EP0880512A1 - Neue aromatische piperazinederivate von substituierten cykloazanen, verfahren zu ihrer herstellung, ihre pharmazeutische zubereitungen und ihre anwendung als medikament - Google Patents

Neue aromatische piperazinederivate von substituierten cykloazanen, verfahren zu ihrer herstellung, ihre pharmazeutische zubereitungen und ihre anwendung als medikament

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Publication number
EP0880512A1
EP0880512A1 EP97902427A EP97902427A EP0880512A1 EP 0880512 A1 EP0880512 A1 EP 0880512A1 EP 97902427 A EP97902427 A EP 97902427A EP 97902427 A EP97902427 A EP 97902427A EP 0880512 A1 EP0880512 A1 EP 0880512A1
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EP
European Patent Office
Prior art keywords
compound
formula
dichloromethane
mixture
methanol
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EP97902427A
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English (en)
French (fr)
Inventor
Serge Halazy
Catherine Jorand-Lebrun
Peter Pauwels
Philippe Chopin
Marc Marien
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Pierre Fabre Medicament SA
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Pierre Fabre Medicament SA
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Publication of EP0880512A1 publication Critical patent/EP0880512A1/de
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid

Definitions

  • the present invention relates to new aromatic piperazines derived from substituted cycloazanes, as well as to their process of preparation, the pharmaceutical compositions containing them and their use as medicaments.
  • Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and a neuromodulator involved in many physiological and pathological processes. Serotonin plays an important role both in the nervous system and in the cardiovascular and gastrointestinal systems. At the central level, serotonin controls functions as varied as sleep, locomotion, food intake, learning and memory, endocrine modulations, sexual behavior, thermoregulation. In the medulla, serotonin plays an important role in the control systems of the afferent peripheral nociceptives (cf. A. Moulignier, Rev. Neurol. (Paris), 1 50.3-15, 1 994).
  • Serotonin can play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggression, panic attacks, obsessive compulsive disorders, schizophrenia, tendency to suicide), certain neurodegenerative disorders (dementia of the Alzheimer type, Parkinsonism , Huntington's chorea), anorexia, bulimia, alcoholism-related disorders, stroke, pain, migraine, or various headaches (R. Glennon, Neurosci. Biobehavioral Reviews, 14.35 , 1990).
  • certain psychiatric disorders anxiety, depression, aggression, panic attacks, obsessive compulsive disorders, schizophrenia, tendency to suicide
  • certain neurodegenerative disorders disementia of the Alzheimer type, Parkinsonism , Huntington's chorea
  • anorexia bulimia
  • alcoholism-related disorders stroke, pain, migraine, or various headaches
  • receptors are mainly subdivided into 4 main classes (5HT ⁇ , 5HT2, 5HT3 and 5HT4) which themselves include subclasses such as the 5HTj receptors which are mainly divided into 5HTIA, 5HTJB, 5HTID (cf. GR Martin, PA Humphrey , Neuropharmacol., 33_, 261, 1994; PR Saxena, Exp. Opin. Invest. Drugs, 3_ (5), 513, 1994).
  • the 5HTJJ) receptors themselves contain several receptor subtypes; thus the 5HTi £, a and 5HTi £) b receptors were cloned and then identified in humans (cf. for example E. Hamel et al., Mol.
  • Compounds having a selective antagonist activity at the level of the central 5HTID receptors can therefore exert a beneficial effect on subjects suffering from disorders of the central nervous system.
  • such compounds find their utility in the treatment of disorders of locomotion, depression, anxiety, panic attacks, agoraphobia, obsessive compulsive disorders, memory disorders including dementia, amnesia, and appetite disorders, sexual dysfunctions, pain, Alzheimer's disease, Parkinson's disease.
  • the 5HT ⁇ rj antagonists also find their utility in the treatment of endocrine disorders such as hyperprolactinemia, treatment of vasospasms, hypertension and gastrointestinal disorders in which changes in motility and secretion occur.
  • the compounds according to the present invention are potent and selective antagonists of the 5HT i £> receptors and more particularly receptors recently identified as 5HT n) a and 5HT j [ ) b in humans and therefore find their utility, alone or in combination with other molecules, as medicines and more particularly as therapeutic means for the curative and preventive treatment of disorders linked to serotonin.
  • the derivatives of the present invention are distinguished from the prior art not only by their new chemical structure which unambiguously distinguishes them from the previously described derivatives but also by their original biological profile, in particular as regards their selectivity and their effectiveness as antagonists at the level of the serotonin receptor subtypes (5HTi D ⁇ and R).
  • the present invention relates to products of general formula (Ij
  • Rj represents hydrogen or linear or branched alkyl comprising
  • Z2 represents O, NH, CH2O or CH2NH
  • R2 and R3, identical or different represent a hydrogen or a group chosen from linear or branched alkyl, alkoxy, thioether, nitrile, trifluoromethyl or halogen (F, Cl, Br, I), or, R2 and R3, when they are adjacent, taken together, form a 5 or 6-membered ring so as to constitute, for example, a naphthyl, a tetrahydronaphthyl, a benzopyran or a benzodioxane,
  • Ar j represents an aromatic residue (phenyl, naphthyl or pyridyl) which can be variously substituted for example by one or more groups chosen from a linear or branched alkyl comprising from 1 to 6 carbon atoms, a trifluoromethyl, a trifluoromethoxy, a 2,2 , 2-trifluoroethyl, phenyl, benzyl, cycloalkyl comprising from 3 to 7 carbon atoms, hydroxyl, thiol, alkoxy (OR4), thioether (SR4), nitro (NO2), nitrile (CN) , an amine (NH2 or NR4R4 '), an amine derivative (NHCOR4, NHSO2R4, NHCONR4R'4, NHCO2R4, NHS02NR4R'4), a halogen (fluorine, chlorine, bromine or iodine), a carbonyl (COH, COR4, COOR4, CONR4R'4)
  • R4 represents an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms
  • R'4 represents a hydrogen or an alkyl residue, linear or branched, comprising from 1 to 6 carbon atoms and their hydrate salts, solvates and bioprecursors physiologically acceptable for therapeutic use.
  • geometric and optical isomers of the compounds of general formula (I) also form part of the present invention as well as their mixture in racemic form.
  • physiologically acceptable salts of the compounds of general formula (I) are included the salts obtained by addition of organic or inorganic acids such as chlorohydrates, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoates, p-toluenesulfonates, methanesulfonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates.
  • organic or inorganic acids such as chlorohydrates, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoates, p-toluenesulfonates, methanesulfonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succ
  • bioprecursors as used in the present invention applies to compounds whose structure differs from that of the compounds of formula (I) but which, when administered to an animal or to a human being, are converted into the organism into a compound of formula (I).
  • a particularly appreciated class of compounds of formula (I) corresponds to the compounds of formula (la)
  • Ar j, Z], X-Y, Z2 and K ⁇ are defined as in formula I and R2 represents a radical CH3, OCH3 or a chlorine.
  • the compounds of the present invention can be prepared by various methods which will be dependent on the nature of Ar j, Z ⁇ , X, Y, Z2 and R ⁇ .
  • Ar j, Z ⁇ and XY are defined as above and Y 'represents a leaving group such as a halogen (chlorine, bromine or iodine), a tosylate, a mesylate or a triflate with an aryl piperazine of general formula (III ):
  • Y ' is described as above in the presence of an organic or inorganic base such as pyridine, DiPEA, DMAP, DBU, K2CO3, CS2CO3 or CaC ⁇ 3 in an anhydrous polar aprotic solvent such as THF, DMF, DME, DMSO or methyl ethyl ketone at a temperature between - 10 ° C and 30 ° C.
  • an organic or inorganic base such as pyridine, DiPEA, DMAP, DBU, K2CO3, CS2CO3 or CaC ⁇ 3
  • an anhydrous polar aprotic solvent such as THF, DMF, DME, DMSO or methyl ethyl ketone
  • Rj ' is equivalent to R ⁇ as defined above or R' i represents a protective group such as t-butoxycarbonyl or tosyl (which will be transformed into R] later) and Y represents chlorine, bromine, an iodine, a tosylate or a mesylate.
  • This reaction is preferably carried out in a polar anhydrous solvent such as DMF, acetonitrile, THF, n-butanol, t-butanol or DMSO, generally at reflux temperature of the solvent used, in the presence of a base.
  • organic or inorganic generally used for this type of reaction, such as potassium, sodium or calcium carbonate.
  • R2 and R3 are defined as above and X "represents a function which can subsequently be converted into an amine (such as for example a nitro group) either with a bis (haloethyl) amine derivative of formula (VII) under the conditions described previously for this type of reaction, either with an amino acid of general formula (XI)
  • the method of the present invention also includes the use of well known precursors or analogs of the reagents of formula general (XII). It is thus and by way of example that the condensation of intermediates (III) and (IV) with phosgene can be advantageously carried out using diphosgene or triphosgene according to a procedure well known to those skilled in the art. art.
  • a particularly preferred method consists in condensing all of first a cyclic amine of formula (IV) with triphosgene in the presence of triethylamine in an anhydrous solvent such as dichloromethane and to isolate the intermediate of general formula (XIII) thus formed:
  • X i, R ⁇ , R2 and R3 are defined as above and Z2 represents O or NH, in the presence of an organic or inorganic base in a polar aprotic solvent at a temperature between 20 ° and 100 ° C.
  • a particularly preferred method for the preparation of cyclic amines of formula (IV), in the context of the present invention, consists in preparing these derivatives from precursors of general formula XV.
  • P represents a protective group usually used to protect a secondary amine such as for example a benzyl, a benzyl whose aromatic is substituted, an acetyl, a trifluoroacetyl, a benzyloxycarbonyl or a t-butoxycarbonyl.
  • the methods used to transform the precursor of general formula (XV) into cyclic amine IV will obviously depend on the nature of P, and are described in "Protective Groups in Organic Synthesis" T.W. Greene, John Wiley & Sons, 198 1 or "Protecting Group” PJ Kocienski, Thieme Verlag, 1 994. It is understood that the choice of the nature of the protective group P will be determined according to the methods and techniques used for the preparation of intermediaries of formula XV.
  • the preparation methods consist for example of condensing either a phenol (Arj OH) , either an aniline (Ar ⁇ NH2) and an amine of formula (XVI) with a reagent of formula XII by the methods and techniques described above for the preparation of carbamates and ureas.
  • a preferred method of preparing an intermediate of formula (XV) consists in condensing the appropriate tetralone with a cyclic amine of formula XVI, in the presence of p-toluene sulfonic acid in a solvent such as toluene at reflux, followed by the reduction of the enamine thus formed for example by catalytic hydrogenation under hydrogen pressure in the presence of palladium or platinum oxide on carbon.
  • a particularly preferred method of preparing intermediates of formula (XV) in which XY represents NCH 2 , N or NCH2CH2 and Z ⁇ represents (CH2) n , O (CH2) n , NH (CH2) n »S ⁇ 2 (CH2) n consists reducing amides of formula (XV) in which Z ⁇ represents respectively (CH 2 ) n - l CO, O (CH 2 ) n - l CO, NH (CH 2 ) n- l CO, SO 2 (CH 2 ) n .
  • ⁇ CO by known methods for reducing an amide into an amine, such as the use of an aluminum hydride (for example LiAlH4) in a solvent such as THF or ethyl ether.
  • M represents ZnBr, SnR3 where R represents an alkyl group such as butyl or B (OR ') 2 where R' represents a hydrogen or an alkyl and M 'represents Zn, with a vinyl triflate of formula (XXI)
  • a palladium catalyst such as Pd (PPh3) 4 or PdCl2 (PPh3) 2
  • a base such as a secondary or tertiary amine, a potassium, sodium or cesium carbonate and optionally copper iodide in a polar solvent such as DMSO, DMF, THF (cf. Organic Preparation and Procedures int., 27 (2), 127-160, 1995).
  • X-Y represents CH-CH2 and Z i represents (CH2) n.
  • O (CH2) n, CC or CH CH by reduction of double and triple bonds by catalytic hydrogenation (H2, Pd / C for example).
  • a polar anhydrous solvent such as ethyl ether, THF or DME, at a temperature between - 20 ° C and 60 ° C, followed by acid hydrolysis of the reaction medium.
  • L and the carboxyl to which it is attached constitute the activated form of a carboxylic acid suitable for the formation of an amide or of an ester by condensation with an amine or an alcohol by the methods and techniques well known in the art. skilled in the art.
  • the intermediates of formula XV are prepared by a reductive amination reaction, using for example NaBH4 or NaBH3CN as reducing agent between an aniline of formula Ar j NH2 and a piperidone of formula XXVI
  • the reductive amination reaction as described above can also be used for the preparation of compounds of formula XV in which Z ⁇ represents (CH2) n NH, O (CH2) nNH or S ⁇ 2 (CH2) n NH from amines of formula XXVII and of aldehyde respectively of formulas Ar ⁇ (CH2) n - l CHO, Ar ⁇ O (CH2) n - i CHO or S ⁇ 2 (CH2) n - l CHO or from amines of formula Ar ⁇ ( CH2) n NH2, Ar! ⁇ (CH2) n NH2 or Ar ⁇ S02 (CH2) n NH2 with piperidone XXVI.
  • the intermediates of formula XV in which Z ⁇ represents OCONH or NHCONH and XY represents CH-CH2 are prepared by condensation of an aminopiperidine of formula XXVII and a phenol (Arj OH) or an aniline (Ar j NH2) with an electrophile of formula XII according to the methods and techniques described above for the preparation of carbamates or ureas.
  • the intermediates of formula XV are prepared by condensation of a hydroxy piperidine of formula (XXIX) with an electrophile of formula (XXVIII) in which Z ' ⁇ represents Z ⁇ truncated by a terminal oxygen and L represents a group thus a halogen (chlorine, bromine or iodine), a tosylate, a mesylate or a triflate.
  • a halogen chlorine, bromine or iodine
  • This condensation can be carried out in the presence of a base, organic (such as a tertiary amine, potassium t-butoxide or even butyllithium) or inorganic (for example, NaH, KH, CS2CO3) in a polar anhydrous solvent such than THF, DME, DMF, DMSO, t-butanol, at a temperature between - 1 5 ° C and 80 ° C.
  • a base organic (such as a tertiary amine, potassium t-butoxide or even butyllithium) or inorganic (for example, NaH, KH, CS2CO3) in a polar anhydrous solvent such than THF, DME, DMF, DMSO, t-butanol, at a temperature between - 1 5 ° C and 80 ° C.
  • organic such as a tertiary amine, potassium t-butoxide or even butyllithium
  • inorganic for example, NaH
  • the intermediates of formula XV in which Z ⁇ represents NHCOO and X- Y represents CH-CH2 are prepared by condensation of an alcohol of formula (XXIX) and an aniline derivative (Ar j NH2) with a reagent of formula XII according to the methods and techniques described above for the preparation of a carbamate.
  • an alternative method of preparation consists in reacting a phenol of formula Ar] OH or an amine of formula Ar] NH2 and an amine of formula (XXXI) defined as above with a compound of formula (XII) by the methods and techniques described above for the preparation of carbamates and ureas.
  • BOC t-butoxycarbonyl
  • the compounds of general formula (I) in which Ar j represents an aromatic substituted by an NH2 group can also be converted into numerous other derivatives of formula (I) such as derivatives in which Ar j represents an aromatic substituted by NR 4 R4 ', NHCOR4, NHCO2R4, NHCOR4, NHSO2R4, NHS0 2 OR 4 , NHSO2NR4R4' by well known methods and techniques for transforming an aromatic amine into amide, carbonate, urea, sulfonamide, sulfonate or sulfonylurea.
  • a compound according to the invention in the form of a salt, for example a salt by addition with an acid
  • this can be achieved by treating the free base of general formula (I) with an appropriate acid, preferably in equivalent quantity, or with creatinine sulfate in an appropriate solvent.
  • the new compounds of general formula (I) When the new compounds of general formula (I) have one or more asymmetric centers, they can be prepared in the form of a racemic mixture or in the form of enantiomers, either by enantion-selective synthesis or by resolution.
  • the compounds of formula (I) having at least one asymmetric center can for example be separated into their enantiomers by the usual techniques such as the formation of diastereomeric pairs by formation of a salt with an optically active acid such as acid (+ ) -di-p-toluoyl-l-tartaric, (+) - camphorsulfonic acid, (-) - camphorsulfonic acid, (+) - phenylpropionic acid, (-) - phenylpropionic acid, followed by fractional crystallization and regeneration of the free base.
  • the compounds of formula (I) in which R j is a hydrogen comprising at least one asymmetric center can also be resolved by the formation of diaste
  • the elementary analyzes were carried out on a Fisons EA 1 108 device.
  • Compound 2 is prepared according to the procedure described in Example 1 from the following reagents: triphosgene (204mg, 0.69mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (555mg, 2.06mmol); triethylamine (290 ⁇ lx2.2.06mmolx2); 1 - (2,4,6-trimethylbenzylcarbonyl) piperazine (2b) (506mg, 2.06mmol); dichloromethane (40ml).
  • the crude is purified by flash chromatography with a mixture (92/8/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 3 is prepared according to the procedure described in Example 1 from the following triphosgene reagents
  • the crude is purified by flash chromatography with a mixture (92/8/1) then (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 4a is prepared according to the same procedure as that described for compound 2a from the following reagents (2-trifluoromethylphenyl) acetic acid (1.14 g, 5.56 mmol); 1-tert-butyloxycarbonylpiperazine (1.04g, 5.56mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.07g, 5.56mmol); 4- dimethylaminopyridine (a tip of a spatula); dichloromethane (50ml). The crude oil is used directly in the next step.
  • Compound 4b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 4a (1.92g, 5.15mmol); trifluoroacetic acid (4.7ml), dichloromethane (25ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia. Mass obtained: 866 mg (Yield: 62%)
  • Compound 4c is prepared according to the same procedure as that described for compound 3a from the following reagents compound 4b (866 mg, 3.18 mmol); lithium aluminum hydride (4.8ml of a 1M solution in ethyl ether, 4.8mmol); ethyl ether (15ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 4 is prepared according to the procedure described for compound 1 from the following reagents: triphosgene (150mg, 0.50mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (310mg, 1.19mmol); pyridine (130 ⁇ lx2,1.64mmolx2); 1- (2-trifluoromethylphenethyl) piperazine (4c) (385mg, 1.19mmol); dichloromethane (40ml). The crude is purified by flash chromatography with a mixture (80/20/1) of dichloromethane / methanol / ammonia.
  • Compound 5a is prepared according to the same procedure as that described for compound 2a from the following reagents: o-tolylacetic acid (500mg, 3.3mmol); l - / e / - / - butyloxycarbonylpiperazine (620mg,
  • Compound 5b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 5a (765mg, 2.4mmol); trifluoroacetic acid (2.2ml), dichloromethane (12ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
  • Compound 6 is prepared according to the procedure described for compound 5 from the following reagents 4-chloro-3- (4-methylpiperazin-1-yl) phenol (148 mg, 0.66mmol), compound 6b (195mg, 0.66mmol) , sodium hydride (50%, 34.6mg, 0.72mmol), THF (17ml).
  • the crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
  • Compound 7a is prepared according to the procedure described in Example 1 from the following reagents: triphosgene (2.21g, 7.75mmol); 4- methoxy-3- (4-methylpiperazin-1-yl) aniline (4.94g, 22.36mmol); pyridine (1.81mlx2.22.36mmolx2); l - (/ er / -butyloxycarbonyl) piperazine (4.16g, 22.36mmol); dichloromethane (200ml).
  • Compound 7b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 7a (9.55g, 22mmol); trifluoroacetic acid (15ml), dichloromethane (150ml). After neutralization of the trifluoroacetic acid, the two phases are evaporated under reduced pressure then the crude product obtained is filtered on silica with a mixture (60/40/1) of dichloromethane / methanol / ammonia.
  • Compound 7 is prepared according to the procedure described for compound 6a from the following reagents: compound 7b (587mg, 1.76mmol); l-bromo-3-phenylpropane (330ml, 2.1 lmmol); cesium carbonate (860mg, 2.64mmol); dimethylformamide (20ml). the crude is purified by flash chromatography with a mixture (91/9/1) of (dichloromethane / methanol / ammonia). Two products are isolated.
  • Chloroacetyl chloride (2.42ml, 30.4mmol) is added dropwise to a solution of l - / ert-butyloxycarbonylpiperazine (5.15g, 27.6mmol) and calcium carbonate (8.34g, 83.4mmol) in methyl ethyl ketone (60ml) cooled to 0 ° C.
  • the reaction mixture is stirred at this temperature for 1 h 30 then it is filtered through Celite. Celite is rinsed several times with ethyl acetate and a 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulfate, filtered and concentrated to give the expected product.
  • Compound 8c is prepared according to the same procedure as that described for compound 2b from the following reagents compound 8b (1.95g, 5.07mmol); trifluoroacetic acid (5.0ml), dichloromethane (25ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 8d is prepared according to the procedure described for compound 3a from the following reagents: compound 8c (515mg, 2.08mmol); lithium aluminum hydride (3.1 ml of a 1M solution in tetrahydrofuran, 3. lmmol); ethyl ether (10ml). The reaction lasts 3 hours. The reaction crude is used as is in the next step.
  • Compound 11 is prepared according to the procedure described for compound 2a from the following reagents: compound 7b (500mg, 1.5mmol); 2,3-dimethylbenzoic acid (220mg, 1.5mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (290mg, 1.5mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (20ml). The reaction lasts 2 hours. The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 13 is prepared according to the procedure described for compound 1 from the following reagents: compound 7b (604 mg, 1.81 mmol); 5,6,7,8-tetrahydronaphthylamine (301mg, 2.0mmol); triphosgene (202mg, 0.68mmol); pyridine (162mlx2,1.81mmolx2); dichloromethane (60ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 15a is prepared according to the procedure described for compound 6a from the following reagents: bromomethyl-2-naphthylketone (5g, 20mmol); piperazine (8.6g, 2.100mmol); cesium carbonate (9.8g, 30mmol); dimethylformamide (200ml). the crude product is purified by flash chromatography with a mixture (85/1 5/1) and then (80/1 8/2) of dichloromethane / methanol / ammonia.
  • Compound 15 is prepared according to the procedure described for compound 1 from the following reagents: compound 15a (588 mg, 2.3 1 mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (490 mg, 2.31 mmol); triphosgene (250mg, 0.84mmol); pyridine (200mlx2,2.53mmolx2); dichloromethane (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia. Mass obtained: 248 mg (Yield: 21%)
  • Compound 16 is prepared according to the procedure described for compound 1 from the following reagents: 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (457 mg, 2.07 mmol); 1-benzylpiperazine (364mg, 2.07mmol); triphosgene (205mg, 0.69mmol); triethylamine (290mlx2.2.07mmolx2); dichloromethane (40ml).
  • the crude reaction product is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia. Mass obtained: 776 mg (Yield: 89%)
  • Compound 17 is prepared according to the procedure described for compound 1 from the following reagents: 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (398 mg, 1.80 mmol); 4-fluorobenzyloxopiperidine (608 mg, 2.93 mmol); triphosgene (180mg, 0.60mmol); pyridine (150mlx2, 1.80mmolx2); dichloromethane (40ml). The crude reaction is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 18 is prepared according to the procedure described for compound 1 from the following reagents 4-methoxy-3- (4- methylpiperazin-1-yl) aniline (480mg, 2.17mmol); benzylpiperidine (382ml, 2.17mmol); triphosgene (215mg, 0.72mmol); triethylamine (300mlx2.2.17mmolx2); dichloromethane (40ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 19 is prepared according to the procedure described for compound 1 from the following reagents 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (516 mg, 2.33 mmol); 4- (3-phenylpropan-1 - yl) piperidine (473mg, 2.33mmol); triphosgene (231mg, 0.78mmol); triethylamine (330mlx2,2.33mmolx2); dichloromethane (40ml). The crude reaction product is purified by flash chromatography with a mixture (94/6/1) of dichloromethane / methanol / ammonia.
  • Compound 20 is prepared according to the procedure described for compound 1 from the following reagents: 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (375 mg, 1.70 mmol); compound 20a (380mg, 1.76mmol); triphosgene (168mg, 00.57mmol); triethylamine (235mlx2.1.70mmolx2); dichloromethane (40ml).
  • the crude reaction product is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 21 is prepared according to the procedure described for compound 1 from the following reagents 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (665mg, 3.00mmol); compound 21a (680mg, 3.15mmol); triphosgene (297mg, 3.00mmol); triethylamine (243mlx2.3.00mmolx2); dichloromethane (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • the dihydrochloride monohydrate of l -benzyl-4-aminopiperidine (9g, 34mmol) is desalted and then dissolved in dichloromethane (70ml) in the presence of triethylamine (7.13ml, 51mmol). This is cooled in an ice bath and then the benzoyl chloride (3.74ml, 40mmol) is added slowly. The reaction mixture is then brought to ambient temperature, stirred for Omn and then poured onto an ice bath. The pH of the aqueous phase is brought to ⁇ 1 1 with a dilute sodium hydroxide solution and then the phases are separated. The organic phase is washed with a saturated sodium chloride solution before being dried over magnesium sulfate, filtered and concentrated.
  • Compound 22 is prepared according to the procedure described for compound 1 from the following reagents 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (433 mg, 1.96 mmol); compound 22b (400mg, 1.96mmol); triphosgene (210mg, 0.72mmol); pyridine (170mlx2.2.15mmolx2); dichloromethane (60ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 23a is prepared according to the same procedure as that described for compound 2a from the following reagents: (2-fluorophenyl) acetic acid
  • Compound 23b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 23a (9.49g, 29.5mmol); trifluoroacetic acid (20ml), dichloromethane (200ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia. Mass obtained: 4.63g (YId: 71%)
  • Compound 23c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 23b (3.53g, 15.9mmol); lithium aluminum hydride (25 ml of an IM solution in ethyl ether, 25 mmol); ethyl ether (50ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 23 is prepared according to the procedure described for compound 1 from the following reagents: triphosgene (371mg, 1.25mmol); 4- methoxy-3- (4-methylpiperazin-1-yl) aniline (828mg, 3.75mmoI); pyridine
  • the crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • a solution of diethylazodicarboxylate (8.7ml; 20.91mmol; 40% in toluene) diluted in tetrahydrofuran (20ml) is added dropwise to a solution of l-benzyl-4-hydroxypiperidine (4.0g, 20.92mmol), phenol ( 1.95g, 20.92mmol) and triphenylphosphine (5.48g, 20.89mmol) in tetrahydrofuran (50ml).
  • the reaction mixture is stirred for 43 h then it is poured onto ice and extracted three times with ethyl acetate.
  • the combined organic phases are then washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
  • Reaction crude is impregnated on silica and then purified by flash chromatography with a mixture (50/50/0) and then (50/50/5) of petroleum ether / ethyl acetate / ethanol
  • Compound 24b is prepared according to the procedure described for compound 22b from the following reagents: compound 24a (4.14g, 15.5mmol); palladium hydroxide (300mg); acetic acid (50ml); methanol (160ml). The crude reaction product is purified by flash chromatography with a mixture (70/30/1) and then (60/40/1) of petroleum ether / ethanol / ammonia.
  • Compound 24 is prepared according to the procedure described for compound 1 from the following reagents: 4-methoxy-3- (4-methylpiperazin-1-yl) aniline 5 (500mg, 2.26mmol); compound 24b (400mg, 2.26mmol); triphosgene (225mg, 0.76mmol); pyridine (175mlx2.2.26mmolx2); dichloromethane (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Crude reaction is impregnated on silica and purified by flash chromatography with a mixture (70/50/5/1) and then (70/50/10/1) of petroleum ether / ethyl acetate / ethanol / ammonia.
  • Compound 25b is prepared according to the procedure described for compound 22b from the following reagents: compound 25a (3.43g, 12.0mmol); palladium hydroxide (440mg); acetic acid (40ml); methanol (160ml). The crude reaction product is purified by flash chromatography with a gradient from (90/10) to (100/0) of (dichloromethane / methanol).
  • Compound 25 is prepared according to the procedure described for compound 1 from the following reagents: 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (500mg, 2.26mmol); compound 25b (400mg, 2.26mmol); triphosgene (225mg, 0.76mmol); pyridine (315mlx2.4.01mmolx2); dichloromethane (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 28 is prepared according to the procedure used for compound 27 from the following reagents: 1-naphthylsulfonyl chloride (671mg, 296mmol); compound 7b (493mg, 1.48mmol); IN sodium hydroxide solution (1.5ml); dichloromethane (5ml). The crude reaction product is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 29a is prepared according to the procedure described for compound 24a from the following phenol reagents (2.28g, 24.25mmol); 4-hydroxymethylpiperidine (2.5g, 24.25mmol); diethylazodicarboxylate (11ml; 24.25mmol; 40% in toluene); triphenylphosphine (6.36g, 24.25mmol); tetrahydrofuran (70ml).
  • the crude reaction product is purified by flash chromatography with a mixture (95/5/1) and then (50/50/5) of dichloromethane / methanol / ammonia.
  • Compound 29 is prepared according to the procedure described for compound 1 from the following reagents: 4-methoxy-3- (4-methyIpiperazin-1-yl) aniline (255mg, 1.15mmol); compound 29a (220mg, 1.15mmol); triphosgene (114mg, 0.76mmol); pyridine (90mlx2,1.15mmolx2); dichloromethane (40ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • N-benzylpiperidone (9.45ml, 53.0mmol) in tetrahydrofuran (50ml) is added dropwise to a solution of LDA (prepared from diisopropylamine (7.95ml, 58.3mmol) and butyllithium (36.5ml 1.6M solution in hexane, 58.3mmmmol)) in tetrahydrofuran (50ml) at -78 ° C.
  • LDA prepared from diisopropylamine (7.95ml, 58.3mmol) and butyllithium (36.5ml 1.6M solution in hexane, 58.3mmmmol)
  • tetrahydrofuran 50ml
  • the reaction mixture is stirred for 30 minutes at -78 ° C. and then a solution of N-phenyltrifluoromethanesulfonimide (20g, 56mmol) in tetrahydrofuran (50ml) is cann
  • Compound 30b l-benzyl-4-phenvlethvnyI-1,2,3,6-tetrahydropyridine
  • a solution of compound 30a (6g, 18.7mmol); phenylacetylene (3.1ml, 28.05mmol); triethylamine (5.1ml, 36.9mmol) and dichloro-bw-triphenylphosphinepalladium (300mg) in dimethylformamide (75ml) is heated to 75 ° C for 1 hour 30 minutes under an argon atmosphere. After this time, the dimethylformamide is evaporated under vacuum and then the reaction crude is taken up in water and extracted three times with ethyl acetate.
  • Compound 30 is prepared according to the procedure described for compound 5 from the following reagents: 4-chloro-3- (4-methylpiperazin-1-yl) phenol (720mg, 3.17mmol); compound 30c (780mg, 3.17mmol); sodium hydride (50%, 167mg, 3.48mmol); tetrahydrofuran (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.
  • Compound 31a is prepared according to the procedure described for compound 30a from the following reagents: 1- / ert-butoxycarbonylpiperidone (20.0g, 100.4mmol); diisopropylamine (8.08ml, HOmmol); butyllithium (68.8ml of a 1.6M solution in hexane, 1 10mmol); N-phenyltrifluoromethanesulfonimide (38.2g, 107mmol); tetrahydrofuran (300ml).
  • the crude reaction product is purified by rapid chromatography on a neutral alumina column with a mixture (90/10) of petroleum ether / ethyl acetate.
  • Compound 31b is prepared according to the procedure described for compound 30b from the following reagents: compound 31a (4g, 10.3mmol); phenylacetylene (1.73ml, 15.7mmol); triethylamine (5.0ml, 36.1mmol); dichloro-b / s- triphenylphosphinepalladium (170mg); dimethylformamide (40ml).
  • compound 31a (4g, 10.3mmol); phenylacetylene (1.73ml, 15.7mmol); triethylamine (5.0ml, 36.1mmol); dichloro-b / s- triphenylphosphinepalladium (170mg); dimethylformamide (40ml).
  • the crude product obtained is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.
  • Compound 31d is prepared according to the procedure used for compound 2b from the following reagents; compound 31c (830mg, 2.87mmol); trifluoroacetic acid (2.8ml); dichloromethane (15ml). The crude reaction product is purified by flash chromatography with a gradient from (90/10/1) to (0/100/1) of dichloromethane / methanol / ammonia.
  • Compound 31 is prepared according to the procedure described for compound 1 from the following reagents: 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (515mg, 2.33mmol); compound 31d (440mg, 2.33mmol); triphosgene (230mg, 0.77mmol); pyridine (180mlx2.2.33mmolx2); dichloromethane (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of i o dichloromethane / methanol / ammonia.
  • Compound 32a is prepared according to the procedure used for compound 2a from the following reagents: aniline (2ml, 21.8mmol); ⁇ -tert-butyloxycarbonylpiperidine-4-carboxylic acid (5g, 21.8mmol); triethylamine
  • Compound 32b is prepared according to the procedure used for compound 2b from the following reagents: compound 32a (6.05g, 19.9mmol); acid trifluoroacetic (20ml); dichloromethane (100ml). The reaction crude is directly engaged in the next step.
  • Compound 32 is prepared according to the procedure described for compound 1 from the following reagents: 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (2.67 g, 12.1 mmol); compound 32b (2.47g, 12.1mmol); triphosgene (1.2g, 4.05mmol); pyridine (935mlx2,12.1mmolx2); dichloromethane (135ml).
  • the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 33 is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 32 (500 mg, 1.1 mmol); lithium aluminum hydride (1.8 ml of an IM solution in tetrahydrofuran, l . ⁇ mmol); tetrahydrofuran (10ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 30 (540mg, 1.24mmol) is hydrogenated (31 PSI) on Lindlar palladium (130mg) in solution in ethanol (25ml) and in the presence of quinoline (520ml). After 24 hours, the reaction mixture is filtered through celite and then purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
  • Compound 35a is prepared according to the same procedure as that described for compound 2a from the following reagents: (2-methoxyphenyl) acetic acid (3.0g, 18.05mmol); l- / e / 7-butyloxycarbonylpiperazine (3.36g, 18.05mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.46g, 18.05mmol); triethylamine (1.32ml, 18.05mmol); 4- dimethylaminopyridine (a tip of a spatula); dichloromethane (60ml).
  • the crude reaction product is purified by flash chromatography with a mixture (5/5) of ethyl acetate / petroleum ether. Mass obtained: 4.78g (YId: 79%)
  • Compound 35b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 35a (2.0g, 5.08mmol); trifluoroacetic acid (5ml); dichloromethane (30ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
  • Compound 35c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 35b (1.40g, 5.98mmol); lithium aluminum hydride (9ml of an IM solution in tetrahydrofuran, 9mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 35 is prepared according to the procedure described for compound 1 from the following reagents: triphosgene (225mg, 0.76mmol); 4- methoxy-3- (4-methylpiperazin-1-yl) aniline (500mg, 2.26mmol); pyridine (180 ⁇ lx2,2.26mmolx2); l- (2-methoxyphenethyi) piperazine (35c) (497mg, 2.26mmol); dichloromethane (50ml).
  • the crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
  • Compound 36a is prepared according to the same procedure as that described for compound 2a from the following reagents: (3,4,5-trimethoxyphenyl) acetic acid (2.0g, 8.88mmol); l- / er / -butyloxycarbonyl-piperazine (1.65g, 8.88mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.70g, 8.88mmol); triethylamine (0.65ml, 8.88mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (60ml).
  • the crude reaction product is purified by flash chromatography with a mixture (5/5) of ethyl acetate / petroleum ether.
  • Compound 36b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 36a (3.40g, 8.63mmol); trifluoroacetic acid (9ml); dichloromethane (50ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
  • Compound 36c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 36b (2.30g, 7.82mmol); lithium aluminum hydride (12ml of an IM solution in tetrahydrofuran, 12mmol); tetrahydrofuran (30ml). The crude is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
  • Compound 37a is prepared according to the same procedure as that described for compound 2a from the following reagents: 2-naphthylacetic acid (1.0g, 5.37mmol); l- / er / -butyloxycarbonylpiperazine (1.0g, 5.37mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.03g, 5.37mmol); triethylamine (0.39ml, 5.37mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (5/5 / 0.1) of ethyl acetate / petroleum ether / ammonia.
  • Compound 37b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 37a (1.63g, 4.60mmol); trifluoroacetic acid (5ml); dichloromethane (20ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia. Mass obtained: 1.15g (Yield: 98%)
  • Compound 37c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 37b (1.15g, 4.52mmol); lithium aluminum hydride (7 ml of an IM solution in tetrahydrofuran, 7 mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.
  • Compound 37 is prepared according to the same procedure as that described for compound 36 from the following reagents: compound 37c (0.50g, 2.08mmol); butyllithium (1.6ml of a 1.6M solution in hexane, 2.50mmol); compound 36d (0.67g, 2.08mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia. Mass obtained: 0.67g (Yield: 66%)
  • Compound 38a is prepared according to the same procedure as that described for compound 2a from the following reagents: 1-naphthylacetic acid (1.0g, 5.37mmol); l-ter / -butyloxycarbonylpiperazine (1.0g, 5.37mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.03g, 5.37mmol); triethylamine (0.39ml, 5.37mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (5/5 / 0.1) of ethyl acetate / petroleum ether / ammonia.
  • Compound 38b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 38a (1.58g, 4.46mmol); trifluoroacetic acid (4.5ml); dichloromethane (20ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
  • Compound 38c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 38b (0.92g, 3.62mmol); lithium aluminum hydride (5.5ml of an IM solution in the tetrahydrofuran, 5.5mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
  • Compound 38 is prepared according to the same procedure as that described for compound 36 from the following reagents: compound 38c (0.21g, 0.88mmol); butyllithium (0.7ml of a 1.6M solution in hexane, 1.06mmol); compound 36d (0.28g, 0.88mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (93/7/1) of dichloromethane / methanol / ammonia.
  • Compound 39a is prepared according to the same procedure as that described for compound 2a from the following reagents: (2,3-difluorophenyl) acetic acid (1.0g, 5.81mmol); l- / ert-butyloxycarbonylpiperazine (1.08g, 5.81mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1 lg, 5.81mmo ⁇ ); triethylamine (0.43ml, 5.81mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (25ml).
  • the crude reaction product is purified by flash chromatography with a mixture (5/5 / 0.1) of ethyl acetate / petroleum ether / ammonia.
  • Compound 39b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 39a (1.51g, 4.44mmol); trifluoroacetic acid (5ml); dichloromethane (20ml). The crude is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.
  • Compound 39c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 39b (0.88g, 3.66mmol); lithium aluminum hydride (5.5 ml of an IM solution in tetrahydrofuran, 5.5 mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (94/6/1) of dichloromethane / methanol / ammonia.
  • Compound 39 is prepared according to the same procedure as that described for compound 36 from the following reagents: compound 39c (0.14g, 0.62mmol); butyllithium (0.5ml of a 1.6M solution in hexane, 0.74mmol); compound 36d (0.20g, 0.62mmol); tetrahydrofuran (10ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia. Mass obtained: 0.1 lg (Yield: 38%)
  • Compound 40a is prepared according to the same procedure as that described for compound 2a from the following reagents (4-trifluoromethylphenyl) acetic acid (1.0g, 4.90mmol); 1-ter / -butyloxycarbonyl-piperazine (0.91g, 4.90mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.94g, 4.90mmol); triethylamine (0.34ml, 4.90mmol); 4- dimethylaminopyridine (a tip of a spatula); dichloromethane (50ml).
  • the crude reaction product is purified by flash chromatography with a mixture (5/5 / 0.1) of ethyl acetate / petroleum ether / ammonia.
  • Compound 40b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 40a (1.44g, 3.87mmol); trifluoroacetic acid (4ml); dichloromethane (20ml). The crude is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.
  • Compound 40c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 40b (1.0g, 3.68mmol); lithium aluminum hydride (5.5ml of an IM solution in the tetrahydrofuran, 5.5mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (94/6/1) of dichloromethane / methanol / ammonia.
  • Compound 40 is prepared according to the same procedure as that described for compound 36 from the following reagents: compound 40c (0.37g, 1.43mmol); butyllithium (1.08ml of a 1.6M solution in rhexane, 1.72mmol); compound 36d (0.46g, 1.43mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (92/8/1) of dichioromethane / methanol / ammonia.
  • Compound 41a is prepared according to the same procedure as that described for compound 2a from the following reagents: (2-fluoro-3-trifluoromethylphenyl) acetic acid (3.0 g, 13.51 mmol); 1 - / er / -buty loxycarbonyl-piperazine (2.52g, 13.51 mmol); 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride (2.59g, 13.51mmol); triethylamine (1.80ml, 13.51mmol); 4- dimethylaminopyridine (a tip of a spatula); dichloromethane (60ml).
  • the crude reaction product is purified by flash chromatography with a mixture (4/6) of ethyl acetate / petroleum ether.
  • Compound 41b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 41a (4.69g, 12.02mmol); trifluoroacetic acid (13ml); dichloromethane (50ml). The crude is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.
  • Compound 41c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 41b (2.71g, 9.36mmol); lithium aluminum hydride (14 ml of an IM solution in ether, 14 mmol); ether (50ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
  • Compound 41 is prepared according to the same procedure as that described for compound 36 from the following reagents: compound 41c (1.16g, 3.62mmol); butyllithium (2.7ml of a 1.6M solution in hexane, 4.34mmol); compound 36d (1.0g, 3.62mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia. Mass obtained: 1.1 1g (Yield: 59%)
  • Compound 42a is prepared according to the same procedure as that described for compound 2a from the following reagents: phenylacetic acid (1.0g, 7.35mmol); 1-tert-butyloxycarbonylhomopiperazine (1.47g, 7.35mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.41g, 13.51mmol); triethylamine (0.54ml, 7.35mmol); 4-dimethylamino-pyridine (a tip of a spatula); dichloromethane (60ml).
  • the crude reaction product is purified by flash chromatography with a mixture (5/5 / 0.1) of ethyl acetate / petroleum ether / ammonia.
  • Compound 42b is prepared according to the same procedure as that described for compound 2b from the following reagents: compound 42a (1.76g, 5.53mmol); trifluoroacetic acid (6ml); dichloromethane (20ml). The crude is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.
  • Compound 42c is prepared according to the same procedure as that described for compound 3a from the following reagents: compound 42b (1.01g, 2.63mmol); lithium aluminum hydride (7ml of an IM solution in tetrahydrofuran, 14mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.
  • Compound 42 is prepared according to the same procedure as that described for compound 36 from the following reagents: compound 42c (0.40g, 1.56mmol); butyllithium (1.2ml of a 1.6M solution in hexane, 1.87mmol); compound 36d (0.63g, 1.56mmol); tetrahydrofuran (20ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
  • the derivatives of the present invention are potent 5HTi £> receptor antagonists as shown by the linkage studies and the antagonism studies of the inhibition of adenylate cyclase (stimulated by forskolin) by a 5HTi £> agonist than serotonin, sumatriptan or 5-CT, studies which have been carried out at the level of human receptors cloned 5HT] £) ⁇ and 5HTiD ⁇ .
  • the human receptors 5HT ⁇ rj a and 5HTi £) b were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40,143 (1991) and Weinshenk et al., Proc. Natl. Acad. Sci. 89.3630 (1992). Transient transfection and permanent transfection of the genes for these receptors was carried out in Cos-7 and CHO-Kj cell lines using an electroporator.
  • the HeLa HA7 cell line expressing the human 5HTj ⁇ receptor was obtained from Tulco (Duke Univ., Durham, N.C., USA) and cultivated according to the method of Fargin et al., J. Biol. Chem. 264.14848 (1989).
  • the incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand [3H] -5CT (final concentration: 2nM) for the 5HTi £> a and 5HTiDb and [3H] receptors -80H-DPAT (final concentration: 1 nM) for the SHTIA receptor and 0.05 ml of the test molecule (final concentrations from 0.1 nM to 1000 nM) or 10 ⁇ M (final concentration) of seretonin (5HT i D a and HT i Db) OR 1 U M (final concentration) of spiroxatrine (5 HT IA).
  • the new compounds derived from aryl piperazines which are part of the present invention are powerful and selective antagonists of the 5HT receptors ⁇ o and have the advantage of being particularly selective for the 5HT receptors i £) human in particular compared to the 5HT receptors j ⁇ ,
  • the derivatives of the present invention are further capable of inhibiting the contraction induced by 5-hydroxytryptamine in the rabbit saphenous vein rings and of antagonizing the inhibition induced by 5-carboxamidotryptamine (5CT) at the level of release. of serotonin in guinea pig brain slices.
  • 5-carboxamidotryptamine 5CT
  • the comparison described above demonstrates, by way of illustration, that the products of the present invention have the advantage of having better affinity and better selectivity in particular with respect to the 5 HT IA receptor, at the receptor level. 5 HT IQ and in particular at the 5HT i D a receptor.
  • the derivatives of the present invention are also capable of controlling the growth and proliferation of type C ⁇ glial cells transfected by the 5HT i £> ⁇ receptor gene and by the 5HT ⁇ rj a receptor gene stimulated by a hormonal mediator such as serotonin.
  • the examples of the present invention inhibit the incorporation of labeled thymidine (stimulated with 0.1 ⁇ M sumatriptan) with an IC 50 of 10 to 100 nM (method described by P. Pauwels et al., J . of Neurochemistry, in press).
  • the derivatives of the present invention therefore also find their utility in the treatment of cancers and other disorders linked to cell proliferation.
  • compositions containing, as active ingredients, a compound of general formula (I) or a physiologically acceptable salt of a compound of formula (I) associated with one or more agents therapeutic agents, such as, for example antidepressant agents such as tricyclic antidepressants (eg amitryptyline, clomipramine, desipramine, imipramine), monoamine oxidase inhibitors (eg isocarboxazide, moclobemide, phenelzine or tranylcyclopramine), inhibitors of re- serotonin uptake (e.g.
  • antidepressant agents such as tricyclic antidepressants (eg amitryptyline, clomipramine, desipramine, imipramine), monoamine oxidase inhibitors (eg isocarboxazide, moclobemide, phenelzine or tranylcyclopramine), inhibitors of re- serotonin uptake (e.g.
  • fluvoxamine fluvoxamine, sertraline, fluoxetine, paroxetine or citalopram
  • serotonin and norepinephrine re-uptake inhibitors e.g. milnacipran
  • 0: 2 antagonists mimetics of a compound that can be used to treat a wide range of diseases and conditions.
  • the derivatives of the present invention or their physiologically acceptable salts can also be administered in the form of pharmaceutical compositions, in combination with a 5 -HT JA receptor antagonist.
  • a 5 -HT JA receptor antagonist such as, for example, pindolol, WAY 1001 35, UH-30 1 or WAY 100635. This association is also part of the present invention.
  • the present invention also relates to pharmaceutical compositions containing as active ingredient a compound of general formula I or one of its acceptable salts for pharmaceutical use, mixed or associated with a suitable excipient.
  • These compositions can take, for example, the form of solid, liquid compositions, emulsions, lotions or creams.
  • compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
  • the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon.
  • inert diluents such as starch, cellulose, sucrose, lactose or silica
  • These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
  • compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
  • inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
  • These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
  • the sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
  • solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents can be used.
  • These compositions may also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
  • compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
  • the doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 0.001 g and 1 g (preferably between 0.005 g and 0.25 g) per day, preferably orally for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance , preferably from 1 mg to 50 mg. In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
  • the following examples illustrate compositions according to the invention [in these examples, the term "active component" designates one or more (generally one) of the compounds of formula (I) according to the present invention]:
  • They can be prepared by direct compression or by passing through wet granulation.
  • the direct compression procedure is preferred but it may not be suitable in all cases depending on the doses and the physical properties of the active component.
  • the active component is passed through a sieve with a mesh opening of 250 ⁇ m on a side, it is mixed with the excipients and it is compressed using 6.0 mm punches. Tablets with other mechanical strengths can be prepared by varying the compression weight with the use of appropriate punches.
  • the active component is passed through a sieve with a mesh opening of 250 ⁇ m and mixed with lactose, starch and pregelatinized starch.
  • the mixed powders are moistened with purified water, they are granulated, dried, sieved and mixed with magnesium stearate.
  • the lubricated granules are put into tablets as for the formulas by direct compression.
  • a coating film can be applied to the tablets using suitable film-forming materials, for example methylcellulose or hydroxypropyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated.
  • the active component is passed through a 250 ⁇ m mail opening sieve and mixed with the other substances.
  • the mixture is introduced into hard gelatin capsules No. 2 on an appropriate filling machine.
  • Other dosage units can be prepared by changing the filling weight and, if necessary, changing the size of the capsule.
  • the active component, the buffer, the flavor, the color and the preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 80 ° C. and the sucrose is dissolved therein and then cooled. The two solutions are combined, the volume is adjusted and mixed. The syrup obtained is clarified by filtration.
  • a suspension of the active component in Witepsol H 1 5 is prepared and it is introduced into an appropriate machine with suppository molds of 1 g. Liquid for administration by intravenous injection
  • Sodium chloride can be added to adjust the tone of the solution and adjust the pH to maximum stability and / or to facilitate the dissolution of the active component by means of a dilute acid or alkali or by adding buffer salts. appropriate.
  • the solution is prepared, clarified and introduced into suitable size vials which are sealed by melting the glass.
  • the liquid can also be sterilized for injection by heating in an autoclave according to one of the acceptable cycles.
  • the solution can also be sterilized by filtration and introduced into a sterile ampoule under aseptic conditions.
  • the solution can be introduced into the ampoules in a gaseous atmosphere.
  • the active component is micronized in a fluid energy mill and made into fine particles before mixing with lactose for tablets in a high energy mixer.
  • the powder mixture is introduced into hard gelatin capsules No. 3 on an appropriate encapsulating machine.
  • the contents of the cartridges are administered using a powder inhaler. Pressure aerosol with metering valve
  • mg / dose for 1 can micronized active component 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for pharmaceutical use 22.25 5.34 g dichlorodifluoromethane for pharmaceutical use 60.90 14.62 g
  • the active component is micronized in a fluid energy mill and put into the state of fine particles.
  • the oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C and the micronized drug is introduced into the solution using a mixer with a high shearing effect.
  • the suspension is introduced in measured quantity into aluminum aerosol cans on which are fixed appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the boxes by injection through the valves.

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EP97902427A 1996-02-02 1997-02-03 Neue aromatische piperazinederivate von substituierten cykloazanen, verfahren zu ihrer herstellung, ihre pharmazeutische zubereitungen und ihre anwendung als medikament Withdrawn EP0880512A1 (de)

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FR9601273A FR2744449B1 (fr) 1996-02-02 1996-02-02 Nouvelles piperazines aromatiques derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
FR9601273 1996-02-02
PCT/FR1997/000203 WO1997028141A1 (fr) 1996-02-02 1997-02-03 Nouvelles piperazines aromatiques derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments

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FR2744449A1 (fr) 1997-08-08
FR2744449B1 (fr) 1998-04-24
AU1607497A (en) 1997-08-22
JP2000505795A (ja) 2000-05-16
MX9806255A (es) 1998-11-29
CN1214047A (zh) 1999-04-14
BR9707251A (pt) 1999-04-06
WO1997028141A1 (fr) 1997-08-07

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