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WO2009078498A1 - Biarylpyrazole-4-carboxamides comme ligands des récepteurs cannabinoïdes cb1 - Google Patents

Biarylpyrazole-4-carboxamides comme ligands des récepteurs cannabinoïdes cb1 Download PDF

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Publication number
WO2009078498A1
WO2009078498A1 PCT/KR2007/006590 KR2007006590W WO2009078498A1 WO 2009078498 A1 WO2009078498 A1 WO 2009078498A1 KR 2007006590 W KR2007006590 W KR 2007006590W WO 2009078498 A1 WO2009078498 A1 WO 2009078498A1
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Prior art keywords
pyrazole
carboxamide
dichlorophenyl
chlorophenyl
oxadiazol
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Inventor
Sung-Han Lee
Hee Jeong Seo
Jinhwa Lee
Min-Ah Kim
Jeong Min Kim
Suk Youn Kang
Kwang-Woo Ahn
Suk Ho Lee
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GC Biopharma Corp
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Green Cross Corp Korea
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel biarylpyrazole 4-carboxamide compound which is effective as a cannabinoid CBi receptor ligand.
  • CBi cannabinoid receptor belongs to G-protein-coupled receptor (GPCR) type and is coupled to inhibitory G proteins (GQJo)) to inhibit certain adenylyl cyclase isozymes, leading to decreased cAMP production, decreased Ca 2+ conductance, increased K + conductance, and increased mitogen-activated protein kinase activity (see Di Marzo et al, Nat. Rev. Drug Discovery 2004, 3, 771-784; Rhee, M. H. et al., J. Neurochem. 1998, 77, 1525-1534).
  • GPCR G-protein-coupled receptor
  • GQJo inhibitory G proteins
  • cannabinoids in the central nervous system (CNS) and neuronal tissues
  • CNS central nervous system
  • neuronal tissues The major physiological effect of cannabinoids (in the central nervous system (CNS) and neuronal tissues) is the modulation of neurotransmitter release via activation of presynaptic CB 1 receptors located on distinct types of axon terminals throughout the brain (see Howlett, A. C. et al., Neuropharmacology 2004, 47 (Suppl. 1), 345-358).
  • the CBi receptor is mainly expressed in several brain areas including the limbic system (amygdala, hippocampus), hypothalamus, cerebral cortex, cerebellum, and basal ganglia.
  • the cerebellum and basal ganglia cannabinoids modulate the locomotor activity.
  • cannabinoids influence learning, memory, emotion, and motivation, and through activation of CB 1 receptors in the limbic system-hypothalamus axis, cannabinoids have an important role in the control of appetite.
  • CB 1 receptors can also be found in peripheral tissues including urinary bladder, testis, prostate, GI tract, heart, lung, adrenal gland, parotid gland, bone marrow, uterus, ovary, and adipose tissue (see Cota, D. et al., /. Clin. Invest. 2003, 112, 423-431; Ravinet Trillou, C. et al., Int. J. Obes. Relat. Metab. Disord. 2004, 28, 640-648; Galiegue, S. et al., Eur. J. Biochem. 1995, 232, 54-61; Howlett, A. C. et al., Pharmacol. Rev. 2002, 54, 161-202).
  • CB 1 receptor antagonists can influence energy homeostasis by central and peripheral mechanisms and may represent promising targets to treat diseases that are characterized by impaired energy balance.
  • rimonabant SR141716
  • rodents see Arnone, M. et al., Psychopharmacology (Berlin) 1997, 132, 104-106
  • primates see Simiand, J.; Keane, M.; Keane, P. E.; Soubrie, P. Behav. Pharmacol. 1998, 9, 179-181
  • CB 1 antagonists are currently the subject of intense studies, which were published in several reviews (see Adam, J. et al., Expert Opin.Ther. Patents, 2002, 12(10), 1475-1489; Hertzog, D. L. Expert Opin.Ther. Patents, 2004, 14(10), 1435-1452; Lange, J. H. M. et al., Drug Discov. Today, 2005, 10, 693-702; Bishop, M. J. J Med. Chem., 2006, 49(14), 4008-4016).
  • CIVCB 2 agonists have been clinically used as an antiemetic agent to stimulate appetite.
  • cannabinoid receptor agonists include the management of multiple sclerosis, spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilatation that accompanies advanced cirrhosis and cancer ⁇ see Singh, J., Exp. Clin. Pharmacol, 2006, 28(3): 177).
  • Y is O or S
  • R 1 and R 2 are each independently hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-12 carbocycle, substituted C 3-12 carbocycle, NR 3 R 4 , -CHR 5 (CO)OR 7 , -CHR 5 (CO) NR 3 R 4 , or R 1 and R 2 are fused to each other together with the nitrogen atom to which they are bonded to form a 4- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more substituents selected from the group consisting of C 1-3 alkyl, benzyl, phenyl, Ci -3 alkoxy or halogen; R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-7 alkyl, C 3-8 carbocycle, substituted C 3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle and acyl; or are fused to each other together with the nitrogen atom to
  • R 5 is hydrogen, C 1-4 alkyl, substituted C 1-4 alkyl, C 3-6 carbocycle, substituted C 3-6 carbocycle, (CH 2 ) n -C 3-6 carbocycle or (CH 2 ) n -R 6 , n being 1, 2 or
  • R 6 is phenyl, furan, thiophene, tetrahydrofuran, tetrahydropyran or dioxane;
  • R 7 is C 1-4 alkyl, substituted C 1-4 alkyl, C 3-8 carbocycle, substituted C 3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle;
  • R 8 is hydrogen, NR 3 R 4 , C 3-8 carbocycle, substituted C 3-8 carbocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, Ci -8 alkyl optionally substituted by alkoxy or halogen, C 2-6 alkenyl optionally substituted by alkoxy or halogen, (CH 2 ) m -C 3-6 carbocycle optionally substituted by alkoxy or halogen, or (CH 2 ) m -R 9 , m being 1 or 2;
  • R 9 is phenyl, furanyl, benzofuranyl, thienyl, benzothienyl, pyridinyl, pyrimidiny
  • R 10 , Rii, Ri 2 , Ri 3 , R H and Ri 5 are each independently hydrogen, halogen, cyano, Ci -3 alkyl, Q. 3 alkoxy, C 1-3 sulfanyl or trifluoromethyl.
  • R 1 , R 2 , R 8 and Rj 0 to Ri 5 have the same meanings as defined above.
  • alkyl refers to a straight or branched chain saturated hydrocarbon radical.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.
  • substituted alkyl refers to a straight or branched chain saturated hydrocarbon radical, which is optionally substituted by one or more substituents selected from the group consisting of C 1-3 alkyl optionally having one to three fluorine substituents, C 2-3 alkenyl, C 2-3 alkynyl, Ci -2 alkoxy optionally having one to three fluorine substituents, sulfanyl, sulfinyl, sulfonyl, oxo, hydroxy, mercapto, amino, guanidino, carboxy, aminocarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, aminosulfonyl, sulfonylamino, carboxyamide, ureido, nitro, cyano and halogen.
  • alkenyl refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond.
  • alkenyl as used herein include, but are not limited to, ethenyl and propenyl.
  • substituted alkenyl refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond, which has optional substituents selected from the group consisting of C 1-3 alkyl optionally having one to three fluorine substituents, amino, aryl, cyano and halogen.
  • alkynyl refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond.
  • alkynyl as used herein include, but are not limited to, acetylenyl and 1-propynyl.
  • substituted alkynyl refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond, optionally having one or more substituents selected from the group consisting of C 1-3 alkyl optionally having one to three fluorine substituents, amino, aryl and halogen.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • carbocycle refers to a non-aromatic cyclic hydrocarbon radical composed of three to seven carbon atoms. Five-to seven-membered rings may contain a double bond in the ring structure.
  • Carbocycle groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cycloheptyl.
  • substituted carbocycle refers to a non-aromatic cyclic hydrocarbon radical composed by three to seven carbon atoms, which is optionally substituted with one or more substituents selected from the group consisting of C 1-3 alkyl optionally having one to three fluorine substituents, C 2-3 alkenyl, C 2-3 alkynyl, C 1-2 alkoxy optionally having one to three fluorine substituents, sulfanyl, sulf ⁇ nyl, sulfonyl, oxo, hydroxy, mercapto, amino, guanidino, carboxy, aminocarbonyl, aryl, aryloxy, heteroaryl, heterocyclic, aminosulfonyl, sulfonylamino, carboxyamide, nitro, ureido, cyano and halogen.
  • substituents selected from the group consisting of C 1-3 alkyl optionally having one to three fluorine substituents, C 2-3 alkenyl, C 2-3 al
  • aryl refers to an optionally substituted benzene ring or refers to a ring system which may result by fusing one or more optional substituents.
  • exemplary optional substituents include substituted Cj -3 alkyl, substituted C 2-3 alkenyl, substituted C 2-3 alkynyl, heteroaryl, heterocyclic, aryl, alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, nitro, cyano, halogen, or ureido.
  • Such a ring or ring system may be optionally fused to aryl rings (including benzene rings) optionally having one or more substituents, carbocycle rings or heterocyclic rings.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, indanyl, anthracyl or phenanthryl, as well as substituted derivatives thereof.
  • heteroaryl refers to an optionally substituted monocyclic five to six-membered aromatic ring containing one or more heteroatomic substitutions selected from S, SO, SO 2 , O, N, or N-oxide, or refers to such an aromatic ring fused to one or more rings such as heteroaryl rings, aryl rings, heterocyclic rings, or carbocycle rings (e. g., a bicyclic or tricyclic ring system), each having optional subsituents.
  • optional substituents are selected from the group consisting of substituted C 1-3 alkyl, substituted C 2-3 alkenyl, substituted C 2-3 alkynyl, heteroaryl, heterocyclic, aryl, C 1-3 alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, nitro, cyano, halogen or ureido.
  • heteroaryl groups used herein include, but are not limited to, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzothiophenyl, benzopyrazinyl, benzotriazolyl, benzo[l,4]dioxanyl, benzofuranyl, 9H-a-carbolinyl, cinnolinyl, furanyl, furo[2,3-b]pyridinyl, imidazolyl, imidazolidinyl, imidazopyridinyl, isoxazolyl, isothiazolyl, isoquinolinyl, indolyl, indazolyl, indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl
  • heterocyclic refers to a three to seven-membered ring containing one or more heteroatomic moieties selected from S, SO, SO 2 , O, N, or N-oxide, optionally substituted with one or more substituents selected from the group which includes substituted C 1-3 alkyl, substituted C 2-3 alkenyl, substituted C 2-3 alkynyl, heteroaryl, heterocyclic, aryl, Ci -3 alkoxy optionally having one to three fluorine substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, sulfanyl, sulfmyl, sulfonyl, aminosulfonyl, sulfonylamino, carboxyamide, aminocarbonyl, carboxy, oxo, hydroxy, mercapto, amino, mtro, cyano, hal
  • Such a ring can be saturated or have one or more degrees of unsaturation.
  • Such a ring may be optionally fused to one or more "heterocyclic" ring(s), aryl ring(s), heteroaryl ring(s) or carbocycle ring(s), each having optional substituents.
  • heterocyclic moieties include, but are not limited to,
  • 1,4-dioxanyl 1,3-dioxanyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, imidazolidine-2,4-dionepiperidinyl, piperazinyl, piperazine-2,5-dionyl, morpholinyl, dihydropyranyl, dihydrocinnolinyl, 2,3-dihydrobenzo [1,4]
  • alkoxy refers to the group -OR 3 , where R a is alkyl as defined above.
  • alkoxy groups useful in the present invention include, but are not limited to, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy.
  • aralkoxy refers to the group -OR a R b , wherein R a is alkyl and R b is aryl as defined above.
  • aryloxy refers to the group -OR b , wherein R b is aryl as defined above.
  • mercapto refers to the group -SH.
  • sulfanyl refers to the group -SR C , wherein R c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • sulfinyl refers to the group -S-(O)R C , wherein R c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • sulfonyl refers to the group -S(O) 2 R C , wherein
  • R c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • hydroxy refers to the group -OH.
  • amino refers to the group -NH 2 .
  • the amino group is optionally substituted by substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • cyano refers to the group -CN.
  • aminosulfonyl refers to the group -S(O) 2 NH 2 .
  • the aminosulfonyl group is optionally substituted by substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • sulfonylamino refers to the group -NHS(O) 2 R c wherein R c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • carboxyamide refers to the group -NHC(O)R 0 wherein R c is substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • carboxy refers to the group -C(O)OH.
  • the carboxy group is optionally substituted by substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • aminocarbonyl refers to the group -C(O)NH 2 .
  • the aminocarbonyl group is optionally substituted by substituted alkyl, substituted carbocycle, aryl, heteroaryl or heterocyclic, as defined above.
  • ureido refers to the group -NHC(O)NHR d wherein R d is hydrogen, alkyl, carbocycle or aryl as defined above.
  • guanidino refers to the group -NHCHSfH)NH 2 .
  • acyl refers to the group -C(O)R 6 , wherein R e is alkyl, carbocycle, or heterocyclic as defined herein.
  • aroyl refers to the group -C(O)R b , wherein R b is aryl as defined herein.
  • heteroaroyl refers to the group -C(O)R f , wherein R f is heteroaryl as defined herein.
  • acyloxy refers to the group -OC(O)R 6 , wherein R e is alkyl, carbocycle, or heterocyclic as defined herein.
  • aroyloxy refers to the group -OC(O)R b , wherein R b is aryl as defined herein.
  • heteroaroyloxy refers to the group -OC(O)R f , wherein R f is heteroaryl as defined herein.
  • the present invention also includes a pharmaceutically acceptable salt and an addition salt of the inventive compound, such as a hydrochloride, hydrobromide or trifluoroacetate addition salt and a sodium, potassium and magnesium salt.
  • a pharmaceutically acceptable salt and an addition salt of the inventive compound such as a hydrochloride, hydrobromide or trifluoroacetate addition salt and a sodium, potassium and magnesium salt.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are incorporated within the scope of the present invention.
  • One embodiment of the present invention is to provide a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 8 , R 10 , Rn, Ri 2 , R 13 , R H and R 15 have the same meanings as defined above.
  • Another embodiment of the present invention is provide a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 8 , Rio 5 Rn 5 Ri 2? R B5 Ri 4 , and R 15 have the same meanings as defined above.
  • Preferred compounds useful in the present invention are selected from the group consisting of:
  • the compound of formula (Ia) may be illustratively prepared by the synthetic rout shown in Reaction Scheme 1.
  • Reaction Scheme 1
  • Reaction Scheme 1 comprises the steps of: (i) subjecting an 1,3,4-oxadiazole compound of formula (Ha) to bromination using NBS (N-bromosuccinimide) to obtain an activated 4-pyrazole intermediate such as the bromomethyl derivative of formula (Ilia);
  • the 1,3,4-oxadiazole compound of formula (Ha) used as a starting material in preparing the compound of formula (Ia) may be prepared by reacting a carboxylic acid derivative (5) with a hydrazide compound (7) or a semicarbazide compound (12) in the presence of a coupling agent, e.g., EDCI, DMAP; and cyclizing the resulting acyl hydrazide intermediate (9 or 14) using a dehydrating agent, as shown in Reaction Scheme 2.
  • a coupling agent e.g., EDCI, DMAP
  • R 3 , R 4 and R 8 have the same meanings as defined above.
  • the cyclization may be conducted using Burgess reagent as a dehydrating agent while applying microwave irradiation thereon (see Leber, J. D. et al., WO 2005/032550), or using triphenylphosphine with carbon tetrachloride and a base such triethylamine in a suitable solvent such as acetonitrile and THF or using phosphorus(III) oxychloride in refluxing 1,4-dioxane.
  • Burgess reagent as a dehydrating agent while applying microwave irradiation thereon (see Leber, J. D. et al., WO 2005/032550), or using triphenylphosphine with carbon tetrachloride and a base such triethylamine in a suitable solvent such as acetonitrile and THF or using phosphorus(III) oxychloride in refluxing 1,4-dioxane.
  • the acyl hydrazide intermediate (9) used in Reaction Scheme 2 may be also prepared by treating an ester compound of formula (4) with hydrazine in refluxing EtOH and coupling the resulting hydrazide compound (A) with a corresponding acid in the presence of coupling reagents such as DMAP and EDCI, as shown in Reaction Scheme 3.
  • R 8 has the same meanings as defined above.
  • the carboxylic acid derivative (5) used in Reaction Scheme 2 may be prepared by a conventional method, e.g., by treating an acetophenone derivative (1) with an organic base such as lithium hexamethyldisilazide (LHMDS) to produce a corresponding alkali metal salt (2); reacting the resulting salt with an equimolar amount of diethyl oxalate to provide a ketoester salt (3); reacting the salt (3) with a hydrazine derivative in refluxing acetic acid to obtain a ⁇ yrazole-3-carboxylic ester (4); and transforming the ester (4) into an acid form (5) using an alkaline agent such as potassium hydroxide or lithium hydroxide, followed by acidification (see Barth, F. et al., US Patent No 5,462,960), as shown in Reaction Scheme 4.
  • Reaction Scheme 4 an alkaline agent such as potassium hydroxide or lithium hydroxide, followed by acidification (see Barth, F. et al.
  • the hydrazide compound (7) used in Reaction Scheme 2 may be prepared by treating an ester or a carboxylic acid with hydrazine, and also, the semicarbazide compound (12) may be prepared by treating carbamyl chloride or isocynate with hydrazine, as shown in Reaction Scheme 5.
  • the compound of formula (Va) may be also prepared by converting a pyrazole-3-carboxylic ester (4) to a bromide compound (15) using NBS in the presence of a catalytic amount of benzoyl peroxide or AIBN; subjecting the bromide compound (15) to transformation into an alcohol compound (16) by the action of silver nitrate in aqueous acetone; protecting the alcohol compound (16) with TIPSCl (triisopropylsilyl chloride) in the presence of a suitable base such as imidazole and subsequently treating the intermediate with hydrazine to produce a hydrazide compound (17); coupling the hydrazide compound (17) with carboxylic acid in the presence of appropriate coupling reagents such as EDC and HOBt to produce a corresponding acyl hydrazide compound (18); and cyclizing the acyl hydrazide compound (18) using Burgess reagent, followed by deprotecting the silyl group of the
  • R 8 has the same meaning as defined above.
  • the compound of formula (Ib) may be illustratively prepared by the synthetic rout shown in Reaction Scheme 7.
  • Reaction Scheme 7 comprises the steps of: (i) subjecting a thiadiazole compound of formula (lib) to bromination using NBS (N-bromosuccinimide) to obtain an activated 4-pyrazole intermediate such as the bromomethyl derivative of formula (HIb);
  • the thiadiazole compound of formula (lib) used as a starting material in preparing the compound of formula (Ib) may be prepared by reacting a carboxylic acid derivative (5) with a hydrazide compound (7) in the presence of coupling agents, e.g., EDCI, DMAP; and cyclizing the resulting product using a Lawesson's reagent, which can be conducted with microwave irradiation (see Kiryanov, A. A., Sampson, P., Seed, A. J., /. Org. Chem. 2001, 665, 7925-7929), as shown in Reaction Scheme 8.
  • coupling agents e.g., EDCI, DMAP
  • Lawesson's reagent which can be conducted with microwave irradiation (see Kiryanov, A. A., Sampson, P., Seed, A. J., /. Org. Chem. 2001, 665, 7925-7929), as shown in Reaction Scheme 8.
  • R 8 has the same meaning as defined above.
  • the compound of formula (Vb) may be also prepared by cyclizing an acyl hydrazide compound (18) using Lawesson's reagent, followed by deprotecting the silyl group of the resulting compound (20) with TBAF, as shown in Reaction Scheme 9.
  • R 8 has the same meaning as defined above.
  • the inventive biarylpyrazole 4-carboxamide compound i.e., ⁇ yrazole-3-azole-4-carboxamide compound of formula (I) is effective as a cannabinoid CB 1 receptor ligand, thereby preventing or treating obesity and obesity-related metabolic disorders.
  • the present invention provides a pharmaceutical composition for preventing or treating obesity and obesity-related metabolic disorders, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention provides a method for preventing or treating obesity and obesity-related metabolic disorders in a mammal, which comprises administering the compound of formula (I) to the mammal.
  • the present invention provides a method for inhibiting cannabinoid CB 1 receptor in a mammal, which comprises administering the compound of formula (I) to the mammal.
  • the term "obesity-related metabolic disorders” refers to chronic diseases that require treatment to reduce the excessive health risks associated with obesity and exemplary disorders include type 2 diabetes mellitus, cardiovascular and hypertension, hyperlipidaemia, fibrinolytic abnormalities.
  • the pharmaceutical composition may be administered orally, intramuscularly or subcutaneously.
  • the formulation for oral administration may take various forms such as a syrup, tablet, capsule, cream and lozenge.
  • a syrup formulation will generally contain a suspension or solution of the compound or its salt in a liquid carrier, e.g., ethanol, peanut oil, olive oil, glycerine or water, optionally with a flavoring or coloring agent.
  • any one of pharmaceutical carriers routinely used for preparing solid formulations may be used.
  • examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • any of the routine encapsulation procedures may be employed, e.g., using the aforementioned carriers in a hard gelatin capsule shell.
  • any of the pharmaceutical carrier routinely used for preparing dispersions or suspensions may be prepared using an aqueous gum, cellulose, silicate or oil.
  • the formulation for intramuscular or subcutaneous administration may take a liquid form such as a solution, suspension and emulsion which includes aqueous solvents such as water, physiological saline and Ringer's solution; or lipophilic solvents such as fatty oil, sesame oil, corn oil and synthetic fatty acid ester.
  • aqueous solvents such as water, physiological saline and Ringer's solution
  • lipophilic solvents such as fatty oil, sesame oil, corn oil and synthetic fatty acid ester.
  • the composition is formulated in a specific dosage form for a particular patient.
  • Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg of the compound of formula (I) or its pharmaceutically acceptable salt.
  • the suitable daily dosage for oral administration is about 0.01 mg/Kg to
  • 40 mg/Kg of the compound of formula (I) or its pharmaceutically acceptable salt may be administered 1 to 6 times a day, depending on the patient's condition.
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • Microwave reaction was conducted with a Biotage microwave reactor.
  • Mass spectra were obtained with either a Micromass, Quattro LC Triple Quadruple Tandem Mass Spectometer, ESI or Agilent, 1 lOOLC/MSD, ESI.
  • ESI Quattro LC Triple Quadruple Tandem Mass Spectometer
  • Agilent 1 lOOLC/MSD
  • ESI ESI
  • Step 1 2-(4-(Bromomethyl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-lH- pyrazol-3-yl)-5-tert-butyI-l,3,4-oxadiazole (Ilia)
  • Step 3 (3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chIorophenyl)-l-(2,4- dichlorophenyl)-lH-pyrazol-4-yl)methanol (Va)
  • Step 4 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4- dich ⁇ orophenyl)-lH-pyrazole-4-carbaldehyde (Via)
  • the filtered white solid was diluted with CH 2 Cl 2 (50ml) and washed with brine.
  • Step 5 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yI)-5-(4-chlorophenyl)-l-(2,4- dichlorophenyI)-lH-pyrazole-4-carboxylic acid (Vila)
  • Step 6 3-(5-tert-Butyl-l,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-N-isopropyl-lH-pyrazole-4-carboxamide (Ia)
  • the residue (crude acyl chloride) was diluted with CH 2 Cl 2 (10 ml), to which isopropylamine (40 ⁇ L, 0.46 mmol) and triethylamine (0.13 ml, 0.93 mmol) were added and stirred for 2 hours at room temperature.
  • the resultant was concentrated in vacuo and diluted with EtOAc.
  • the organic layer was washed with aq. saturated NaHCO 3 solution, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel column chromatography (Biotage) to obtain the title compound as a solid (103mg, 63%).
  • the compounds of the present invention were analyzed for their binding characteristics for CB 1 and CB 2 and the pharmacological activity thereof in accordance with the method disclosed in [Devane WA, Dysarz FA 3 rd , Johnson MR, Melvin LS and Howlett AC, Determination and characterization of a cannabinoid receptor in rat brain, MoI. Pharmacol., 34(5): 605-13(1998)].
  • the analysis was performed using [ 3 H]CP-55940 which is a selectively radioactivity-labeled 5-(l,l-dimethyheptyl)-2[5- hydroxy-2-(3-hydroxy ⁇ ropyl)-cyclohexyl]-phenol, purchased from PerkinElmer Life Sciences, Inc. (Boston, Massachusetts, U.S.A.), through a rat CB-I receptor binding protocol as follows.
  • the tissue obtained from the brain of SD rats was homogenized with a Dounce homogenate system in TME(50 mM Tris, 3 mM MgCl 2 and 1 mM EDTA, pH 7.4) at 4 " C 5 and the homogenate was centrifuged at 48,00Og for 30 min. at 4 °C . The pellet was resuspended in 5 ml of TME and the suspension was divided into aliquots and stored at -70 °C until its use in the following assay.
  • test compound 2 ⁇ i was diluted in dimethylsulphoxide and was added to a deep well of a polypropylene plate, to which 50 ⁇ i of [ 3 H]CP-55940 diluted in a ligand buffer solution (0.1 % bovine serum albumin(B AS)-KTME) was added.
  • tissue concentrations were determined by Bradford protein analysis, and 148 ⁇ i of brain tissue of the required concentration was added to the plate.
  • the plate was covered and placed in a 30 °C incubator for 60 min, and then transformed on GF/B filtermat pretreated in polyethylenimine (PEI) using a cell harvester. Each filter was washed five times and dried at 60 ° C for 1 hr.
  • PEI polyethylenimine
  • the inventive compounds are effective as a cannabinoid CB 1 receptor ligand.

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Abstract

L'invention porte sur un nouveau composé biarylpyrazole-4-carboxamide représenté par la formule (I) ou sur un sel pharmaceutiquement acceptable de celui-ci, qui est efficace comme ligand des récepteurs cannabinoïdes CB1, qui est utile pour prévenir ou traiter l'obésité et des troubles métaboliques se rapportant à l'obésité. La présente invention porte également sur un procédé de préparation de ce composé ou de son sel, sur une composition pharmaceutique les contenant et sur un procédé pour prévenir ou traiter l'obésité et des troubles métaboliques liés à l'obésité.
PCT/KR2007/006590 2007-12-17 2007-12-17 Biarylpyrazole-4-carboxamides comme ligands des récepteurs cannabinoïdes cb1 Ceased WO2009078498A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10336730B2 (en) 2015-08-05 2019-07-02 Bristol-Myers Squibb Company Substituted glycine derived FXIA inhibitors
WO2022132803A1 (fr) * 2020-12-14 2022-06-23 The Board Of Trustees Of The Leland Stanford Junior University Agonistes du récepteur cb2

Citations (4)

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Publication number Priority date Publication date Assignee Title
DE2906252A1 (de) * 1979-02-19 1980-08-28 Merck Patent Gmbh Pyrazolderivate, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung
EP0418845A1 (fr) * 1989-09-22 1991-03-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés de pyrazole, leur procédé de préparation et composition pharmaceutique les contenant
WO2004035566A1 (fr) * 2002-10-18 2004-04-29 Pfizer Products Inc. Ligands des recepteurs des cannabinoides et applications de ceux-ci
WO2006087480A1 (fr) * 2005-02-21 2006-08-24 Sanofi-Aventis DERIVES DE (l,5-DIPHENYL-lH-PYRAZOL-3-YL)OXADIAZOLE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2906252A1 (de) * 1979-02-19 1980-08-28 Merck Patent Gmbh Pyrazolderivate, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung
EP0418845A1 (fr) * 1989-09-22 1991-03-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés de pyrazole, leur procédé de préparation et composition pharmaceutique les contenant
WO2004035566A1 (fr) * 2002-10-18 2004-04-29 Pfizer Products Inc. Ligands des recepteurs des cannabinoides et applications de ceux-ci
WO2006087480A1 (fr) * 2005-02-21 2006-08-24 Sanofi-Aventis DERIVES DE (l,5-DIPHENYL-lH-PYRAZOL-3-YL)OXADIAZOLE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE

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Title
ELKHOLY Y.M. ET AL.: "Studies with pyrazol-3-carboxylic acid hydrazide: the synthesis of new pyrazolyloxadiazole and pyrazolyltriazole derivatives", PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 181, no. 9, 2006, pages 2037 - 2049 *
SAYED H.H. ET AL.: "Conversion of 3-arylazo-5-phenyl-2(3H)-furanones into other heterocycles of anticipated biological activity.", ARCHIV DER PHARMAZIE, vol. 340, no. 6, 2007, pages 315 - 319 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10336730B2 (en) 2015-08-05 2019-07-02 Bristol-Myers Squibb Company Substituted glycine derived FXIA inhibitors
US10899743B2 (en) 2015-08-05 2021-01-26 Bristol-Myers Squibb Company Substituted glycine derived FXIA inhibitors
WO2022132803A1 (fr) * 2020-12-14 2022-06-23 The Board Of Trustees Of The Leland Stanford Junior University Agonistes du récepteur cb2

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