EP1583758A1 - Derivat von 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-n-(piperidin-1-yl)-1h-pyrazol-3-carboxamid, seine herstellung und seine therapeutische verwendung - Google Patents

Derivat von 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-n-(piperidin-1-yl)-1h-pyrazol-3-carboxamid, seine herstellung und seine therapeutische verwendung

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Publication number
EP1583758A1
EP1583758A1 EP03799645A EP03799645A EP1583758A1 EP 1583758 A1 EP1583758 A1 EP 1583758A1 EP 03799645 A EP03799645 A EP 03799645A EP 03799645 A EP03799645 A EP 03799645A EP 1583758 A1 EP1583758 A1 EP 1583758A1
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EP
European Patent Office
Prior art keywords
formula
compound
treatment
derivative
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03799645A
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English (en)
French (fr)
Inventor
Gilles Miscoria
Murielle Rinaldi
Joseph Schofield
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Sanofi Aventis France
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Sanofi Aventis France
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Publication date
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Publication of EP1583758A1 publication Critical patent/EP1583758A1/de
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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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Definitions

  • the present invention relates to a derivative of 5- (4-bromophenyl) -1- (2,4- dichloropheny l) -4-ethyl-N- (piperidin- 1 -y 1) - 1 H-pyrazole-3 -carboxamide, its preparation and its therapeutic application.
  • the subject of the present invention is a compound corresponding to formula (I):
  • the compound of formula (I) can exist in the salt state.
  • Such addition salts form part of the invention.
  • salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids useful, for example, for the purification or isolation of the compounds of formula (I) also form part of the invention.
  • the compound of formula (I) can also exist in the form of hydrates or of 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.
  • the compound of formula (I) which is the subject of the invention is 5- (4-bromophenyl) -1- (2,4-dichlorophenyl) -4-ethyl-N- (piperidin-1 -yl) -1H-pyrazole -3 -carboxamide.
  • the compound of formula (I) can be prepared according to the process which follows. This process is characterized in that a functional derivative of 5- (4-bromophenyl) -1- (2,4-dichlorophenyl) -4-ethyl-1H-pyrazole-3-carboxamide acid of formula is treated: with a 1-aminopiperidine derivative of formula
  • reaction is carried out in basic medium, for example in the presence of triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran.
  • inert solvent such as dichloromethane or tetrahydrofuran.
  • an activated ester for example, can be used as functional derivative of acid (II), acid chloride, anhydride, a mixed anhydride, a C1-C4 alkyl ester in which the alkyl is straight or branched.
  • an activated ester for example, can be used.
  • the> -nitrophenyl ester, or the free acid suitably activated, for example, with N, N-dicyclohexylcarbodiimide or with benzotriazol hexafluorophosphate-N-oxotris (dimethylamino) phosphonium (BOP).
  • the acid chloride of formula (II) obtained by reaction of thionyl chloride with the acid of formula (II) can be reacted in an inert solvent, such as benzene or toluene, or a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, at a temperature between 0 ° C and the reflux temperature of the solvent.
  • an inert solvent such as benzene or toluene, or a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, at a temperature between 0 ° C and the reflux temperature of the solvent
  • the nitrosoamine derivative of formula (N) is prepared from 4-hydroxypiperidine by the action of sodium nitrite in water.
  • the reduction of the nitrosamine derivative of formula (N) is carried out in the presence of lithium aluminum hydride in an anhydrous solvent such as tetrahydrofuran (THF).
  • anhydrous solvent such as tetrahydrofuran (THF).
  • the oil obtained is chromatographed on alumina, eluting with a CHC 4 / MeOH mixture (96/4; v / v).
  • the organic phase is washed with a 5% Na2C ⁇ 3 solution, a saturated NaCl solution, then dried over Mg SO4 and concentrated to dryness under vacuum.
  • the residue obtained is purified by chromatography on silica, eluting with a toluene / ethyl acetate mixture (80/20; v / v). After removing the solvent, 3.7 g of the expected product are obtained, which crystallizes from isopropyl ether, mp 178 ° C.
  • the compound according to the invention has been the subject of pharmacological tests making it possible to determine its antagonistic action of the CBi cannabinoid receptors.
  • the toxicity of the compound of formula (I) is compatible with its use as a medicament.
  • the present invention relates to medicaments which comprise a compound of formula (I), or one of its pharmaceutically acceptable salts, solvates or hydrates.
  • Medications can be helpful in preventing or treating diseases involving the CBj cannabinoid receptors.
  • the compound of formula (I) is useful as a psychotropic drug, in particular for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, as well as for the treatment of disorders linked to the use of psychotropic substances, in particular in the case of substance abuse and / or dependence on a substance, including alcohol dependence and nicotine dependence.
  • the compound of formula (I) according to the invention can be used as a medicament for the treatment of migraine, stress, diseases of psychosomatic origin, attacks of panic attacks, epilepsy, movement disorders , especially dyskinesia or Parkinson's disease, tremors and dystonia.
  • the compound of formula (I) according to the invention can also be used as a medicament in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of attention or alertness disturbances.
  • the compound of formula (I) can be useful as a neuroprotective, in the treatment of ischemia, head trauma and the treatment of neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette syndrome.
  • the compound of formula (I) according to the invention can be used as. drug for the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.
  • the compound of formula (I) according to the invention can be used as a medicament in the treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or conduct food, in particular as an appetite suppressant or for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin dependent diabetes.
  • the compound of formula (I) according to the invention can be used as a medicament in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, asthma, Raynaud's syndrome, glaucoma, fertility disorders, phenomena inflammatory, diseases of the immune system, in particular autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, strokes as well as as drugs for cancer chemotherapy and for the treatment of Guillain-Barré syndrome.
  • autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, strokes as well as as drugs for cancer chemotherapy and for the treatment of Guillain-Barré syndrome.
  • the compound of formula (I) is very particularly useful for the treatment of psychotic disorders, in particular schizophrenia; for the treatment of appetite disorders and obesity for the treatment of memory and cognitive disorders; for the treatment of alcohol dependence, nicotine dependence, that is to say for alcohol withdrawal and for smoking cessation.
  • 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 the compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate 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 of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or its salt, solvate or hydrate, if any, can be administered in unit administration form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal administration forms , by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal administration forms , 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.
  • 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.
  • the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.
  • the present invention also relates to a method of treating the pathologies indicated above which comprises administering to a patient an effective dose of a compound according to the invention, or a pharmaceutically acceptable salts or hydrates or solvates.

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EP03799645A 2002-12-23 2003-12-19 Derivat von 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-n-(piperidin-1-yl)-1h-pyrazol-3-carboxamid, seine herstellung und seine therapeutische verwendung Withdrawn EP1583758A1 (de)

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FR0216688 2002-12-23
FR0216688A FR2849032B1 (fr) 2002-12-23 2002-12-23 Derive de 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-n -(piperidin-1-yl)-1h-pyrazole-3-carboxamide, sa preparation, son application en therapeuthique
PCT/FR2003/003814 WO2004058744A1 (fr) 2002-12-23 2003-12-19 Derive de 5-(4-bromophenyl)-1-(2,4-dichlorophenly)-4-ethyl-n-(piperidin-1-yl)-1h-pyrazole-3-carboxamide, sa preparation son application en therapeutique

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EP (1) EP1583758A1 (de)
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AU (1) AU2003299362A1 (de)
FR (1) FR2849032B1 (de)
WO (1) WO2004058744A1 (de)

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EP1574211A1 (de) 2004-03-09 2005-09-14 Inserm Verwendung von CB1-Rezeptor-Antagonisten zur Herstellung eines Arzneimittels zur Behandlung von Lebererkrankungen
EP2368881A1 (de) * 2005-01-10 2011-09-28 University of Connecticut Neue, auf Cannabinoidrezeptoren einwirkende Heteropyrazolanalaoga
CA2613678A1 (en) 2005-06-02 2006-12-07 Glenmark Pharmaceuticals S.A. Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
US7923465B2 (en) 2005-06-02 2011-04-12 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
JP5069894B2 (ja) * 2005-10-21 2012-11-07 田辺三菱製薬株式会社 ピラゾール化合物
JP2010500300A (ja) 2006-08-08 2010-01-07 サノフィ−アベンティス アリールアミノアリール−アルキル−置換イミダゾリジン−２，４−ジオン、それらの製造法、それらの化合物を含有する薬剤、およびそれらの使用
HUP0600925A3 (en) * 2006-12-19 2009-03-30 Richter Gedeon Nyrt Dyaril-pyrazoles as cb1 antagonists, their use and pharmaceutical compositions containine them
JP4994295B2 (ja) * 2007-04-20 2012-08-08 田辺三菱製薬株式会社 医薬組成物
EP2025674A1 (de) 2007-08-15 2009-02-18 sanofi-aventis Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
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EP2683702B1 (de) 2011-03-08 2014-12-24 Sanofi Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
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US8895547B2 (en) 2011-03-08 2014-11-25 Sanofi Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120052A1 (de) 2011-03-08 2012-09-13 Sanofi Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
US8871758B2 (en) 2011-03-08 2014-10-28 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
EP2683699B1 (de) 2011-03-08 2015-06-24 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
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FR2849032B1 (fr) 2006-04-28
US20060004055A1 (en) 2006-01-05
FR2849032A1 (fr) 2004-06-25
AU2003299362A1 (en) 2004-07-22
WO2004058744A1 (fr) 2004-07-15
JP2006513197A (ja) 2006-04-20

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