 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 from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000, even more preferably 1 to 150 milligrams of active substance to be administered during one or several intakes per day.
  • Binding affinity to CB1 receptor was evaluated according to a modification of the method described by Govaerts et al., Eur J Pharmac Sci 23, 233-243 (2004). The respective parts of the description is hereby incorporated by reference and forms part of the present disclosure.
  • cerebellum from male wistar rats 250-30Og were carefully dissected on ice and homogenates were prepared with Potter-Helveheim in a cold 50 mM Tris-HCI solution containing 5 mM MgCI 2 , 1 mM EDTA and 0.25 M sucrose, pH 7.4. The suspension was centrifuged at 1 ,000 x g for 5 minutes. The supernatants were collected and centrifuged 50,000 x g for 15 minutes. The resulting pellets were then resuspended in Tris-HCI buffer without sucrose, homogenized and incubated for 15 min at 37 0 C in an orbital shaker bath and centrifuged again at 50,000 x g for 15 min.
  • Pellets were weighted, resuspended in Tris-HCI buffer without sucrose, homogenized with Ultraturrax at 13,500 rpm for 3 x 5 seconds and alicuoted in 0.9 ml volumes in Eppendorf tubes. Alicuotes were centrifuged at 20,800 x g for 5 minutes, supernatants discarded and pellets were frozen at -8O 0 C until use. Total protein concentration was determined using the Bio-Rad Lowry method based kit.
  • Binding data were analyzed by non-linear regression with the software GraphPad Prism Version 3.03.
  • 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 (Harlan, 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.
  • mice 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 Hypothermia:
  • 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
  • CB1 Chinese hamster ovary (CHO) cells stably expressing recombinant human cannabinoid 1 receptor (CB1) were cultured in nutrient mixture Ham's F 12 supplemented with 10 % heat-inactivated fetal bovine serum, 2 mM L-glutamine, 50 U/ml penicillin, 50 U/ml streptomycin and 0.5 mg/ml geneticin.
  • culture flasks were washed twice with phosphate buffered saline and scraped. Then, cells were collected by centrifugation (200 x g, 10 min) and stored dry at -8O 0 C.
  • Cells were homogenized in ice-cold 20 mM HEPES, 10 mM EDTA (pH 7.5) and centrifuged at 40,000 x g for 15 min at 4 0 C. The pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5) and centrifuged for 15 min at 4 0 C. The final pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5), and divided in aliquots and stored at -8O 0 C until use.
  • the reaction was performed in 96-well plates. Membranes (15 ⁇ g protein/well) were incubated for 60 min at 30 0 C in buffer (50 mM HEPES, 100 mM KCI, 5 mM MgCI 2 ,1 mM EDTA, 0.1 % wt/vol bovine serum albumin, 5 ⁇ M GDP, saponin (10 ⁇ g/ml), 0.5 nM [ 35 S]GTPyS, pH 7.4) with compound at 1 ⁇ M final concentration in either the absence or presence of dose response curve of agonist WIN 55,212-2 between 3 nM and 3 ⁇ M.
  • buffer 50 mM HEPES, 100 mM KCI, 5 mM MgCI 2 ,1 mM EDTA, 0.1 % wt/vol bovine serum albumin, 5 ⁇ M GDP, saponin (10 ⁇ g/ml), 0.5 nM [ 35 S]GTPyS, pH 7.4
  • P alcohol preferring
  • the following protocol may be used to evaluate the effects of alcohol intake in alcohol preferring (P) female rats (e.g. bred at Indiana University) with an extensive drinking history.
  • P rats Lumeng, L, et al..”Different sensitivities to ethanol in alcohol-preferring and- nonpreferring rats,"Pharmacol, Biochem Behav., 16, 125-130 (1982).
  • mice Female rats are given 2 hours of access to alcohol (10% v/v and water, 2-bottle choice) daily at the onset of the dark cycle. The rats are maintained on a reverse cycle to facilitate experimenter interactions. The animals are initially assigned to four groups equated for alcohol intakes: Group 1 -vehicle; Group 2-positive control (e. g. 5.6 mg/kg AM251 ; Group3-low dose test compound; and Group 4-high dose of test compound. Test compounds are generally mixed into a vehicle of 30% (w/v) - cyclodextrin in distilled water at a volume of 1-2 ml/kg. Vehicle injections are given to all groups for the first two days of the experiment.
  • mice upon arrival mice are individually housed and given unlimited access to powdered rat chow, water and a 10 % (w/v) alcohol solution. After 2-3 weeks of unlimited access, water is restricted for 20 hours and alcohol is restricted to only 2 hours access daily. This is done in a manner that the access period was the last 2 hours of the dark part of the light cycle.
  • mice are considered stable when the average alcohol consumption for 3 days is 20% of the average for all 3 days.
  • Day 1 of test consists of all mice receiving vehicle injection (sc or ip). Thirty to 120 minutes post injection access is given to alcohol and water. Alcohol consumption for that day is calculated (g/kg) and groups are assigned so that all groups have equivocal alcohol intake.
  • day 2 and 3 mice are injected with vehicle or drug and the same protocol as the previous day is followed.
  • Day 4 iss wash out and no injections are given. Data is analyzed using repeated measures ANOVA. Change in water or alcohol consumption is compared back to vehicle for each day of the test. Positive results would be interpreted as a compound that was able to significantly reduce alcohol consumption while having no effect on water
  • the chambers are opened and the animals are administered a single dose of compound (the usual dose range is 0.001 to 10 mg/kg) by oral gavage (or other route of administration as specified, i. e. , sc, ip, iv).
  • Drugs are prepared in methylcellulose, water or other specified vehicle (examples include PEG400, 30% beta-cyclo dextran and propylene glycol).
  • Oxygen consumption and ambulatory activity are measured every 10 minutes for an additional 1-6 hours post-dosing.
  • the Oxymax calorimeter software calculates the oxygen consumption (ml/kg/h) based on the flow rate of air through the chambers and difference in oxygen content at inlet and output ports.
  • the activity monitors have 15 infrared light beams spaced one inch apart on each axis, ambulatory activity is recorded when two consecutive beams are broken and the results are recorded as counts.
  • An intravenous nicotine self-administration model or place preference model may be used to assess the effects of a test compound on nicotine dependence (see, e.g., Vastola, et al. Physiol. Behav. 77:107-114, 2002; Brower, et al., Brain Res. 930:12- 20, 2002).
  • Sprague-Dawley rats are used in this study (Vastola, et al., 2002). Animals are housed in a temperature-controlled, 12h/12h illumination cycle with ad libitum access to food and water. Conditioning and testing are conducted in a chamber divided into two compartments with a door separating the two compartments. Behavior of the animals is recorded by video camera. Animals are habituated to the injection procedure for several days. The animals are then placed into the test chamber and given free access to both compartments. The initial preference for a particular compartment is determined. For the conditioning trials, animals are injected with nicotine and restricted to the nonpreferred compartment, or the animals are injected with saline and restricted to the preferred compartment. On test day, the door separating the compartments is removed, the animal is placed in the center of the chamber and allowed to move freely between compartments. Time spent in each compartment is scored. Preferential occupancy of the nicotine compartment follows from the conditioned reinforcing effects of nicotine.
  • Self-administration in animals is a predictor of a compound's abuse potential in humans. Modifications to this procedure may also be used to identify compounds that prevent or block the reinforcing properties of drags that have abuse potential. A compound that extinguishes the self- administration of a drag may prevent that drag's abuse or its dependence.
  • Sprague-Dawley rats are used in this study. Initially, animals are housed in a temperature-controlled, 12h/12h illumination cycle with ad libitum access to food and water. The animals are then implanted with jugular catheters which exit through the animal's back, and each animal is placed in an individual operant chamber (Brower, et al., 2002). The catheters are connected to a computer-driven syringe pump which is located outside of the chamber. The chamber contains two levers with a green light located above each lever. The light is illuminated when nicotine is available.
  • a self-administration test animals are placed in the operant chambers and the levers are randomly designated as an active and inactive lever. Each response on the active lever produces an infusion of nicotine. Presses on the inactive lever have no effect, but are also recorded. Animals are then trained to self -administer nicotine over a set period of time by having drag access during each daily session. Illumination of the chamber house light signals the beginning of the session and the availability of nicotine. When the session ends, the house light is turned off. Initially, a nicotine infusion occurs with every press of the active lever. Once lever-pressing behavior has been established, the number of presses to produce a nicotine infusion is increased. After stable nicotine self-administration is obtained, the effect of a test compound on the nicotine- reinforced behavior may be evaluated. Administration of this test compound prior to the session can either potentiate, extinguish, or produce no change to the self-administrating behavior. Tests are conducted every two days, and the order of the administration of the test compound doses is controlled.
  • the Morris water maze is a behavioral in vivo test to measure spatial orientation learning and memory through a complex learning task. It is highly suitable for testing compounds that enhance learning and memory.
  • a circular water tank or pool (diameter 2 m, height 0.7 m) is filled with water, and a 10 cm2 platform is placed 1- 1.5 cm below the water surface at a defined location within the pool. The escape platform is not visible for an animal swimming in the water tank. For the experiment, a rat or mouse is placed into the pool to swim freely.
  • the animals have the task to localize the submerged platform, and the time and distance required for successful retrieval is measured.
  • Multiple extra-maze cues are provided by the furniture in the room, including desks, computer equipment, a second water tank, the presence of the experimenter, and by a radio on a shelf that is playing softly.
  • test compounds are administered orally or intraperitoneally on the day of the experiment at a defined time (e.g., 30 minutes before the first swim test). Control animals are dosed with the corresponding vehicle not containing test compound. Active compounds yield shorter times and distances to localize the platform (i.e., the better the animal remembers the location of the platform, the shorter the distance covered and the faster the platform is reached).
  • the test can also be carried out using transgenic or cognitively impaired animals. Cognitive impairment is induced either by old age or experimentally through brain lesions, such as bilateral lesions of the entorhinal cortex in rats. Such lesions can be induced by intracerebral injections of the excitotoxin ibotenic acid.
  • the object recognition task is used to assess the effects of compounds on the cognitive performance of rodents.
  • a rat is placed in an open field, in which two identical objects are located. The rats inspects both objects during the initial trial of the test. After a certain retention interval (e.g., 24 hours), a second trial is carried out.
  • a certain retention interval e.g. 24 hours
  • a second trial is carried out.
  • one of the two objects used in the first trial (the "familiar 1 object) and a novel object are placed in the open field, and the inspection time at each of the objects is measured. Good retention is reflected by higher exploration times towards the novel compared with the 'familiar' object.
  • Administration of the putative cognition enhancer prior to the first trial predominantly allows assessment of the effects on acquisition, and on the consolidation processes.
  • Administration of the test compound after the first trial allows to assess the effects on consolidation processes, whereas administration before the second trial allows to measure effects on retrieval processes.
  • the passive avoidance task assesses memory performance in rats and mice.
  • the inhibitory avoidance uses an apparatus consisting of a box with two compartments separated by a guillotine door that can be operated by the experimenter. One compartment is illuminated with bright light, and the other compartment is dark. A threshold of 2 cm separates the two compartments when the guillotine door is 15 raised. When the door is open, the illumination in the dark compartment is about 2 lux. The light intensity is about 500 lux at the center of the floor of the light compartment.
  • Two habituation sessions, one shock session, and a retention session are given, separated by inter-session intervals of 24 hours. During the habituation sessions and the retention session, the rat is allowed to explore the apparatus for 300 seconds.
  • the rat is placed in the light compartment, facing the wall opposite to the guillotine door. After an accommodation period of 15 seconds, the guillotine door is opened so that all parts of the apparatus can be visited freely. Rats normally avoid brightly lit areas and will enter the dark compartment within a few seconds.
  • the guillotine door between the compartments is lowered as soon as the rat has entered the dark compartment with all paws, and a scrambled 1 mA footshock is administered for 2 seconds. Then the rat is removed from the apparatus and returned into its home cage. The procedure during the retention session is identical to that of the habituation sessions.
  • the step-through latency that is, the first latency of entering the dark compartment (in seconds) during the retention session is an index of the memory performance of the animal: a better retention is assumed if the latency to enter the dark compartment is longer.
  • a test compound is given 30 minutes before the shock session, together with 1 mg/kg scopolamine. Scopolamine impairs the memory performance during the retention session 24 hours later. If the test compound increases the enter latency compared with the scopolamine-treated controls, it is considered to possess cognition enhancing activity.
  • the T-maze spontaneous alternation task assesses the spatial memory performance in mice.
  • the start arm and the two goal arms of the T-maze are provided with guillotine doors that can be operated manually by the experimenter.
  • a mouse is put into the start arm at the beginning of training.
  • either the left or right goal arm is blocked by lowering the respective guillotine door (forced trial).
  • the mouse After the mouse has been released from the start arm, it will explore the maze, eventually entering the open goal arm, and return to the start position, where it will be confined for 5 seconds, by lowering the guillotine door. Then, the animal can choose freely between the left and right goal arm (all guillotine-doors opened) during 14 additional trials (free choice trials). As soon as a mouse has entered one goal arm, the other arm is closed. The mouse eventually returns to the start arm and is free to visit whichever arm it wants after having been confined to the start arm for 5 seconds. After completion of 14 free choice trials in one session, the animal is removed from the maze.
  • a forced swim or tail suspension model may be used to assess the efficacy of antidepressant compounds (see , e.g., Porsolt, et al., Nature 266:730-732, 1977; Stem, et al., Psychopharmacology 85:367-370, 1985).
  • Rats or mice are placed in a cylinder filled with water 23-25 0 C from which no escape is possible. Initially, animals struggle and try to escape, but eventually adopt a characteristic immobile posture and make no further attempts to escape except for small movements needed their head above water. Animals are dosed with a compound and the activity (swimming or climbing) or immobility is measured by an observer. The immobility is considered by some to reflect a 'behavioral despair 1 in which animals cease to struggle to escape the aversive situation.
  • TCAs clinically used antidepressants
  • MAOIs MAOIs
  • SSRIs atypicals
  • At least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, whereas drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. There are false positives (psychostimulants) but relatively few false negatives ([beta]-adrenergic agonists).
  • test is sensitive to muscle-relaxant (benzodiazepines) and sedative (neuroleptics) effects, leading to enhanced immobility. False positives and false negatives can often be screened by measuring if the compound produces locomotor stimulation or sedation.
  • mice When suspended by the tail, mice will initially struggle and try to escape and then alternate between active escape attempts and immobililty. In this test, animals are dosed with a compound and the immobility is measured by an observer for 6 min. Porsolt describes the immobile behavior as 'behavioral despair' which animals cease to struggle to escape the aversive situation.
  • a large variety of clinically antidepressants tricyclics, MAOIs, SSRIs, and atypicals reduce immobility in this model. The test has a good predictive validity for antidepressant activity and works for most antidepressant classes including but has some false positives (psychostimulants).
  • the test is sensitive to muscle-relaxant (benzodiazepines) and sedative (neuroleptics) effects, which lead to enhanced immobility. False positives and false negatives can often be screened by measuring if the compound produces locomotor stimulation or sedation. Strain differences in the tail suspension test have been found in mice. The tail suspension test has some face validity but its construct validity is rather weak.
  • a prepulse inhibition model may be used to assess the efficacy of antipsychotic compounds (see Swerdlow and Geyer, Schizophrenia Bulletin 24: 285-301 , 1998).
  • Prepulse inhibition is the process whereby a relatively mild stimulus, the prepulse, suppresses the response to a strong, startle-eliciting stimulus when the prepulse precedes the startle stimulus by a brief duration (about 10 to 500 milliseconds).
  • Prepulse inhibition is a cross-species phenomenon (ie, it is present in mammals ranging from mice to humans), yet it is relatively absent among schizophrenic patients.
  • the deficit in PPI in schizophrenic patients is thought to reflect the loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation.
  • mice or rats are administered compounds and individually placed into a holder on a transducer platform to measure whole body startle.
  • the holder is housed in a startle chamber with background white noise. Following a brief habituation period, animals are given multiple trials of a weak auditory prepulse stimululs, followed by a strong auditory startle stimulus. Four types of trials are given: prepulse plus startle, prepulse alone, startle alone, and no stimulation. PPI is measured as the amount of inhibition of startle following the prepulse and is expressed as the percentage of basic startle. As a control, measurements are taken in the no stimulation and prepulse alone trials. PPI is considered a test with good predictive, face and construct validity for schizophrenia. Putative antipsychotics can be tested alone to determine if they enhance PPI.
  • antipsychotics can be screened to determine if they block various agents that disrupt PPI (apomorphine, d- amphetamine, PCP, ketamine, DOI).
  • PPI apomorphine, d- amphetamine, PCP, ketamine, DOI.
  • mutant mice with or without drugs can be screened using the PPI procedure.
  • An elevated plus maze model may be used to assess the efficacy of anxiolytic compounds (see Pellow and File, Pharm. Biochem. Behav. 24, 525-529, 1986).
  • the elevated plus maze is widely used as an anxiety paradigm that examines the conflict between the drive to explore and the aversiveness of heights and open spaces of rats or mice.
  • the maze is a cross made up of two open and two closed arms that is raised above the ground. The combination of light, the open arms, and the height is thought to produce unconditioned fear or anxiety responses in mice or rats.
  • the test apparatus is an open top maze constructed of opaque plastic with alternating open and enclosed arms. For rats, each arm is 45-55 cm long and 8-12 cm wide, with the sides of the enclosed arms 35-45 cm high, the juncture approximately 10 x 10 cm, and the maze is elevated 45-55 cm above the floor.
  • the mouse elevated plus maze consists of two closed arms (15 x 6 x 30 cm) and two open arms (1 x 6 x 30 cm) forming a cross, with a quadrangular center (6 x 6cm).
  • the maze is placed 50 cm above the floor. Testing is performed in a room free of noise and distraction. On test days animals are administered drug or vehicle. If a pretreatment period is necessary, the animals are returned to the home cage for the duration of the pretreatment time; otherwise, the animals are placed in a clear plastic holding chamber singly or with cage mates for 1-10 minutes prior to test time. Rats are then placed in the center of the maze always oriented in the same direction, either consistently facing an open arm or an enclosed arm.
  • Drugs affecting erectile function may be tested by measuring the effect on apomorphine- evoked increases in intracavernous pressure in the awake rat as described by Andersson, et al., (J. Urol. 161 : 1707-17 ] 2, 1999).
  • One end of a polyethylene tubing is implanted into the cavernosal space of the penis of male Sprague-Dawley rats. After recovery from the surgery, intracavernous pressure is recorded using a pressure transducer connected to a multichannel pen-recorder. Erections are induced by administration of apomorphine (100-250 ug/kg s.c.) with or without test compound, and the results are compared for the treated group and the non-treated group.
  • Female Sexual Dysfunction is induced by administration of apomorphine (100-250 ug/kg s.c.) with or without test compound, and the results are compared for the treated group and the non-treated group.
  • Systems to test compounds for the treatment of female sexual dysfunction include in vitro and in situ models using vaginal or clitoral smooth muscle preparations, histological evaluation, and vaginal blood flow assessments.
  • In vivo studies of sexual responses focus on behavioral paradigms involving lordotic posturing and receptivity, as well as indices of motivation using a dual chamber pacing method (see, e.g., Hale, et al., Int. J. Impot. Res. 15 Suppl 5: S75-79, 2003).
  • Example 1 1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H- pyrazole-S-carbonylJ-arninol-i-methyl-piperidinium iodide
  • Example 51 N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 4,5-dihydropyrazole-3-carboxamide
  • N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0.15 g, 0.33 mmol) 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 mmol) was added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was present. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered.

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Abstract

La présente invention concerne des sels d'ammonium quaternaire de composés pyrazoliniques substitués, des procédés d'élaboration correspondants, des médicaments comprenant ces composés, ainsi que leur utilisation pour l'élaboration d'un médicament de médecine humaine et vétérinaire.
PCT/EP2006/006971 2005-07-15 2006-07-15 Sels d'ammonium quaternaire de composes pyrazoliniques substitues, elaboration, utilisation medicamenteuse WO2007009697A1 (fr)

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EP05384025.2 2005-07-15
EP05384026A EP1749821A1 (fr) 2005-07-15 2005-07-15 Sels de dérives pyrazoline, leur préparation et leur utilisation comme medicaments médicaments
EP05384026.0 2005-07-15
EP05384025A EP1749820A1 (fr) 2005-07-15 2005-07-15 Sels de dérives pyrazoline, leur préparation et leur utilisation comme medicaments médicaments
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Citations (3)

* Cited by examiner, † Cited by third party
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WO2001070700A1 (fr) * 2000-03-23 2001-09-27 Solvay Pharmaceuticals B.V. Derives de 4,5-dihydro-1h-pyrazole ayant une activite antagoniste de cb¿1?
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