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WO2009050318A1 - Dérivés pyrazoliques d'amides d'acides gras utilisés comme activateurs spécifiques de récepteurs ppar-alpha, procédé de préparation et utilisation - Google Patents

Dérivés pyrazoliques d'amides d'acides gras utilisés comme activateurs spécifiques de récepteurs ppar-alpha, procédé de préparation et utilisation Download PDF

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Publication number
WO2009050318A1
WO2009050318A1 PCT/ES2008/000653 ES2008000653W WO2009050318A1 WO 2009050318 A1 WO2009050318 A1 WO 2009050318A1 ES 2008000653 W ES2008000653 W ES 2008000653W WO 2009050318 A1 WO2009050318 A1 WO 2009050318A1
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WO
WIPO (PCT)
Prior art keywords
fatty acid
acid amides
ppar
pyrazolic
derivatives
Prior art date
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Ceased
Application number
PCT/ES2008/000653
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English (en)
Spanish (es)
Inventor
Fernando RODRÍGUEZ DE FONSECA
Manuel MACÍAS GONZÁLEZ
María Antonia SERRANO CRIADO
María Pilar GOYA LAZA
Mario Hernan Alvarado
José ELGUERO BERTOLINI
Nadine Jagerovic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Consejo Superior de Investigaciones Cientificas CSIC
Instituto Mediterraneo para el Avance de la Biotecnologia y la Investigacion Sanitaria (Fundacion Imabis)
Original Assignee
Consejo Superior de Investigaciones Cientificas CSIC
Instituto Mediterraneo para el Avance de la Biotecnologia y la Investigacion Sanitaria (Fundacion Imabis)
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Publication of WO2009050318A1 publication Critical patent/WO2009050318A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D231/10—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
    • 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • 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
    • 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

Definitions

  • the object of the invention relates to a new class of pyrazole derivatives and their pharmaceutically acceptable salts, solvates and hydrates, which show selective affinity for the alpha subtype of peroxisome proliferator-activated receptors (PPAR) and, therefore, , modulate the actions regulated by these receptors, specifically the induction of satiety and control of intake, the decrease in the gain of body mass and the regulation of lipid metabolism.
  • PPAR peroxisome proliferator-activated receptors
  • PPAR peroxisome proliferator
  • PPARgamma and PPARdelta see Kota, BP et al. Pharmacol Res. 51 (2005): 85.
  • Activation of the PPARgamma subtype by ligands enhances the actions of insulin in man and reduces circulating glucose levels in rodent models of diabetes.
  • the PPARgamma receptor which is expressed in adipose tissue, plays a central role in the regulation of adipocyte differentiation in vitro. Less is known about the biology of the PPARdelta subtype, although it seems to play an important role in the control of hyperglycemia and hyperlipemia, see Berger, J. and Moller, D. E Annu. Rev. Med. 53 (2002): 409 and Berger, J. et al. J. Biol. Chem. 274 (1999): 6718-6725.
  • the activation of the PPARalfa subtype by its natural ligands is related to the control of circulating lipid levels.
  • Medium and long chain fatty acids and eicosanoids have been described, see Forman, BM et al. Proc. Nati Acad. ScI. USA 94 (1997): 4312, which produce a substantial reduction in plasma triglycerides, a moderate reduction in cholesterol associated with low density lipoproteins (LDL) and a satiety effect. Therefore, the alpha subtype of this family of receptors is presented as a very interesting therapeutic target for the treatment of diseases related to metabolic disorders such as dyslipidemia, cardiovascular disease, diabetes and obesity, see Cheng, PT et al. Mini. Rev. Med. Chem.
  • Dyslipidemia are disorders in lipid metabolism that are characterized by abnormal concentrations of one or more types of lipids (eg, Cholesterol and Triglycerides), and / or apolipoproteins (eg, Type A, B, C and E), and / or lipoproteins (eg low density (LDL), very low density (VLDL) and intermediate density (IDL)).
  • LDL low density
  • VLDL very low density
  • IDL intermediate density
  • the cholesterol molecule is transported normally bound to LDL lipoproteins. The elevation of the levels of this composition is directly related to the risk of coronary heart disease.
  • HDL-cholesterol A smaller percentage of the cholesterol molecule is transported through the HDL lipoproteins, whose main function is to extract the cholesterol deposited in the arterial walls and transport it to the liver for its elimination via intestine. It has been described that an elevated level of HDL-cholesterol is associated with the decrease in the risk of coronary disease. Therefore, in the treatment of dyslipidemia, it is equally important both to lower LDL-cholesterol levels and to raise HDL-cholesterol levels, see Gordon, T. et al. Am. J. Med. 62 (1977): 707, Stampfer, MJ. et al. N. England J. Med., 325 (1991): 373 and Kannel, WB et al. Ann. Internal / Med. 90 (1979): 85-91.
  • fibrate derivatives are being used clinically, such as clofibrate, see Arduini, A. et al. WO 20020-9682 (2002), bezafibrate and fenofibrate, see Cheng, K. et al. WO 2002-15845 (2002).
  • fibrate derivatives are being used clinically, such as clofibrate, see Arduini, A. et al. WO 20020-9682 (2002), bezafibrate and fenofibrate, see Cheng, K. et al. WO 2002-15845 (2002).
  • glitazones (benzyl-2,4-thiazolidinedione derivatives) have been approved for use in the treatment of diabetes. These include isaglitazon, see IsM, S. et al. WO 2003018010 (2003), troglitazon, rosiglitazon and pioglitazon, see HuIIn, B. et al. Current Pharm. Design 2
  • the invention relates to a new class of molecules, specifically pyrazolic derivatives of fatty acid amides as specific activators of PPAR-alpha receptors, as well as to their preparation process and use. These molecules can be used for the preparation of a drug for the induction of satiety and control of intake, modulation of body fat and regulation of lipid metabolism as well as the preparation of a medicament for the treatment of diabetes, obesity, metabolic syndrome and cardiovascular diseases.
  • Figure 1 Structural formula of pyrazolic derivatives of fatty acid amides.
  • Figure 2 Scheme of the process for preparing pyrazolic derivatives of fatty acid amides.
  • Figure 3 Ethyl 5- (4-chlorophenyl) -l-phenylpyrazol-3-carboxylate formula.
  • Figure 4 Formula of ethyl l, 5-di- (4-chlorophenyl) pyrazol-3-carboxylate.
  • Figure 7 Formula of / ⁇ A (Hexadecyl) -5- (4-chlorophenyl) -l-phenyl-1 / fpyrazol-3-carboxamide.
  • Figure 8 Formula of / V- (Hexadecyl) -l, 5-di- (4-chlorophenyl) -l / fpyrazol-3-carboxamide.
  • Figure 9 Interaction between PPARalfa and the TIF2 coactivator induced by ligand by GST pul ⁇ down. The value of the vector with only GST was subtracted from all compounds and solvent (DMSO). The samples were detected and quantified with respect to the amount of PPARalpha used in a Phosphoimager (Fuji FLA 300 reader). A 15% SDS-PAGE gel is shown. DESCRIPTION OF THE INVENTION
  • the present invention is a continuation of a previous project in which the endogenous fatty acid oleiletanolamide (OEA) was described as a new ligand capable of activating the PPARalfa subtype and its action as a satiety inducer and controller of the intake in rats, inhibitor of Ia body mass gain and the regulator of lipid metabolism, see Piomelli, D and Rodr ⁇ guez de Fonseca, F. US 6911474 (2005).
  • OOA endogenous fatty acid oleiletanolamide
  • the compounds described below are a new class of substituted derivative pyrazole molecules that, in general, were able to induce the interaction between PPARalfa and its coactivators in solution, some of them, even more effectively than the OAS, by means of tests. vitro. They also showed effects similar to those of the reference molecule in the in vivo tests.
  • these new compounds are useful in improving the physiological conditions regulated by agonists of PPAR alpha receptors, such as those related to the modulation of body fat and
  • Ia inhibition of intake thus showing great potential for application in the treatment of diseases or pathological situations arising from the above conditions, while reducing the adverse effects of current treatments.
  • the compounds of the present invention correspond to pyrazole derivatives with aryl substituents in positions 1 and 5, with hydrogen in position 4 and carboxamide groups in position 3 corresponding to formula A (see Figure 1) where Xa and Xb are identical or different and each independently represents a hydrogen atom or a halogen atom and R represents linear alkyl or linear alkenyl groups with a number of C atoms comprised between 14 and 20.
  • the object of the present invention corresponds to the following derivatives pyrazolic fatty acid amides: - / ⁇ A (Oleyl) -5- (4-chlorophenyl) -l-phenyl-l / f pyrazol-3-carboxamide, 4 (M AO 6)
  • Figure 1 The preparation and obtaining of the collected compounds can be carried out according to the reaction scheme described in Figure 2 for formula A.
  • Figure 1 The synthetic route described in Figure 2 was initially carried out through the preparation of the diketoester 1, see Gardner TS, Wenis E, Lee J., J. Org. Chem., 1961, 26, 1514., from the reaction of acetophenone and diethyl oxalate in basic medium.
  • Pyrazolic esters 2-3 were prepared, see a) Finar I. L, Hurlock R. 1, J. Chem. Soc, 1958, 3259, by reaction of the diketoester 1 with the respective arylhydrazine in equimolar proportions for a period of time comprised between 24 and 48 hours. In general, the reaction has been described to give predominantly the l / fpyrazol-3-carboxylate isomer, see Ashton W. T., Doss G.A., J. Heterocyclic Chem., 1993, 30, 307; b) Murray W. V., Wachter M. P., J. Heterocyclic Chem., 1989, 26, 1389. Prior to the next transformation, the carboxylic ester is separated by ether extraction followed by washing with bicarbonate solution and water.
  • Physiologically acceptable salts include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases, as well as quaternary ammonium acid addition salts.
  • the present invention relates to a method for modulating the alpha subtype of receptors activated by the peroxisome proliferator by contacting the receptor with at least one compound represented by the structural formula of Figure 1, and its pharmaceutically acceptable salts, solvates and hydrates.
  • a "PPAR-alpha ligand” is a compound that binds to a human PPAR-alpha and coactivating molecules to give rise to transcription processes as described later in the binding assay.
  • GST Pyrazolic fatty acid derivatives may be used for the preparation of a medicament intended for the prevention or treatment of any pathology mediated by PPAR-alpha.
  • the present invention refers to the methods and compositions containing the products represented by the structural formula of Figure 1 and its pharmaceutically acceptable salts, solvates and hydrates, which achieve a decrease in appetite and gain in Ia body mass when administered to laboratory animals (eg rats, mice, rabbits). Therefore, pyrozole derivatives may be used for the preparation of medication for the induction of satiety and control of intake, modulation of body fat and regulation of lipid metabolism. Another possible use would be for the preparation of a medicament for the treatment of diabetes, obesity, metabolic syndrome and cardiovascular diseases. In cosmetics they could be used particularly for the reduction of subcutaneous fat.
  • the compounds of this invention can be prepared by the usual organic chemistry as illustrated by the accompanying operative examples. The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to exemplify the general procedures. In accordance with the foregoing, the following section of examples is not intended to limit in any way the scope of the invention contemplated herein.
  • Example 1 Preparation and obtaining of l, 5-diarylpyrazol-3-ethyl carboxylate, 2-3.
  • the extract was dried (Na 2 SO 4 ) and after subsequent rotary evaporation of the solvent, the l / fpyrazol-3-carboxylate isomer was predominantly obtained as a viscous yellow oil which was purified by column chromatography on silica gel using as an eluent AcOEt / Hexane (1/9).
  • the compound represented in Figure 4 was prepared following the procedure described above using 3.0 g (11.78 mmol) of ethyl 4-chlorophenyl-2,4-dioxobutanoate 1 and 2.11 g (11, as a starting reagent. 78 mmol) of 4-chlorophenylhydrazine hydrochloride in glacial acetic acid (10 ml). The solution was refluxed for 48 hours and treated as described in the general procedure; 2.55 g of a yellow solid were obtained.
  • the compound represented in Figure 5 was prepared following the procedure described above using 0.61 g (2.29 mmol) of the commercial oleylamine dissolved in anhydrous CH 2 CI 2 (50 ml), 1.15 ml (as starting reagent. 2.29 mmol) of the commercial 2M solution of AI (CH 3 ) 3 in heptane and 0.15 g (0.45 mmol) of ethyl 5- (4-chlorophenyl) -l-phenylpyrazol-3-carboxylate 2 in anhydrous CH 2 CI 2 (50 ml), the mixture was heated at reflux for 24 hours and treated as described in the general procedure; 0.22 g of a yellow wax was obtained.
  • the compound of Figure 6 was prepared following the procedure described above using 0.92 g (3.46 mmol) of the commercial oleylamine dissolved in anhydrous CH 2 CI 2 (50 ml), 1.73 ml (3) as a starting reagent , 46 mmol) of the commercial 2M solution of AI (CH 3 ) 3 in heptane and 0.25 g (0.69 mmol) of the dissolved l, 5-di- (4-chlorophenyl) pyrazol-3-carboxylate 3 in anhydrous CH 2 CI 2 (50 ml), the mixture was heated at reflux for 20 hours and treated as described in the general procedure; 0.35 g of a yellow wax was obtained.
  • the compound of Figure 7 was prepared following the procedure described above using 0.92 g (3.82 mmol) of the commercial 1-hexadecylamine dissolved in anhydrous CH 2 CI 2 (50 mL), 1.91 mL as a starting reagent (3.82 mmol) of the commercial 2M solution of AI (CH 3 ) 3 in heptane and 0.25 g (0.76 mmol) of ethyl 5- (4-dorophenyl) -l-phenylpyrazol-3-carboxylate 2 dissolved in anhydrous CH 2 CI 2 (50 ml), the mixture was heated at reflux for 48 hours and treated as described in the general procedure; 0.36 g of a white solid were obtained.
  • the compound of Figure 8 was prepared following the procedure described above using 0.83 g (3.46 mmol) of the commercial 1-hexadecylamine dissolved in anhydrous CH 2 CI 2 (50 mL), 1.73 mL as a starting reagent (3.46 mmol) of the commercial 2M solution of AI (CH 3 ) 3 in heptane and 0.25 g (0.69 mmol) of the ethyl l, 5-di- (4-chlorophenyl) pyrazol-3-carboxylate 3 dissolved in anhydrous CH 2 CI 2 (50 ml), the mixture was heated at reflux for 20 hours and treated as described in the general procedure; 0.34 g of a white solid were obtained.
  • Control group treated with the 5% tween-80 vehicle in physiological serum. After 15 minutes of administration, the containers were placed with a known amount of food (usually 30-40 g) and a bottle of fresh water. These food containers were weighed at 30, 60, 120 and

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Abstract

L'invention concerne une nouvelle classe de dérivés pyrazoliques d'amides d'acides gras et leurs sels, solvates et hydrates pharmaceutiquement acceptables, qui présentent une affinité sélective pour le sous-type alpha des récepteurs activés par le proliférateur de peroxisomes (PPAR) et qui modulent, par conséquent, les actions régulées par lesdits récepteurs, en particulier l'induction de satiété et le contrôle de l'ingestion, la diminution du gain de masse corporelle et la régulation du métabolisme lipidique.
PCT/ES2008/000653 2007-10-15 2008-10-09 Dérivés pyrazoliques d'amides d'acides gras utilisés comme activateurs spécifiques de récepteurs ppar-alpha, procédé de préparation et utilisation Ceased WO2009050318A1 (fr)

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ESP200702691 2007-10-15
ES200702691A ES2291147B1 (es) 2007-10-15 2007-10-15 Derivados pirazolicos de amidas de acidos grasos como activadores especificos de receptores ppar-alfa, procedimiento de preparacion y utilizacion.

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WO2009050318A1 true WO2009050318A1 (fr) 2009-04-23

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6509367B1 (en) * 2001-09-22 2003-01-21 Virginia Commonwealth University Pyrazole cannabinoid agonist and antagonists
US20030018081A1 (en) * 2001-03-27 2003-01-23 Regents Of The University Of California Methods, compounds, and compositions for reducing body fat and modulating fatty acid metabolism
US20030199536A1 (en) * 2002-04-15 2003-10-23 Research Triangle Institute Compounds having unique CB1 receptor binding selectivity and methods for their production and use
WO2007028849A1 (fr) * 2005-09-08 2007-03-15 Consejo Superior De Investigaciones Científicas Derives de pirazolcarboxamide, procede d'obtention et applications comme antagonistes/agonistes inverses du recepteur cannabinoide cb1 et opioide mu

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030018081A1 (en) * 2001-03-27 2003-01-23 Regents Of The University Of California Methods, compounds, and compositions for reducing body fat and modulating fatty acid metabolism
US6509367B1 (en) * 2001-09-22 2003-01-21 Virginia Commonwealth University Pyrazole cannabinoid agonist and antagonists
US20030199536A1 (en) * 2002-04-15 2003-10-23 Research Triangle Institute Compounds having unique CB1 receptor binding selectivity and methods for their production and use
WO2007028849A1 (fr) * 2005-09-08 2007-03-15 Consejo Superior De Investigaciones Científicas Derives de pirazolcarboxamide, procede d'obtention et applications comme antagonistes/agonistes inverses du recepteur cannabinoide cb1 et opioide mu

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WILEY, J.L. ET AL.: "Novthe pyrazole cannabinoids: insights into CB 1 receptor recognition and activation.", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS., vol. 296, no. 3, 2001, pages 1013 - 1022 *

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ES2291147B1 (es) 2008-11-01

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