WO2007009700A2 - Utilisation de composes pyrazoliniques substitues pour le traitement de parametres des lipides du syndrome metabolique - Google Patents

Utilisation de composes pyrazoliniques substitues pour le traitement de parametres des lipides du syndrome metabolique Download PDF

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WO2007009700A2
WO2007009700A2 PCT/EP2006/006974 EP2006006974W WO2007009700A2 WO 2007009700 A2 WO2007009700 A2 WO 2007009700A2 EP 2006006974 W EP2006006974 W EP 2006006974W WO 2007009700 A2 WO2007009700 A2 WO 2007009700A2
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group
optionally
mono
substituted
phenyl
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PCT/EP2006/006974
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WO2007009700A3 (fr
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Helmut H. Buscmann
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Laboratorios Del Dr. Esteve, S.A.
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Priority claimed from EP05384013A external-priority patent/EP1749527A1/fr
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Publication of WO2007009700A3 publication Critical patent/WO2007009700A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to the use of substituted pyrazoline compounds for the treatment of metabolic syndrome, especially the lipid parameters of the metabolic syndrome in humans and animals.
  • the metabolic syndrome is a widespread disease, particularly in the United States and Europe. Based on survey data from 1988 to 1994 and 2000 census data, the American Center for Disease Control and Prevention estimates that 47 million people in the US have metabolic syndrom. Thus, there is an urgent need for effective therapy of the metabolic syndrome.
  • the present invention relates to the use of a substituted pyrazoline compounds of general formula I
  • R 1 represents hydrogen or a linear or branched, substituted or unsubstituted, saturated or unsaturated, Ci-4-alkyl group,
  • SH 1 SR 10 , SOR 10 , NH 2 . NHR 10 , NR 10 R 11 , -(C O)-NH 2 .
  • R 10 and optionally R 11 for each substituent independently represent linear or branched C 1 - 6 alkyl
  • 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,
  • these lipid parameters do not include triglyceride levels.
  • treatment does also include prophylaxis.
  • the metabolic syndrome and definitions thereof are described in detail by Eckel et al., The Lancet, Vol. 365 (2005), 1415-1428, included herewith by reference.
  • One of the respective definitions was established by the WHO in 1998 (as described in Alberti et al., Diabet. Med. 1998, 15, pages 539-53, the respective description thereof is herewith incorporated by reference and forms part of the present disclosure).
  • the other, more widely accepted, definition of the metabolic syndrome was established by the Adult Treatment Panel (ATP III) of the US National Cholesterol Education Program (NCEP) in 2001, as described in JAMA 2001; 285; 2486-97, the respective description thereof is herewith incorporated by reference and forms part of the present disclosure.
  • the metabolic syndrome is characterized by an interaction of several physiological parameters such as triglycerides, lipids, blood pressure, glucose levels and insuline levels.
  • the pyrazoline compounds as defined herein also have a beneficial effect on the ratio of low density lipoprotein (LDL) to high density lipoprotein (HDL) 1 i.e. they lower the LDL-levels and/or elevate the HDL levels; they are also useful as coating material or co-coating material in stents in order to prevent restenosis.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • inventively used pyrazoline compounds seem to be distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively little undesired effects, i.e. effects which do not positively contribute to or even interfere with the well being of the patient.
  • the present invention relates to the use of a substituted pyrazoline compounds of general formula I
  • R 1 represents hydrogen or a linear or branched, substituted or unsubstituted, saturated or unsaturated, Ci-4-alkyl group,
  • stereoisomers optionally in form of one o ⁇ 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 o ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof,
  • these lipid parameters do not include triglyceride levels.
  • neither of R 2 , R 3 or R 4 may represent SO 2 R 8 in para-position with R 8 being methyl.
  • 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. 0
  • 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.
  • Ci -2 -alkyl represents C1- or C2-alkyl
  • Ci-3-alkyl represents C1-, C2- or C3-alkyl
  • d-4-alkyl represents C1-, C2-, C3- or C4-alkyl
  • Ci -5 -alkyl represents C1-, C2-, C3-, C4-, or C5-alkyl
  • C ⁇ -alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl
  • Ci-7-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • d- ⁇ -alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
  • Ci.io-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,
  • C 3-4 -cycloalkyl represents C3- or C4-cycloalkyl
  • C 3 . 5 - cycloalkyl represents C3-, C4- or C ⁇ -cycloalkyl
  • C 3-6 -cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl
  • C 3-7 -cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl
  • C 3 - 8 -cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl
  • C 4-5 -cycloalkyl represents C4- or C5-cycloalkyl
  • C 4 - 6 -cycloalkyl represents C4-, C5- or C6-cycloalkyl
  • C 4-7 -cycloalkyl represents C4-, C5-, C6- or CT-cycloal
  • 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 -methyl pentyl, cyclopropyl, 2- methylcyclopropyl, cyclopropyl methyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl, (if substituted also CHF2, CF 3 or CH 2 OH) as well as pyrazolinone, oxopyrazolinone, [1
  • substituents here are F, Cl and OH.
  • the hydrogen radical can also be replaced by OCi.
  • Ci -3 -alkyl or Ci -3 -alkyl in each case mono- or polysubstituted or unsubstituted, in particular methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
  • 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 Cl, a CF 3 , a CN, an NO 2 , an NRR, a Ci- 6 -alkyl (saturated), a Ci-e-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 the active compound with other molecules and ions in particular complexes which are complexed via ionic interactions. It especially includes physiologically acceptable salts, which is to be used equivalents to pharmacologically acceptable salts.
  • 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.
  • polar solvent especially including hydrates and alcoholates, e.g. methanolate.
  • the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • 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.
  • the invention also covers the use of any prodrug of the compounds described for the invention.
  • 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).
  • 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 Ci -6 - alkyl group, a halogen atom, or CF 3 , preferably R 2 , R 3 and R 4 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • R 5 and R 6 independently of each other represent a linear or branched Ci-6-alkyl group, a halogen atom, or CF 3 , preferably R 5 and R 6 independently of each other represent methyl, ethyl, F 1 Cl, 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 Il
  • R 1 represents hydrogen or a linear or branched, substituted or unsubstituted, saturated or unsaturated, Ci-4-alkyl group,
  • R 12 or R 13 independently of each other represent a linear or branched d- ⁇ - alkyl group, a linear or branched Ci- 6 -alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, NO 2 , SH 1 NH 2 , hydrogen, methyl, ethyl, F 1 Cl, Br and CF 3 ,
  • R 14 or R 15 independently of each other represent a linear or branched C1- 6 - alkyl group, a linear or branched Ci- 6 -alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, NO 2 , SH, NH 2 , methyl, ethyl, F, Cl, Br and CF 3 ,
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to general formula Il is selected from compounds according to general formula Ha or lib or any mixture thereof
  • R 12 and R 13 independently of each other represent hydrogen, a linear or branched CV 6 -alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • R 14 , and R 15 independently of each other represent a linear or branched d- ⁇ -alkyl group, a halogen atom, or CF 3 , preferably R 14 and R 15 independently of each other represent methyl, ethyl, F 1 Cl 1 Br and CF 3 .
  • R »13 represents Cl and R 12 represents hydrogen.
  • R 14 and R 15 each represent Cl.
  • R 1 represents hydrogen, methyl or ethyl, preferably hydrogen.
  • 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 optionally at least mono-substituted mono- or polycyclic ring system, or an -
  • 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 -SO 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
  • 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,
  • 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 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- 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 - NR 19 R 2 °-moiety, preferably R 18 represents a saturated, optionally at least mono- substituted, optionally one or more nitrogen-atoms as ring member containing C 3 ⁇ cycloaliphatic group, which may be condensed with an optionally at least mono- substituted mono- or polycyclic ring system, or an -NR 19 R 2 °-moiety, more preferably R 18 represents a pyrrol
  • R 19 and R 20 identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted d- 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 (-CH2-) or ethylene (-CH 2 -CH 2 )-group, an -SO2-R 21 -moiety, or an -NR 22 R 23 -moiety, preferably
  • R 21 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3 - 8 cycloaliphatic group, which may be condensed with a mono- or polycyclic ring- system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH2-CH 2 )-group, preferably R 21 represents a C- ⁇ - 6 -alkyl group, a saturated, optionally at least mono-substituted cycloaliphatic group, which may be condensed with a mono- or polycycl
  • Ci -6 alkyl groups is system, or a phenyl group, which is optionally substituted with one or more Ci -6 alkyl groups.
  • R 22 and R 23 represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono- substituted Ci-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 (-CH 2 -) or ethylene (-CH 2 -CH 2 )-group, preferably R 22 and R 23 , identical or different, represent a hydrogen atom or a Ci- ⁇ alkyl radical.
  • 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 20 -moiety,
  • R 19 represents a hydrogen atom or a linear or branched Ci_6-alkyl group
  • R 20 represents a linear or branched Ci -6 alkyl group, an -SO 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, CWalkyl groups, and R 21 represents a phenyl group, which is optionally substituted with one or more C1- 6 alkyl groups, which may be identical or different,
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof.
  • Another aspect of the invention is the use of one or more pyrazoline compounds or mixtures as defined herein for the manufacture of a medicament for improvent of cardiovascular and/or metabolic risk factors, such as one or more of the following factors:
  • Elevated triglycerides whereby elevated levels of triglycerides are preferably understood as being > 150 mg/dl,
  • Low HDL cholesterol whereby low levels of HDL cholesterol are preferably understood as being ⁇ 40 mg/dl in men and ⁇ 50 mg/dl in women,
  • Hypertension whereby hypertension is preferably understood as being > 130/85 mmHg,
  • Impaired fasting glucose whereby impaired fasting glucose levels are preferably understood as being > 110 mg/dl,
  • Another aspect of the invention is the use of one or more pyrazoline compounds or mixtures as defined herein for the manufacture of a medicament for the treatment of the weight independent aspects of metabolic syndrome.
  • Another aspect of the invention is a method for improving cardiovascular and/or metabolic risk factors, such as one or more of the following factors: Elevated triglycerides, whereby elevated levels of triglycerides are preferably understood as being > 150 mg/dl,
  • Low HDL cholesterol whereby low levels of HDL cholesterol are preferably understood as being ⁇ 40 mg/dl in men and ⁇ 50 mg/dl in women,
  • Hypertension whereby hypertension is preferably understood as being > 130/85 mmHg,
  • Impaired fasting glucose whereby impaired fasting glucose levels are preferably understood as being > 110 mg/dl,
  • a subject preferably a human.
  • Another aspect of the invention is a method for treating of the weight independent aspects of metabolic syndrome.
  • inventively used substituted pyrazoline compounds of general formula (I) given above, 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.
  • Another aspect of the invention is the use of the compounds according to general formula I or Il or their combination with compounds of general formula X for the manufacture of a medicament for the treatment of cardiovascular risk factors caused by metabolic/food disorders, especially a combination of consequences of these disorders.
  • Another aspect of the invention is the use of the compounds according to general formula I or Il or their combination with compounds of general formula X for the manufacture of a medicament for the treatment of the metabolic syndrome, especially of its weight independent aspects, preferably with the proviso (disclaimer) to exclude Triglyceride levels.
  • 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 0 C to the boiling point of the reaction medium.
  • Suitable reaction times may vary for example from several minutes to several hours.
  • reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula IV is preferably 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.
  • reaction of the compound of general formula (V) with an optionally substituted phenyl hydrazin of general formula (Vl) is preferably carried out in a suitable reaction medium such as d-4-alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • a suitable reaction medium such as d-4-alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid.
  • reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 0 C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • the carboxylic group of the compound of general formula (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, leading to a compound according to general formula (Vila).
  • the compounds of general formula (VII) are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a Ci -4 alkyl ester, an activated ester such as p-nitrophenylester.
  • Other well known methods for the activation of acids include the activation with N,N-dicyclohexylcarbodiimide or benzotriazol-N- oxotris(dimethylamino) phosphonium hexafluorophosphate (BOP)).
  • said activated compound of general formula (Vila) 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° C to the boiling point of the solvent and reaction times from several minutes to several hours.
  • said activated compound of general formula (Vila) is a mixed anhydride
  • said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula (Vila) 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 Il with R 1 being a a linear or branched, substituted or unsubstituted, saturated or unsaturated, Ci-4-alkyl group.
  • a represented in general formula Vila represents a leaving group
  • said compound being optionally isolated and/or optionally purified
  • at least one compound of general formula (Vila) is reacted with a compound of general formula R 18 H, wherein R 18 represents an -NR 19 R 20 - moiety, wherein R 19 and R 20 have the meaning given above for compounds of general formula X 1 to yield a substituted pyrazoline compound of general formula X, wherein R 18 represents an -NR 19 R 20 -moiety
  • R 18 represents an -NR 19 R 20 -moiety
  • substituted pyrazoline compounds of general formula I or Il 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, especially using chiral bases like brucine, quinine, (-)- Cinchonidine, (+)-Cinchonine or R-(+)-1-Phenylethylamine.
  • 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.
  • Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NH n R4-n] + , wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranched Ci-4-alkyl-radical.
  • suitable reaction media are, for example, any of the ones given above.
  • Solvates, preferably hydrates, of the 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, Ia, Ib, II, Ha, lib and X given below, their corresponding N-oxides, corresponding salts thereof and corresponding solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances.
  • 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, intraperitoneal Iy, 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 compositions 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 fromi to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
  • Another aspect of the present invention relates to an active substance combination
  • an active substance combination comprising as component (A) one or more of the substituted pyrazoline compounds as defined herein and as component (B) an agent selected from the group consisting of antihyertensive agents, agents for treating insuline resistance and agents for treating dyslipidemia.
  • Suitable antihyertensive agents, agents for treating insuline resistance and agents for treating dyslipidemia as well as their dosages are well known to those skilled in the art.
  • Antihyertensive agents may preferably be selected from the group consisting of Hydrochlorothiazide, Furosemide, Triamterene.Triamterene/hydrochlorothiazide, Spironolactone, Eplerenone, Amlodipine, Nifedipine, Diltiazem, Verapamil, Atorvastatin/amlodipine, Enalapril, Lisinopril, Ramipril, Lisinopril/hydrochlorothiazide, Benazepril/amlodipine, Losartan, Valsartan, Irbesartan, Candesartan cilexetil, Olmesartan, Losartan/hydrochlorothiazide, Valsartan/hydrochlorothiazide, HCT/CoDiovan/Cotareg, Atenolol, Metoprolol tartrate, Metoprolol succinate and Carvedilol.
  • Agents for treating insuline resistance may preferably be selected from the group consisting of Metformin, Metformin extended release, Pioglitazone, Rosiglitazone and Metformin/rosiglitazone.
  • Agents for treating dyslipidemia may preferably be selected from the group consisting of Colesevelam, Cholestyramine, Clofibrate, Fenofibrate, Fulcro/Secalip, Bezafibrate, Gemfibrozil, Ciprofibrate, Niacin, Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, Lovastatin/niacin, Atorvastatin/amlodipine and Simvastatin/ezetimibe.
  • Another aspect of the present invention is method of treating metabolic syndrome comprising administering to a subject, preferably a human, a therapeutically effective amount of at least one substituted pyrazoline compound, or mixtures, as defined herein.
  • a subject preferably a human
  • a therapeutically effective amount of at least one substituted pyrazoline compound, or mixtures, as defined herein is administered to a subject, preferably a human.
  • 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 0 C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield).
  • 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 0 C and a solution of 5-(4-chlorophenyl)-1-(2,4- dichlorophenyO- ⁇ -dihydro-pyrazole-S-carboxylic acid chloride obtained in step (b) in methylene chloride (15 mL) was added dropwise.
  • the resulting reaction mixture was stirred at room temperature (approximately 25 0 C) overnight.
  • This compound was obtained in form of an oil.
  • N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0,15 g, 332 mmoles) was dissolved in 7 ml of dichlorom ethane. The resulting solution was ice-cooled to 0 0 C and m-chloroperbenzoic acid (0,204 g, 0,83 mmoles) added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was remaining. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered.
  • the compound according to example 0 is an inhibitor of high blood levels of triglicerides and on the hand other factors like insulin - whose levels are reduced - and which contribute to the metabolic syndrome are also influenced. Decreases of plasma insulin are indicative of an improvement of insulin sensitivity, which is a positive sign for metabolic syndrome as in dietary- induced obese animal models like the one used here basal insulin is raised.
  • mice Male mice (C57BL76J). Mice were divided in 2 groups:
  • the animals of both groups were fed with a High Fat Diet.
  • Plasma Insulin for the control was 285.7 ⁇ 57.9 (pmol/l) and for the Group treated with compound example 0 (Group II) was 156.4 ⁇ 38.6 (pmol/l). This was statistically significant at p ⁇ 0.05 using ANOVA factorial.

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Abstract

La présente invention concerne l'utilisation de composés pyrazoliniques substitués pour le traitement de paramètres des lipides du syndrome métabolique en médecine humaine et vétérinaire.
PCT/EP2006/006974 2005-07-15 2006-07-15 Utilisation de composes pyrazoliniques substitues pour le traitement de parametres des lipides du syndrome metabolique WO2007009700A2 (fr)

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EP05384013A EP1749527A1 (fr) 2005-07-15 2005-07-15 Utilisation des derivés du pyrazole pour le traitement du syndrome métabolique
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1384477A1 (fr) * 2001-04-06 2004-01-28 Laboratorios Del Dr. Esteve, S.A. Utilisation de derives de pyrazolines dans l'elaboration d'un medicament pour la prevention et/ou le traitement de maladies proliferatives cellulaires
US20040122033A1 (en) * 2002-12-10 2004-06-24 Nargund Ravi P. Combination therapy for the treatment of obesity
WO2005077909A1 (fr) * 2004-02-17 2005-08-25 Laboratorios Dr. Esteve S.A. Composes de pyrazoline substitues permettant de reduire le taux de triglycerides dans le sang

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FR2861303A1 (fr) * 2003-10-24 2005-04-29 Sanofi Synthelabo Utilisation d'un derive de pyrazole pour la preparation de medicaments utiles dans la prevention et le traitement du syndrome metabolique

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Publication number Priority date Publication date Assignee Title
EP1384477A1 (fr) * 2001-04-06 2004-01-28 Laboratorios Del Dr. Esteve, S.A. Utilisation de derives de pyrazolines dans l'elaboration d'un medicament pour la prevention et/ou le traitement de maladies proliferatives cellulaires
US20040122033A1 (en) * 2002-12-10 2004-06-24 Nargund Ravi P. Combination therapy for the treatment of obesity
WO2005077909A1 (fr) * 2004-02-17 2005-08-25 Laboratorios Dr. Esteve S.A. Composes de pyrazoline substitues permettant de reduire le taux de triglycerides dans le sang

Non-Patent Citations (3)

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Title
"Der Begriff "Metabolisches Syndrom" ist unklar" DEUTSCHE APOTHEKER ZEITUNG, vol. 42, 20 October 2005 (2005-10-20), page 8, XP002360775 *
ECKEL R H ET AL: "The metabolic syndrome" LANCET THE, LANCET LIMITED. LONDON, GB, vol. 365, no. 9468, 16 April 2005 (2005-04-16), pages 1415-1428, XP004849990 ISSN: 0140-6736 cited in the application *
SIDDALL R: "RIO-DIABETES: RIMONABANT SHOWS PROMISE IN TYPE 2 DIABETES" BRITISH JOURNAL OF CARDIOLOGY, LONDON, GB, vol. 12, no. 4, July 2005 (2005-07), page 257, XP009053958 ISSN: 0969-6113 *

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