WO2005077909A1 - Substituted pyrazoline compounds for reducing triglycerides in blood - Google Patents

Substituted pyrazoline compounds for reducing triglycerides in blood Download PDF

Info

Publication number
WO2005077909A1
WO2005077909A1 PCT/EP2005/001465 EP2005001465W WO2005077909A1 WO 2005077909 A1 WO2005077909 A1 WO 2005077909A1 EP 2005001465 W EP2005001465 W EP 2005001465W WO 2005077909 A1 WO2005077909 A1 WO 2005077909A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally
group
branched
linear
disorders
Prior art date
Application number
PCT/EP2005/001465
Other languages
French (fr)
Inventor
Rosa Cuberes Altisen
Bonifacio Guitierrez Silva
Jordi Frigola-Constansa
Original Assignee
Laboratorios Dr. Esteve S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP04021974A external-priority patent/EP1637522A1/en
Application filed by Laboratorios Dr. Esteve S.A. filed Critical Laboratorios Dr. Esteve S.A.
Priority to JP2006553505A priority Critical patent/JP2007522252A/en
Priority to CA002556568A priority patent/CA2556568A1/en
Priority to EP05715327A priority patent/EP1718619A1/en
Priority to AU2005212817A priority patent/AU2005212817A1/en
Priority to US10/589,743 priority patent/US7998996B2/en
Priority to BRPI0507790-7A priority patent/BRPI0507790A/en
Publication of WO2005077909A1 publication Critical patent/WO2005077909A1/en
Priority to IL177454A priority patent/IL177454A0/en
Priority to NO20064186A priority patent/NO20064186L/en

Links

Classifications

    • 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
    • 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
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers

Definitions

  • the present invention relates to 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.
  • Triglycerides are the chemical form in which most fat exists in food as well as in the body. Triglycerides are present in blood plasma and, in association with cholesterol, form the plasma lipids. Triglycerides in blood plasma are derived from fats consumed directly or are synthesized from e.g. carbohydrates. Superfluous food intake is converted to triglycerides and transported to fat cells to be stored. Elevated triglycerides may also be a consequence of disease states, such as untreated diabetes mellitus. Excess of triglycerides in plasma (hypertriglyceridemia) is linked to the occurrence of coronary artery disease and possibly other disorders.
  • the present invention relates to substituted pyrazoline compounds of general formula
  • R 1 represents hydrogen or a linear or branched C ⁇ -4 -alkyl group
  • Preferred linear or branched, saturated or unsaturated aliphatic groups which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl.
  • alkyl and cycloalkyl radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
  • C ⁇ - 2 -alkyl represents C1- or C2-alkyl, C ⁇ .
  • 3 -alkyl represents C1-, C2- or C3-alkyl
  • d ⁇ -alkyl represents C1-, C2-, C3- or C4-alkyl
  • C ⁇ -5 -aIkyl represents C1-, C2-, C3-, C4-, or C5-alkyl
  • Ci- 7 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • C 1-8 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
  • C ⁇ - ⁇ 0 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and C ⁇ - ⁇ 8
  • C 3-4 -cycloalkyl represents C3- or C4-cycloalkyl
  • C 3 - 5 - cycloalkyl represents C3-, C4- or C5-cycloalkyl
  • C3-6-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl
  • C 3-7 -cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl, C 3 .
  • cycloalkyl in respect of cycloalkyl, the term also includes saturated cycloalkyls in which one or 2 carbon atoms are replaced by a heteroatom, S, N or O.
  • mono- or polyunsaturated, preferably monounsaturated, cycloalkyls without a heteroatom in the ring also in particular fall under the term cycloalkyl as long as the cycloalkyl is not an aromatic system.
  • alkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, 1- methylpropyl, 2-methylpropyl, 1 ,1-dimethylethyl, pentyl, 1 ,1-dimethylpropyl, 1 ,2- dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2- methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl, (if substituted also CHF 2 , CF 3 or CH 2 OH) as well as pyrazolinone, oxopyrazol
  • substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical by F, CI, Br, I, NH 2 , SH or OH
  • Particularly preferred substituents here are, F, CI and OH.
  • the hydrogen radical can also be replaced by OC ⁇ - 3 -alkyl or C ⁇ -3 -alkyl (in each case mono- or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
  • (CH 2 ) 3 . 6 is to be understood as meaning -CH 2 -CH 2 -CH2-, -CH 2 -CH 2 -CH 2 - CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH2-CH2-,
  • (CH 2 ) 1-4 is to be understood as meaning -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - and -CH2-CH2-CH2-
  • (CH 2 ) 4 -5 is to be understood as meaning -CH2-CH2-CH2- and -CH 2 -CH 2 -CH 2 -CH 2 - CH 2 -CH 2 -, etc.
  • aryl radical is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or monosubstituted or polysubstituted.
  • a heteroaryl radical is understood as meaning heterocyclic ring systems which have at least one unsaturated ring and can contain one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur and can also be mono- or polysubstituted.
  • heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole and quinazoline.
  • substituted is understood as meaning substitution of the aryl or heteroaryl by R, OR, a halogen, preferably F and/or CI, a CF 3 , a CN, an N0 2 , an NRR, a C ⁇ - 6 -alkyl (saturated), a C ⁇ . 6- alkoxy, a C 3-8 - cycloalkoxy, a C 3-8 -cycloalkyl or a C 2 . 6 -alkylene.
  • salt is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
  • a counter-ion a cation or anion
  • complexes of trje active compound with other molecules and ions in particular complexes which are complexed via ionic interactions.
  • physiologically acceptable salt means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
  • physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals.
  • the salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH4, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
  • physiologically acceptable salts can also be formed with anions or acids in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually protonated, for example on the nitrogen - as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals.
  • the salt formed with a physiologically tolerated acid that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals.
  • physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
  • solvate is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate. r Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon or 15 N-enriched nitrogen are within the scope of this invention.
  • At least one of R 2 , R 3 or R 4 represents hydrogen, while at least one of R 2 , R 3 or R 4 is different from hydrogen.
  • R 7 represents hydrogen
  • R 2 , R 3 and R 4 independently of each other represent hydrogen, a linear or branched C 1 - 6 - alkyl group, a halogen atom, or CF 3 , preferably R 2 , R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 5 and R 6 independently of each other represent a linear or branched C ⁇ -alkyl group, a halogen atom, or CF 3 , preferably R 5 and R 6 independently of each other represent methyl, ethyl, F, CI, Br and CF 3 .
  • R 2 represents a chlorine atom in the 4-position of the phenyl ring, while R 3 and R 4 represent hydrogen.
  • R 5 and R 6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R 7 represents hydrogen.
  • R 1 represents hydrogen, methyl or; ethyl, preferably hydrogen.
  • the compound of general formula I is represented by a compound of general formula II
  • R 1 represents hydrogen or a linear or branched group
  • R 12 or R 13 independently of each other represent a linear or branched C ⁇ -6 - alkyl group, a linear or branched C ⁇ .6-alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, N0 2 , SH, NH 2 , hydrogen, methyl, ethyl, F, CI, Br and CF 3 ,
  • R 14 or R 15 independently of each other represent a linear or branched C-. 6 - alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, N0 2 , SH, NH 2 , methyl, ethyl, F, CI, Br and CF 3 , optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 12 and R 13 independently of each other represent hydrogen, a linear or branched C ⁇ - ⁇ -alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 14 , and R 15 independently of each other represent a linear or branched C ⁇ . 6 -alkyl group, a halogen atom, or CF 3 , preferably R 14 and R 15 independently of each other represent methyl, ethyl, F, CI, Br and CF 3 .
  • R 13 represents CI and R 12 represents hydrogen.
  • R 14 and R 15 each represent CI.
  • R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.
  • Another preferred embodiment of the invention covers also any prodrug of the compounds of the invention described above as well as any medicament comprising this and any use thereof; especially including their esters and ethers.
  • Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002).
  • Another aspect of the invention is a combination of compounds comprising at least one substituted pyrazoline compound of general formula I
  • R 1 represents hydrogen or a linear or branched C ⁇ . 4 -alkyl group
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof;
  • R 16 represents an optionally at least mono-substituted phenyl group
  • R 17 represents an optionally at least mono-substituted phenyl group
  • R 18 represents a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an r optionally at least mono-substituted mono- or polycyclic ring system, or an - NR 19 R 20 -moiety,
  • R 19 and R 20 represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, an -S0 2 -R 21 -moiety, or an - NR 22 R 23 -moiety, with the proviso that R 19 and R 20 do not identically represent hydrogen,
  • R 21 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group,
  • R 22 and R 23 identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, 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
  • At least one of R 2 , R 3 or R 4 represents hydrogen, while at least one of R 2 , R 3 or R 4 is different from hydrogen.
  • At least on of R 5 , R 6 or R 7 represents hydrogen, while at least one R 5 , R 6 or R 7 is different from hydrogen.
  • R 2 , R 3 and R 4 independently of each other represent hydrogen, a linear or branched C ⁇ -6 -alkyl group, a halogen atom, or CF 3 , preferably R 2 , R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 5 , R 6 and R 7 independently of each other represent hydrogen, a linear or branched Ci- ⁇ -alkyl group, a halogen atom, or CF 3 , preferably R 5 , R 6 and R 7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 2 represents a chlorine atom in the 4-position of the phenyl ring, while R 3 and R 4 represent hydrogen.
  • R 5 and R 6 each represent a chlorine atom in the 2- and 4-position of the phenyl ring, while R 7 represents hydrogen.
  • R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.
  • R 1 represents hydrogen or a linear or branched C ⁇ - -alkyl group
  • R 12 , R 13 , R 14 or R 15 independently of each other represent a linear or branched Ci-e-alkyl group, a linear or branched d- ⁇ -alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, N0 2 , SH, NH 2 , hydrogen, methyl, ethyl, F, CI, Br and CF 3 , optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 12 and R 13 independently of each other represent hydrogen, a linear or branched C ⁇ -6 -alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 14 , and R 15 independently of each other represent hydrogen, a linear or branched Ci- ⁇ -alkyl group, a halogen atom, or CF 3 , preferably R 14 and R 15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 . «,
  • R 13 represents CI and R 12 represents hydrogen.
  • R 14 and R 15 each represent CI.
  • R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.
  • R 17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear or branched C ⁇ .
  • R 17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, ethyl, F, CI, Br and CF 3 , more preferably R 17 represents a phenyl group, which is di-substituted with two chlorine atoms in its 2- and 4-position.
  • R 18 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substijuted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an -NR 19 R 20 -moiety, preferably R 18 represents a saturated, optionally at least mono-substituted, optionally one or more nitrogen-atoms as ring member containing C 3 - 8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an -NR
  • R 19 and R 20 identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Ci- ⁇ -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 .
  • R 21 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted C ⁇ -6 aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8 cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or an optionally at least mono- substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH 2 -CH 2 )-group, preferably R 21 represents a Ci- ⁇ -alkyl group, a saturated, optionally at least mono-substituted cycloaliphatic group, which may be condensed with a mono- or polycycl
  • R 22 and R 23 represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C ⁇ -6 aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6 membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH 2 -CH 2 )-group, preferably R 22 and R 23 , identical or different,
  • the compound according to general formula X is represented by a structure wherein R 16 represents a phenyl ring, which is mono-substituted with a halogen atom, preferably a chlorine atom, in its 4-position,
  • R 17 represents a phenyl ring, which is di-substituted with two halogen atoms, preferably chlorine atoms, in its 2- and 4-position,
  • R 18 represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, or an -NR 19 R 0 -moiety,
  • R 19 represents a hydrogen atom or a linear or branched C ⁇ . 6 -alkyl group
  • R 20 represents a linear or branched C ⁇ - 6 alkyl group, an -S0 2 -R 21 -moiety, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, a triazolyl group, whereby each of the heterocyclic rings may be substituted with one or more, identical or different, C ⁇ - 6 -alkyl groups, and
  • R 21 represents a phenyl group, which is optionally substituted with one or more C ⁇ - 6 alkyl groups, which may be identical or different, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the present invention also provides a process for the preparation of substituted pyrazoline compounds of general formula I or II, wherein R 1 is hydrogen, given above, in that at least one benzaldehyde compound of general formula III
  • G represents an OR group with R being a branched or unbranched C 1 - 6 alkyl radical or G represents an 0 " K group with K being a cation, preferably an anorganic kation, more preferably an alkali metal kation, most preferably sodium, to yield a compound of general formula (V)
  • R 1 is a linear or branched C ⁇ - -alkyl group.
  • the reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula IV is preferably carried out in the presence of at least one base, more preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic communications, 26(11), 2229-33, (1996).
  • an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide
  • an alkali metal methoxide such as sodium methoxide
  • Reaction temperature as well as the duration of the reaction may vary over a broad range.
  • Preferred reaction temperatures range from -10 °C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula IV is carried out under acid catalysed conditions, more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1), 147-149, 2001.
  • acid catalysed conditions more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1), 147-149, 2001.
  • the respective description is hereby incorporated by reference and forms part of the disclosure.
  • reaction of the compound of general formula (V) with an optionally substituted phenyl hydrazin of general formula (VI) is preferably carried out in a suitable reaction medium such as C ⁇ - -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • a suitable reaction medium such as C ⁇ - -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid.
  • reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 °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 (VII) 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 (VII) are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a C alkyl ester, an activated ester such as p- nitrophenylester.
  • Other well known methods for the activation of acids include the activation with N,N-dicyclohexylcarbodiimide or benzotriazol-N- oxotris(dimethylamino) phosphonium hexafluorophosphate (BOP)).
  • said activated compound of general formula (VII) is an acid chloride
  • it is preferably prepared by reaction of the corresponding acid of general formula (VII) with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the solvent.
  • an additional solvent may be used.
  • Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofurane or dimethoxyethane. Mixtures of two or more solvents from one class or two or more solvents from different classes may also be used.
  • Preferred reaction temperature range from 0 s C to the boiling point of the solvent and reaction times from several minutes to several hours.
  • said activated compound of general formula (VII) is a mixed anhydride
  • said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula (VII) with ethyl chloroformiate in the presence of a base such as triethylamine or pyridine, in a suitable solvent.
  • the activated compound can be reacted with an alkyl-alcohol to arrive at compounds according to general formulas I or II with R 1 being a a linear or branched C ⁇ -4 -alkyl group.
  • substituted pyrazoline compounds of general formula I or II themselves are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or fractionalized crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.
  • the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula I or II and stereoisomers thereof, wherein at least one compound of general formula I or II having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presenc ⁇ of a suitable reaction medium.
  • Suitable reaction media include, for example, any of the ones given above.
  • Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid
  • suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
  • the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula I or II or stereoisomers thereof, wherein at least one compound of general formula I or II having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium.
  • suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g.
  • reaction media are, for example, any of the ones given above.
  • Solvates, preferably hydrates, of the substituted pyrazoline compounds of general formula I or II, of corresponding stereoisomers, of corresponding N-oxides or of corresponding salts thereof may also be obtained by standard procedures known to those skilled in the art.
  • Substituted pyrazoline compounds of general formula I or II, which comprise nitrogen-atom containing saturated, unsaturated or aromatic rings may also be obtained in the form of their N-oxides by methods well known to those skilled in the art.
  • substituted pyrazoline compounds of general formula I and II given below, their stereoisomers, corresponding N-oxides, corresponding salts thereof and corresponding solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments.
  • substituted pyrazoline compounds of general formula (I) and (II) given below, stereoisomers thereof, N-oxides thereof, corresponding salts and corresponding solvates have the property to regulate triglyceride levels in blood plasma.
  • substituted pyrazoline compounds of general formula X given below stereoisomers thereof, N-oxides thereof, corresponding salts and corresponding solvates have a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CB ⁇ -receptors, i.e. they act as antagonists on these receptors.
  • CBD ⁇ -receptors cannabinoid 1
  • these pyrazoline compounds show litte or no development of tolerance during treatment particularly with respect to food intake. After ending the treatment with the pyrazoline compounds, reduced increase of body weight is found compared to the pre-treatment level.
  • Another aspect of the present invention relates to a Medicament comprising at least one substituted pyrazoline compound of general formula I or II according to the invention and optionally one or more pharmaceutically acceptable excipients.
  • Another aspect of the present invention relates to a Medicament comprising at least one substituted pyrazoline compound of general formula I
  • R 1 represents hydrogen or a linear or branched C ⁇ - 4 -alkyl group
  • At least one of R 2 , R 3 or R 4 represents hydrogen, while at least one of R 2 , R 3 or R 4 is different from hydrogen.
  • At least one of R 5 , R 6 or R 7 represents hydrogen, while at least one R 5 , R 6 or R 7 is different from hydrogen.
  • R 2 , R 3 and R 4 independently of each other represent hydrogen, a linear or branched C ⁇ - 6 -alkyl group, a halogen atom, or CF 3 , preferably R 2 , R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 5 , R 6 and R 7 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF 3 , preferably R 5 , R 6 and R 7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 2 represents a chlorine atom in the 4-position of the phenyl ring, while R 3 and R 4 represent hydrogen.
  • R 5 and R 6 each represent a chlorine atoms in the 2- and 4- position of the phenyl ring, whi e R 7 represents hydrogen.
  • R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.
  • the compound according to formula I is represented by a compound of general formula (II)
  • R 1 represents hydrogen or a linear or branched C ⁇ - 4 -alkyl group
  • R 12 , R 13 , R 14 or R 15 independently of each other represent a linear or branched Ci-e-alkyl group, a linear or branched C ⁇ -6-alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, N0 2 , SH, NH , hydrogen, methyl, ethyl, F, CI, Br and CF 3 , optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • R 12 and R 13 independently of each other represent hydrogen, a linear or branched C ⁇ . 6 -alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 14 , and R 15 independently of each other represent hydrogen, a linear or branched C ⁇ - 6 -alkyl group, a halogen atom, or CF 3 , preferably R 14 and R 15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 .
  • R 13 represents CI and R 12 represents hydrogen.
  • R 14 and R 15 each represent CI.
  • R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.
  • Another aspect of the invention is a medicament comprising at least one combination of compounds according to the invention and optionally one or more pharmaceutically acceptable excipients.
  • the medicament is for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • the medicament is 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.
  • the medicament is 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.
  • CBDi cannabinoid 1
  • the medicament is for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
  • food intake disorders preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
  • the medicament is for the prophylaxis and/or treatment of psychosis.
  • the medicament is for the prophylaxis and/or treatment of alcohol abuse and/or addiction, nicotine abuse and/or addiction, drug abuse and/or addiction and/or medicament abuse and/or addiction, preferably drug abuse and/or addiction and/or nicotine abuse and/or addiction.
  • the medicament is for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheric neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin camcer, colon cancer, bowl cancer and prostate
  • Said medicaments may also comprise any combination of one or more of the substituted pyrazoline compounds of general formula I given above, stereoisomers thereof, corresponding N-oxides thereof, physiologically acceptable salts thereof or physiologically acceptable solvates thereof.
  • medicaments are suitable for the prophylaxis and/or treatment of alcohol abuse, drug abuse and/or medicament abuse, preferably drug abuse and the treatment of obesity.
  • Medicaments and/or drugs which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
  • 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 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 stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
  • These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
  • Solid oral compositions (which are preferred as are liquid ones) may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
  • the tablets may for example be prepared by wet or dry granulation and optionally coated according to the methods well known in normal pharmaceutical practice., in particular with an enteric coating.
  • 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 compositio is may take any convenient form, such as tablets, pellets, 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.
  • 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 froml to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formaula I or II according to the invention (and optionally one or more pharmaceutically acceptable excipients,) for the preparation of a medicament 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.
  • Another preferred aspect of the invention is the use of at least one combination of compounds according to the invention (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
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the prophylaxis and/or treatment of psychosis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or li according to the invention or at least one combination of compounds according to the invention (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 addiction, nicotine abuse and/or addiction, medicament abuse and/or addiction and/or drug abuse and/or addiction, preferably drug abuse and/or addiction or nicotine abuse and/or addiction.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention or at least one combination of compounds according to the invention (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 schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheric neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of general formula I
  • R 1 represents hydrogen or a linear or branched C ⁇ - 4 -alkyl group
  • the stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemjate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof; and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use for the manufacture of a medicament of at least one substituted pyrazoline compound of formula I for which at least one of R 2 , R 3 or R 4 represents hydrogen, while at least one of R 2 , R 3 or R 4 is different from hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which at least on of R 5 , R 6 or R 7 represents hydrogen, while at least one R 5 , R 6 or R 7 is different from hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formuja I for which R 2 , R 3 and R 4 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF 3 , preferably R 2 , R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R 5 , R 6 and R 7 independently of each other represent hydrogen, a linear or branched C ⁇ - 6 -alkyl group, a halogen atom, or CF 3 , preferably R 5 , R 6 and R 7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • R 5 , R 6 and R 7 independently of each other represent hydrogen, a linear or branched C ⁇ - 6 -alkyl group, a halogen
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R 2 represents a chlorine atom in the 4- position of the phenyl ring, while R 3 and R 4 represent hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R 5 and R 6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R 7 represents hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R 1 represents hydrogen, methyl or ethyl, preferably hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula wherein the compound of general formula (I) is represented by a compound of general formula (II)
  • R 1 represents hydrogen or a linear or branched CM-alkyl group
  • R 12 , R 13 , R 14 or R 15 independently of each other represent a linear or branched Ci-e-alkyl group, a linear or branched C 1-6 -alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, N0 2 , SH, NH 2 , hydrogen, methyl, ethyl, F, CI, Br and CF 3 , optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous
  • Another embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R 12 and R 13 independently of each other represent hydrogen, a linear or branched C ⁇ - 6 -alkyI group, a halogen atom, or CF 3 , preferably R 12 and R 13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 forthe manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R 14 , and R 15 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF 3 , preferably R 14 and R 15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF 3 for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R 13 represents CI and R 2 represents hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R 14 and R 5 each represent CI for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R 1 represents hydrogen, methyl or ethyl, preferably hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another embodiment of the invention is the use of at least one substituted pyrazoline compound of formula I or II for which the compound according to formulas I or II is selected from the group consisting of:
  • a medicament for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Example 0 represent a compound according to formula I or II.
  • step a) 4-(4-chlorophenyl)-2-oxo-3-butenoic acid obtained according to step a) (12.6 g, 60 mmoles), 2,4-dichlorophenylhydrazine hydrochloride (12.8 g, 60 mmoles) and glacial acetic acid (200 mL) were mixed under a nitrogen atmosphere and heated to reflux for 4 hours, cooled down to room temperature (approximately 25 °C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield).
  • Example 1 represents compounds according to formula X.
  • Example 1 represents compounds according to formula X.
  • N-aminopiperidine (0.6 mL, 5.6 mmoles) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL).
  • methylene chloride 25 mL
  • the resulting mixture was ice-cooled down to 0°C and a solution of 5-(4-chlorophenyl)-1 -(2,4- dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride obtained in step (c) in methylene chloride (15 mL) was added dropwise.
  • the resulting reaction mixture was stirred at room temperature (approximately 25 °C) overnight.
  • This compound was obtained in form of an oil.
  • This compound was obtained in form of an amorph solid.
  • N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0,15 g, 332 mmoles) was dissolved in 7 ml of dichloromethane. The resulting solution was ice-cooled to 0 °C and m-chloroperbenzoic acid (0,204 g, 0,83 mmoles) added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was remaining. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered.
  • the compound according to example 0 is an inhibitor of high blood levels of triglicerides. This effect has been probed in obese mice fed with high fat diet. In the following paragraphs it is described the method and the results obtained in this study.
  • mice B6 Lep ob/ob obtained from Charles River (France). Mice were divided in 3 groups : I (control), II (vehicle), III (example 0).
  • the animals of the groups II and III were fed with a High Fat Diet (D-12492, Research Diets, NJ, USA), in both cases for 7 weeks (References 1 and 2).
  • the animals of the groups III were fed with a High Fat Diet (D-12492, Research Diets, NJ, USA), in both cases for 7 weeks (References 1 and 2).
  • mice received the vehicle (10 ml/kg/day, po, of the aqueous solution of acacia gum, 5% W/V).
  • Group III was administered with 30 mg/kg/day, po, of the inventive compound 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4,5-dihydro-pyrazole- 3-carboxylic acid according to Example 0.
  • Group I didn't received any treatment. The three groups of mice had the same diet than in the previous period.
  • the blood levels of triglicerides of the animals were determined.
  • the analysis of the whole blood samples was done using test strips "Lipid panel” and the photometric Analyzer Cardio-Check Test System, from PA Instruments Polymer Technology Systems Indianapolis, IN-46268, USA (Distributed in Spain by Novalab Iberica S.A.L, Madrid, Spain).
  • Figure 1 shows the clear reduction of triglyceride levels in blood plasma.
  • the level (Group III) returns to the control level of Group I compared to the clearly raised levels found in the Group II without the treatment with the compound according to Example 0.
  • mice receiving a high fat diet were - after a feeding period of 6 days - either treated p.o. with vehicle (0,5 % HPMC) or with the compound according to example 0 (30 mg/kg/day p.o.).
  • TG levels in blood were determined on day 28 after beginning of the treatment.
  • TG (triglyceride) levels were 1.28 ⁇ 25 mmoles/l in the group treated with vehicle and only 0.80 ⁇ 0.07 mmoles/l in the group treated with the inventive compound 5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid according to Example 0.
  • the results were statistically highly significant with an ANOVA factorial, Fisher ' s post-hoc test of ** * p ⁇ 0.005 vs. vehicle.

Abstract

The present invention relates to 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 animal.

Description

Substituted pyrazoline compounds, their preparation and use as medicaments
The present invention relates to 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.
Triglycerides are the chemical form in which most fat exists in food as well as in the body. Triglycerides are present in blood plasma and, in association with cholesterol, form the plasma lipids. Triglycerides in blood plasma are derived from fats consumed directly or are synthesized from e.g. carbohydrates. Superfluous food intake is converted to triglycerides and transported to fat cells to be stored. Elevated triglycerides may also be a consequence of disease states, such as untreated diabetes mellitus. Excess of triglycerides in plasma (hypertriglyceridemia) is linked to the occurrence of coronary artery disease and possibly other disorders.
Therefore, compounds, which have an effect on triglycerides, especially in blood plasma are useful in the prevention and/or treatment of related disorders.
Thus, it was an object of the present invention to provide novel compounds for use as active substances in medicaments, which are suitable for the regulation especially the reduction of triglyceride levels in the blood plasma.
Said object was achieved by providing the substituted pyrazoline compounds of ,. general formula I given below, their stereoisomers, corresponding salts and corresponding solvates thereof.
It has been found that these compounds have a marked effect on the level of triglycerides in the blood plasma.
Thus, in one of its aspects the present invention relates to substituted pyrazoline compounds of general formula
Figure imgf000004_0001
wherein
R1 represents hydrogen or a linear or branched Cι-4-alkyl group,
R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R8, SH, SR8, SOR8, S02R8, NH2, NHR8, NR8R9, -(C=0)-NH2, -(C=0)-NHR8 or -(C=0)-NR8R9 whereby R8 and R9 for each substituent independently represent linear or branched C1-6 alkyl,
R5 and R6 independently of each other represent a linear or branched Cι-6- alkyl group, a linear or branched Cι.6-alkoxy group, a halogen atom, CH2F, CHF2, CF3) CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2, -(C=0)-NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched Cι-6 alkyl;
R7 represents hydrogen, a linear or branched d-e-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2, -(C=0)- NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched Cι-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
If is very preferred if to these compounds according to formula I the following provisio applies: with the proviso that if R1 and R7 are H and R5 and R6 both represent CI in the 3- and 4-position of the phenyl ring neither of R2, R3 and R4 may represent F in the 4-position of the phenyl ring if the other two of R2, R3 and R4 both represent H.
These compounds had a surprising effect on the blood levels of diet relevant substances, e.g. Triglycerides.
Preferred linear or branched, saturated or unsaturated aliphatic groups, which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl.
In the context of this invention, alkyl and cycloalkyl radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted. In these radicals, Cι-2-alkyl represents C1- or C2-alkyl, Cι.3-alkyl represents C1-, C2- or C3-alkyl, d^-alkyl represents C1-, C2-, C3- or C4-alkyl, Cι-5-aIkyl represents C1-, C2-, C3-, C4-, or C5-alkyl,
Figure imgf000006_0001
represents C1-, C2-, C3-, C4-, C5- or C6-alkyl, Ci-7-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, C1-8-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl, Cι-ι0-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and Cι-ι8-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. Furthermore, C3-4-cycloalkyl represents C3- or C4-cycloalkyl, C3-5- cycloalkyl represents C3-, C4- or C5-cycloalkyl, C3-6-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl, C3-7-cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl, C3.8-cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl represents C4- or C5-cycloalkyl, C -6-cycloalkyl represents C4-, C5- or C6-cycloaIkyl, C4.7-cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl represents C5- or C6-cycloalkyl and C5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl. In respect of cycloalkyl, the term also includes saturated cycloalkyls in which one or 2 carbon atoms are replaced by a heteroatom, S, N or O. However, mono- or polyunsaturated, preferably monounsaturated, cycloalkyls without a heteroatom in the ring also in particular fall under the term cycloalkyl as long as the cycloalkyl is not an aromatic system. The alkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, 1- methylpropyl, 2-methylpropyl, 1 ,1-dimethylethyl, pentyl, 1 ,1-dimethylpropyl, 1 ,2- dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2- methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl, (if substituted also CHF2, CF3 or CH2OH) as well as pyrazolinone, oxopyrazolinone, [1 ,4]-dioxane or dioxolane.
Here, in connection with alkyl and cycloalkyl - unless expressly defined otherwise - the term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical by F, CI, Br, I, NH2, SH or OH, "polysubstituted" radicals being understood as meaning that the replacement takes effect both on different and on the same atoms several times with the same or different substituents, for example three times on the same C atom, as in the case of CF3, or at different places, as in the case of -CH(OH)-CH=CH-CHCI2. Particularly preferred substituents here are, F, CI and OH. In respect of cycloalkyl, the hydrogen radical can also be replaced by OCι-3-alkyl or Cι-3-alkyl (in each case mono- or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF3, methoxy or ethoxy.
The term (CH2)3.6 is to be understood as meaning -CH2-CH2-CH2-, -CH2-CH2-CH2- CH2-, -CH2-CH2-CH2-CH2-CH2- and -CH2-CH2-CH2-CH2-CH2-CH2-, (CH2)1-4 is to be understood as meaning -CH2-, -CH2-CH2-, -CH2-CH2-CH2- and -CH2-CH2-CH2-CH2-, (CH2)4-5 is to be understood as meaning -CH2-CH2-CH2-CH2- and -CH2-CH2-CH2- CH2-CH2-, etc.
An aryl radical is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or monosubstituted or polysubstituted.
A heteroaryl radical is understood as meaning heterocyclic ring systems which have at least one unsaturated ring and can contain one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur and can also be mono- or polysubstituted. Examples which may be mentioned from the group of heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole and quinazoline.
Here, in connection with aryl and heteroaryl, substituted is understood as meaning substitution of the aryl or heteroaryl by R, OR, a halogen, preferably F and/or CI, a CF3, a CN, an N02, an NRR, a Cι-6-alkyl (saturated), a Cι.6-alkoxy, a C3-8- cycloalkoxy, a C3-8-cycloalkyl or a C2.6-alkylene.
The term "salt" is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of trje active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions.
The term "physiologically acceptable salt" means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH4, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
These physiologically acceptable salts can also be formed with anions or acids in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually protonated, for example on the nitrogen - as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals. By this is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
The term "solvate" according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate. r Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon or 15N-enriched nitrogen are within the scope of this invention.
In a preferred embodiment of the invention for a compound according to formula I at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R4 is different from hydrogen.
In a preferred embodiment of the invention for a compound according to formula I R7 represents hydrogen.
In a preferred embodiment of the invention for a compound according to formula I R2, R3 and R4 independently of each other represent hydrogen, a linear or branched C1-6- alkyl group, a halogen atom, or CF3, preferably R2, R3 and R4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In a preferred embodiment of the invention for a compound according to formula I R5 and R6 independently of each other represent a linear or branched C β-alkyl group, a halogen atom, or CF3, preferably R5 and R6 independently of each other represent methyl, ethyl, F, CI, Br and CF3.
In a preferred embodiment of the invention for a compound according to formula I R2 represents a chlorine atom in the 4-position of the phenyl ring, while R3 and R4 represent hydrogen.
In a preferred embodiment of the invention for a compound according to formula I R5 and R6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R7 represents hydrogen.
In a preferred embodiment of the invention for a compound according to formula I R1 represents hydrogen, methyl or; ethyl, preferably hydrogen.
Figure imgf000010_0001
π
In a highly preferred further aspect of the invention the compound of general formula I is represented by a compound of general formula II
wherein
R1 represents hydrogen or a linear or branched
Figure imgf000010_0002
group,
R 12 or R 13 independently of each other represent a linear or branched Cι-6- alkyl group, a linear or branched Cι.6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, hydrogen, methyl, ethyl, F, CI, Br and CF3,
R14 or R15 independently of each other represent a linear or branched C-.6- alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, methyl, ethyl, F, CI, Br and CF3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
In a preferred embodiment of the invention for a compound according to formula II R12 and R13 independently of each other represent hydrogen, a linear or branched Cι- β-alkyl group, a halogen atom, or CF3, preferably R12 and R13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In a preferred embodiment of the invention for a compound according to formula II R14, and R15 independently of each other represent a linear or branched Cι.6-alkyl group, a halogen atom, or CF3, preferably R14 and R15 independently of each other represent methyl, ethyl, F, CI, Br and CF3.
In a preferred embodiment of the invention for a compound according to formula II R13 represents CI and R12 represents hydrogen.
In a preferred embodiment of the invention for a compound according to formula II R14 and R15 each represent CI.
In a preferred embodiment of the invention for a compound according to formula II R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
In another preferred embodiment the compound according to formula I or II is selected from the group consisting of:
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
Another preferred embodiment of the invention covers also any prodrug of the compounds of the invention described above as well as any medicament comprising this and any use thereof; especially including their esters and ethers. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al., Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002).
Another aspect of the invention is a combination of compounds comprising at least one substituted pyrazoline compound of general formula I
Figure imgf000012_0001
wherein
R1 represents hydrogen or a linear or branched Cι.4-alkyl group,
R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a linear or branched Cι.6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R8, SH, SR8, SOR8, S02R8, NH2, NHR8, NR8R9, -(C=0)-NH2> -(C=0)-NHR8 or -(C=0)-NR8R9 whereby R8 and R9 for each substituent independently represent linear or branched Cι-6 alkyl,
R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Ci-β-alkyI groufp, a linear or branched Ci-β-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2, -(C=0)-NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched Cι-6 alkyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof;
and at least one substituted pyrazoline compound of general formula X
Figure imgf000013_0001
X
wherein
R16 represents an optionally at least mono-substituted phenyl group,
R17 represents an optionally at least mono-substituted phenyl group,
R18 represents a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an r optionally at least mono-substituted mono- or polycyclic ring system, or an - NR19R20-moiety,
R19 and R20, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, an -S02-R21-moiety, or an - NR22R23-moiety, with the proviso that R19 and R20 do not identically represent hydrogen,
R21 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group,
R22 and R23, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula I at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R4 is different from hydrogen.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula I at least on of R5, R6 or R7 represents hydrogen, while at least one R5, R6 or R7 is different from hydrogen.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula I R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a halogen atom, or CF3, preferably R2, R3 and R4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula I R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Ci-β-alkyl group, a halogen atom, or CF3, preferably R5, R6 and R7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula I R2 represents a chlorine atom in the 4-position of the phenyl ring, while R3 and R4 represent hydrogen.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula I R5 and R6 each represent a chlorine atom in the 2- and 4-position of the phenyl ring, while R7 represents hydrogen. In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula I R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
In a preferred embodiment of the combination of compounds according to the invention the compound of general formula I is represented by a compound of general formula II
Figure imgf000016_0001
II wherein
R1 represents hydrogen or a linear or branched Cι- -alkyl group,
R12, R13, R14 or R15 independently of each other represent a linear or branched Ci-e-alkyl group, a linear or branched d-β-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, hydrogen, methyl, ethyl, F, CI, Br and CF3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula II R12 and R13 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a halogen atom, or CF3, preferably R12 and R13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula II R14, and R15 independently of each other represent hydrogen, a linear or branched Ci-β-alkyl group, a halogen atom, or CF3, preferably R14 and R15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3. «,
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula II R13 represents CI and R12 represents hydrogen.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula II R14 and R15 each represent CI.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula II R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
In a preferred embodiment of the combination of compounds according to the invention the compound according to formula I or II is selected from the group consisting of:
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula X R16 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear or branched C1-6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, - (C=0)-R', SH, SR', SOR', S02R', NH2, NHR', NR'R", -(C=0)-NH2, -(C=0)-NHR' and -(C=0)-NR'R" whereby R' and R" for each substituent independently represent linear or branched Cι-6 alkyl, preferably R16 represents a phenyl group, which is optionally substituted by one or more substituents selected from the group consisting of methyl, ethyl, F, CI, Br and CF3, more preferably R16 represents a phenyl group, which is mono-substituted with a chlorine atom in the 4-position.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula X R17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear or branched Cι.6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH F, CHF2, CF3, CN, OH, N02, - (C=0)-R\ SH, SR', SOR', S02R', NH2, NHR', NR'R", -(C=0)-NH2, -(C=0)-NHR' and -(C=0)-NR'R", whereby R' and optionally R" for each substituent independently represent linear or branched Cι-6 alkyl, preferably R17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, ethyl, F, CI, Br and CF3, more preferably R17 represents a phenyl group, which is di-substituted with two chlorine atoms in its 2- and 4-position.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula X R18 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substijuted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an -NR19R20-moiety, preferably R18 represents a saturated, optionally at least mono-substituted, optionally one or more nitrogen-atoms as ring member containing C3-8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an -NR19R20- moiety, more preferably R18 represents a pyrrolidinyl group, a piperidinyl group or a piperazinyl group, whereby each of these groups may be substituted with one or more Ci-β-alkyl groups, or an -NR18R19-moiety.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula X R19 and R20, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Ci-β-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8-cycIoaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH2-) or ethylene (-CH2-CH2)-group, an - S02-R 1-moiety, or an -NR22R23-moiety, preferably one of these residues R19 and R20 represents a hydrogen atom and the other one of these residues R19 and R20 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, an -S02-R21 -moiety, or an -NR22R23- moiety, or R19 and R20, identical or different, each represent a Cι-6 alkyl group, more preferably one of these residues R19 and R20 represents a hydrogen atom and the other one of these residues R19 and R20 represents an optionally at least mono- substituted pyrrolidinyl group, an optionally at least mono-substituted piperidinyl group, an optionally at least mono-substituted piperazinyl group, an optionally at least mono-substituted triazolyl group, an -S02-R21-moiety, or an -NR22R23-moiety, or R19 and R20, identical or different, represent a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group or a tert.-butyl group.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula X R21 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted Cι-6 aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8 cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or an optionally at least mono- substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a methylene (-CH2-) or ethylene (-CH2-CH2)-group, preferably R21 represents a Ci-β-alkyl group, a saturated, optionally at least mono-substituted cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or a phenyl group, which is optionally substituted with one or more C1.6 alkyl groups.
In a preferred embodiment of the combination of compounds according to the invention for a compound according to formula X R22 and R23, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Cι-6 aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6 membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH2-) or ethylene (-CH2-CH2)-group, preferably R22 and R23, identical or different, represent a hydrogen atom or a Ci-β alkyl radical.
In a preferred embodiment of the combination of compounds according to the invention the compound according to general formula X is represented by a structure wherein R16 represents a phenyl ring, which is mono-substituted with a halogen atom, preferably a chlorine atom, in its 4-position,
R17 represents a phenyl ring, which is di-substituted with two halogen atoms, preferably chlorine atoms, in its 2- and 4-position,
R18 represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, or an -NR19R 0-moiety,
R19 represents a hydrogen atom or a linear or branched Cι.6-alkyl group,
R20 represents a linear or branched Cι-6 alkyl group, an -S02-R21 -moiety, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, a triazolyl group, whereby each of the heterocyclic rings may be substituted with one or more, identical or different, Cι-6-alkyl groups, and
R21 represents a phenyl group, which is optionally substituted with one or more Cι-6 alkyl groups, which may be identical or different, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
In a preferred embodiment of the combination of compounds according to the invention the combination of compounds comprises at least one compound according to formula X selected from the group consisting of:
N-piperidinyl-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H- pyrazol-3-carboxamide, 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- carboxylic acid-[1 ,2,4]-triazole-4-yl-amide,
5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- carboxylic acid-(4-methyl-piperazin-1 -yl)-amide,
5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- carboxylic acid diethylamide,
[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]- piperidine-1 -yl-methanone,
N-[5-(4-Chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3- carbonyI]-4-methylphenylsulfonamide, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
In a preferred embodiment of the combination of compounds according to the invention the combination of compounds comprises at least one compound according to formula X selected from
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, and
N-piperidinyl-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H- pyrazol-3-carboxamide; each optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate. In another aspect the present invention also provides a process for the preparation of substituted pyrazoline compounds of general formula I or II, wherein R1 is hydrogen, given above, in that at least one benzaldehyde compound of general formula III
Figure imgf000023_0001
(III) wherein R2, R3and R4 have the meaning mentioned above, is reacted with a pyruvate compound of general formula (IV)
Figure imgf000023_0002
(IV), wherein G represents an OR group with R being a branched or unbranched C1-6 alkyl radical or G represents an 0"K group with K being a cation, preferably an anorganic kation, more preferably an alkali metal kation, most preferably sodium, to yield a compound of general formula (V)
Figure imgf000024_0001
(V)
which is optionally isolated and/or optionally purified, and which is reacted with an optionally substituted phenyl hydrazine of general formula (VI)
Figure imgf000024_0002
(VI)
or a corresponding salt thereof, wherein R5, R6 and R7 have the meaning mentioned above, under inert atmosphere, to yield a compound of general formula (VII)
Figure imgf000025_0001
(VII) wherein R2, R3, R4, R5, R6 and R7 have the meaning as given above, which is optionally isolated and/or optionally purified, and optionally esterified to an alkyl-ester if in the substituted pyrazoline compound of general formula I or II according to the invention R1 is a linear or branched Cι- -alkyl group.
The inventive process is also illustrated in scheme I given below:
Scheme I:
Figure imgf000026_0001
The reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula IV is preferably carried out in the presence of at least one base, more preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic communications, 26(11), 2229-33, (1996). The respective description is hereby incorporated by reference and forms part of the disclosure. Preferably said reaction is carried out in a protic reaction medium such as a C alkyl alcohol or mixtures of these.
Reaction temperature as well as the duration of the reaction may vary over a broad range. Preferred reaction temperatures range from -10 °C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
Also preferred the reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula IV is carried out under acid catalysed conditions, more preferably by refluxing the mixture in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1), 147-149, 2001. The respective description is hereby incorporated by reference and forms part of the disclosure.
The reaction of the compound of general formula (V) with an optionally substituted phenyl hydrazin of general formula (VI) is preferably carried out in a suitable reaction medium such as Cι- -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds. Also preferably, 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. Furthermore, the reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
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 °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 (VII) 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. Preferably the compounds of general formula (VII) are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a C alkyl ester, an activated ester such as p- nitrophenylester. Other well known methods for the activation of acids include the activation with N,N-dicyclohexylcarbodiimide or benzotriazol-N- oxotris(dimethylamino) phosphonium hexafluorophosphate (BOP)).
If said activated compound of general formula (VII) is an acid chloride, it is preferably prepared by reaction of the corresponding acid of general formula (VII) with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the solvent. Also preferably an additional solvent may be used. Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofurane or dimethoxyethane. Mixtures of two or more solvents from one class or two or more solvents from different classes may also be used. Preferred reaction temperature range from 0s C to the boiling point of the solvent and reaction times from several minutes to several hours.
If said activated compound of general formula (VII) is a mixed anhydride, said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula (VII) with ethyl chloroformiate in the presence of a base such as triethylamine or pyridine, in a suitable solvent.
Following that the activated compound can be reacted with an alkyl-alcohol to arrive at compounds according to general formulas I or II with R1 being a a linear or branched Cι-4-alkyl group.
During the processes described above the protection of sensitive groups or of reagents may be necessary and/or desirable. The introduction of conventional protective groups as well as their removal may be performed by methods well-known to those skilled in the art.
If the substituted pyrazoline compounds of general formula I or II themselves are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or fractionalized crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.
In a further aspect the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula I or II and stereoisomers thereof, wherein at least one compound of general formula I or II having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presenc^ of a suitable reaction medium. Suitable reaction media include, for example, any of the ones given above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
In yet a further aspect the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula I or II or stereoisomers thereof, wherein at least one compound of general formula I or II having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NHnR4-n]+, wherein n is 0, 1 , 2, 3 or 4 and R represents a branched or unbranched C1-4-alkyl-radical. Suitable reaction media are, for example, any of the ones given above.
Solvates, preferably hydrates, of the substituted pyrazoline compounds of general formula I or II, of corresponding stereoisomers, of corresponding N-oxides or of corresponding salts thereof may also be obtained by standard procedures known to those skilled in the art.
Substituted pyrazoline compounds of general formula I or II, which comprise nitrogen-atom containing saturated, unsaturated or aromatic rings may also be obtained in the form of their N-oxides by methods well known to those skilled in the art.
The purification and isolation of the inventive substituted pyrazoline compounds of general formula I or II, of a corresponding stereoisomer, or salt, 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 substituted pyrazoline compounds of general formula I and II given below, their stereoisomers, corresponding N-oxides, corresponding salts thereof and corresponding solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments.
It has been found that the substituted pyrazoline compounds of general formula (I) and (II) given below, stereoisomers thereof, N-oxides thereof, corresponding salts and corresponding solvates have the property to regulate triglyceride levels in blood plasma.
The combination of compounds comprising substituted pyrazoline compounds of general formula (I) and (II) given below, their stereoisomers, corresponding N-oxides, corresponding salts thereof and corresponding solvates and of substituted pyrazoline compounds of general formula (X) given below, their stereoisomers, corresponding N-oxides, corresponding salts thereof and corresponding solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments.
It has been found that the substituted pyrazoline compounds of general formula X given below, stereoisomers thereof, N-oxides thereof, corresponding salts and corresponding solvates have a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CB^-receptors, i.e. they act as antagonists on these receptors. In particular these pyrazoline compounds show litte or no development of tolerance during treatment particularly with respect to food intake. After ending the treatment with the pyrazoline compounds, reduced increase of body weight is found compared to the pre-treatment level.
Thus, another aspect of the present invention relates to a Medicament comprising at least one substituted pyrazoline compound of general formula I or II according to the invention and optionally one or more pharmaceutically acceptable excipients.
Thus, another aspect of the present invention relates to a Medicament comprising at least one substituted pyrazoline compound of general formula I
Figure imgf000031_0001
wherein
R1 represents hydrogen or a linear or branched Cι-4-alkyl group,
R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Ci-β-alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R8, SH, SR8, SOR8, S02R8, NH2, NHR8, NR8R9, -(C=0)-NH2, -(C=0)-NHR8 or -(C=0)-NR8R9 whereby R8 and R9 for each substituent independently represent linear or branched Cι-6 alkyl,
R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2, -(C=0)-NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched Ci-β alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof; and optionally one or more pharmaceutically acceptable excipients.
In an embodiment of the medicament according to the invention for the compound according to formula I at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R4 is different from hydrogen.
In an embodiment of the medicament according to the invention for the compound according to formula I at least one of R5, R6 or R7 represents hydrogen, while at least one R5, R6 or R7 is different from hydrogen.
In an embodiment of the medicament according to the invention for the compound according to formula I R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a halogen atom, or CF3, preferably R2, R3 and R4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In an embodiment of the medicament according to the invention for the compound according to formula I R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF3, preferably R5, R6 and R7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In an embodiment of the medicament according to the invention for the compound according to formula I R2 represents a chlorine atom in the 4-position of the phenyl ring, while R3 and R4 represent hydrogen.
In an embodiment of the medicament according to the invention for the compound according to formula I R5 and R6 each represent a chlorine atoms in the 2- and 4- position of the phenyl ring, whi e R7 represents hydrogen. In an embodiment of the medicament according to the invention for the compound according to formula I R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
In an embodiment of the medicament according to the invention the compound according to formula I is represented by a compound of general formula (II)
Figure imgf000033_0001
II wherein
R1 represents hydrogen or a linear or branched Cι-4-alkyl group,
R12, R13, R14 or R15 independently of each other represent a linear or branched Ci-e-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH , hydrogen, methyl, ethyl, F, CI, Br and CF3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
In an embodiment of the medicament according to the invention for the compound according to formula II R12 and R13 independently of each other represent hydrogen, a linear or branched Cι.6-alkyl group, a halogen atom, or CF3, preferably R12 and R13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In an embodiment of the medicament according to the invention for the compound according to formula II R14, and R15 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a halogen atom, or CF3, preferably R14 and R15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
In an embodiment of the medicament according to the invention for the compound according to formula II R13 represents CI and R12 represents hydrogen.
In an embodiment of the medicament according to the invention for the compound according to formula II R14 and R15 each represent CI.
In an embodiment of the medicament according to the invention for the compound according to formula II R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
In an embodiment of the medicament according to the invention the compound according to formulas I or II is selected from the group consisting of:
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
Another aspect of the invention is a medicament comprising at least one combination of compounds according to the invention and optionally one or more pharmaceutically acceptable excipients. In an embodiment of the medicaments according to the invention the medicament is for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
In an embodiment of the medicament comprising the compound according to formula I or II according to the invention the medicament is 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.
In an embodiment of the medicament comprising the combination according to the invention the medicament is 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.
In an embodiment of the medicaments according to the invention the medicament is for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
In an embodiment of the medicaments according to the invention the medicament is for the prophylaxis and/or treatment of psychosis.
In an embodiment of the medicaments according to the invention the medicament is for the prophylaxis and/or treatment of alcohol abuse and/or addiction, nicotine abuse and/or addiction, drug abuse and/or addiction and/or medicament abuse and/or addiction, preferably drug abuse and/or addiction and/or nicotine abuse and/or addiction.
In an embodiment of the medicaments according to the invention the medicament is for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheric neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin camcer, colon cancer, bowl 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 colcon cancer, bowel cancer and prostate cancer; medicament- induced movement disorders, dystonia, endotoxemic shock, hemorragic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit.
Said medicaments may also comprise any combination of one or more of the substituted pyrazoline compounds of general formula I given above, stereoisomers thereof, corresponding N-oxides thereof, physiologically acceptable salts thereof or physiologically acceptable solvates thereof.
Particularly preferably said medicaments are suitable for the prophylaxis and/or treatment of alcohol abuse, drug abuse and/or medicament abuse, preferably drug abuse and the treatment of obesity. Medicaments and/or drugs, which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
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 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 stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions. These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
Solid oral compositions (which are preferred as are liquid ones) may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to the methods well known in normal pharmaceutical practice., in particular with an enteric coating.
The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopeias and similar reference texts.
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 compositio is may take any convenient form, such as tablets, pellets, 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 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.
The 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 froml to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formaula I or II according to the invention (and optionally one or more pharmaceutically acceptable excipients,) for the preparation of a medicament 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.
Another preferred aspect of the invention is the use of at least one combination of compounds according to the invention (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.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the prophylaxis and/or treatment of psychosis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or li according to the invention or at least one combination of compounds according to the invention (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 addiction, nicotine abuse and/or addiction, medicament abuse and/or addiction and/or drug abuse and/or addiction, preferably drug abuse and/or addiction or nicotine abuse and/or addiction. Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I or II according to the invention or at least one combination of compounds according to the invention (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 schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheric neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin camcer, colon cancer, bowl 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 colcon cancer, bowel cancer and prostate cancer; medicament- induced movement disorders, dystonia, endotoxemic shock, hemorragic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of general formula I
Figure imgf000041_0001
wherein
R1 represents hydrogen or a linear or branched Cι-4-alkyl group,
R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a linear or branched Ci-β-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R8, SH, SR8, SOR8, S02R8, NH2, NHR8, NR8R9, -(C=0)-NH2, -(C=0)-NHR8 or -(C=0)-NR8R9 whereby R8 and R9 for each substituent independently represent linear or branched Cι-6 alkyl,
R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2, -(C=0)-NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched C1-6 alkyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemjate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof; and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use for the manufacture of a medicament of at least one substituted pyrazoline compound of formula I for which at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R4 is different from hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which at least on of R5, R6 or R7 represents hydrogen, while at least one R5, R6 or R7 is different from hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formuja I for which R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF3, preferably R2, R3 and R4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a halogen atom, or CF3, preferably R5, R6 and R7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R2 represents a chlorine atom in the 4- position of the phenyl ring, while R3 and R4 represent hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R5 and R6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R7 represents hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula I for which R1 represents hydrogen, methyl or ethyl, preferably hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula wherein the compound of general formula (I) is represented by a compound of general formula (II)
Figure imgf000044_0001
II wherein R1 represents hydrogen or a linear or branched CM-alkyl group,
R12, R13, R14 or R15 independently of each other represent a linear or branched Ci-e-alkyl group, a linear or branched C1-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, hydrogen, methyl, ethyl, F, CI, Br and CF3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R12 and R13 independently of each other represent hydrogen, a linear or branched Cι-6-alkyI group, a halogen atom, or CF3, preferably R12 and R13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3forthe manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R14, and R15 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF3, preferably R14 and R15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R13 represents CI and R 2 represents hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R14 and R 5 each represent CI for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
Another preferred embodiment of the invention is the use of at least one substituted pyrazoline compound of formula II for which R1 represents hydrogen, methyl or ethyl, preferably hydrogen for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis. Another embodiment of the invention is the use of at least one substituted pyrazoline compound of formula I or II for which the compound according to formulas I or II is selected from the group consisting of:
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate;
for the manufacture of a medicamentfor the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and are not intended to limit the present invention.
Examples:
Example 0 represent a compound according to formula I or II.
Example 0:
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazoIe-3-carboxylic acid
a) 4-(4-chlorophenyl)-2-oxo-3-butenoic acid
Figure imgf000048_0001
In a three neck flask p-chlorobenzaldehyde (13,3 g, 95 mmoles) and ethyl pyruvate (10 g, 86 mmoles) were dissolved in 150 ml of absolute ethanol.The solution was ice- cooled to 0°C and an aqueous solution of NaOH (3.8 g in 45 mL water) was added dropwise keeping the temperature below or equal to 10°C, whereby a yellow-orange colored precipitate was formed. The reaction mixture was stirred for 1 hour at 0°C and an additional 1.5 hours at room temperature (approximately 25 °C). Afterwards the reaction mixture was cooled down to approximately 5°C and the insoluble sodium salt of 4-(4-chlorophenyl)-2-oxo-3-butenoic acid was isolated by filtration.
The filtrate was left in the refrigerator overnight, whereby more precipitate is formed, which was filtered off, combined with the first fraction of the salt and washed with diethyl ether. The sodium salt of 4-(4-chlorophenyl)-2-oxo-3-butenoic acid was then treated with a solution of 2N HCI, stirred for some minutes and solid 4-(4- chlorophenyl)-2-oxo-3-butenoic acid was separated via filtration and dried to give 12.7 g of the desired product (70% of theoretical yield).
IR (KBr, cm-1 ) : 3500-2500, 1719,3, 1686,5, 1603,4, 1587,8, 1081 ,9.
1H NMR(CDCI3, δ) : 7,4 (d, J=8,4Hz, 2H), 7,5 (d, J=16,1Hz, 1H), 7,6 (d, J=8,4Hz,
2H), 8,1 (d, J=16,1 Hz, 1 H). a2) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid
In an alternative route instead of using ethylpyruvate the salt CH3-C(0)-C(0)-0" Na+ (sodiumpyruvate) was used, dissolved ethanolic water.
b) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid
Figure imgf000049_0001
4-(4-chlorophenyl)-2-oxo-3-butenoic acid obtained according to step a) (12.6 g, 60 mmoles), 2,4-dichlorophenylhydrazine hydrochloride (12.8 g, 60 mmoles) and glacial acetic acid (200 mL) were mixed under a nitrogen atmosphere and heated to reflux for 4 hours, cooled down to room temperature (approximately 25 °C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield).
IR (KBr, cm"1 ) : 3200-2200, 1668,4, 1458, 1251 ,4, 1104,8.
1H NMR (CDCIa, δ) : 3,3 (dd, 1H), 3,7 (dd, 1H), 5,9 (dd, 1 H), 7,09-7,25 (m, 7H).
The Examples 1 to 6 represent compounds according to formula X. Example 1:
N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H- pyrazole-3-carboxamide
(a) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride
Figure imgf000050_0001
Under nitrogen atmosphere 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro- pyrazole-3-carboxylic acid (2.5 g, 6.8 mmols) obtained according to Example 0 was dissolved in 4 mL of in thionyl chloride and heated to reflux for 2.5 hours. The excess thionyl chloride is removed from the reaction mixture under reduced pressure and the resulting crude residue (2.6 g) is used without any further purification.
IR (KBr, cm"1) : 1732,3, 1700, 1533,3, 1478,1 , 1212,9, 826,6.
Starting from this compound compounds according to general formulas I and II wherein R1 is a linear or branched Cι- -alkyl group can be prepared reacting this compound with the appropriate alkyl alcohol.
(b) N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichIorophenyl)-4,5-dihydropyrazole- 3-carboxamide
Figure imgf000051_0001
Under nitrogen atmosphere N-aminopiperidine (0.6 mL, 5.6 mmoles) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL). The resulting mixture was ice-cooled down to 0°C and a solution of 5-(4-chlorophenyl)-1 -(2,4- dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride obtained in step (c) in methylene chloride (15 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature (approximately 25 °C) overnight. Afterwards the reaction mixture was washed with water, followed by a saturated aqueous solution of sodium bicarbonate, then again with water, dried over sodium sulfate, filtered and evaporated to dryness in a rotavapor. The resulting crude solid was crystallized from ethanol. The crystallized solid was removed via filtration and the mother liquors were concentrated to yield a second fraction of crystallized product. The two fractions were combined to give a total amount of 1.7 g (57% of theoretical yield) of N-piperidinyl-5- (4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide having a melting point of 183-186°C.
IR (KBr, cm"1) : 3222,9, 2934,9, 1647,4, 1474,7, 1268,3, 815,6. 1H NMR ( CDCI3, δ) : 1 ,4 (m, 2H), 1 ,7 (m, 4H), 2,8 (m, 4H), 3,3 (dd, J=6,1 y 18,3Hz, 1 H), 3,7 (dd, J=12,5 and 18,3 Hz, 1 H), 5,7 (dd, J=6,1 and 12,5 Hz, 1H), 7,0-7,2 (m, 6H), 7,4 (s, 1 H).
The compounds according to the following examples 2-6 have been prepared analogously to the process described in Example 1 in combination with Example 0. Example 2:
5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- car boxy lie acid-[1 ,2,4]triazol-4-yl amide
Melting point: 134-138 °C.
IR (KBr, cm"1): 3448, 1686, 1477, 1243, 1091 , 821.
1H NMR(CDCI3, δ): 3,1 (dd, J=6,2 and 17,9Hz, 1 H), 3,7 (dd, J=12,3 and
17,9Hz, 1H), 5,9 (dd, J=6,2 and 12,3 Hz, 1 H), 7,2-7,5 (m, 7H), 8,7 (s, 2H), 12,0
(bs, 1 H).
Example 3:
5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- car boxy lie acid-(4-methyl-piperazin-1-yl)-amide hydrochloride
Melting point: 150-155SC.
IR (KBr, cm"1) : 3433, 1685, 1477, 1296, 1246, 1088, 1014, 825.
1H NMR (CDCIs, δ): 2,7 (d, J=4,2Hz, 3H), 3,0-3,4 (m, 9H), 3,6 (dd, J=11 ,9 and
17,9 Hz, 1 H), 5,8 (dd, J=5,5 and 11 ,9 Hz, 1H), 7,1 (d, J=8,4Hz, 2H), 7,25 (2d,
J= 8,4 and 8,7 Hz, 3H), 7,4 (d, J=2,2Hz, 1H), 7,5 (d, J=8,7Hz, 1H), 9,8 (s, 1H),
11 ,2 (bs).
Example 4:
5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- carboxylic acid diethylamide
This compound was obtained in form of an oil.
IR (film, cm"1) : 2974, 1621 , 1471 , 1274, 1092, 820.
1H NMR (CDCI3, δ): 1 ,2 (m, 6H), 3,3-3,9 (m, 6H), 5,6 (dd, J=5,8 and 11 ,7 Hz,
1H), 7-7,25 (m, 7H).
Example 5:
[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazol-3-yl]- piperidin-1 -yl-methanone
Melting point: 105-110QC.
IR (KBr, cm"1) : 2934, 1622, 1470, 1446, 1266, 1010, 817.
1H NMR ( CDCI3, δ): 1 ,7 (m, 6H), 3,4 (dd, J=5,7 and 17,9Hz, 1 H), 3,7 (m, 3H),
3,9 (m, 2H), 5,6 (dd, J=6,1 y 11 ,9 Hz, 1H), 7-7,25 (m, 7H). Example 6:
N-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- carbonyl]-4-methyl-phenylsulfonamide
This compound was obtained in form of an amorph solid.
IR (KBr, cm"1) : 1697, 1481, 1436, 1340, 1169, 1074, 853.
1H NMR (CDCIs, δ): 2,4 (s, 3H), 3,2 (dd, J=6,6 and 18,3Hz, 1H), 3,6 (dd, J=12,8 and
18,3Hz, 1H), 5,8 (dd, J=6,6 and 12,8Hz, 1H), 7 (d, J=8,2Hz, 2H), 7,2 (s, 1 H), 7,3-7,4
(m, 6H), 8 (d, J=8,1Hz, 2H), 9 (s, 1H).
Example 7:
N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4,5- dihydropyrazole-3-carboxamide
Under nitrogen gas as an inert atmosphere N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0,15 g, 332 mmoles) was dissolved in 7 ml of dichloromethane. The resulting solution was ice-cooled to 0 °C and m-chloroperbenzoic acid (0,204 g, 0,83 mmoles) added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was remaining. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered. The filtered solution was evaporated to dryness and the crude product was purified via column chromatography yielding 78 mg (50 % of theoretical yield) of the N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5- dihydropyrazole-3-carboxamide in form of a white solid having a melting point of 115- 120 °C.
IR (KBr, cm"1): 3202, 1678, 1654, 1474, 1309, 1107.
1H-NMR (CDCI3, δ): 1.6 (m, 2H), 1.8-2.0 (m, 4H), 2.55 (m, 2H), 3.3 (dd, J = 6.3 Hz and 18.2 Hz, 1 H), 3.7 (m, 3H), 5.8 (dd, J = 6.3 Hz and 12.5 Hz, 1 H), 7.0-7.3 (m, 7H), 8.5 (s, 1H.) Pharmacological Data/Testing:
The compound according to example 0 is an inhibitor of high blood levels of triglicerides. This effect has been probed in obese mice fed with high fat diet. In the following paragraphs it is described the method and the results obtained in this study.
i. In-vivo testing for regulation of triglycerides in blood plasma
The study was done using six weeks old male mice B6 Lep ob/ob, obtained from Charles River (France). Mice were divided in 3 groups : I (control), II (vehicle), III (example 0).
Group I:
The animals of the group I received the standard diet (D-12450B, Research Diets, NJ, USA).
Group II:
The animals of the groups II and III were fed with a High Fat Diet (D-12492, Research Diets, NJ, USA), in both cases for 7 weeks (References 1 and 2).
Group III:
The animals of the groups III were fed with a High Fat Diet (D-12492, Research Diets, NJ, USA), in both cases for 7 weeks (References 1 and 2).
At the end of the feeding period of 7 weeks, it was started the treatment period (14 days): Group II mice received the vehicle (10 ml/kg/day, po, of the aqueous solution of acacia gum, 5% W/V). Group III was administered with 30 mg/kg/day, po, of the inventive compound 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4,5-dihydro-pyrazole- 3-carboxylic acid according to Example 0. Group I didn't received any treatment. The three groups of mice had the same diet than in the previous period.
At the end of the 14 days period of treatment, the blood levels of triglicerides of the animals were determined. The analysis of the whole blood samples was done using test strips "Lipid panel" and the photometric Analyzer Cardio-Check Test System, from PA Instruments Polymer Technology Systems Indianapolis, IN-46268, USA (Distributed in Spain by Novalab Iberica S.A.L, Madrid, Spain).
The results obtained were the following :
Figure imgf000056_0001
NS : Not significant diference, compared with Group I.
The results showed that Group II mice receiving high fat diet had significantly higher triglicerides blood levels than the control Group I. But the administration of the compound according to Example 0 (Group III) improved the triglicerides blood levels, which were not different of the levels of the group I, which received standard diet.
Figure 1 shows the clear reduction of triglyceride levels in blood plasma. The level (Group III) returns to the control level of Group I compared to the clearly raised levels found in the Group II without the treatment with the compound according to Example 0.
Thus, it has been proved the inhibitory effect of the inventive compound 5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid according to Example 0. on the high blood levels of triglicerides.
References 1.-Lambert P.D. et al.."Cyliary neurotrophic factor activates leptin-like pathways and reduces body fat"
P.N.A.S. 2001 , 28.(8) : 4652-4657
2.- Grasa M.M. et al "Oleoyl-Estrone lowens the body weight of both ob/ob and db/db mice.
Hozm. Metab. Res 2000, 32 : 246-250
II. In-vivo testing for regulation of triglycerides in blood plasma
In a second set of experiments carried out similar to the tests shown above the TG (triglyceride) levels of diet-induced obese mice in blood were determined. Mice receiving a high fat diet were - after a feeding period of 6 days - either treated p.o. with vehicle (0,5 % HPMC) or with the compound according to example 0 (30 mg/kg/day p.o.).
TG levels in blood were determined on day 28 after beginning of the treatment.
TG (triglyceride) levels were 1.28 ± 25 mmoles/l in the group treated with vehicle and only 0.80 ± 0.07 mmoles/l in the group treated with the inventive compound 5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid according to Example 0. The results were statistically highly significant with an ANOVA factorial, Fisher's post-hoc test of *** p<0.005 vs. vehicle.
Thus, again the inhibitory effect of the inventive compound 5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid according to Example 0 on the high blood levels of triglicerides was demonstrated.

Claims

Claims:
1. Substituted pyrazoline compounds of general formula I,
Figure imgf000058_0001
wherein
R1 represents hydrogen or a linear or branched CM-alkyl group,
R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R8, SH, SR8, SOR8, S02R8, NH2, NHR8, NR8R9, -(C=0)-NH2, -(C=0)-NHR8 or -(C=0)-NR8R9 whereby R8 and R9 for each substituent independently represent linear or branched Cι-6 alkyl,
R5 and R6 independently of each other represent a linear or branched Ci-e- alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2, -(C=0)-NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched Ci-e alkyl; R7 represents hydrogen, a linear or branched Ci-e-alkyl group, a linear or branched Cι.6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2> -(C=0)- NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched Cι-6 alkyl; with the proviso that if R1 and R7 are H and R5 and R6 both represent CI in the 3- and 4-position of the phenyl ring neither of R2, R3 and R4 may represent F in the 4-position of the phenyl ring if the other two of R2, R3 and R4 both represent H; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
2. Compounds according to claim 1 , characterized in that at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R4 is different from hydrogen.
3. Compounds according to any one of claims 1 or 2, characterized in that R7 represents hydrogen.
4. Compounds according to any one of claims 1 to 3, characterized in that R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF3, preferably R2, R3 and R4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
5. Compounds according to any one of claims 1 to 4, characterized in that R5 and R6 independently of each other represent a linear or branched Cι-6-alkyl group, a halogen atom, or CF3) preferably R5 and R6 independently of each other represent methyl, ethyl, F, CI, Br and CF3.
6. Compounds according to any one of claims 1 to 5, characterized in that R2 represents a chlorine atom in the 4-position of the phenyl ring, while R3 and R4 represent hydrogen.
7. Compounds according to any one of claims 1 to 6, characterized in that R5 and R6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R7 represents hydrogen.
8. Compounds according to any one of claims 1 to 7, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
9. Compounds of general formula II according to one or more of claims 1 to 8
Figure imgf000060_0001
π wherein
R1 represents hydrogen or a linear or branched Cι-4-alkyI group, R 12 or R 13 jnc|epenc|ently of each other represent a linear or branched Ci-e- alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, hydrogen, methyl, ethyl, F, CI, Br and CF3,
R14 or R15 independently of each other represent a linear or branched Ci-e- alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, methyl, ethyl, F, CI, Br and CF3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
10. Compounds according to claim 9 characterized in that R12 and R13 independently of each other represent hydrogen, a linear or branched Ci-e- alkyl group, a halogen atom, or CF3, preferably R12 and R13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
11. Compounds according to any one of claims 9 or 10, characterized in that R14, and R15 independently of each other represent a linear or branched Cι-6-alkyl group, a halogen atom, or CF3, preferably R14 and R15 independently of each other represent methyl, ethyl, F, CI, Br and CF3.
12. Compounds according to any one of claims 9 to 11 , characterized in that R13 represents CI and R12 represents hydrogen.
13. Compounds according to any one of claims 9 to 12, characterized in that R14 and R15 each represent CI.
14. Compounds according to any one of claims 9 to 13, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
15. Compounds according to one or more of claims 1 to 14 selected from the group consisting of:
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
16. Combination of compounds comprising at least one substituted pyrazoline compound of general formula I
Figure imgf000062_0001
wherein
R1 represents hydrogen or a linear or branched Cι-4-alkyl group,
R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R8, SH, SR8, SOR8, S02R8, NH2, NHR8, NR8R9, -(C=0)-NH2, -(C=0)-NHR8 or -(C=0)-NR8R9 whereby R8 and R9 for each substituent independently represent linear or branched Cι-6 alkyl,
R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R1°, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2, -(C=0)-NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched C1-6 alkyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof;
and at least one substituted pyrazoline compound of general formula X
Figure imgf000063_0001
wherein
R16 represents an optionally at least mono-substituted phenyl group,
R17 represents an optionally at least mono-substituted phenyl group, R18 represents a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an - NR19R20-moiety,
R19 and R20, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, an -S02-R21 -moiety, or an - NR2 R23-moiety, with the proviso that R19 and R20 do not identically represent hydrogen,
R21 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group,
R22 and R23, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono^or polycyclic ring system, or an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a linear or branched alkylene group, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
17. Combination of compounds according to claim 16, characterized in that at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R4 is different from hydrogen.
18. Combination of compounds according to any one of claims 16 or 17, characterized in that at least on of R5, R6 or R7 represents hydrogen, while at least one R5, R8 or R7 is different from hydrogen.
19. Combination of compounds according to any one of claims 16 to 18, characterized in that R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a halogen atom, or CF3, preferably R2, R3 and R4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
20. Combination of compounds according to any one of claims 16 to 19, characterized in that R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Cι.6-alkyl group, a halogen atom, or CF3, preferably R5, R6 and R7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
21. Combination of compounds according to any one of claims 16 to 20, characterized in that R2 represents a chlorine atom in the 4-position of the phenyl ring, while R3 and R4 represent hydrogen.
22. Combination of compounds according to any one of claims 16 to 21 , characterized in that R5 and R6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R7 represents hydrogen.
23. Combination of compounds according to any one of claims 16 to 22, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
24. Combination of compounds according to any one of claims 16 to 23 characterized in that the compound of general formula I is represented by a compound of general formula II
Figure imgf000066_0001
II wherein
R1 represents hydrogen or a linear or branched Cι.4-alkyl group,
R12, R13, R14 or R15 independently of each other represent a linear or branched Cι-6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, hydrogen, methyl, ethyl, F, CI, Br optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
25. Combination of compounds according to claim 24 characterized in that R12 and R13 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF3, preferably R12 and R13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
26. Combination of compounds according to any one of claims 24 or 25, characterized in that R14, and R15 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a halogen atom, or CF3, preferably R14 and R15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
27. Combination of compounds according to any one of claims 24 to 26, characterized in that R13 represents CI and R12 represents hydrogen.
28. Combination of compounds according to any one of claims 24 to 27, characterized in that R14 and R15 each represent CI.
29. Combination of compounds according to any one of claims 24 to 28, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
30. Combination of compounds according to one or more of claims 16 to 29 characterized in that the compound according to formula I or II selected from the group consisting of:
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
31. Combination of compounds according to any of claims 16 to 30, characterized in that R16 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear or branched Cι-6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R', SH, SR', SOR', S02R', NH2, NHR', NR'R", -(C=0)-NH , -(C=0)-NHR' and -(C=0)-NR'R" whereby R' and R" for each substituent independently represent linear or branched Cι-6 alkyl, preferably R16 represents a phenyl group, which is optionally substituted by one or more substituents selected from the group consisting of methyl, ethyl, F, CI, Br and CF3, more preferably R16 represents a phenyl group, which is mono-substituted with a chlorine atom in the 4-position.
32. Combination of compounds according to any of claims 16 to 31 , characterized in that R17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of a linear or branched Cι-6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R', SH, SR', SOR', S02R', NH2, NHR', NR'R", -(C=0)-NH2, -(C=0)-NHR' and -(C=0)-NR'R", whereby R' and optionally R" for each substituent independently represent linear or branched Cι-6 alkyl, preferably R17 represents a phenyl group, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, ethyl, F, CI, Br and CF3, more preferably R17 represents a phenyl group, which is di-substituted with two chlorine atoms in its 2- and 4-position.
33. Combination of compounds according to one or more of claims 16 to 32, characterized in that R18 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8 cycloaliphatic group, which may be condensed with an optionally at least mono-jsubstituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an -NR19R20-moiety, preferably R18 represents a saturated, optionally at least mono-substituted, optionally one or more nitrogen-atoms as ring member containing C3-β cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an -NR19R20-moiety, more preferably R18 represents a pyrrolidinyl group, a piperidinyl group or a piperazinyl group, whereby each of these groups may be substituted with one or more Cι-6-alkyl groups, or an -NR18R19-moiety.
34. Combination of compounds according to one or more of claims 16-33, characterized in that R19 and R20, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted Ci-β-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH2-) or ethylene (-CH2-CH2)-group, an -S02-R21-moiety, or an -NR22R23-moiety, preferably one of these residues R19 and R20 represents a hydrogen atom and the other one of these residues R19 and R20 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3-8-cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, an -S02-R21 -moiety, or an - NR22R23-moiety, or R19 and R20, identical or different, each represent a Cι-6 alkyl group, more preferably one of these residues R19 and R20 represents a hydrogen atom and the other one of these residues R19 and R20 represents ari optionally at least mono-substituted pyrrolidinyl group, an optionally at least mono-substituted piperidinyl group, an optionally at least mono-substituted piperazinyl group, an optionally at least mono-substituted triazolyl group, an - S02-R21 -moiety, or an -NR^R^-moiety, or R19 and R20, identical or different, represent a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group or a tert.-butyl group.
35. Combination of compounds according to one or more of claims 16-34, characterized in that R21 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted C1.6 aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.β cycloaliphatic group, which may be condensed with a mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a methylene (-CH2-) or ethylene (-CH2-CH2)-group, preferably R21 represents a Ci-e-alkyl group, a saturated, optionally at least mono-substituted cycloaliphatic group, which may be condensed with a mono- or polycyclic ring- system, or a phenyl group, which is optionally substituted with one or more Cι- 6 alkyl groups.
36. Combination of compounds according to one or more of claims 16-35, characterized in that R22 and R23, identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C1-6 aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C3.8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6 membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH2-) or ethylene (-CH2-CH2)-group, preferably R22 and R23, identical or different, represent a hydrogen atom or a C1-6 alkyl radical.
37. Combination of compounds according to any of claims 16 to 36 characterized in that the compound according to general formula X is represented by a structure wherein
R16 represents a phenyl ring, which is mono-substituted with a halogen atom, preferably a chlorine atom, in its 4-position,
R17 represents a phenyl ring, which is di-substituted with two halogen atoms, preferably chlorine atoms, in its 2- and 4-position,
R18 represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, or an -NR19R20-moiety,
R19 represents a hydrogen atom or a linear or branched Cι-6-alkyl group,
R20 represents a linear or branched Cι-6 alkyl group, an -S02-R21 -moiety, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, a triazolyl group, whereby each of the heterocyclic rings may be substituted with one or more, identical or different, Cι-6-alkyl groups, and
R21 represents a phenyl group, which is optionally substituted with one or more C1-6 alkyl groups, which may be identical or different, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
38. Combination of compounds according to one or more of claims 16 to 37, characterized in that it comprises at least one compound according to formula X selected from the group consisting of: N-piperidinyl-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H- pyrazol-3-carboxamide,
5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- carboxylic acid-[1 ,2,4]-triazole-4-yl-amide,
5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- carboxylic acid-(4-methyl-piperazin-1 -yl)-amide,
5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3- carboxylic acid diethylamide,
[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-yl]- piperidine-1 -yl-methanone,
N-[5-(4-Chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3- carbonyl]-4-methylphenylsulfonamide, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
39. Combination of compounds according to one or more of claims 16 to 38, characterized in that it comprises at least
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, and
N-piperidinyl-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H- pyrazol-3-carboxamide; each optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate
0. Process for the manufacture of substituted pyrazoline compounds of general formula I or II, wherein R1 is hydrogen, according to one or more of claims 1 to 15, characterized in that at least one benzaldehyde compound of general formula III
Figure imgf000073_0001
(III) wherein R2, R3 and R4 have the meaning according to one or more of claims 1- 8, is reacted with a pyruvate compound of general formula (IV)
Figure imgf000073_0002
(IV), wherein G represents an OR group with R being a branched or unbranched Ci-6 alkyl radical or G represents an 0"K group with K being a cation.to yield a compound of general formula (V)
Figure imgf000074_0001
(V) which is optionally isolated and/or optionally purified, and which is reacted with an optionally substituted phenyl hydrazine of general formula (VI)
Figure imgf000074_0002
(VI) or a corresponding salt thereof, wherein R5, R6 and R7 have the meaning according to one or more of claims 1 -8, under inert atmosphere, to yield a compound of general formula (VII)
Figure imgf000075_0001
(VII) wherein R2, R3, R4, R5, R6 and R7 have the meaning as given above, which is optionally isolated and/or optionally purified, and optionally esterified to an alkyl-ester if in the substituted pyrazoline compound of general formula I according to one or more of claims 1 to 15 R1 is a linear or branched Cι-4-alkyl group.
41. Medicament comprising at least one substituted pyrazoline compound of general formula I or II according to one or more of claims 1 to 15, and optionally one or more pharmaceutically acceptable excipients.
42. Medicament comprising at least one substituted pyrazoline compound of general formula I
Figure imgf000076_0001
wherein
R1 represents hydrogen or a linear or branched Cι.4-alkyl group,
R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Ci-β-alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R8, SH, SR8, SOR8, S02R8, NH2, NHR8, NR8R9, -(C=0)-NH2, -(C=0)-NHR8 or -(C=0)-NR8R9 whereby R8 and R9 for each substituent independently represent linear or branched Cι-6 alkyl,
R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a linear or branched Cι.6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH , -(C=0)-NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R11 for each substituent independently represent linear or branched d-β alkyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemfite or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof; and optionally one or more pharmaceutically acceptable excipients.
43. Medicament according to claim 42, characterized in that at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R4 is different from hydrogen.
44. Medicament according to any one of claims 42 or 43, characterized in that at least on of R5, R6 or R7 represents hydrogen, while at least one R5, R6 or R7 is different from hydrogen.
45. Medicament according to any one of claims 42 to 44, characterized in that R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Cι.6-alkyl group, a halogen atom, or CF3, preferably R2, R3 and R4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
46. Medicament according to any one of claims 42 to 45, characterized in that R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Cι.6-alkyl group, a halogen atom, or CF3, preferably R5, R6 and R7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
47. Medicament according to any one of claims 42 to 46, characterized in that R ,2 represents a chlorine atom in the 4-position of the phenyl ring, while R3 and R' represent hydrogen.
48. Medicament according to any one of claims 42 to 47, characterized in that R5 and R6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R7 represents hydrogen.
49. Medicament according to any one of claims 42 to 48, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
50. Medicament according to one or more of claims 42 to 49 characterized in that the compound of general formula (I) is represented by a compound of general formula (II)
Figure imgf000078_0001
π wherein
R1 represents hydrogen or a linear or branched Cι-4-alkyl group,
R12, R13, R14 or R15 independently of each other represent a linear or branched Ci-e-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, hydrogen, methyl, ethyl, F, CI, Br and CF3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
51. Medicament according to claim 50 characterized in that R12 and R1^ independently of each other represent hydrogen, a linear or branched Ci-e- alkyl group, a halogen atom, or CF3, preferably R12 and R13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
52. Medicament according to any one of claims 50 or 51 , characterized in that R14, and R15 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a halogen atom, or CF3, preferably R14 and R15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
53. Medicament according to any one of claims 50 to 52, characterized in that R13 represents CI and R12 represents hydrogen.
54. Medicament according to any one of claims 50 to 53, characterized in that R 14 and R15 each represent CI.
55. Medicament according to any one of claims 50 to 54, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
56. Medicament according to one or more of claims 42 to 55 characterized in that the compound according to formulas I or II is selected from the group consisting of:
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
57. Medicament comprising at least one combination of compounds according to one or more of claims 16 to 39 and optionally one or more pharmaceutically acceptable excipients.
58. Medicament according to claim 42 to 57 for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
59. Medicament according to one or more of claims 42 to 56 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.
60. Medicament according to claim 57 for the modulation of cannabinoid- receptors, preferably cannabinoid 1 (CBι) 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.
61. Medicament according to one or more of claims 42 to 57 for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
62. Medicament according to one or more of claims 42 to 57 for the prophylaxis and/or treatment of psychosis.
63. Medicament according to one or more of claims 42 to 57 for the prophylaxis and/or treatment of alcohol abuse and/or addiction, nicotine abuse and/or addiction, drug abuse and/or addiction and/or medicament abuse and/or addiction, preferably drug abuse and/or addiction and/or nicotine abuse and/or addiction.
64. Medicament according to one or more of claims 42 to 57 for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheric neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin camcer, colon cancer, bowl 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 colcon cancer, bowel cancer and prostate cancer; medicament- induced movement disorders, dystonia, endotoxemic shock, hemorragic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit.
65. Use of at least one substituted pyrazoline compound according to one or more of claims 1 - 15 or at least one combination of compounds according to one or more of claims 16 to 39 and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
66. Use of at least one substituted pyrazoline compound according to one or more of claims 1 - 15 and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament 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.
67. Use of at least one combination of compounds according to one or more of claims 16 to 39 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.
68. Use of at least one substituted pyrazoline compound according to one or more of claims 1-15 or at least one combination of compounds according to one or more of claims 16 to 39 and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
69. Use of at least one substituted pyrazoline compound according to one or more of claims 1 -15 or at least one combination of compounds according to one or more of claims 16 to 39 and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of psychosis.
70. Use of at least one substituted pyrazoline compound according to one or more of claims 1-15 or at least one combination of compounds according to one or more of claims 16 to 39 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 addiction, nicotine abuse and/or addiction, medicament abuse and/or addiction and/or drug abuse and/or addiction, preferably drug abuse and/or addiction or nicotine abuse and/or addiction.
71. Use of at least one substituted pyrazoline compound according to one or more of claims 1-15 or at least one combination of compounds according to one or more of claims 16 to 39 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 schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheric neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin camcer, colon cancer, bowl 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 colcon cancer, bowel cancer and prostate cancer; medicament- induced movement disorders, dystonia, endotoxemic shock, hemorragic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit. Use of at least one substituted pyrazoline compound of general formula
Figure imgf000084_0001
wherein
R1 represents hydrogen or a linear or branched Cι.4-alkyl group,
R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Ci-e-alkyl group, a linear or branched Ci-β-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R8, SH, SR8, SOR8, S02R8, NH2, NHR8, NR8R9, -(C=0)-NH2, -(C=0)-NHR8 or -(C=0)-NR8R9 whereby R8 and R9 for each substituent independently represent linear or branched C1-6 alkyl,
R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Cι-6-alkyl group, a linear or branched Cι-6-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, -(C=0)-R10, SH, SR10, SOR10, NH2, NHR10, NR10R11, -(C=0)-NH2, -(C=0)-NHR10 and -(C=O)-NR10R11, whereby R10 and optionally R 1 for each substituent independently represent linear or branched Cι-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof; and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
73. Use according to claim 72, characterized in that at least one of R2, R3 or R4 represents hydrogen, while at least one of R2, R3 or R4 is different from hydrogen.
74. Use according to any one of claims 72 or 73, characterized in that at least on of R5, R6 or R7 represents hydrogen, while at least one R5, R6 or R7 is different from hydrogen.
75. Use according to any one of claims 72 to 74, characterized in that R2, R3 and R4 independently of each other represent hydrogen, a linear or branched Ci-e- alkyl group, a halogen atom, or CF3, preferably R2, R3 and R4 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
76. Use according to any one of claims 72 to 75, characterized in that R5, R6 and R7 independently of each other represent hydrogen, a linear or branched Ci-e- alkyl group, a halogen atom, or CF3, preferably R5, R6 and R7 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
77. Use according to any one of claims 72 to 76, characterized in that R2 represents a chlorine atom in the 4-position of the phenyl ring, while R3 and R4 represent hydrogen.
78. Use according to any one of claims 72 to 77, characterized in that R5 and R6 each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R7 represents hydrogen.
79. Use according to any one of claims 72 to 78, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
80. Use according to one or more of claims 72 to 79 characterized in that the compound of general formula (I) is represented by a compound of general formula (II)
Figure imgf000086_0001
II wherein
R1 represents hydrogen or a linear or branched CM-alkyl group,
R12, R13, R14 or R15 independently of each other represent a linear or branched Ci-6-alkyl group, a linear or branched Ci-e-alkoxy group, a halogen atom, CH2F, CHF2, CF3, CN, OH, N02, SH, NH2, hydrogen, methyl, ethyl, F, CI, Br and CF3, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
81. Use according to claim 80 characterized in that R12 and R13 independently of each other represent hydrogen, a linear or branched Cι.6-alkyl group, a halogen atom, or CF3, preferably R12 and R13 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
82. Use according to any one of claims 80 or 81 , characterized in that R14, and R15 independently of each other represent hydrogen, a linear or branched Ci-e- alkyl group, a halogen atom, or CF3, preferably R14 and R15 independently of each other represent hydrogen, methyl, ethyl, F, CI, Br and CF3.
83. Use according to any one of claims 80 to 82, characterized in that R13 represents CI and R12 represents hydrogen.
84. Use according to any one of claims 80 to 83, characterized in that R14 and R15 each represent CI.
85. Use according to any one of claims 80 to 84, characterized in that R1 represents hydrogen, methyl or ethyl, preferably hydrogen.
86. Use according to one or more of claims 72 to 85 characterized in that the compound according to formulas I or II is selected from the group consisting of:
5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid, optionally in the form of a corresponding N-oxide, a corresponding salt or a corresponding solvate.
PCT/EP2005/001465 2004-02-17 2005-02-14 Substituted pyrazoline compounds for reducing triglycerides in blood WO2005077909A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
JP2006553505A JP2007522252A (en) 2004-02-17 2005-02-14 Substituted pyrazoline compounds, their preparation and their use as pharmaceuticals
CA002556568A CA2556568A1 (en) 2004-02-17 2005-02-14 Substituted pyrazoline compounds for reducing triglycerides in blood
EP05715327A EP1718619A1 (en) 2004-02-17 2005-02-14 Substituted pyrazoline compounds for reducing triglycerides in blood
AU2005212817A AU2005212817A1 (en) 2004-02-17 2005-02-14 Substituted pyrazoline compounds for reducing triglycerides in blood
US10/589,743 US7998996B2 (en) 2004-02-17 2005-02-14 Substituted pyrazoline compounds for reducing triglycerides in blood
BRPI0507790-7A BRPI0507790A (en) 2004-02-17 2005-02-14 substituted pyrazoline compound, process for its manufacture, medicines and their uses
IL177454A IL177454A0 (en) 2004-02-17 2006-08-10 Substituted pyrazoline compounds for reducing triglycerides in blood
NO20064186A NO20064186L (en) 2004-02-17 2006-09-15 Substituted pyrazoline compositions to reduce blood triglycerides

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
ES200400378 2004-02-17
ES200400378 2004-02-17
US80453404A 2004-03-19 2004-03-19
US10/804,534 2004-03-19
EP04021974.3 2004-09-16
EP04021974A EP1637522A1 (en) 2004-09-16 2004-09-16 Substituted pyrazoline compounds for reducing triglycerides in blood

Publications (1)

Publication Number Publication Date
WO2005077909A1 true WO2005077909A1 (en) 2005-08-25

Family

ID=34864786

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/001465 WO2005077909A1 (en) 2004-02-17 2005-02-14 Substituted pyrazoline compounds for reducing triglycerides in blood

Country Status (10)

Country Link
EP (1) EP1718619A1 (en)
JP (1) JP2007522252A (en)
KR (1) KR20060135815A (en)
AU (1) AU2005212817A1 (en)
BR (1) BRPI0507790A (en)
CA (1) CA2556568A1 (en)
IL (1) IL177454A0 (en)
NO (1) NO20064186L (en)
RU (1) RU2006133260A (en)
WO (1) WO2005077909A1 (en)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1743889A1 (en) * 2005-07-15 2007-01-17 Laboratorios del Dr. Esteve S.A. Sustituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
EP1743639A1 (en) * 2005-07-15 2007-01-17 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of coagulation related diseases
EP1743637A1 (en) * 2005-07-15 2007-01-17 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazole compounds and combinations thereof for the treatment of the metabolic syndrome
EP1745781A1 (en) * 2005-07-15 2007-01-24 Laboratorios Del Dr. Esteve, S.A. Combination of pyrazoline type cannabinoid receptor antagonist and statin
EP1746090A1 (en) * 2005-07-15 2007-01-24 Laboratorios del Dr. Esteve S.A. Sustituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009701A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazole compounds and combinations thereof for the treatment of the metabolic syndrome
WO2007009704A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
WO2007009707A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of coagulation related diseases
WO2007009700A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome
WO2007009706A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009702A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009698A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A Combination of pyrazoline type cannabinoid receptor antagonist and statin
EP1749526A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
EP1749527A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome
US7390835B2 (en) 2003-10-30 2008-06-24 Merck & Co., Inc. Aralkyl amines as cannabinoid receptor modulators
EP1944296A1 (en) * 2007-01-15 2008-07-16 Laboratorios del Dr. Esteve S.A. Amorphous phase of a substituted pyrazoline, its preparation and use as medicaments
EP1944295A1 (en) * 2007-01-15 2008-07-16 Laboratorios del Dr. Esteve S.A. Non-racemic mixtures of (R)-N-piperidinyl-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide and (S)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide
EP1946779A1 (en) * 2007-01-16 2008-07-23 Laboratorios del Dr. Esteve S.A. Combination of substituted pyrazolines and agent for treating dyslipidemia
EP1947088A1 (en) * 2007-01-17 2008-07-23 Laboratorios del Dr. Esteve S.A. Substituted pyrazoline compounds with ACAT inhibition activity, their preparation and use as medicaments
WO2008087030A1 (en) * 2007-01-17 2008-07-24 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds with acat inhibition activity, their preparation and use as medicaments
WO2008087029A1 (en) * 2007-01-17 2008-07-24 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds with acat inhibition activity
EP1950203A1 (en) * 2007-01-24 2008-07-30 Laboratorios del Dr. Esteve S.A. Substituted pyrazoline compounds with ACAT, their preparation and use as medicaments
ES2330716A1 (en) * 2005-07-15 2009-12-14 Laboratorios Del Dr.Esteve, S.A. Pharmaceutical formulations of substituted pyrazoline compounds

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200533657A (en) * 2004-02-17 2005-10-16 Esteve Labor Dr Substituted pyrazoline compounds, their preparation and use as medicaments
KR101395658B1 (en) 2012-09-20 2014-05-16 서울대학교산학협력단 Compositions for preventing and treating osseous metabolic disease comprising 4-(5-(2-methoxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
KR101466377B1 (en) * 2012-10-22 2014-12-01 건국대학교 산학협력단 dimethoxyphenyldihydropyrazolylnaphthalenol derivatives, preparing method of the same and Use in anti-cancer agent thereof
SI2920165T1 (en) * 2012-11-16 2017-02-28 Bristol-Myers Squibb Company Dihydropyrazole gpr40 modulators
BR112015011031A2 (en) * 2012-11-16 2017-07-11 Bristol Myers Squibb Co dihydropyrazole grp40 modulators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1209326A (en) * 1966-09-27 1970-10-21 Carter Wallace The preparation of 3-methyl-5-pyrazole carboxylic acid amides
WO1988005046A2 (en) * 1987-01-05 1988-07-14 E.I. Du Pont De Nemours And Company Insecticidal pyrazolines
EP1384477A1 (en) * 2001-04-06 2004-01-28 Laboratorios Del Dr. Esteve, S.A. Utilization of pyrazoline derivatives in the preparation of a medicament for the prevention and/or treatment of proliferative cell diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1209326A (en) * 1966-09-27 1970-10-21 Carter Wallace The preparation of 3-methyl-5-pyrazole carboxylic acid amides
WO1988005046A2 (en) * 1987-01-05 1988-07-14 E.I. Du Pont De Nemours And Company Insecticidal pyrazolines
EP1384477A1 (en) * 2001-04-06 2004-01-28 Laboratorios Del Dr. Esteve, S.A. Utilization of pyrazoline derivatives in the preparation of a medicament for the prevention and/or treatment of proliferative cell diseases

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7390835B2 (en) 2003-10-30 2008-06-24 Merck & Co., Inc. Aralkyl amines as cannabinoid receptor modulators
WO2007009707A3 (en) * 2005-07-15 2007-04-19 Esteve Labor Dr Use of substituted pyrazoline compounds for the treatment of coagulation related diseases
ES2334967A1 (en) * 2005-07-15 2010-03-17 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, their preparation and use as medicaments
EP1745781A1 (en) * 2005-07-15 2007-01-24 Laboratorios Del Dr. Esteve, S.A. Combination of pyrazoline type cannabinoid receptor antagonist and statin
WO2007009706A3 (en) * 2005-07-15 2007-04-19 Esteve Labor Dr Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009701A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazole compounds and combinations thereof for the treatment of the metabolic syndrome
WO2007009704A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
WO2007009707A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of coagulation related diseases
WO2007009700A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome
WO2007009706A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009702A2 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009698A1 (en) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A Combination of pyrazoline type cannabinoid receptor antagonist and statin
EP1749526A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
EP1749527A1 (en) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome
WO2007009700A3 (en) * 2005-07-15 2007-04-05 Esteve Labor Dr Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome
WO2007009702A3 (en) * 2005-07-15 2007-04-05 Esteve Labor Dr Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009701A3 (en) * 2005-07-15 2007-04-12 Esteve Labor Dr Use of substituted pyrazole compounds and combinations thereof for the treatment of the metabolic syndrome
WO2007009704A3 (en) * 2005-07-15 2007-04-19 Esteve Labor Dr Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
EP1743889A1 (en) * 2005-07-15 2007-01-17 Laboratorios del Dr. Esteve S.A. Sustituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
EP1746090A1 (en) * 2005-07-15 2007-01-24 Laboratorios del Dr. Esteve S.A. Sustituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
EP1743637A1 (en) * 2005-07-15 2007-01-17 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazole compounds and combinations thereof for the treatment of the metabolic syndrome
ES2336883A1 (en) * 2005-07-15 2010-04-16 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, their preparation and use as medicaments
EP1743639A1 (en) * 2005-07-15 2007-01-17 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of coagulation related diseases
ES2330716A1 (en) * 2005-07-15 2009-12-14 Laboratorios Del Dr.Esteve, S.A. Pharmaceutical formulations of substituted pyrazoline compounds
ES2327203A1 (en) * 2005-07-15 2009-10-26 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of coagulation related diseases
ES2326857A1 (en) * 2005-07-15 2009-10-20 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome
ES2326723A1 (en) * 2005-07-15 2009-10-16 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazole compounds for the treatment of cardiovascular risk factors caused by metabolic/food disorders
ES2326725A1 (en) * 2005-07-15 2009-10-16 Laboratorios Del Dr. Esteve, S.A. Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
ES2320084A1 (en) * 2007-01-15 2009-05-18 Laboratorios Del Dr. Esteve S.A. Non-racemic mixtures of (R)-N-piperidinyl-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide and (S)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide
ES2328327A1 (en) * 2007-01-15 2009-11-11 Esteve Labor Dr Amorphous phase of a substituted pyrazoline, its preparation and use as medicaments
EP1944296A1 (en) * 2007-01-15 2008-07-16 Laboratorios del Dr. Esteve S.A. Amorphous phase of a substituted pyrazoline, its preparation and use as medicaments
EP1944295A1 (en) * 2007-01-15 2008-07-16 Laboratorios del Dr. Esteve S.A. Non-racemic mixtures of (R)-N-piperidinyl-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide and (S)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide
ES2324139A1 (en) * 2007-01-16 2009-07-30 Laboratorios Del Dr. Esteve, S.A. Combination of substituted pyrazolines and agent for treating dyslipidemia
EP1946779A1 (en) * 2007-01-16 2008-07-23 Laboratorios del Dr. Esteve S.A. Combination of substituted pyrazolines and agent for treating dyslipidemia
WO2008087029A1 (en) * 2007-01-17 2008-07-24 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds with acat inhibition activity
WO2008087030A1 (en) * 2007-01-17 2008-07-24 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds with acat inhibition activity, their preparation and use as medicaments
EP1947088A1 (en) * 2007-01-17 2008-07-23 Laboratorios del Dr. Esteve S.A. Substituted pyrazoline compounds with ACAT inhibition activity, their preparation and use as medicaments
EP1950203A1 (en) * 2007-01-24 2008-07-30 Laboratorios del Dr. Esteve S.A. Substituted pyrazoline compounds with ACAT, their preparation and use as medicaments

Also Published As

Publication number Publication date
IL177454A0 (en) 2006-12-10
JP2007522252A (en) 2007-08-09
RU2006133260A (en) 2008-04-10
KR20060135815A (en) 2006-12-29
NO20064186L (en) 2006-11-14
BRPI0507790A (en) 2007-07-17
EP1718619A1 (en) 2006-11-08
CA2556568A1 (en) 2005-08-25
AU2005212817A1 (en) 2005-08-25

Similar Documents

Publication Publication Date Title
EP1718619A1 (en) Substituted pyrazoline compounds for reducing triglycerides in blood
US7994200B2 (en) Cycloalkane-substituted pyrazoline derivatives, their preparation and use as medicaments
EP1849775A1 (en) Cycloalkane-substituted pyrazoline compounds, their preparation and use as medicaments
EP1743637A1 (en) Use of substituted pyrazole compounds and combinations thereof for the treatment of the metabolic syndrome
EP1637522A1 (en) Substituted pyrazoline compounds for reducing triglycerides in blood
US7998996B2 (en) Substituted pyrazoline compounds for reducing triglycerides in blood
WO2007009706A2 (en) Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009704A2 (en) Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
EP1746090A1 (en) Sustituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
EP1749526A1 (en) Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes
ES2337005B1 (en) COMPOUNDS OF PIRAZOLINA AZEPAN OR AZOCANSUSTITUIDOS, ITS PREPARATION AND ITS USE AS MEDICINES.
WO2007009702A2 (en) Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
EP1743638A1 (en) Pharmaceutical formulations of substituted pyrazoline compounds
EP1743889A1 (en) Sustituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood
WO2007009699A2 (en) Use of substituted pyrazoline compounds and their derivatives for the treatment of cannabinoid system-associated diseases
EP1743642A1 (en) Use of substituted pyrazoline compounds and their derivatives for the treatment of cannabinoid system-associated diseases
EP1749527A1 (en) Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome
ES2325569B1 (en) CICLOALCANOSUSTITUID PIRAZOLINE COMPOUNDS, ITS PREPARATION AND ITS USE AS MEDICATIONS
MXPA06009335A (en) Substituted pyrazoline compounds for reducing triglycerides in blood
WO2007009707A2 (en) Use of substituted pyrazoline compounds for the treatment of coagulation related diseases
WO2007009683A2 (en) Pharmaceutical formulations of substituted pyrazoline compounds
ES2327204B1 (en) OCTAHYDROPENTALENSUS INSTITUTED PIRAZOLINE COMPOUNDS, THEIR PREPARATION AND THEIR USE AS MEDICINES.
ES2327379B1 (en) INDOLINSTITUTED PIRAZOLINE COMPOUNDS, THEIR PREPARATION AND THEIR USE AS MEDICINES.
WO2007009700A2 (en) Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome
EP1849776A1 (en) Azepane- or Azocane-substituted pyrazoline compounds, their preparation and use as medicaments

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
WWE Wipo information: entry into national phase

Ref document number: 12006501565

Country of ref document: PH

Ref document number: 177454

Country of ref document: IL

Ref document number: 4634/DELNP/2006

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 549204

Country of ref document: NZ

Ref document number: 2556568

Country of ref document: CA

Ref document number: PA/a/2006/009335

Country of ref document: MX

Ref document number: 06081177

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 2006553505

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

WWE Wipo information: entry into national phase

Ref document number: 2005212817

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2005715327

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2005212817

Country of ref document: AU

Date of ref document: 20050214

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005212817

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1020067018876

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 200607744

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2006133260

Country of ref document: RU

WWE Wipo information: entry into national phase

Ref document number: 200580011530.5

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2005715327

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020067018876

Country of ref document: KR

ENP Entry into the national phase

Ref document number: PI0507790

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 10589743

Country of ref document: US