EP2108012A2 - Substituierte n-(4-cyan-1h-pyrazol-3-yl)methylamin-derivate, ihre herstellung und ihre therapeutische verwendung - Google Patents

Substituierte n-(4-cyan-1h-pyrazol-3-yl)methylamin-derivate, ihre herstellung und ihre therapeutische verwendung

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Publication number
EP2108012A2
EP2108012A2 EP08761730A EP08761730A EP2108012A2 EP 2108012 A2 EP2108012 A2 EP 2108012A2 EP 08761730 A EP08761730 A EP 08761730A EP 08761730 A EP08761730 A EP 08761730A EP 2108012 A2 EP2108012 A2 EP 2108012A2
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EP
European Patent Office
Prior art keywords
group
formula
chlorophenyl
compound
phenyl
Prior art date
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Application number
EP08761730A
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English (en)
French (fr)
Inventor
Francis Barth
Christian Congy
Serge Martinez
Murielle Rinaldi-Carmona
Martine Vernhet
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Sanofi SA
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Sanofi Aventis France
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Publication of EP2108012A2 publication Critical patent/EP2108012A2/de
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    • 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
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to substituted N- (4-cyano-1H-pyrazol-3-yl) methylamine derivatives, their preparation and their therapeutic application.
  • Diphenylpyrazole derivatives having an affinity for the CB 2 receptors of cannabinoids have been described in particular in patents US Pat. No. 5,624,941, EP 0 576 357, EP 0 656 354, EP 1 150 961 and in the international application.
  • Novel N- [(4-cyano-1H-pyrazol-3-yl) methyl] amine derivatives have now been found to possess centrally and / or peripherally located cannabinoid CB 1 receptor antagonist properties.
  • the subject of the present invention is compounds corresponding to formula (I):
  • X represents a group -C- > a group -C-NH-, a group -SO 2 N (R 5 ) - ;
  • Ri represents: an unsubstituted (C2-C12) alkyl or a (C1-C12) alkyl substituted one or more times with substituents independently selected from: a) a fluorine atom; b) a (C 1 -C 4) alkoxy; c) a (C3-C7) cycloalkyl; d) a phenyl which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, a group
  • AIk an OAIk group
  • e phenoxy, phenylthio, phenylsulfonyl in which the phenyl is unsubstituted or substituted one or more times with substituents independently selected from a halogen atom, an Alk group, a group
  • OAIk OAIk
  • a pyridyloxy wherein the pyridyl is unsubstituted or substituted one or more times with substituents independently selected from a halogen atom, an Alk group, an OAUc group
  • an aromatic heterocyclic radical chosen from pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl and pyridyl, said radical being unsubstituted or substituted one or more times with substituents chosen independently from an atom of halogen, an AIk group, an OAIk group; .
  • non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, an Alk group, an OAlk group, a phenyl or a phenylsulfonyl in which the phenyl is - even unsubstituted or substituted by a halogen atom; .
  • a phenyl which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, an Alk group, an OAlk group, a methylenedioxy group, a -NHAIk group, a -N (Alk) 2 group, a cyano group, a nitro, a (C 1 -C 4) alkylcarbonyl group, a (C 1 -C 4) alkoxycarbonyl group, or a phenyl, phenoxy, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, thiadiazolyl or pyridyl radical, said radical being unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl;
  • an aromatic heterocyclic radical selected from pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, pyridyl, indolyl,
  • 1,3-benzothiazolyl said radical being unsubstituted or substituted one or more times with substituents independently selected from a halogen atom, an Alk group, an OAlk group;
  • R 2 represents a hydrogen atom or a (C 1 -C 4) alkyl
  • R.3 represents a phenyl which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, an Alk group or an OAlk group
  • R 4 represents a phenyl which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, an Alk group or an OAlk group
  • R 5 represents a hydrogen atom or a (C 1 -C 4) alkyl
  • Alk represents a (C 1 -C 4) alkyl which is unsubstituted or substituted one or more times with a fluorine atom.
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful for purifying or isolating the compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) may exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
  • halogen atom is meant a bromine, chlorine, fluorine or iodine atom.
  • a lkyl e> means a linear or branched alkyl radical of one to four carbon atoms or respectively of one to twelve carbon atoms, such as methyl, ethyl propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl.
  • alkoxy is meant a linear or branched alkoxy radical of one to four carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy radical.
  • (C3-C7) cycloalkyl is meant a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • C3-C12 non-aromatic carbocyclic radicals include mono or polycyclic radicals, fused, bridged or spiranic.
  • Monocyclic radicals include (C3-C7) cycloalkyls.
  • the fused, bridged or spiro di- or tricyclic radicals include, for example, norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl radicals; bicyclo [3.1.1] heptyl.
  • X represents a group -C-, a group -C-NH-
  • unsubstituted phenyl mono- or disubstituted with substituents independently selected from halogen, Alk, OAlk, methylenedioxy, -N (Alk) 2, cyano, (C 1 -C 4) alkylcarbonyl (C1-C4) alkoxycarbonyl; or from a phenyl or pyrrolyl radical; . 2,3-dihydrobenzofuranyl;
  • R3 represents a phenyl monosubstituted by a halogen atom or a group
  • R 4 represents a phenyl mono- or disubstituted with a halogen atom
  • R 5 represents a hydrogen atom or a (C 1 -C 4) alkyl
  • X represents a group -C-, a group -C-NH-
  • R3 represents 4-chlorophenyl or 4-methoxyphenyl
  • R4 represents a 2-bromophenyl, a 2-chlorophenyl, a 2,4-dichlorophenyl; in the form of a base or of addition salts with acids and with the state of hydrates or solvates.
  • formula (IA) in which:
  • X represents a group -C 2 -
  • R-3 represents 4-chlorophenyl or 4-methoxyphenyl
  • R 4 represents a 2-bromophenyl, a 2-chlorophenyl, a 2,4-dichlorophenyl y in the base state or addition salts with acids, and in the state of hydrates or solvates.
  • X represents a group -C il-N ⁇ -
  • R-2 represents a hydrogen atom
  • R3 represents a 4-chlorophenyl
  • R4 is 2-chlorophenyl or 2,4-dichlorophenyl; in the form of a base or of addition salts with acids and with the state of hydrates or solvates.
  • leaving group a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure of an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
  • Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation are given in Advances in Organic Chemistry, J. Tuesday, 3 rd Edition, Wiley Interscience, 1985, p. 310-316.
  • the compounds of formula (I) can be prepared according to a process which is characterized in that a compound of formula:
  • reaction is carried out in the presence of a coupling agent used in peptide chemistry such as 1,3-dicyclohexylcarbodiimide or hexafluorophosphate.
  • a coupling agent used in peptide chemistry such as 1,3-dicyclohexylcarbodiimide or hexafluorophosphate.
  • benzotriazol-1-yl-oxytris (dimethylamino) phosphonium or benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium hexafluorophosphate or 2- (1H-benzotriazol-1-yl) -1,3,3,3-tetrafluoroborate, 3-tetramethyl uranium, in the presence of a base such as triethylamine, N, N-diisopropylethylamine or 4-dimethylaminopyridine, in a solvent such as dichloromethane, dichloroethane, NN-dimethylformamide or tetrahydrofuran at a temperature of between -10 ° C and the reflux temperature of the solvent.
  • a base such as triethylamine, N, N-diisopropylethylamine or 4-dimethylaminopyridine
  • the acid chloride As the functional derivative of the acid (III) it is possible to use the acid chloride, the anhydride, a mixed anhydride, a C 1 -C 4 alkyl ester in which the alkyl is straight or branched, an activated ester, for example the p-nitrophenyl ester.
  • a solvent such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an atmosphere inert, at a temperature between 0
  • One variant consists in preparing the mixed anhydride of the acid of formula (III) by reacting ethyl chloroformate with the acid of formula (III), in the presence of a base such as triethylamine, and in doing so react with the compound of formula (II), in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.
  • the compounds of formula (I) thus obtained may subsequently be separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography.
  • R3 and R4 are as defined for a compound of formula (I) and Y represents a leaving group as defined above, preferably a halogen atom or an activated hydroxy group such as a methanesulfonate group, benzene sulfonate, p-toluenesulfonate or triflate, with a compound of formula:
  • the reaction is carried out in a solvent such as N, N-dimethylformamide, acetonitrile, dichloromethane, toluene or propan-2-ol, and in the presence or absence of a base.
  • a base is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-diisopropylethylamine. methylmorpholine.
  • the reaction is carried out at a temperature between 0 ° C. and the reflux temperature of the solvent.
  • an alkali metal halide such as sodium iodide
  • R3 and R4 are as defined for a compound of formula (I), with hydrazine hydrate, in a solvent such as methanol or ethanol and at a temperature between room temperature and room temperature. reflux of the solvent.
  • the compounds of formula (III) are known or are prepared according to known methods.
  • R3 and R4 are as defined for a compound of formula (I), according to conventional methods.
  • a compound of formula (XIII) is treated with a halogenating agent such as PCI5, PBrc, HBr, BBrc or SOCl2 in a solvent such as dichloromethane or toluene and at a temperature between 0 ° C and the reflux temperature of the solvent.
  • a halogenating agent such as PCI5, PBrc, HBr, BBrc or SOCl2
  • solvent such as dichloromethane or toluene
  • Y represents a methanesulphonate, a benzenesulphonate, a p-toluenesulphonate or a trifluoromethanesulphonate
  • a compound of formula (XIII) is reacted with a sulphonyl chloride of formula W-SO2-
  • W is methyl, phenyl, p-tolyl or trifluoromethyl.
  • the reaction is carried out in the presence of a base such as triethylamine, pyridine or N, N-diisopropylethylamine, in a solvent such as dichloromethane or toluene and at a temperature of between -20 ° C. and the reaction temperature. reflux of the solvent.
  • a base such as triethylamine, pyridine or N, N-diisopropylethylamine
  • R3 and R4 are as defined for a compound of formula (I) and Z is (C1-C2) alkoxy.
  • the reaction is carried out in the presence of a reducing agent such as sodium borohydride, potassium borohydride or lithium aluminum hydride, in the presence of lithium chloride, in a solvent such as tetrahydrofuran, and at a temperature between room temperature and the reflux temperature of the solvent.
  • a reducing agent such as sodium borohydride, potassium borohydride or lithium aluminum hydride
  • the compounds of formula (XIV) are prepared by reacting a compound of formula: R 3 -C-CH 2 -CN (XV) in which R 3 is as defined for a compound of formula (I) with a compound of formula:
  • R4 is as defined for a compound of formula (I) and Z represents a (Cj-C2) alkoxy, in the presence of a base such as sodium ethoxide, in a solvent such as ethanol and at a temperature between room temperature and the reflux temperature of the solvent.
  • the compounds of formula (XV) are known, commercially available or 1 - prepared according to known methods.
  • PyBOP Benzotriazol-1-yloxytris (pyrrolidino) - phosphonium hexafluorophosphate.
  • Silica H silica gel 60 H marketed by Merck (DARMSTAD)
  • Buffer solution pH 2: solution of 16.66 g of KHSO4 and 32.32 g of K2SO4 in 1 liter of water.
  • the compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry).
  • the molecular peak (MH) and the retention time (tr) are measured in minutes.
  • a symmetry C18 2.1 x 50 mm, 3.5 ⁇ m column was used at 30 ° C, flow rate 0.4 ml / minute.
  • the eluent is composed as follows:
  • solvent A 0.005% trifluoroacetic acid (TFA) in water at pH 3.15;
  • solvent B 0.005% of TFA in acetonitrile.
  • the eluent is composed as follows:
  • solvent A 0.025% TFA in water
  • solvent B 0.025% of TFA in acetonitrile.
  • UV detection is performed by a diode array detector between 210 and 400 nm and ESI positive chemical ionization mass detection.
  • the eluent is composed as follows:
  • solvent A 0.025% trifluoroacetic acid (TFA) in water
  • solvent B 0.025% of TFA in acetonitrile.
  • UV detection is performed by a diode array detector between 210 and 400 nm and ESI positive chemical ionization mass detection.
  • Method 4 M 2 An X Terra MS Cl 8 column of 2 x 100 mm, 3.5 ⁇ m, is used at 30 ° C., flow rate 0.4 ml / minute.
  • the eluent is composed as follows:
  • solvent A 0.005% TFA in water at pH 3.1;
  • solvent B 0.005% of TFA in acetonitrile.
  • a solution of 25 g of 2-chloroaniline in 200 ml of a solution of 24% HCl and 400 ml of water is cooled to 5 ° C. and a solution of 13.5 g of sodium nitrite is added dropwise. in 60 ml of water.
  • This solution of diazonium salt thus obtained is added to a mixture of 32.2 g of ethyl 2-chloro-3-oxobutanoate and 16.1 g of sodium acetate in 750 ml of EtOH previously cooled to 5 °. C. and then left stirring for 2 hours 30 minutes, allowing the temperature to rise to ambient temperature.
  • the precipitate formed is filtered off, washed with water and dried. 49 g of the expected compound are obtained.
  • Me, Et, Pr, n-Bu and t-Bu respectively represent methyl, ethyl, propyl, n-butyl and tert-butyl groups.
  • the compounds of formula (I) have a very good in vitro affinity (IC50 ⁇ 1.10-7M) for cannabinoid CB1 human or rodent receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994. 350, 240-244).
  • the toxicity of the compounds of formula (I) is compatible with their use as a medicament.
  • the subject of the invention is medicaments for human or veterinary medicine which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a solvate or a hydrate of the compound of formula (I).
  • the compounds according to the invention can be used in humans or animals (in particular in mammals including, but not limited to, dogs, cats, horses, cattle, sheep) in the treatment or prevention of diseases involving cannabinoid receptors CB].
  • the compounds of formula (I) are useful as psychotropic drugs, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, attention deficit and hyperactivity disorder (ADHD) in hyperkinetic children and for the treatment of disorders related to the use of psychotropic substances, particularly in cases of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction.
  • the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders , especially dyskinesias or Parkinson's disease, tremors and dystonia.
  • the compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementia, Alzheimer's disease, as well as in the treatment of attention disorders or alertness.
  • the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischemia, head trauma and the treatment of acute or chronic neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette's syndrome. .
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, peripheral acute pain, chronic pain of inflammatory origin, pain induced by anticancer treatment.
  • the compounds of formula (I) according to the invention can be used as medicaments in human or veterinary medicine in the treatment and prevention of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or eating behaviors, especially for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemia, metabolic syndrome.
  • the compounds of formula (I) according to the invention are useful in the treatment and prevention of obesity and the risks associated with obesity, in particular cardiovascular risks.
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment and prevention of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, liver diseases such as chronic cirrhosis, fibrosis, hepatic steatosis, steatohepatitis; as well as endocrine disorders, cardiovascular disorders, hypotension, atherosclerosis, hemorrhagic shock, septic shock, asthma, chronic bronchitis, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertility disorders, termination of pregnancy, premature delivery, inflammatory phenomena, diseases of the immune system, particularly autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases leading to demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke and as drugs for cancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and osteoporosis.
  • liver diseases such as chronic cir
  • the compounds of formula (I) are particularly useful for the treatment of psychiatric disorders, in particular schizophrenia, attention and alertness disorders, attention deficit and hyperactivity disorder (ADHD) in hyperkinetic children; for the treatment of appetite and obesity disorders; for the treatment of memory deficits and cognitive disorders; for the treatment of substance dependence and withdrawal, particularly alcohol dependence, nicotine addiction, alcohol withdrawal and smoking cessation; acute or chronic neurodegenerative diseases.
  • psychiatric disorders in particular schizophrenia, attention and alertness disorders, attention deficit and hyperactivity disorder (ADHD) in hyperkinetic children
  • ADHD attention deficit and hyperactivity disorder
  • ADHD attention deficit and hyperactivity disorder
  • the compounds of formula (I) according to the present invention are useful in the preparation of medicaments useful in the treatment and prevention of appetite disorders, appetite disorders, metabolic disorders, obesity , type II diabetes, metabolic syndrome, dyslipidemia, gastrointestinal disorders, inflammatory phenomena, immune system diseases, psychotic disorders, alcohol dependence, nicotine addiction.
  • the present invention relates to the use of a compound of formula (I), or of one of its addition salts with a pharmaceutically acceptable acid or of its solvates or hydrates for the treatment of disorders and diseases indicated above.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or of one of its addition salts with a pharmaceutically acceptable acid or a solvate or hydrate of said compound, as well as at least one pharmaceutically acceptable excipient. .
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • compositions according to the present invention may contain, besides a compound of formula (I), one (or more) other active ingredient useful in the treatment of the disorders and diseases indicated above.
  • an antihyperlipidemic agent or an antihypercholesterolemic agent an antihyperlipidemic agent or an antihypercholesterolemic agent
  • a nicotinic agonist a partial nicotinic agonist
  • an antidepressant an antispychotic, an anxiolytic
  • an anticancer agent or an antiproliferative agent an anticancer agent or an antiproliferative agent
  • nonsteroidal or steroidal anti-inflammatory drug a nonsteroidal or steroidal anti-inflammatory drug
  • an anti-infective agent a nonsteroidal or steroidal anti-inflammatory drug
  • angiotensin II AT 1 receptor antagonist is meant a compound such as candesartan cilexitil, eprosartan, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan, each of these compounds may itself be associated with a diuretic such as hydrochlorothiazide.
  • inhibitor of the conversion enzyme is meant a compound such as alacepril, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril, zofenopril, each such compounds may itself be associated with a diuretic such as hydrochlorothiazide or indapamide or a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • a diuretic such as hydrochlorothiazide or indapamide
  • a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • calcium antagonist is meant a compound such as amlodipine, aranidipine, benidipine, bepridil, cilnidipine, diltiazem, efonidipine hydrochloride ethanol, fasudil, felodipine, isradipine, lacidipine, lercanidipine hydrochloride, manidipine, mibefradil hydrochloride, nicardipine, nifedipine, nilvadipine, nimodipine, Nisoldipine, Nitrendipine, Terodiline, Verapamil.
  • beta-blocker is meant a compound such as acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevololol, bisoprolol, bopindolol, bucumolol, bufetolol, bunitrolol, butofilolol, carazolol, cardolol, carvedilol, cloranolol, epanolol, esmolol.
  • Antihyperlipidemic or antihypercholesterolaemic means a compound selected from fibrates such as alufibrate, beclobrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate; statins (HMG-CoA reductase inhibitors), such as atorvastatin, fluvastatin sodium, lovastatin, pravastatin, rosuvastatin, simvastatin, or a compound such as acipimox, aluminum nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicoclonate, nicotinic acid , beta-sitosterol, tiadenol.
  • statins HMG-CoA reductase inhibitors
  • antidiabetic means a compound belonging to one of the following classes: sulfonylureas, biguanidines, alpha glucosidase inhibitors, thiazolidinedione, methaglinides, such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide , glimepiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, voglibose, as well as insulin and insulin analogues.
  • sulfonylureas biguanidines
  • alpha glucosidase inhibitors such
  • a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine, sibutramine, a topiramate, a lipase inhibitor (orlistat cetilistat ), a PPAR (Peroxisome Proliferator Activated Receptor Agonist) agonist, a dopamine agonist, a leptin receptor agonist, a serotonin reuptake inhibitor, a beta-agonist, a CCK-A agonist, an inhibitor of NPY, an MC4 receptor agonist, an MCH receptor antagonist (Melanin Concentrating
  • Hormone an orexin antagonist, a phosphodiesterase inhibitor, an inhibitor of l ⁇ HSD (11- ⁇ -hydroxy steroid dehydrogenase), an inhibitor of DPP-IV (dipeptidyl peptidase IV), an antagonist (or inverse agonist of histamine H3, a Ciliary Neurotrophic Factor (CNTF), a Growth Hormone Secretagogue (GHS) receptor agonist, a ghrelin modulator, a diacyglycerol acyltransferase inhibitor (DGAT), a phosphodiesterase inhibitor (PDE), a thyroid hormone agonist, an antagonist of glucocorticoid receptors, a stearoyl-CoA-desaturase inhibitor (SCD), a phosphate, glucose, fatty acid, dicarboxylate transporter modulator, a 5HT2 antagonist, a 5HTg antagonist, a bombesin agonist.
  • l ⁇ HSD 11- ⁇ -hydroxy steroid dehydr
  • opioid antagonist is meant a compound such as naltrexone, naloxone or nalmefene.
  • agent useful in the treatment of alcoholism and withdrawal symptoms is meant acamprosate, benzodiazepines, beta-blockers, clonidine, carbamazepine.
  • beneficial agent, for treating osteoporosis is meant, for example, bisphosphonates such as etidronate, clodronate, tiludronate, risedronate.
  • PTP 1 B English Protein Tyrosine Phosphase -IB
  • agonists of the VPAC 2 receptors GLK modulators, retinoid modulators, glycogen phosporylase inhibitors (HGLPa), glucagon antagonists, glucose-6 phosphate inhibitors, pyruvate dehydrogenase kinase (PKD) activators, RXR modulators, FXR, LXR, SGLT inhibitors
  • Sodium-dependent Glucose Transporter inhibitors of CETP (English Cholesterylester Transfer Protein), squalene synthetase inhibitors, squalene epoxidase inhibitors, triglyceride synthesis inhibitors, LDL receptor inducers (Low English).
  • Density Lipoprotein IBAT inhibitors, FBPase inhibitors (fructose-1,6-biphosphatase), modulators of
  • CART Cocaine-Amphetamine-Regulated Transcript
  • MC4 modulators Melanocortin 4
  • orexin receptor antagonists
  • the compound of formula (I), or one of its addition salts with a pharmaceutically acceptable acid or one of its solvates or hydrates and the other associated active ingredient may be administered simultaneously , separated or spread over time.
  • “separate use” is meant the administration, at the same time, of the two compounds of the composition according to the invention each included in a distinct pharmaceutical form.
  • Extended use means the sequential administration of the first compound of the composition of the invention, included in a pharmaceutical form, then the second compound of the composition according to the invention, included in a separate pharmaceutical form. . In this case, the lapse of time elapsing between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or one of its addition salts with a pharmaceutically acceptable acid or its solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for prophylaxis or treatment disorders or diseases above.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
  • the dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or more doses, preferably 0.02 to 50 mg / kg. There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the practice Usually, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
  • the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its addition salts with a pharmaceutically acceptable acid or its hydrates or solvates.

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EP08761730A 2007-01-05 2008-01-02 Substituierte n-(4-cyan-1h-pyrazol-3-yl)methylamin-derivate, ihre herstellung und ihre therapeutische verwendung Withdrawn EP2108012A2 (de)

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FR0700095A FR2911136B1 (fr) 2007-01-05 2007-01-05 Derives de n-(4-cyano-1h-pyrazol-3-yl)methylamine substitues leur preparation et leur application en therapeutique.
PCT/FR2008/000005 WO2008099076A2 (fr) 2007-01-05 2008-01-02 Derives de n-(4-cyano-l h-p yrazol-3 -yl)methylamine substitues, leur preparation et leur application en therapeutique

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WO2014134391A1 (en) 2013-02-28 2014-09-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors
AR094929A1 (es) 2013-02-28 2015-09-09 Bristol Myers Squibb Co Derivados de fenilpirazol como inhibidores potentes de rock1 y rock2
JP6975515B2 (ja) * 2016-07-20 2021-12-01 エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft Ｔｒｐａ１モデュレーターとしてのスルホニルシクロアルキルカルボキサミド化合物
CA3166630A1 (en) 2020-01-03 2021-07-08 Berg Llc Polycyclic amides as ube2k modulators for treating cancer

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FR2692575B1 (fr) * 1992-06-23 1995-06-30 Sanofi Elf Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant.
FR2713225B1 (fr) 1993-12-02 1996-03-01 Sanofi Sa N-pipéridino-3-pyrazolecarboxamide substitué.
ES2141916T3 (es) * 1993-11-30 2000-04-01 Searle & Co Pirazolil-bencenosulfonamidas sustituidas para el tratamiento de la inflamacion.
FR2789079B3 (fr) 1999-02-01 2001-03-02 Sanofi Synthelabo Derive d'acide pyrazolecarboxylique, sa preparation, les compositions pharmaceutiques en contenant
US7393842B2 (en) * 2001-08-31 2008-07-01 University Of Connecticut Pyrazole analogs acting on cannabinoid receptors
US7247628B2 (en) * 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
FR2856683A1 (fr) 2003-06-25 2004-12-31 Sanofi Synthelabo Derives de 4-cyanopyrazole-3-carboxamide, leur preparation et leur application en therapeutique
FR2864958B1 (fr) * 2004-01-12 2006-02-24 Sanofi Synthelabo Derive de n-[(1,5-diphenyl-1h-pyrazol-3-yl)methyl] sulfonamide, leur preparation et leur application en therapeutique.
FR2888236B1 (fr) * 2005-07-08 2007-09-21 Sanofi Aventis Sa Derives de n-[(1,5-diphenyl-1h-pyrazol-3-yl)methyl] sulfonamide, leur preparation et leur application en therapeutique

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US20100041709A1 (en) 2010-02-18
FR2911136B1 (fr) 2009-02-20
FR2911136A1 (fr) 2008-07-11

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