WO1997028141A1 - Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs - Google Patents

Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs Download PDF

Info

Publication number
WO1997028141A1
WO1997028141A1 PCT/FR1997/000203 FR9700203W WO9728141A1 WO 1997028141 A1 WO1997028141 A1 WO 1997028141A1 FR 9700203 W FR9700203 W FR 9700203W WO 9728141 A1 WO9728141 A1 WO 9728141A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
dichloromethane
mixture
methanol
Prior art date
Application number
PCT/FR1997/000203
Other languages
French (fr)
Inventor
Serge Halazy
Catherine Jorand-Lebrun
Peter Pauwels
Philippe Chopin
Marc Marien
Original Assignee
Pierre Fabre Medicament
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pierre Fabre Medicament filed Critical Pierre Fabre Medicament
Priority to AU16074/97A priority Critical patent/AU1607497A/en
Priority to EP97902427A priority patent/EP0880512A1/en
Priority to CA 2245718 priority patent/CA2245718A1/en
Priority to BR9707251A priority patent/BR9707251A/en
Priority to JP9527377A priority patent/JP2000505795A/en
Publication of WO1997028141A1 publication Critical patent/WO1997028141A1/en

Links

Classifications

    • 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
    • C07D295/205—Radicals derived from carbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D211/08—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
    • 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
    • C07D211/08—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
    • 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
    • C07D211/08—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
    • 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
    • C07D211/08—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
    • 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
    • C07D211/40—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
    • C—CHEMISTRY; METALLURGY
    • 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.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Addiction (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Compounds of formula (I), wherein R1 is hydrogen or straight or branched C1-6 alkyl, Z2 is O, NH, CH2O or CH2NH, each of R2 and R3, which are the same or different, is hydrogen or a group selected from straight or branched alkyl, alkoxy, thioether, nitrile, trifluoromethyl or halogen (F, Cl, Br, I), or, when they are adjacent, R2 and R3, taken together, form a 5- or 6-membered ring in order to form, e.g., naphthyl, tetrahydronaphthyl, benzopyrane or benzodioxane, X-Y is NCH2, CH-CH2, C=CH, N or NCH2CH2, and Z1 is -(CH2)n, -(CH2)n CO-, -CO-, -CO(CH2)n-, -SO2-, -SO2(CH2)n-, -O(CH2)n-, -O(CH2)nCO-, -OCO-, -NH(CH2)n-, -NH(CH2)nCO-, -NHCO-, -NHCO(CH2)n-, -NH(CH2)nSO2-, -NHSO2-, -NHSO2(CH2)n-, -CH=CHCO-, -CCCO- -(CH2)nSO2-, -O(CH2)nSO2-.

Description

NO U V EL LES PI P ERAZINE S A ROMA TI QU ES DÉRI VÉES DE CYCLOAZ AN ES SUBSTITUES , A INSI QUE LEUR PROCEDE DE PREPARATION , LES COM POSIT I ON S PH A RMA CEUTIQU ES ET LEUR UTI L I SATION COMME MEDI CAMENTS N U V EL ROMA TI P P ERAZIN S DERIVED FROM SUBSTITUTED CYCLOAZ AN ES, AS WELL AS THEIR PREPARATION PROCESS, THE PH A RMA CEUTICAL COM POSIT I ONS AND THEIR USE AS MEDI CAMENTS
La présente invention se rapporte à de nouvelles piperazines aromatiques dérivées de cycloazanes substitués, ainsi qu'à leur procédé de préparation, les compositions pharmaceutiques les contenant et leur utilisation comme médicaments.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.
La sérotonine ou 5-hydroxytryptamine (5-HT) est un neurotransmetteur et un neuromodulateur impliqué dans de nombreux processus physiologiques et pathologiques. La sérotonine joue un rôle important tant au niveau du système nerveux qu'au niveau des systèmes cardiovasculaires et gastro-intestinaux. Au niveau central, la sérotonine contrôle des fonctions aussi variées que le sommeil, la locomotion, la prise de nourriture, l'apprentissage et la mémoire, les modulations endocriniennes, le comportement sexuel, la thermorégulation. Dans la moelle, la sérotonine joue un rôle important dans les systèmes de contrôle des afférentes nociceptives périphériques (cf. A . Moulignier, Rev . Neurol. (Paris), 1 50,3- 15 , 1 994).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).
La sérotonine peut jouer un rôle important dans divers types de conditions pathologiques tels que certains désordres psychiatriques (anxiété, dépression, agressivité, attaques de panique, désordres compulsifs obsessionnels, schizophrénie, tendance au suicide), certains désordres neurodégénératifs (démence de type Alzheimer, Parkinsonisme, chorée de Huntington), l'anorexie, la boulimie, les troubles liés à l'alcoolisme, les accidents vasculaires cérébraux, la douleur, la migraine, ou encore les céphalées diverses (R. Glennon, Neurosci . Biobehavioral Reviews, 14,35, 1 990).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).
De nombreuses études pharmacologiques récentes ont mis en évidence la diversité des récepteurs de la sérotonine ainsi que leur implication respective dans ses divers modes d'action (cf. E. Zifa, G. Fillion, Pharm Reviews, 44,401, 1992 ; S. Langer, N. Brunello, G. Racagni, J. Mendelecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications", Karger Ed. (1992) ; B.E. Léonard, Int. Clin. Psycho-pharmacology, 7,13-21 (1992) ; R.W. Fuller; J. Clin. Psychiatry, 53,36-45 (1992) ; D.G. Grahame-Smith, Int. Clin. Psychopharmacology, 6, suppl.4, 6-13, (1992). Ces récepteurs sont subdivisés principalement en 4 grandes classes (5HTι, 5HT2, 5HT3 et 5HT4) qui comportent elles-mêmes des sous-classes telles que les récepteurs 5HTj qui sont divisés principalement en 5HTIA, 5HTJB, 5HTID (cf. G.R. Martin, P. A. Humphrey, Neuropharmacol., 33_,261, 1994 ; P.R. Saxena, Exp. Opin. Invest. Drugs, 3_(5), 513, 1994). Les récepteurs 5HTJJ) renferment eux-mêmes plusieurs sous-types de récepteurs ; c'est ainsi que les récepteurs 5HTi£,a et 5HTi£)b ont été clones puis identifiés chez l'homme (cf. par exemple E. Hamel et coll., Mol. Pharmacol. ,44,242, 1993 ; G.W. Rebeck et coll., Proc. Natl. Acad. Sci. USA, 9J_,3666, 1994). Par ailleurs, il a été démontré récemment que les récepteurs 5HTιg chez les rongeurs et 5HTi£> chez les autres espèces étaient capables de contrôler la libération de sérotonine dans les terminaisons nerveuses (cf. M. Briley, C. Moret, Cl. Neuropharm. 16,387, 1993 ; B.E. Léonard, Int. Clin. Psychopharmacol., 9,7, 1994) ainsi que la libération d'autres neurotransmetteurs tels que la norepinéphrine, la dopamine ou l'acétylcholine (M. Harrrington, J. Clin. Psychiatry, 53, 10, 1992).Numerous recent pharmacological studies have demonstrated the diversity of serotonin receptors as well as their respective involvement in its various modes of action (cf. E. Zifa, G. Fillion, Pharm Reviews, 44.401, 1992; S. Langer, N. Brunello, G. Racagni, J. Mendelecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications", Karger Ed. (1992); BE Léonard, Int. Clin. Psycho-pharmacology, 7, 13-21 (1992); RW Fuller; J. Clin. Psychiatry, 53, 36-45 (1992); DG Grahame-Smith, Int. Clin. Psychopharmacology, 6, suppl. 4, 6-13, (1992). These receptors are mainly subdivided into 4 main classes (5HTι, 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. Pharmacol., 44,242, 1993; GW Rebeck et al. ., Proc. Natl. Acad. Sci. USA, 9J_, 3666, 1994). Furthermore, it has recently been demonstrated that the 5HTιg receptors in rodents and 5HTi £> in other species are capable of controlling the release of serotonin in the nerve endings (cf. M. Briley, C. Moret, Cl. Neuropharm. 16,387, 1993; BE Léonard, Int. Clin. Psychopharmacol., 9,7, 1994) as well as the release of other neurotransmitters such as norepinephrine, dopamine or acetylcholine (M. Harrrington, J. Clin. Psychiatry, 53, 10, 1992).
Les composés ayant une activité antagoniste sélective au niveau des récepteurs 5HTID centraux tels que les composés nouveaux décrits dans la présente invention peuvent donc exercer un effet bénéfique sur des sujets souffrant de troubles du système nerveux central. En particulier, de tels composés trouvent leur utilité dans le traitement des troubles de la locomotion, de la dépression, de l'anxiété, des attaques de panique, l'agoraphobie, les désordres compulsifs obsessionnels, les désordres de la mémoire incluant la démence, l'amnésie, et les troubles de l'appétit, les dysfonctionnements sexuels, la douleur, la maladie d'Alzheimer, la maladie de Parkinson. Les antagonistes 5HTιrj trouvent également leur utilité dans le traitement des désordres endocriniens tels que l'hyperprolactinémie, le traitement des vasospasmes, de l'hypertension et des désordres gastro¬ intestinaux dans lesquels interviennent des changements au niveau de la motilité et de la sécrétion.Compounds having a selective antagonist activity at the level of the central 5HTID receptors such as the new compounds described in the present invention can therefore exert a beneficial effect on subjects suffering from disorders of the central nervous system. In particular, 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 5HTιrj 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.
Les composés selon la présente invention sont des antagonistes puissants et sélectifs des récepteurs 5HT i £> et plus particulièrement des récepteurs récemment identifiés comme 5HT n)a et 5HT j [)b chez l'homme et de ce fait trouvent leur utilité, seuls ou en association avec d'autres molécules, comme médicaments et plus particulièrement comme moyens thérapeutiques pour le traitement tant curatif que préventif de désordres liés à la sérotonine.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.
L'état antérieur de la technique dans ce domaine est illustré notamment par les brevets EP-0533266, EP-0533267 et EP-0533268, GB- 2273930, WO-9415920, GB-2276160, GB-22761 61 , GB-2276162, GB- 2276163 , GB-22761 64, GB-2276165, WO-9504729, WO-9506044, WO- 9506637, WO-951 1243 et F 9408981 qui décrivent des dérivés aromatiques comme antagonistes 5HTi j), et les publications récentes qui décrivent le GR 127,935 comme antagoniste 5HT i ]} (cf. M. Skingle et coll ., J. of Psychopharm. 8( 1 ), 14, 1994 ; S . Starkey, M. Skingle, Neuropharmacol. , 31,393 , 1994).The prior art in this field is illustrated in particular by patents EP-0533266, EP-0533267 and EP-0533268, GB-2273930, WO-9415920, GB-2276160, GB-22761 61, GB-2276162, GB - 2276163, GB-22761 64, GB-2276165, WO-9504729, WO-9506044, WO- 9506637, WO-951 1243 and F 9408981 which describe aromatic derivatives as 5HTi j) antagonists, and recent publications which describe GR 127,935 as a 5HT antagonist i]} (cf. M. Skingle et al., J. of Psychopharm. 8 (1), 14, 1994; S. Starkey, M. Skingle, Neuropharmacol., 31.393, 1994).
Les dérivés de la présente invention se distinguent de l'art antérieur non seulement par leur structure chimique nouvelle qui les distingue sans ambiguïté des dérivés précédemment décrits mais également par leur profil biologique original, en particulier en ce qui concerne leur sélectivité et leur efficacité comme antagonistes au niveau des sous-types de récepteurs de la sérotonine (5HTi Dα et R) . La présente invention concerne des produits de formule générale (IjThe 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 α and R). The present invention relates to products of general formula (Ij
Figure imgf000006_0001
Figure imgf000006_0001
dans laquellein which
Rj représente un hydrogène ou un alkyle linéaire ou ramifié comprenant deRj represents hydrogen or linear or branched alkyl comprising
1 à 6 atomes de carbone,1 to 6 carbon atoms,
Z2 représente O, NH, CH2O ou CH2NH, R2 et R3 identiques ou différents représentent un hydrogène ou un groupe choisi parmi un alkyle linéaire ou ramifié, un alcoxy, thioether, nitrile, trifluoromethyle ou halogène (F, Cl, Br, I), ou, R2 et R3 , lorsqu'ils sont adjacents, pris ensemble, forment un cycle à 5 ou 6 chaînons façon à constituer par exemple un naphtyle, un tétrahydronaphtyle, un benzopyrane ou un benzodioxane,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,
X-Y représente NCH2, CH-CH2, C=CH, N ou NCH2CH2, Zi représente -(CH2)n-, -(CH2)n c°-> -CO-, -CO(CH2)n-, -SO2-, -S02(CH2)n-, -O(CH2)n-, -O(CH2)nCO-, -OCO-, -NH(CH2)n-, - NH(CH2)nCO-, -NHCO-, -NHCO(CH2)n-, -NH(CH2)nS02-, -NHSO2-, - NHS02(CH2)n-, -CH=CHCO-,-CCCO- -(CH2)nSθ2-, -O(CH2)nSθ2--XY represents NCH2, CH-CH2, C = CH, N or NCH2CH2, Zi represents - (CH2) n -, - (CH2) n c ° -> -CO-, -CO (CH 2 ) n -, -SO2- , -S02 (CH 2 ) n -, -O (CH2) n -, -O (CH 2 ) n CO-, -OCO-, -NH (CH 2 ) n -, - NH (CH2) n CO-, -NHCO-, -NHCO (CH2) n -, -NH (CH2) n S02-, -NHSO2-, - NHS02 (CH2) n -, -CH = CHCO -, - CCCO- - (CH2) n Sθ2-, -O (CH 2 ) n Sθ2--
Dans le cas particulier où X-Y représente CH-CH2, Z i peut également représenter -O-,In the particular case where X-Y represents CH-CH2, Z i can also represent -O-,
-NH-, -CONH-, -SO2NH-, -OCONH-, -NHCOO-, -NHCONH-, -(CH2)nNH-, -(CH2)nO-, -CO(CH2)nNH-, -NH(CH2)nO-, -NH(CH2)nNH-, -O(CH2)nNH-, -O(CH2)nO-, -CO(CH2)nO-, -SO2(CH2)nNH-, -SO2(CH2)nO- , - (CH2)nSO2NH-, -(CH2)nCONH-, -O(CH2)nSO2NH-, -0(CH2)nCONH-, - NH(CH2)nSO2NH-, -NH(CH2)nCONH-, -NHCO(CH2)nNH-,-NH-, -CONH-, -SO2NH-, -OCONH-, -NHCOO-, -NHCONH-, - (CH2) n NH-, - (CH2) n O-, -CO (CH2) n NH-, - NH (CH2) n O-, -NH (CH2) n NH-, -O (CH 2 ) n NH-, -O (CH2) n O-, -CO (CH 2 ) n O-, -SO 2 ( CH2) n NH-, -SO 2 (CH2) n O-, - (CH 2 ) nSO 2 NH-, - (CH 2 ) n CONH-, -O (CH 2 ) n SO 2 NH-, -0 ( CH 2 ) n CONH-, - NH (CH 2 ) n SO 2 NH-, -NH (CH 2 ) n CONH-, -NHCO (CH 2 ) n NH-,
NHS02(CH2)nNH- dans lesquels n représente un nombre entier compris entre 1 et 6, Dans le cas particulier où X-Y représente CH-CH2 ou C=CH> Z l peut également représenter -CH=CH-, -CC-,NHS02 (CH2) n NH- in which n represents an integer between 1 and 6, In the particular case where XY represents CH-CH2 or C = CH > Z l can also represent -CH = CH-, -CC-,
Arj représente un reste aromatique (phenyl, naphtyl ou pyridyl) pouvant être diversement substitué par exemple par un ou plusieurs groupes choisis parmi un alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone, un trifluoromethyle, un trifluorométhoxy, un 2,2,2-trifluoroéthyle, un phényle, un benzyle, un cycloalkyle comprenant de 3 à 7 atomes de carbone, un hydroxyle, un thiol, un alcoxy (OR4), thioether (SR4), un nitro (NO2), un nitrile (CN), une amine (NH2 ou NR4R4'), un dérivé d'aminé (NHCOR4, NHSO2R4, NHCONR4R'4, NHCO2R4, NHS02NR4R'4), un halogène (fluor, chlore, brome ou iode), un carbonyle (COH, COR4, COOR4, CONR4R'4) ou un hétérocycle pouvant éventuellement être substitué tel qu'un hétérocycle à 5 membres pouvant contenir de 1 à 4 héteroatomes choisis parmi l'oxygène, le soufre ou l'azote ou par deux substituants sur des carbones voisins pouvant former un cycle avec le reste aromatique auquel ils sont attachés, ou encore, le reste Ar-Z i représente un tétrahydronaphtyle dont la liaison avec X met en oeuvre un carbone saturé,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) or a heterocycle which can optionally be substituted such as a 5-membered heterocycle which can contain from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen or by two substituents on neighboring carbons which can form a cycle with the aromatic remainder to which they are attached, or the rest Ar-Z i rep has a tetrahydronaphthyl whose bond with X implements a saturated carbon,
R4 représente un reste alkyle, linéaire ou ramifié, comprenant de 1 à 6 atomes de carbone, R'4 représente un hydrogène ou un reste alkyle, linéaire ou ramifié, comprenant de 1 à 6 atomes de carbone et leurs sels hydrates, solvates et bioprécurseurs physiologiquement acceptables pour l'usage thérapeutique.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.
Les isomères géométriques et optiques des composés de formule générale (I) font également partie de la présente invention ainsi que leur mélange sous forme racémique.The 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.
Parmi les sels physiologiquement acceptables des composés de formule générale (I) sont inclus les sels obtenus par addition d'acides organiques ou inorganiques tels que les chlorohydrates, bromhydrates, sulfates, phosphates, benzoates, acétates, naphtoates, p-toluènesulfonates, méthanesulfonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maléates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates.Among the 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.
L'expression "bioprécurseurs" telle qu'elle est utilisée dans la présente invention s'applique à des composés dont la structure diffère de celle des composés de formule (I) mais qui, administrés à un animal ou à un être humain sont convertis dans l'organisme en un composé de formule (I).The expression “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).
Une classe particulièrement appréciée de composés de formule (I) correspond aux composés de formule (la)A particularly appreciated class of compounds of formula (I) corresponds to the compounds of formula (la)
Figure imgf000008_0001
Figure imgf000008_0001
dans laquelle Ar j , Z ] , X-Y, Z2 et K \ sont définis comme dans la formule I et R2 représente un radical CH3 , OCH3 ou un chlore.in which Ar j, Z], X-Y, Z2 and K \ are defined as in formula I and R2 represents a radical CH3, OCH3 or a chlorine.
Les composés de la présente invention peuvent être préparés par différentes méthodes qui seront dépendantes de la nature d'Ar j , Z \ , X, Y, Z2 et R \ .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 \.
On comprendra que dans certaines réactions ou suites de réactions chimiques qui conduisent à la préparation de composés de formule générale (I) il soit nécessaire ou souhaitable de protéger des groupes sensibles éventuels dans les intermédiaires de synthèse afin d'éviter des réactions secondaires indésirables. Ceci peut être réalisé par l'utilisation (introduction et déprotection) des groupes protecteurs conventionnels tels que ceux décrits dans "Protective groups in Organic Synthesis" , T.W. Greene, John Wiley & Sons, 198 1 et "Protecting Groups" , P.J. Kocienski, Thieme Verlag, 1994. Les groupes protecteurs appropriés seront donc introduits et enlevés lors de l'étape la plus appropriée pour ce faire et en utilisant les méthodes et techniques décrites dans les références citées précédemment.It will be understood that in certain reactions or sequences of chemical reactions which lead to the preparation of compounds of general formula (I) it is necessary or desirable to protect possible sensitive groups in the synthesis intermediates in order to avoid undesirable side reactions. This can be achieved by the use (introduction and deprotection) of conventional protective groups such as those described in "Protective groups in Organic Synthesis", TW Greene, John Wiley & Sons, 198 1 and "Protecting Groups", PJ Kocienski, Thieme Verlag, 1994. The appropriate protective groups will therefore be introduced and removed during the most appropriate step to do this and using the methods and techniques described in the references cited above.
Les composés de formule générale (I) dans laquelle Ar j , Z \ , X-Y, R j , R2> R3 sont décrits comme précédemment et Z2 représente -CH2O- ou -CH2NH- sont préparés par condensation d'un intermédiaire de formule (II) :The compounds of general formula (I) in which Ar j, Z \, XY, R j, R2 > R3 are described as above and Z2 represents -CH2O- or -CH2NH- are prepared by condensation of an intermediate of formula (II ):
Figure imgf000009_0001
dans laquelle Ar j , Z \ et X-Y sont définis comme précédemment et Y' représente un groupe partant tel qu'un halogène (chlore, brome ou iode), un tosylate, un mésylate ou un triflate avec une aryl pipérazine de formule générale (III) :
Figure imgf000009_0001
in which 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 ):
Figure imgf000009_0002
Figure imgf000009_0002
dans laquelle X' représente O ou NH et R j , R2 et R3 sont décrits comme précédemment. La condensation des arylpipérazines de formule (III) avec les électrophiles de formule (II) est réalisée en présence d'une base organique ou inorganique telle que NaH, KH, DiPEA, DBU, pyridine, DMAP, K2CO3, CaCθ3 , CS2CO3, en présence éventuellement d'un iodure tel que Nal, KI, BU4NI, dans un solvant anhydre polaire tel que le THF, le DME, le n-butanol, le t-butanol, le DMF, le DMSO, la méthyléthylcétone, à une température comprise entre 20° et 80°. Les intermédiaires de formule générale (II) sont aisément préparés par condensation d'une amine cycl ique de formule générale (IV)in which X 'represents O or NH and R j, R2 and R3 are described as above. The condensation of the arylpiperazines of formula (III) with the electrophiles of formula (II) is carried out in the presence of an organic or inorganic base such as NaH, KH, DiPEA, DBU, pyridine, DMAP, K2CO3, CaCθ3, CS2CO3, in the presence optionally an iodide such as Nal, KI, BU4NI, in a polar anhydrous solvent such as THF, DME, n-butanol, t-butanol, DMF, DMSO, methyl ethyl ketone, at a temperature between 20 ° and 80 °. The intermediates of general formula (II) are easily prepared by condensation of a cyclic amine of general formula (IV)
^~\^ ~ \
ArrZ — X NH ( IV )ArrZ - X NH (IV)
\\
Y- /Y- /
dans laquelle Ar j , Z \ , X-Y sont définis comme précédemment et un chlorure d'acide de formule générale (V) :in which Ar j, Z \, X-Y are defined as above and an acid chloride of general formula (V):
Y' - CH2 - C(0)C1 (V)Y '- CH 2 - C (0) C1 (V)
dans laquelle Y' est décrit comme précédemment en présence d'une base organique ou inorganique telle que la pyridine, la DiPEA, la DMAP, le DBU, K2CO3 , CS2CO3 ou CaCθ3 dans un solvant anhydre aprotique polaire tel que le THF, le DMF, le DME, le DMSO ou la méthyléthylcétone à une température comprise entre - 10° C et 30° C.in which Y 'is described as above in the presence of an organic or inorganic base such as pyridine, DiPEA, DMAP, DBU, K2CO3, CS2CO3 or CaCθ3 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.
Les intermédiaires de formule générale (III) sont préparés par diverses méthodes et techniques bien connues de l'homme de métier pour la préparation des arylpipérazines et dont le choix est dépendant de ia nature de X' et de R \ , R2, R3 - C'est ainsi que, dans le cas particulier où X' est un oxygène, les intermédiaires de formule (III) sont accessibles par condensation d'une arylamine de formule (VI) :The intermediates of general formula (III) are prepared by various methods and techniques well known to those skilled in the art for the preparation of arylpiperazines and the choice of which is dependent on the nature of X 'and R \, R2, R3 - C 'is thus that, in the particular case where X' is an oxygen, the intermediates of formula (III) are accessible by condensation of an arylamine of formula (VI):
(VI)(VI)
Figure imgf000010_0001
dans laquelle R2 et R3 sont définis comme précédemment avec un dérivé d'aminé de formule (VII) :
Figure imgf000010_0001
in which R2 and R3 are defined as above with an amine derivative of formula (VII):
R i -N-(CH2CH2Y)2 (VII)R i -N- (CH 2 CH 2 Y) 2 (VII)
dans laquelle Rj ' est équivalent à R\ tel que défini comme précédemment ou R' i représente un groupe protecteur tel qu'un t-butoxycarbonyle ou un tosyle (qui sera transformé en R ] ultérieurement) et Y représente un chlore, un brome, un iode, un tosylate ou un mesylate. Cette réaction est réalisée préférentiellement dans un solvant anhydre polaire tel que le DMF, l'acétonitrile, le THF, le n-butanol, le t-butanol ou le DMSO, généralement à température de reflux du solvant utilisé, en présence d'une base organique ou inorganique généralement utilisée pour ce type de réaction, telle qu'un carbonate de potassium, de sodium ou de calcium.in which 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.
Les composés de formule générale (III) dans lesquels X' représente NH sont préparés par condensation d'une amine aromatique de formule générale (X)The compounds of general formula (III) in which X 'represents NH are prepared by condensation of an aromatic amine of general formula (X)
Figure imgf000011_0001
Figure imgf000011_0001
dans laquelle R2 et R3 sont définis comme précédemment et X" représente une fonction qui pourra ultérieurement être transformée en amine (telle que par exemple un groupe nitro) soit avec un dérivé de bis(halogénoéthyl)amine de formule (VII) dans les conditions décrites précédemment pour ce type de réaction, soit avec un aminoacide de formule générale (XI)
Figure imgf000012_0001
in which 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)
Figure imgf000012_0001
dans laquelle R' j est défini comme précédemment, en présence d'anhydride acétique, suivi de la réduction de la dicétopipérazine intermédiaire ainsi formée avec par exemple un borane. Dans les deux cas, le dérivé de formule (III) sera finalement obtenu après transformation du groupe représenté par X" en amine. S'il s'agit d'un groupe nitro, cette transformation sera effectuée selon les méthodes et techniques bien connues de l'homme de métier pour transformer un nitroaromatique en un dérivé d'aniline telles que par exemple l'emploi de Nickel de Raney ou de catalyseur au rhodium en présence d'hydrazine, l'hydrogénation sur charbon-palladium à pression atmosphérique, ou encore l'utilisation de SnCl2 ou de zinc.in which R ′ j is defined as above, in the presence of acetic anhydride, followed by the reduction of the intermediate diketopiperazine thus formed with for example a borane. In both cases, the derivative of formula (III) will finally be obtained after transformation of the group represented by X "into an amine. If it is a nitro group, this transformation will be carried out according to the well known methods and techniques of the skilled person to transform a nitroaromatic into an aniline derivative such as for example the use of Raney nickel or rhodium catalyst in the presence of hydrazine, hydrogenation on carbon-palladium at atmospheric pressure, or alternatively the use of SnCl2 or zinc.
Les composés de formule générale (I) dans laquelle Ar} , Z \ , X-Y, R } , R2 et R3 sont décrits comme précédemment et Z2 représente O ou NH sont préparés par condensation d'un intermédiaire de formule générale (III) dans laquelle X' représente O ou NH, et R j , R2 et R3 sont définis comme précédemment, et d'une amine cyclique de formule (IV) dans laquelle Ar ] , Z \ , X-Y sont définis comme précédemment, avec un dérivé de formule générale (XII) :The compounds of general formula (I) in which Ar}, Z \, XY, R}, R 2 and R3 are described as above and Z2 represents O or NH are prepared by condensation of an intermediate of general formula (III) in where X 'represents O or NH, and R j, R2 and R3 are defined as above, and of a cyclic amine of formula (IV) in which Ar], Z \, XY are defined as above, with a derivative of formula general (XII):
X
Figure imgf000012_0002
 X
Figure imgf000012_0002
dans laquelle X \ et X2, identiques ou différents représentent chacun un groupe partant tel qu'un halogène (en particulier le chlore), un groupe O- alkyle (en particulier le groupe OCCI3), un groupe succinimyle, phtalyle ou imidazolyle. La méthode de la présente invention comprend également l'utilisation de précurseurs ou analogues bien connus des réactifs de formule générale (XII). C'est ainsi et à titre d'exemple que la condensation des intermédiaires (III) et (IV) avec le phosgène peut être avantageusement effectuée à l'aide de diphosgène ou de triphosgene selon une procédure bien connue de l'homme de l'art.in which X \ and X2, identical or different, each represent a leaving group such as a halogen (in particular chlorine), an O-alkyl group (in particular the group OCCI3), a succinimyl, phtalyl or imidazolyl group. 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.
Les méthodes et techniques choisies pour la mise en oeuvre de la préparation des composés de formule (I) dans laquelle Z2 représente O ou NH par condensation des dérivés de formules (III) dans laquelle X' représente O ou NH et de dérivés de formule (IV) avec un réactif de formule (XII) telles que le choix de l'ordre des réactifs, les temps de réaction, l'isolation et/ou la purification des intermédiaires, la température de la réaction à différentes étapes de la condensation, la nature du ou des solvants, la présence de co-réactifs (tels qu'une base organique ou inorganique, par exemple une amine tertiaire) ou de catalyseurs et le choix du réactif (XII) (choix de X j et X2) seront déterminés par la nature de Arj , Z j , Z2 (O ou NH), X-Y et K \ .The methods and techniques chosen for carrying out the preparation of the compounds of formula (I) in which Z 2 represents O or NH by condensation of the derivatives of formulas (III) in which X 'represents O or NH and of derivatives of formula (IV) with a reagent of formula (XII) such as the choice of the order of the reagents, the reaction times, the isolation and / or the purification of the intermediates, the temperature of the reaction at different stages of the condensation, the nature of the solvent (s), the presence of co-reagents (such as an organic or inorganic base, for example a tertiary amine) or catalysts and the choice of reagent (XII) (choice of X j and X2) will be determined by the nature of Arj, Z j, Z 2 (O or NH), XY and K \.
C'est ainsi que, une méthode particulièrement appréciée pour la préparation de dérivés de formule (I) dans laquelle Z2 = NH et Ar j , Z \ , X-Y et R j , R2, R3 sont définis comme précédemment, consiste à faire réagir un intermédiaire de formule (III) dans laquelle X' représente NH avec du triphosgene en présence d'une base telle que la triéthylamine dans un solvant anhydre tel que le dichloromethane et d'ajouter ensuite un composé de formule (IV) dans laquelle Ar j , Z \ et X-Y sont définis comme précédemment en présence d'une base telle qu'une amine tertiaire.Thus, a particularly preferred method for the preparation of derivatives of formula (I) in which Z2 = NH and Ar j, Z \, XY and R j, R2, R3 are defined as above, consists in reacting a intermediate of formula (III) in which X 'represents NH with triphosgene in the presence of a base such as triethylamine in an anhydrous solvent such as dichloromethane and then adding a compound of formula (IV) in which Ar j, Z \ and XY are defined as above in the presence of a base such as a tertiary amine.
Dans le cas de la préparation de dérivés de formule générale (I) dans laquelle Ar j , Z \ , X-Y et R \ , R2, R3 sont définis comme précédemment et Z2 représente un oxygène, une méthode particulièrement appréciée consiste à condenser tout d'abord une amine cyclique de formule (IV) avec du triphosgene en présence de triéthylamine dans un solvant anhydre tel que le dichloromethane et d'isoler l'intermédiaire de formule générale (XIII) ainsi formé :
Figure imgf000014_0001
In the case of the preparation of derivatives of general formula (I) in which Ar j, Z \, XY and R \, R2, R3 are defined as above and Z2 represents oxygen, 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:
Figure imgf000014_0001
avant de le condenser avec un nucléophile de formule générale (III) dans laquelle X' représente un oxygène, en présence d'une base organique ou inorganique telle que NaH, KH, t-BuOK dans un solvant aprotique polaire tel que le THF ou le DMF.before condensing it with a nucleophile of general formula (III) in which X ′ represents oxygen, in the presence of an organic or inorganic base such as NaH, KH, t-BuOK in a polar aprotic solvent such as THF or DMF.
Doivent également être considérées comme faisant partie de la présente invention les méthodes qui permettent de préparer les produits de formule (I) dans laquelle Z2 représente O ou NH par condensation d'une amine cyclique de formule (IV) avec un dérivé de formule générale (XIV) :The methods which make it possible to prepare the products of formula (I) in which Z2 represents O or NH must also be considered to be part of the present invention by condensation of a cyclic amine of formula (IV) with a derivative of general formula ( XIV):
Figure imgf000014_0002
Figure imgf000014_0002
dans laquelle X i , R \ , R2 et R3 sont définis comme précédemment et Z2 représente O ou NH, en présence d'une base organique ou inorganique dans un solvant polaire aprotique à une température comprise entre 20° et 100° C .in which 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.
Les intermédiaires de formule générale IV dans laquelle Ar j , Z \ et X-Y sont définis comme précédemment sont préparées d'une manière générale par différentes méthodes et techniques bien connues de l'homme de l'art, telles que décrites par exemple dans les brevets DE 2801 1 95, EP 7067 (800 123 ), EP 12643 (800625), FR 2459795 (8101 1 6), EP 372776 (900613 ), FR 2678270 (92123 1 ), FR 2675801 (921 030), EP 580398 (940126), WO 940 1403 (940120) ainsi que les publications J. Med . Chem. 34, 301 1 , ( 1991 ); J . Chem. Soc. Chem. Comm. 2, 142, ( 1989); Tetrahedron 47, 5 161 ( 1991 ) ; Synthesis ϋ, 1023 ( 1991 ); Izobretaniya 37, 89 ( 1 992) et Tetrahedron Lett. 35, 973, ( 1 994).The intermediates of general formula IV in which Ar j, Z \ and XY are defined as above are generally prepared by various methods and techniques well known to those skilled in the art, as described for example in the patents DE 2801 1 95, EP 7067 (800 123), EP 12643 (800625), FR 2459795 (8101 1 6), EP 372776 (900613), FR 2678270 (92123 1), FR 2675801 (921 030), EP 580398 (940126) ), WO 940 1403 (940 120) as well as the publications J. Med. Chem. 34, 301 1, (1991); J. Chem. Soc. Chem. Comm. 2, 142, (1989); Tetrahedron 47, 5 161 (1991); Synthesis ϋ, 1023 (1991); Izobretaniya 37, 89 (1 992) and Tetrahedron Lett. 35, 973, (1 994).
Une méthode particulièrement appréciée de la préparation des aminés cycliques de formule (IV), dans le cadre de la présente invention, consiste à préparer ces dérivés à partir de précurseurs de formule générale XV .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.
/ \/ \
Ar.-Z— XX NN— P (XV)Ar.-Z— XX NN— P (XV)
\\
Y _/Y _ /
dans laquelle Ar j , Z \ et X-Y sont définis comme précédemment et P représente un groupe protecteur habituellement utilisé pour protéger une amine secondaire tel que par exemple un benzyle, un benzyle dont l'aromatique est substitué, un acétyle, un trifluoroacétyle, un benzyloxycarbonyle ou un t-butoxycarbonyle. Les méthodes utilisées pour transformer le précurseur de formule générale (XV) en amine cyclique IV dépendra bien évidemment de la nature de P, et sont décrites dans "Protective Groups in Organic Synthesis" T.W. Greene, John Wiley & Sons, 198 1 ou encore "Protecting Group" P.J. Kocienski, Thieme Verlag, 1 994. Il est bien entendu que le choix de la nature du groupe protecteur P sera déterminé en fonction des méthodes et techniques mises en oeuvre pour la préparation des intermédiaires de formule XV.in which Ar j, Z \ and XY are defined as above and 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.
Dans le cas particulier où X-Y représente NCH2, N ou NCH2CH2, une méthode particulièrement appréciée de préparation des composés de formule XV consiste à condenser un intermédiaire de formule XVI / \In the particular case where XY represents NCH2, N or NCH2CH2, a particularly appreciated method of preparing the compounds of formula XV consists in condensing an intermediate of formula XVI / \
H" X N — PH "X N - P
\ v / (xvi)\ v / (xvi)
dans laquelle P représente un groupe protecteur d'une amine tel que décrit précédemment, avec un électrophile de formule XVIIin which P represents a protective group of an amine as described above, with an electrophile of formula XVII
An - Z i - L (XVII)An - Z i - L (XVII)
dans laquelle Ar j et Z \ sont définis comme précédemment et L représente un groupe partant. La nature de L et les conditions expérimentales utilisées pour réaliser cette condensation dépendront surtout de la nature de Z \ . C'est ainsi que, dans le cas où Z \ représente -(CH2)n-, O(CH2)n-, CO(CH2)n> NH(CH2)n, NHCO(CH2)n, SO2(CH2)n, NHSO2(CH2)n; cette condensation pourra être réalisée entre un intermédiaire de formule (XVI) et un électrophile de formule XVII dans laquelle L sera choisi parmi Cl, Br, I, OTs, OMs, OTf, en présence d'une base organique (tel que par exemple une amine tertiaire) ou inorganique (tel que par exemple CS2CO3 , K2CO3 ou Na2CÛ3) dans un solvant anhydre polaire tel que le THF, le DME, le DMF ou le DMSO, l'isopropanol ou le t-butanol, à une température comprise entre 0°C et 80°C. Une méthode de préparation alternative mais particulièrement appréciée de ces mêmes dérivés de formule (XV) dans laquelle X représente un azote et Z \ représente (CH2)n, NH(CH2)n, O(CH2)n> Sθ2(CH2)n. NHSO2(CH2) n ou NHCO(CH2)n consiste à condenser une amine cyclique de formule (XVI) dans laquelle X représente un azote avec un aldéhyde de formule XVIII :in which Ar j and Z \ are defined as above and L represents a leaving group. The nature of L and the experimental conditions used to carry out this condensation will depend above all on the nature of Z \. Thus, in the case where Z \ represents - (CH2) n -, O (CH2) n -, CO (CH2) n> NH (CH 2 ) n , NHCO (CH 2 ) n , SO 2 ( CH 2 ) n , NHSO 2 (CH2) n ; this condensation can be carried out between an intermediate of formula (XVI) and an electrophile of formula XVII in which L will be chosen from Cl, Br, I, OTs, OMs, OTf, in the presence of an organic base (such as for example a tertiary amine) or inorganic (such as for example CS2CO3, K2CO3 or Na2CO3) in a polar anhydrous solvent such as THF, DME, DMF or DMSO, isopropanol or t-butanol, at a temperature between 0 ° C and 80 ° C. An alternative but particularly appreciated method of preparation of these same derivatives of formula (XV) in which X represents a nitrogen and Z \ represents (CH2) n , NH (CH 2 ) n , O (CH2) n > Sθ2 (CH 2 ) n . NHSO 2 (CH 2 ) n or NHCO (CH2) n consists in condensing a cyclic amine of formula (XVI) in which X represents a nitrogen with an aldehyde of formula XVIII:
OO
////
ArrZ2 CAr r Z 2 C
\ (xvm) dans laquelle Ar j est défini comme précédemment et Z2 représente un reste Z \ tronqué d'un méthylène, dans les conditions bien connues sous l'appelation "amination réductrice" telles que par exemple celles décrites dans Synlett, 1079, 1995. Dans le cas où Z \ représente (CH2)nCO, 0(CH2)nCO, NH(CH2)nCO, CH ≈ CHCO, CCCO, CO ou SO2(CH2)nCO, la condensation d'une amine cyclique de formule XVI sera effectuée avec un dérivé d'acide carboxylique de formule (XVII) dans laquelle L représente un chlore ou encore l'intermédiaire (XVII) représente une forme activée d'un acide carboxylique propice à la formation d'une amide par réaction avec une amine par les méthodes et techniques bien connues de l'homme de l'art pour ce type de transformation. Dans le cas où Z j représente NHSO2, SO2, O(CH2)nSO2 NH(CH2)nSO2 ou (CH2)nSO2, les intermédiaires de formule (XVI) sont condensés avec des chlorures de sulfonyle de formule XVII dans laquelle L représente Cl, par les méthodes bien connues de l'homme de l'art pour préparer une sulfonamide à partir d'un chlorure de sulfonyle et d'une amine.\ (xvm) in which Ar j is defined as above and Z2 represents a truncated residue Z \ of a methylene, under the conditions well known under the name "reductive amination" such as for example those described in Synlett, 1079, 1995. In the case where Z \ represents (CH2) n CO, 0 (CH 2 ) n CO, NH (CH 2 ) n CO, CH ≈ CHCO, CCCO, CO or SO 2 (CH 2 ) n CO, the condensation of a cyclic amine of formula XVI will be carried out with a carboxylic acid derivative of formula (XVII) in which L represents chlorine or else the intermediate (XVII) represents an activated form of a carboxylic acid which is favorable for the formation of an amide by reaction with an amine by the methods and techniques well known to those skilled in the art for this type of transformation. In the case where Z j represents NHSO2, SO2, O (CH2) n SO 2 NH (CH2) n SO 2 or (CH 2 ) n SO 2 , the intermediates of formula (XVI) are condensed with sulfonyl chlorides of formula XVII in which L represents Cl, by methods well known to those skilled in the art for preparing a sulfonamide from a sulfonyl chloride and an amine.
Dans le cas des composés de formules (XV) dans laquelle Ar i , et P sont définis comme précédemment, X représente un azote et Z \ représente OCO ou NHCO, les méthodes de préparation consistent par exemple à condenser soit un phénol (Arj OH), soit une aniline (Ar ι NH2) et une amine de formule (XVI) avec un réactif de formule XII par les méthodes et techniques décrites précédemment pour la préparation de carbamates et d'urées.In the case of the compounds of formulas (XV) in which Ar i, and P are defined as above, X represents a nitrogen and Z \ represents OCO or NHCO, the preparation methods consist for example of condensing either a phenol (Arj OH) , either an aniline (Ar ι 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.
Dans le cas particulier où Ar j Z j représente un tétrahydronaphtyle dont la liaison avec X met en oeuvre un carbone saturé et X représente un azote, une méthode appréciée de préparation d'intermédiaire de formule (XV) consiste à condenser la tétralone appropriée avec une amine cyclique de formule XVI, en présence d'acide p-toluène sulfonique dans un solvant tel que le toluène à reflux, suivi de la réduction de l 'énamine ainsi formée par exemple par hydrogénation catalytique sous pression d'hydrogène en présence de palladium ou oxyde de platine sur charbon. Une méthode particulièrement appréciée de préparation des intermédiaires de formule (XV) dans laquelle X-Y représente NCH2, N ou NCH2CH2 et Z \ représente (CH2)n, O(CH2)n, NH(CH2)n» Sθ2(CH2)n consiste à réduire des amides de formule (XV) dans lesquelles Z \ représente respectivement (CH2)n- l CO, O(CH2) n- l CO, NH(CH2)n- l CO, SO2(CH2)n. ι CO par les méthodes connues pour permettre de réduire une amide en amine, telles que l'utilisation d'un hydrure d'aluminium (par exemple LiAlH4) dans un solvant tel que le THF ou l'éther éthylique.In the particular case where Ar j Z j represents a tetrahydronaphthyl whose bond with X implements a saturated carbon and X represents a nitrogen, 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 »Sθ2 (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 . ι 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.
Les intermédiaires de formule générale (XV) dans laquelle Ar i et P sont définis comme précédemment et X-Y représente C=CH et Z \ représente (CH2)n> O(CH2)n ou CH=CH sont préparés par couplage d'un organométallique de formules XIX ou XXThe intermediates of general formula (XV) in which Ar i and P are defined as above and XY represents C = CH and Z \ represents (CH2) n > O (CH2) n or CH = CH are prepared by coupling of an organometallic of formulas XIX or XX
Ar i - Z i - M (XIX)Ar i - Z i - M (XIX)
Ar ] - Z i - M' - Z i - Ar (XX)Ar] - Z i - M '- Z i - Ar (XX)
dans lesquels M représente ZnBr, SnR3 où R représente un groupe alkyle tel qu'un butyle ou B(OR')2 où R' représente un hydrogène ou un alkyle et M' représente Zn, avec un triflate vinylique de formule (XXI)in which 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)
Figure imgf000018_0001
Figure imgf000018_0001
en présence d'un dérivé du palladium tel que par exemple Pd(PPh3)4, éventuellement d'une base telle qu'une amine tertiaire, un carbonate de potassium, sodium ou césium, de chlorure de lithium lorsque M = SnR3 et dans un solvant aprotique polaire tel que le THF, le DME ou le DMF à une température comprise entre 20° et 80°C ( cf "Organometallics in synthesis", M. Schlosser, John Wiley & son, 1994). Les triflates intermédiaires de formule XXI sont préparés par exemple par la méthode décrite dans Synthesis, 993 , 1991 .in the presence of a palladium derivative such as for example Pd (PPh3) 4, optionally a base such as a tertiary amine, potassium carbonate, sodium or cesium, of lithium chloride when M = SnR3 and in a polar aprotic solvent such as THF, DME or DMF at a temperature between 20 ° and 80 ° C (see "Organometallics in synthesis", M. Schlosser, John Wiley & son, 1994). The triflates intermediates of formula XXI are prepared for example by the method described in Synthesis, 993, 1991.
Les intermédiaires de formule XV dans laquelle Z \ représente un reste éthynyl et X représente C=CH sont préparés par couplage de triflates de formule XXI avec un acétylénique aromatique de formule XXIIThe intermediates of formula XV in which Z \ represents an ethynyl residue and X represents C = CH are prepared by coupling triflates of formula XXI with an aromatic acetylenic of formula XXII
Ar - C ≡ C - H (XXII)Ar - C ≡ C - H (XXII)
en présence d'un catalyseur au palladium tel que Pd(PPh3)4 ou PdCl2(PPh3)2, d'une base telle qu'une amine secondaire ou tertiaire, un carbonate de potassium, sodium ou césium et éventuellement d'iodure de cuivre dans un solvant polaire tel que le DMSO, le DMF, le THF (cf Organic Préparation and Procédures int., 27(2), 127- 160, 1995).in the presence of a palladium catalyst such as Pd (PPh3) 4 or PdCl2 (PPh3) 2, of 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).
Les intermédiaires de formule générale (XV) dans laquelle Aτ \ et P sont définis comme précédemment, X-Y représente CH-CH2 et Z i représente (CH2)n. O(CH2)n peuvent être préparés à partir des intermédiaires de formule générale (XV) dans laquelle Arj et P sont définis comme précédemment, X-Y représente C=CH et Z \ représente (CH2)n. O(CH2)n, CC ou CH=CH par réduction des liaisons doubles et triples par hydrogénation catalytique (H2,Pd/C par exemple).The intermediaries of general formula (XV) in which Aτ \ and P are defined as above, X-Y represents CH-CH2 and Z i represents (CH2) n. O (CH2) n can be prepared from intermediates of general formula (XV) in which Arj and P are defined as above, X-Y represents C = CH and Z \ 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).
Les dérivés des formules XV dans laquelle Z j représente CO, (CH2)nCO ou encore O(CH2)nCO et X-Y représente C=CH, sont préparés par couplage d'un intermédiaire de formule XIX dans laquelle Z \ est omis ou représente (CH2)n > C>(CH2)n et M représente SnR3 où R représente un groupe alkyle avec un triflate de formule XXI, en présence d'un catalyseur au palladium tel que Pd(PPh3)4 éventuellement de chlorure de lithium et d'une base telle que le carbonate de potassium sous pression de monoxyde de carbone dans un solvant polaire tel que le THF selon la méthode décrite dans "Organometallics in synthesis", M. Schlosser, John Wiley & son, 1 994. Les intermédiaires de formule XV dans laquelle Z \ représente CO et X-Y représente CH-CH2 sont préparés par condensation d'un dérivé aromatique "Ar i H" avec un chlorure d'acide, selon les méthodes et techniques connues sous le nom de réaction de Friedel-Craft, telles que par exemple décrites dans J. Med. Chem. 33 , 903, 1990. Une méthode alternative (dont le choix dépendra essentiellement de la nature de Ar j ) de préparation de composés de formule XV dans laquelle Z \ représente CO et X-Y représente CH-CH2 consiste à condenser un dérivé organométallique Ar j -M dans laquelle M représente MgCl, MgBr ou Li avec un nitrile de formule XXIIIThe derivatives of formulas XV in which Z j represents CO, (CH2) nCO or also O (CH2) nCO and XY represents C = CH, are prepared by coupling of an intermediate of formula XIX in which Z \ is omitted or represents ( CH2) n> C> (CH2) n e t M represents SnR3 where R represents an alkyl group with a triflate of formula XXI, in the presence of a palladium catalyst such as Pd (PPh3) 4 optionally of lithium chloride and d a base such as potassium carbonate under pressure of carbon monoxide in a polar solvent such as THF according to the method described in "Organometallics in synthesis", M. Schlosser, John Wiley & son, 1 994. The intermediates of formula XV in which Z \ represents CO and XY represents CH-CH2 are prepared by condensation of an aromatic derivative "Ar i H" with an acid chloride, according to the methods and techniques known as the reaction of Friedel-Craft, such as for example described in J. Med. Chem. 33, 903, 1990. An alternative method (the choice of which will essentially depend on the nature of Ar j) for the preparation of compounds of formula XV in which Z \ represents CO and XY represents CH-CH2 consists in condensing an organometallic derivative Ar j - M in which M represents MgCl, MgBr or Li with a nitrile of formula XXIII
Figure imgf000020_0001
Figure imgf000020_0001
dans un solvant anhydre polaire tel que l'éther éthylique, le THF ou le DME, à une température comprise entre - 20° C et 60° C, suivi de l'hydrolyse acide du milieu réactionnel.in 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.
Les intermédiaires de formule générale (XV) dans laquelle Z \ représente (CH2)n, O(CH2)n, NH(CH2)n, S02(CH2)n et X-Y représente CH-CH2 peuvent également être préparés par condensation d'un nucléophile de formule générale XXIVThe intermediates of general formula (XV) in which Z \ represents (CH 2 ) n , O (CH 2 ) n, NH (CH 2 ) n, S0 2 (CH 2 ) n and XY represents CH-CH 2 can also be prepared by condensation of a nucleophile of general formula XXIV
Figure imgf000020_0002
Figure imgf000020_0002
(dont une méthode de préparation est décrite dans le brevet US 4335 127 ; 1 982) avec un dérivé de formule XVII dans laquelle Z \ représente (CH2)n> O(CH2)n> Sθ2(CH2)n et L esr défini comme précédemment. Dans le cas particulier où Z i représente OCO ou NHCO et X-Y représente CH-CH2 ou C=CH, une méthode appréciée de préparation des intermédiaires de formule (I) consiste à condenser un phénol (Ar j OH) ou une aniline (Ar j NH2) avec un dérivé de formule XXV(a preparation method of which is described in US Pat. No. 4,335,127; 1,982) with a derivative of formula XVII in which Z \ represents (CH2) n > O (CH2) n> Sθ2 (CH2) n and L esr defined as previously. In the particular case where Z i represents OCO or NHCO and XY represents CH-CH2 or C = CH, a popular method for preparing the intermediates of formula (I) consists in condensing a phenol (Ar j OH) or an aniline (Ar j NH2) with a derivative of formula XXV
Figure imgf000021_0001
Figure imgf000021_0001
dans laquelle L et le carboxyle auquel il est attaché constituent la forme activée d'un acide carboxylique propice à la formation d'un amide ou d'un ester par condensation avec une amine ou un alcool par les méthodes et techniques bien connues de l'homme de l'art.in which 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.
Dans le cas particulier où Z \ représente NH et X-Y représente CH-CH2, les intermédiaires de formule XV sont préparés par une réaction d'amination réductrice, utilisant par exemple NaBH4 ou NaBH3CN comme agent réducteur entre une aniline de formule Ar j NH2 et une pipéridone de formule XXVIIn the particular case where Z \ represents NH and XY represents CH-CH2, 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
Figure imgf000021_0002
Figure imgf000021_0002
dans laquelle P est défini comme précédemment.in which P is defined as above.
Dans les cas particuliers où X-Y représente CH-CH2 et Z \ représente CONH, SO2NH, (CH2)nNH, CO(CH2)nNH ou O(CH2)NH, les intermédiaires de formule XV sont préparés par condensation d'une amino pipéridine de formule XXVII
Figure imgf000022_0001
In the special cases where XY represents CH-CH2 and Z \ represents CONH, SO 2 NH, (CH 2 ) n NH, CO (CH 2 ) n NH or O (CH 2 ) NH, the intermediates of formula XV are prepared by condensation of an amino piperidine of formula XXVII
Figure imgf000022_0001
avec un électrophile de formule XXVIIIwith an electrophile of formula XXVIII
Ar! Z' i - L (XXVIII)Ar! Z 'i - L (XXVIII)
dans laquelle Z' \ représente Z i tronqué du reste NH terminal et L est défini comme précédemment. Cette condensation sera effectuée par différentes techniques et méthodes qui dépendront de la nature de Z' j et L et qui sont similaires aux techniques et méthodes précédemment décrites pour la condensation des intermédiaires XVI et XVII (dans lequel X représente un azote). La réaction d'amination réductrice telle que décrite précédemment peut également être mise en oeuvre pour la préparation de composés de formule XV dans laquelle Z \ représente (CH2)n NH, O(CH2)nNH ou Sθ2(CH2)nNH à partir des aminés de formule XXVII et d'aldéhyde respectivement de formules Ar ι (CH2)n- l CHO, Arι O(CH2)n- i CHO ou Sθ2(CH2)n- l CHO ou à partir d'aminés de formule Ar ι (CH2)n NH2, Ar ! θ(CH2)nNH2 ou Ar ι S02(CH2)nNH2 avec la pipéridone XXVI .in which Z '\ represents Z i truncated from the remainder NH terminal and L is defined as above. This condensation will be carried out by different techniques and methods which will depend on the nature of Z ′ j and L and which are similar to the techniques and methods previously described for the condensation of intermediates XVI and XVII (in which X represents a nitrogen). 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 Sθ2 (CH2) n NH from amines of formula XXVII and of aldehyde respectively of formulas Ar ι (CH2) n - l CHO, Arι O (CH2) n - i CHO or Sθ2 (CH2) n - l CHO or from amines of formula Ar ι ( CH2) n NH2, Ar! θ (CH2) n NH2 or Ar ι S02 (CH2) n NH2 with piperidone XXVI.
Les intermédiaires de formule XV dans laquelle Z \ représente OCONH ou NHCONH et X-Y représente CH-CH2 sont préparés par condensation d'une aminopiperidine de formule XXVII et d'un phénol (Arj OH) ou d'une aniline (Ar j NH2) avec un électrophile de formule XII selon les méthodes et techniques décrites précédemment pour la préparation de carbamates ou d'urées.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.
Dans le cas particulier où Z \ représente O et X-Y représente CH-CH2, les intermédiaires de formule XV sont préparés par une réaction de Mitsunobu à partir d'un dérivé Ar j OH et d'un dérivé hydroxyle de pipéridine de formule (XXIX)
Figure imgf000023_0001
In the particular case where Z \ represents O and XY represents CH-CH2, the intermediates of formula XV are prepared by a Mitsunobu reaction starting from a derivative Ar j OH and of a hydroxyl derivative of piperidine of formula (XXIX)
Figure imgf000023_0001
dans laquelle P est défini comme précédemment.in which P is defined as above.
Dans le cas particulier où X-Y représente CH-CH2 et Z \ représente (CH2)nO, 0(CH2)nO, NH(CH2)nO, CO(CH2)nO ou SO2(CH2)nO, les intermédiaires de formule XV sont préparés par condensation d'une hydroxy pipéridine de formule (XXIX) avec un électrophile de formule (XXVIII) dans lequel Z' \ représente Z \ tronqué d'un oxygène terminal et L représente un groupe partant tel qu'un halogène (chlore, brome ou iode), un tosylate, un mesylate ou un triflate. Cette condensation peut être réalisée en présence d'une base, organique (telle qu'une amine tertiaire, le t-butylate de potassium ou encore le butyllithium) ou inorganique (par exemple, NaH, KH, CS2CO3) dans un solvant anhydre polaire tel que le THF, le DME, le DMF, le DMSO, le t-butanol, à une température comprise entre - 1 5 ° C et 80° C.In the particular case where XY represents CH-CH2 and Z \ represents (CH 2 ) n O, 0 (CH 2 ) n O, NH (CH 2 ) n O, CO (CH 2 ) n O or SO 2 (CH 2 ) n O, 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. 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.
Les intermédiaires de formule XV dans laquelle Z \ représente NHCOO et X- Y représente CH-CH2 sont préparés par condensation d'un alcool de formule (XXIX) et d'un dérivé d'aniline (Ar j NH2) avec un réactif de formule XII selon les méthodes et techniques décrites précédemment pour la préparation d'un carbamate.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.
Les intermédiaires de formule XV dans lesquels Z \ représente NHSO2, SO2, (CH2)nS02, O(CH2)nSθ2 ou NH(CH2)nSO2 et X-Y représente CH-CH2 sont préparés par condensation d'un chlorure de sulfonyle répondant à la formule XXXThe intermediates of formula XV in which Z \ represents NHSO2, SO2, (CH 2 ) n SO2, O (CH 2 ) n Sθ2 or NH (CH 2 ) n SO 2 and XY represents CH-CH 2 are prepared by condensation of a sulfonyl chloride corresponding to formula XXX
Ar Z j - Cl (XXX) avec un nucléophile de formule XXIV dans un solvant aprotique polaire tel que l'éther éthylique ou le THF à une température comprise entre 0° et 60° C.Ar Z j - Cl (XXX) with a nucleophile of formula XXIV in a polar aprotic solvent such as ethyl ether or THF at a temperature between 0 ° and 60 ° C.
Doivent être également considérées comme faisant partie de la présente invention, des méthodes de synthèse alternatives des composés de formule (I) dans laquelle X-Y représente NCH2, N, NCH2CH2 qui consistent à condenser des intermédiaires de formule générale (XXXI)Also to be considered as forming part of the present invention, alternative methods of synthesis of the compounds of formula (I) in which X-Y represents NCH2, N, NCH2CH2 which consist in condensing intermediates of general formula (XXXI)
Figure imgf000024_0001
Figure imgf000024_0001
dans laquelle Z2, R ] , R2 e t R3 sont définis comme précédemment avec un électrophile de formule (XVII) dans laquelle Z \ et L sont définis comme précédemment et ceci, selon les méthodes et techniques décrites précédemment pour la condensation de XVI avec XVII et dont le choix dépendra essentiellement de la nature de Z \ .in which Z2, R], R2 and R3 are defined as above with an electrophile of formula (XVII) in which Z \ and L are defined as above and this, according to the methods and techniques described above for the condensation of XVI with XVII and the choice of which will essentially depend on the nature of Z \.
Dans le cas particulier des composés de formule (I) avec X = N et Z \ = OCO ou NHCO, une méthode alternative de préparation consiste à faire réagir un phénol de formule Ar] OH ou une amine de formule Ar ] NH2 et une amine de formule (XXXI) définie comme précédemment avec un composé de formule (XII) par les méthodes et techniques décrites précédemment pour la préparation de carbamates et d'urées.In the particular case of the compounds of formula (I) with X = N and Z \ = OCO or NHCO, 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.
Dans le cas particulier des composés de formule générale (I) dans laquelle R i représente un hydrogène, il est préférable de mettre en oeuvre, pour certaines réactions qui le nécessitent, des intermédiaires réactionnels dans lesquels R i représente un groupe protecteur tel que par exemple un t- butoxycarbonyl (BOC) qui sera introduit préalablement par condensation de l'intermédiaire approprié dans lequel R \ = H avec un réactif adéquat tel que (BOC)2θ, BOC-ON = C (CN)-Ph, BOC-ONH2 - Ceci permettra de préparer, selon les méthodes et techniques présentées préalablement, des intermédiaires de formule générale (I) dans lesquels R i = BOC et de transformer ces intermédiaires en produits finaux de formule générale (I) dans lesquels R i =H après déprotection du t-butoxycarbonyl selon les méthodes et techniques bien connues pour ce type de transformation telle que l'utilisation d'acide (HCl, CF3CO2H, H2SO4) en milieu organique.In the particular case of the compounds of general formula (I) in which R i represents a hydrogen, it is preferable to use, for certain reactions which require it, reaction intermediates in which R i represents a protective group such as for example a t-butoxycarbonyl (BOC) which will be introduced beforehand by condensation of the appropriate intermediate in which R \ = H with a suitable reagent such as (BOC) 2θ, BOC-ON = C (CN) -Ph, BOC-ONH2 - This will make it possible to prepare, according to the methods and techniques presented previously, intermediaries of general formula (I) in which R i = BOC and to transform these intermediaries into final products of general formula ( I) in which R i = H after deprotection of t-butoxycarbonyl according to the methods and techniques well known for this type of transformation such as the use of acid (HCl, CF3CO2H, H2SO4) in an organic medium.
Doivent également être considérées comme faisant partie intégrale de la présente invention toutes les méthodes qui permettent de transformer un dérivé de formule (I) en un autre dérivé de formule (I) dans laquelle au moins un des substituants Ar j , Z i , X-Y, Z2, R i , R2 o u R-3 sont différents, par les méthodes et techniques bien connues de l 'homme de l 'art. C 'est ainsi, et à titre d'exemple, que les dérivés de formule générale (I) dans lesquels Ari représente un phényle substitué par un groupe NO2 peuvent être transformés en dérivés de formule (I) dans lesquels Ari représente un phényle substitué en même position par un groupe NH2 par les méthodes et techniques bien connues pour ce type de réduction telles que décrites par exemple dans "Comprehensive Organic Transformation" , p. 41 2 ; R. C. Larock, VCH, 1989, parmi lesquelles on peut citer l'hydrogénation atmosphérique catalysée au palladium sur charbon, l'utilisation du SnCl2, de zinc, de Ni de Raney ou encore de catalyseur au rhodium en présence d'hydrazine. Les composés de formule générale (I) dans lesquels Ar j représente un aromatique substitué par un groupement NH2 peuvent eux aussi être transformés en de nombreux autres dérivés de formule (I) tels que des dérivés dans lesquels Ar j représente un aromatique substitué par NR4R4', NHCOR4, NHCO2R4, NHCOR4, NHSO2R4, NHS02OR4, NHSO2NR4R4' par les méthodes et techniques bien connues pour transformer une amine aromatique en amide, carbonate, urée, sulfonamide, sulfonate ou sulfonylurée. Lorsque l'on désire isoler un composé selon l'invention à l'état de sel, par exemple de sel par addition avec un acide, on peut y parvenir en traitant la base libre de formule générale (I) par un acide approprié de préférence en quantité équivalente, ou par le sulfate de créatinine dans un solvant approprié.Also to be considered as an integral part of the present invention all the methods which make it possible to transform a derivative of formula (I) into another derivative of formula (I) in which at least one of the substituents Ar j, Z i, XY, Z2, R i, R2 or R-3 are different, by the methods and techniques well known to those skilled in the art. It is thus, and by way of example, that the derivatives of general formula (I) in which Ari represents a phenyl substituted by an NO2 group can be converted into derivatives of formula (I) in which Ari represents a phenyl substituted in same position by an NH2 group by the methods and techniques well known for this type of reduction as described for example in "Comprehensive Organic Transformation", p. 41 2; RC Larock, VCH, 1989, among which mention may be made of atmospheric hydrogenation catalyzed with palladium on carbon, the use of SnCl2, zinc, Raney's Ni or else a rhodium catalyst in the presence of hydrazine. 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. When it is desired to isolate 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.
Lorsque les procédés décrits ci-dessus pour préparer les composés de l'invention donnent des mélanges de stéréoisomères, ces isomères peuvent être séparés par des méthodes conventionnelles telles que la chromatographie preparative.When the processes described above for preparing the compounds of the invention give mixtures of stereoisomers, these isomers can be separated by conventional methods such as preparative chromatography.
Lorsque les nouveaux composés de formule générale (I) possèdent un ou plusieurs centres asymétriques, ils peuvent être préparés sous forme de mélange racémique ou sous forme d'énantiomères que ce soit par synthèse énantionsélective ou par résolution. Les composés de formule (I) possédant au moins un centre asymétrique peuvent par exemple être séparés en leurs énantiomères par les techniques habituelles telles que la formation de paires diastéréomériques par formation d'un sel avec un acide optiquement actif tel que l'acide (+)-di-p-toluoyl-l-tartrique, l'acide (+)-camphorsulfonique, l'acide (-)-camphorsulfonique, l'acide (+)-phénylpropionique, l'acide (-)- phénylpropionique, suivie par cristallisation fractionnée et régénération de la base libre. Les composés de formule (I) dans lesquels R j est un hydrogène comprenant au moins un centre asymétrique peuvent également être résolus par formation d'amides diastéréomériques qui sont séparés par chromatographie et hydrolyses pour libérer l'auxiliaire chiral .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 diastereomeric amides which are separated by chromatography and hydrolysed to release the chiral auxiliary.
Les exemples qui suivent illustrent l'invention sans toutefois en limiter la portée.The following examples illustrate the invention without, however, limiting its scope.
Les spectres RMN du proton ont été enregistrés sur un appareil Brϋcker AC 200 . Les déplacements chimiques sont exprimés en ppm et les abréviations suivantes ont été utilisées : "s" pour singulet; "se" pour singulet élargi, "d " pour doublet, "dd" pour doublet de doublet, "t" pour triplet, "q" pour quadruplet,"sx" pour sextuplet, "m" pour multiplet, " M" pour massif.The proton NMR spectra were recorded on a Brϋcker AC 200 device. The chemical shifts are expressed in ppm and the following abbreviations have been used: "s" for singlet; "se" for extended singlet, "d" for doublet, "dd" for doublet of doublet, "t" for triplet, "q" for quadruplet, "sx" for sextuplet, "m" for multiplet, "M" for solid.
Les spectres infrarouge ont été enregistrés sur un appareil Nicolet 5 1 OP. Les bandes d'absorption sont données en cm~ l -The infrared spectra were recorded on a Nicolet 5 1 OP device. The absorption bands are given in cm ~ l -
Les analyses élémentaires ont été réalisées sur un appareil Fisons EA 1 108.The elementary analyzes were carried out on a Fisons EA 1 108 device.
EXEMPLE 1 Difumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4- phénéthylpipérazin-l -ylamideEXAMPLE 1 N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- phenethylpiperazin-1-ylamide difumarate
Figure imgf000027_0001
Figure imgf000027_0001
11
Une solution de 4-méthoxy-3-(4-méthylpipérazin- l -yl)aniline pouvant être préparée selon la méthode décrite dans le brevet européen 0533266- 1 1 (500mg, 2.26mmol) et de triéthylamine (3 15μl, 2.27mmol) dans le dichloromethane ( 10ml) est canulée lentement sur une solution de triphosgene (225mg, 0.76mmol) dans le dichloromethane (30ml) sous atmosphère d'azote. Pendant cette opération, le mélange réactionnel est refroidi avec un bain de glace. Il est ensuite ramené à température ambiante pendant 20mn avant l'ajout de la 4- phénéthylpipérazine (430mg, 2.26mmol) et la triéthylamine (3 1 5μl, 2.27mmol) diluées dans le dichloromethane (10ml). Après 2 h à température ambiante, le mélange est dilué avec de l'eau puis extrait trois fois avec de l'acétate d'éthyle. Les phases organiques sont rassemblées, lavées une fois avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium et concentrées. Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.A solution of 4-methoxy-3- (4-methylpiperazin-1-yl) aniline which can be prepared according to the method described in European patent 0533266-1 (1 mg (500 mg, 2.26 mmol)) and triethylamine (3 15 μl, 2.27 mmol) in dichloromethane (10ml) is cannulated slowly on a solution of triphosgene (225mg, 0.76mmol) in dichloromethane (30ml) under nitrogen atmosphere. During this operation, the reaction mixture is cooled with an ice bath. It is then brought to room temperature for 20 minutes before the addition of 4-phenethylpiperazine (430 mg, 2.26 mmol) and triethylamine (3 1 5 μl, 2.27 mmol) diluted in dichloromethane (10 ml). After 2 h at room temperature, the mixture is diluted with water and then extracted three times with ethyl acetate. The organic phases are combined, washed once with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 831mg (Rdt : 84%)Mass obtained: 831 mg (Yield: 84%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H35N5O2-2C4H4O4Elementary Analysis for: C25H35N5O2-2C4H4O4
Calculées: C 59.18 ; H 6.47 ; N 10.46 ; Expérimentales: C 58.75 ; H 6.53 ;N 10.40Calculated: C 59.18; H 6.47; N 10.46; Experimental: C 58.75; H 6.53; N 10.40
Masse : 438 (MH+), 248, 191, 136Weight: 438 (MH +), 248, 191, 136
IR (KBr): 3400,3028,1707,1639,1508IR (KBr): 3400,3028,1707,1639,1508
RMN IH (DMSO) : 2.42-2.48 (m,9H); 2.74 (M,6H); 3.00 (M,4H); 3.35 (M,4H); 3.71 (s,3H); 6.57 (s,4H); 6.79 (d,lH); 7.09-7.31 (m,7H); 8.29 (s,lH).1 H NMR (DMSO): 2.42-2.48 (m, 9H); 2.74 (M, 6H); 3.00 (M, 4H); 3.35 (M, 4H); 3.71 (s, 3H); 6.57 (s, 4H); 6.79 (d, 1H); 7.09-7.31 (m, 7H); 8.29 (s, 1H).
Point de fusion : 120°C Melting point: 120 ° C
EXEMPLE 2EXAMPLE 2
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl)-4-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) -4- fumarate
(2,4,6-triméthylbenzylcarbonyl)pipérazin- l-ylamide(2,4,6-trimethylbenzylcarbonyl) piperazin-l-ylamide
Figure imgf000029_0001
Figure imgf000029_0001
Composé 2a : 1 -(2,4, 6-t rimé thylbenzylcar bonyl)-4-(/'£?r/- butyloxycarbonyl) pipérazineCompound 2a: 1 - (2,4,6-t rhymed thylbenzylcar bonyl) -4 - (/ '£? R / - butyloxycarbonyl) piperazine
Une solution de /er/-butyloxycarbonylpipérazine ( 1 .05 g,5.61 mmol) et d'acide mésitylacétique (1 .0g,5.61 mmol) dans le dichloromethaneA solution of / er / -butyloxycarbonylpiperazine (1.05 g, 5.61 mmol) and mesitylacetic acid (1.00g, 5.61 mmol) in dichloromethane
(50ml) est agitée pendant trois jours à température ambiante en présence du chlorhydrate de la l -(3 -diméthylaminopropyl)-3 - éthylcarbodiimide ( 1 .08g,5.61 mmol), de triéthylamine(50ml) is stirred for three days at room temperature in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.08 g, 5.61 mmol), of triethylamine
(800ml,5.61 mmol) et de 4-diméthylaminopyridine (une pointe de spatule). Après dilution dans l'eau, le mélange est extrait trois fois à l'acétate d'éthyle, puis les phases organiques rassemblées sont lavées avec une solution saturée en chlorure de sodium, séchées sur sul fate de magnésium, filtrées et concentrées. Le brut est purifié par chromatographie-éclair avec un mélange (90/9/ 1 ) de dichloromethane/ méthanol/ammoniaque.(800ml, 5.61 mmol) and 4-dimethylaminopyridine (a tip of a spatula). After dilution in water, the mixture is extracted three times with ethyl acetate, then the combined organic phases are washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 1.7g (Rdt : 88%)Mass obtained: 1.7g (Yield: 88%)
RMN I H (CDCI3) : 1 .45 (s,9H); 2. 1 8 (s,6H); 2.23 (s,3H); 3.43 (M.4H); 3.56 (M,4H); 3.61 (s,2H); 6.83 (s,2H) .1 H NMR (CDCl3): 1.45 (s, 9H); 2. 18 (s, 6H); 2.23 (s, 3H); 3.43 (M.4H); 3.56 (M, 4H); 3.61 (s, 2H); 6.83 (s, 2H).
Composé 2b: l-(2,4,6-triméthyIbenzylcarbonyl)pipérazinc L'acide trifluoroacétique (4.9ml) est additionné lentement à une solution du composé 2a ( 1 .7g;4.91 mmol) dans le dichloromethane (25ml) maintenue à 0°C. Le mélange réactionnel est ensuite ramené à température ambiante et la réaction est suivie par chromatographie sur couche mince. Après 1 h, la réaction est complétée. L'acide trifluoroacétique est neutralisé avec une solution saturée en hydrogénocarbonate de sodium. Les phases sont séparées et la phase organique est lavée avec une solution saturée en chlorure de sodium séchée sur sulfate de magnésium et concentrée. Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/10/ 1 ) de dichlorométhane/méthanol/ammoniaque.Compound 2b: 1- (2,4,6-trimethylIbenzylcarbonyl) piperazinc Trifluoroacetic acid (4.9ml) is added slowly to a solution of compound 2a (1.7g; 4.91mmol) in dichloromethane (25ml) kept at 0 ° C. The reaction mixture is then brought to ambient temperature and the reaction is followed by thin layer chromatography. After 1 h, the reaction is completed. The trifluoroacetic acid is neutralized with a saturated solution of sodium hydrogencarbonate. The phases are separated and the organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude reaction product is purified by flash chromatography with a mixture (90/10/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 1 .08 g (Rdt : 89 %)Mass obtained: 1.08 g (Yield: 89%)
RMN I H (CDC13) : 1 .25 (se, l H); 2.22 (s,6H); 2.25 (s,3 H); 2.86 (M,4H); 3.61 (M,6H); 6.85 (s,2H).1 H NMR (CDCl 3 ): 1.25 (sc, 1 H); 2.22 (s, 6H); 2.25 (s, 3H); 2.86 (M, 4H); 3.61 (M, 6H); 6.85 (s, 2H).
Composé 2 : Le composé 2 est préparé suivant la procédure décrite dans l'exemple 1 à partir des réactifs suivants : triphosgene (204mg,0.69mmol) ; 4-méthoxy-3-(4-méthylpipérazin- l -yl)aniline (555mg,2.06mmol) ; triéthylamine (290μlx2,2.06mmolx2) ; l -(2,4,6- triméthylbenzylcarbonyl)pipérazine (2b) (506mg, 2.06mmol) ; dichloromethane (40ml).Compound 2: 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 (290μlx2.2.06mmolx2); 1 - (2,4,6-trimethylbenzylcarbonyl) piperazine (2b) (506mg, 2.06mmol); dichloromethane (40ml).
Le brut est purifié par chromatographie-éclair avec un mélange (92/8/ 1 ) puis (90/9/1 ) de dichlorométhane/méthanol/ammoniaque.The crude is purified by flash chromatography with a mixture (92/8/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 756 mg (Rdt : 75 %)Mass obtained: 756 mg (Yield: 75%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther. Analyse Elémentaire pour: C28H39N5O3-C4H4O4This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether. Elementary Analysis for: C28H39N5O3-C4H4O4
Calculées: C 63.04 ; H 7.11 ; N 11.49 ; Expérimentales: C 62.91 ; HCalculated: C 63.04; H 7.11; N 11.49; Experimental: C 62.91; H
7.46 ; N 11.127.46; N 11.12
Masse (DCI/NH3) : 494 (MH+),248,222Mass (DCI / NH3): 494 (MH +), 248.222
IR (KBr): 3440,3315,3012,2907,2861,1637,1512,1439,1222IR (KBr): 3440,3315,3012,2907,2861,1637,1512,1439,1222
RMN IH (DMSO) : 2.10 (s,6H); 2.18 (s,3H);2.32 (s,3H); 2.62 (M,4H); 2.97 (M,4H); 3.47 (M,8H); 3.65 (s,2H); 3.71 (s,3H); 6.55 (s,2H); 6.80 (m,3H); 7.04 (m,2H); 8.37 (s,lH).1 H NMR (DMSO): 2.10 (s, 6H); 2.18 (s, 3H); 2.32 (s, 3H); 2.62 (M, 4H); 2.97 (M, 4H); 3.47 (M, 8H); 3.65 (s, 2H); 3.71 (s, 3H); 6.55 (s, 2H); 6.80 (m, 3H); 7.04 (m, 2H); 8.37 (s, 1H).
Point de fusion : 197°CMelting point: 197 ° C
EXEMPLE 3EXAMPLE 3
Difumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- difumarate
(2,4,6-triméthylphénéthyl)pipérazin-l-ylamide(2,4,6-trimethylphenethyl) piperazin-1-ylamide
Figure imgf000031_0001
Figure imgf000031_0001
Composé 3a : l-(2,4,6-trîméthyIphénéthyI)pipérazineCompound 3a: l- (2,4,6-trîméthyIphénéthyI) pipérazine
A une suspension du composé 2b (551mg,2.24mmol) dans l'éther éthylique (10ml) est ajoutée lentement une solution d'hydrure de lithium et d'aluminium ( 3.4ml d'une solution 1M dans l'éther éthylique, 3.4mmol). Après l/2h, le mélange réactionnel est neutralisé lentement par une solution 3M de soude puis filtré sur Célite. Les phases sont séparées et la phase organique est séchée sur sulfate de magnésium, filtrée et concentrée. Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1 ) de dichloromethane/ méthanol/ammoniaque.To a suspension of compound 2b (551mg, 2.24mmol) in ethyl ether (10ml) is slowly added a solution of lithium aluminum hydride (3.4ml of a 1M solution in ethyl ether, 3.4mmol ). After 1/2 hour, the reaction mixture is slowly neutralized with a 3M sodium hydroxide solution and then filtered through Celite. The phases are separated and the organic phase is dried over magnesium sulfate, filtered and concentrated. The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 413mg (Rdt : 79%)Mass obtained: 413 mg (YId: 79%)
RMN I H (CDC13) : 1 .67 (s, l H); 2.25 (s,3H); 2.3 1 (s,6H); 2.36-2.45 (m,2H); 2.55 (M,4H); 2.78-2.87 (m,2H) ; 2.96 (t,4.9Hz,4H); 6.84 (s,2H).1 H NMR (CDCl 3 ): 1.67 (s, 1H); 2.25 (s, 3H); 2.3 1 (s, 6H); 2.36-2.45 (m, 2H); 2.55 (M, 4H); 2.78-2.87 (m, 2H); 2.96 (t, 4.9Hz, 4H); 6.84 (s, 2H).
Composé 3 : Le composé 3 est préparé suivant la procédure décrite dans l'exemple 1 à partir des réactifs suivants triphosgeneCompound 3: Compound 3 is prepared according to the procedure described in Example 1 from the following triphosgene reagents
(172mg,0.58mmol) ; 4-méthoxy-3-(4-méthylpipérazin- l -yl)aniline (384mg, 1 .74mmol) ; triéthylamine (244μlx2, 1 .74mmolx2); l -(2,4,6- triméthylphénéthyl)pipérazine (3a) (403mg, 1 .74mmol) ; dichloromethane (40ml).(172mg, 0.58mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (384 mg, 1.74 mmol); triethylamine (244μlx2, 1.74mmolx2); 1 - (2,4,6-trimethylphenethyl) piperazine (3a) (403 mg, 1.74 mmol); dichloromethane (40ml).
Le brut est purifié par chromatographie-éclair avec un mélange (92/8/ 1 ) puis (90/9/ 1 ) de dichlorométhane/méthanol/ammoniaque.The crude is purified by flash chromatography with a mixture (92/8/1) then (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 792 mg (Rdt : 95 %)Mass obtained: 792 mg (Yield: 95%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C28H4 1 N5O2-2C4H4O4-O.64H2O- O.5C4H 1 0OElementary Analysis for: C28H4 1 N5O2-2C4H4O4-O.64H2O- O.5C4H 1 0O
Calculées: C 60.02 ; H 7.33 ; N 9.21 ; Expérimentales: C 59.87 ; H 7.26 ; N 9. 1 8Calculated: C 60.02; H 7.33; N 9.21; Experimental: C 59.87; H 7.26; N 9. 1 8
Masse (DCI/NH3 ) : 480(MH+),248,233, 136 IR (KBr) : 3440,2914,1683,1643,1512,1262,985Mass (DCI / NH3): 480 (MH +), 248.233, 136 IR (KBr): 3440,2914,1683,1643,1512,1262,985
RMN IH (DMSO) : 2.16 (s,3H); 2.23 -s,6H); 2.40 (M,5H); 2.49 (M,4H); 2.74 (M,6H); 3.00 (M,4H); 3.45 (M,4H); 3.72 (s,3H);6.58 (s,4H); 6.80 (m,3H); 7.05 (m,2H); 8.29 (s,lH).1 H NMR (DMSO): 2.16 (s, 3H); 2.23 -s, 6H); 2.40 (M, 5H); 2.49 (M, 4H); 2.74 (M, 6H); 3.00 (M, 4H); 3.45 (M, 4H); 3.72 (s, 3H); 6.58 (s, 4H); 6.80 (m, 3H); 7.05 (m, 2H); 8.29 (s, 1H).
Point de fusion : 103°CMelting point: 103 ° C
EXEMPLE 4EXAMPLE 4
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl)-4-(2- trifluorométhylphénéthyI)pipérazin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) -4- (2-trifluoromethylphenethyl) piperazin-1-ylamide fumarate
Figure imgf000033_0001
Figure imgf000033_0001
Composé 4a : l-(2-trifluorométhylbenzylcarbonyl)-4-(/έ?r/- butyloxycarbonyl) pipérazineCompound 4a: l- (2-trifluoromethylbenzylcarbonyl) -4 - (/ έ? R / - butyloxycarbonyl) piperazine
Le composé 4a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants acide (2- trifluorométhylphényl)acétique (1.14g,5.56mmol); l-tert- butyloxycarbonylpipérazine (1.04g,5.56mmol); chlorhydrate de la l-(3- diméthylaminopropyl)-3-éthylcarbodiimide (1.07g,5.56mmol); 4- diméthylaminopyridine (une pointe de spatule); dichloromethane (50ml). Le brut est engagé directement dans l'étape suivante.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.
Masse obtenue : 1.92g (Rdt : 93%)Mass obtained: 1.92g (Yield: 93%)
RMN IH (CDCl3) : 1.43 (s,9H); 3.40 (M,6H); 3.62 (M,2H); 3.86 (s,2H); 7.35 (te,7.5Hz,2H); 7.50 (d,7.6Hz,lH); 7.63 (d,7.5Hz, IH). Composé 4b; l-(2-trifluorométhylbenzylcarbonyl)pipérazinc1 H NMR (CDCl 3 ): 1.43 (s, 9H); 3.40 (M, 6H); 3.62 (M, 2H); 3.86 (s, 2H); 7.35 (te, 7.5Hz, 2H); 7.50 (d, 7.6Hz, 1H); 7.63 (d, 7.5Hz, IH). Compound 4b; l- (2-trifluoromethylbenzylcarbonyl) piperazinc
Le composé 4b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 4a (1.92g,5.15mmol); acide trifluoroacétique (4.7ml), dichloromethane (25ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque. Masse obtenue : 866 mg (Rdt : 62%)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%)
RMN IH (CDCl3) : 2.75-2.88 (m,4H); 3.41 (t,4.4Hz,2H); 3.64 (t,4.9Hz,2H); 3.87 (s,2H); 7.36 (M,2H); 7.50 (d,7.4Hz,lH); 7.65 (de,8.9Hz,lH).1 H NMR (CDCl 3 ): 2.75-2.88 (m, 4H); 3.41 (t, 4.4Hz, 2H); 3.64 (t, 4.9Hz, 2H); 3.87 (s, 2H); 7.36 (M, 2H); 7.50 (d, 7.4Hz, 1H); 7.65 (from, 8.9Hz, 1H).
Composé 4c : l-(2-trifluorométhylphénéthyl)pipérazineCompound 4c: 1- (2-trifluoromethylphenethyl) piperazine
Le composé 4c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants composé 4b (866mg,3.18mmol); hydrure de lithium et d'aluminium (4.8ml d'une solution 1M dans l'éther éthylique, 4.8mmol); éther éthylique (15ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 385mg (Rdt : 45%)Mass obtained: 385 mg (Yield: 45%)
RMN IH (CDC13) : 1.84 (se,lH); 2.53 (M,6H); 2.92 (M,6H); 7.24-7.62 (m,4H).IH NMR (CDC1 3): 1.84 (sc, lH); 2.53 (M, 6H); 2.92 (M, 6H); 7.24-7.62 (m, 4H).
Composé 4 : Le composé 4 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : triphosgene (150mg,0.50mmol) ; 4-méthoxy-3-(4-méthylpipérazin-l-yl)aniline (310mg,1.19mmol) ; pyridine (130μlx2,1.64mmolx2) ; l-(2- trifluorométhylphénéthyl)pipérazine (4c) (385mg, 1.19mmol) ; dichloromethane (40ml). Le brut est purifié par chromatographie-éclair avec un mélange (80/20/1) de dichlorométhane/méthanol/ammoniaque.Compound 4: 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 (130μlx2,1.64mmolx2); 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.
Masse obtenue : 423 mg (Rdt : 70 %)Mass obtained: 423 mg (Yield: 70%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C26H34F3N5O2-C4H4O4-O.55H2OElementary Analysis for: C26H34F3N5O2-C4H4O4-O.55H2O
Calculées: C 57.05 ; H 6.24 ; N 11.09 ; Expérimentales: C 56.92 ; H 6.35 ; N 10.80Calculated: C 57.05; H 6.24; N 11.09; Experimental: C 56.92; H 6.35; No. 10.80
IR (KBr) : 3422,2952,2838,1642,1508IR (KBr): 3422,2952,2838,1642,1508
RMN IH (DMSO) : 2.40 (s,3H); 2.51 (M,6H); 2.72 (M,4H); 3.01 (M,6H); 3.45 (M,4H); 3.74 (s,3H); 6.59 (s,2H); 6.81 (d,8.7Hz,lH); 7.08 (m,2H); 7.40-7.72 (m,4H); 8.31 (s,lH).1 H NMR (DMSO): 2.40 (s, 3H); 2.51 (M, 6H); 2.72 (M, 4H); 3.01 (M, 6H); 3.45 (M, 4H); 3.74 (s, 3H); 6.59 (s, 2H); 6.81 (d, 8.7Hz, 1H); 7.08 (m, 2H); 7.40-7.72 (m, 4H); 8.31 (s, 1H).
Point de fusion : 124°CMelting point: 124 ° C
EXEMPLE 5EXAMPLE 5
Fumarate du 4-(2-méthylbenzylcarbonyl)pipérazin-l-yloate de [4- chloro-3-(4-méthy!pipérazin-l -y 1)] phényle4- (2-methylbenzylcarbonyl) piperazin-1-yloate [4- chloro-3- (4-methyl! Piperazin-1-y 1)] phenyl fumarate
Figure imgf000035_0001
Composé 5a : l -(2-méthyIbenzylcarbonyI)-4-(/έ?/7-butyloxy carbonyl) pipérazine
Figure imgf000035_0001
Compound 5a: l - (2-methylIbenzylcarbonyI) -4 - (/ έ? / 7-butyloxy carbonyl) piperazine
Le composé 5a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide o-tolylacétique (500mg,3.3mmol); l -/e/-/-butyloxycarbonylpipérazine (620mg,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,
3.3mmol); chlorhydrate de la l -(3-diméthylaminopropyl)-3- éthylcarbodiimide (688mg,3.3mmol); triéthymamine (460ml,3.3mmol); 4-diméthylaminopyridine (une pointe de spatule); dichloromethane (30ml). Le brut est purifié par chromatographie-éclair avec un mélange ( 100/0/ 1 ) puis (95/5/1 ) de dichlorométhane/méthanol/ammoniaque.3.3mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (688mg, 3.3mmol); triethymamine (460ml, 3.3mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (30ml). The crude is purified by flash chromatography with a mixture (100/0/1) and then (95/5/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 803mg (Rdt : 76%)Mass obtained: 803 mg (YId: 76%)
Analyse Elémentaire pour: C ι gH26N2θ3Elementary Analysis for: C ι gH26N2θ3
Calculées: C 67.90 ; H 8.23 ; N 8.80 ; Expérimentales: C 67.49 ; H 8.21 ; N 8.74Calculated: C 67.90; H 8.23; N 8.80; Experimental: C 67.49; H 8.21; No. 8.74
IR (KBr) : 2972,2913 , 1 701 , 1636IR (KBr): 2972.2913, 1,701, 1636
RMN IH (CDCl3) : 1 .42 (s,9H); 2.25 (s,3 H); 3.36 (M,6H); 3.60 (M,2H); 3.73 (s,2H); 7.05-7. 1 5 (m,4H).1 H NMR (CDCl 3 ): 1.42 (s, 9H); 2.25 (s, 3H); 3.36 (M, 6H); 3.60 (M, 2H); 3.73 (s, 2H); 7.05-7. 1 5 (m, 4H).
Composé 5b: l-(2-méthylbenzylcarbonyl)pipérazineCompound 5b: 1- (2-methylbenzylcarbonyl) piperazine
Le composé 5b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 5a (765mg,2.4mmol); acide trifluoroacétique (2.2ml), dichloromethane ( 12ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1 ) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 436 mg (Rdt : 83%)Mass obtained: 436 mg (Yield: 83%)
Analyse Elémentaire pour: C 1 3H 1 8N2O Calculées: C 69.80 ; H 8.38 ; N 12.52 ; Expérimentales: C 69.93 ; H 8.44 ; N 12.44Elementary Analysis for: C 1 3H 1 8N2O Calculated: C 69.80; H 8.38; N 12.52; Experimental: C 69.93; H 8.44; N 12.44
RMN IH (CDCl3) : 2.26 (s,3H); 2.71 (t,4.8Hz,2H); 2.83 (t,5.1 Hz,2H); 3.37 (t,5.OHz,2H); 3.64 (t,5.1Hz,2H); 3.66 (s,2H); 4.75 (s,lH); 7.14 (m,4H).1 H NMR (CDCl 3 ): 2.26 (s, 3H); 2.71 (t, 4.8Hz, 2H); 2.83 (t, 5.1 Hz, 2H); 3.37 (t, 5.OHz, 2H); 3.64 (t, 5.1Hz, 2H); 3.66 (s, 2H); 4.75 (s, 1H); 7.14 (m, 4H).
Composé 5c : l-chlorocarbonyl-4-(2-méthylbenzylcarbonyl) pipérazineCompound 5c: l-chlorocarbonyl-4- (2-methylbenzylcarbonyl) piperazine
Une solution du composé 5b (300mg,l .37mmol) et de pyridine (110ml,1.37mmol) dans le dichloromethane (10ml) est canulée lentement sur une solution de triphosgene (136mg,0.46mmol) dans le dichloromethane (10ml) maintenue à 0°C. Le mélange est ensuite ramené à température ambiante et laissé l/2h avant d'être dilué avec de l'eau. La phase organique est alors lavée avec une solution saturée en chlorure de sodium, séchée sur sulfate de magnésium et concentrée. Le brut est purifié par chromatographie-éclair avec un mélange (40/60) d'éther de pétrole/acétate d'éthyle .A solution of compound 5b (300mg, 1.37mmol) and pyridine (110ml, 1.37mmol) in dichloromethane (10ml) is slowly cannulated on a solution of triphosgene (136mg, 0.46mmol) in dichloromethane (10ml) kept at 0 ° C. The mixture is then brought back to room temperature and left 1/2 hour before being diluted with water. The organic phase is then washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified by flash chromatography with a mixture (40/60) of petroleum ether / ethyl acetate.
Masse obtenue : 26img (Rdt : 67%)Mass obtained: 26img (Yield: 67%)
IR (KBr) : 2923,2890,1721,1643IR (KBr): 2923.2890,1721,1643
RMN IH (CDCl3) : 2.26 (s,3H); 3.45-3.71 (M,8H); 3.68 (s,2H); 7.12 (m,4H).1 H NMR (CDCl 3 ): 2.26 (s, 3H); 3.45-3.71 (M, 8H); 3.68 (s, 2H); 7.12 (m, 4H).
Composé 5 : Une solution de 4-chloro-3-(4-méthylpipérazin-l- yl)phénol préparé suivant la méthode décrite dans le brevet français n° 9408981 (21 lmg,0.93mmol) dans le tétrahydrofurane (4ml) est canulée sur une suspension d'hydrure de sodium (50%,49mg,l .02mmol) dans le tétrahydrofurane (10ml) maintenue à 0°C. Le mélange réactionnel est ensuite ramené à température ambiante et agité pendant 20mn. Après ce temps, une solution du composé 5c (261 mg,0.93 mmol) est additionnée et le mélange est agité pendant encore l h. Il est dilué avec de l'eau et extrait trois fois avec de l'acétate d'éthyle. Les phases organiques réunies sont lavées avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium, filtrées et concentrées. Le brut est purifié par chromatographie-éclair avec un mélange (95/5/ 1 ) de dichlorométhane/méthanol/ammoniaque.Compound 5: A solution of 4-chloro-3- (4-methylpiperazin-1-yl) phenol prepared according to the method described in French patent n ° 9408981 (21 mg, 0.93mmol) in tetrahydrofuran (4ml) is cannulated on a suspension of sodium hydride (50%, 49mg, 1.02mmol) in tetrahydrofuran (10ml) maintained at 0 ° C. The reaction mixture is then brought to ambient temperature and stirred for 20 min. After this In time, a solution of compound 5c (261 mg, 0.93 mmol) is added and the mixture is stirred for a further 1 h. It is diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 394 mg (Rdt : 90 %)Mass obtained: 394 mg (Yield: 90%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H3 1 CIN4O3-C4H4O4Elementary Analysis for: C25H3 1 CIN4O3-C4H4O4
Calculées: C 59.33 ; H 6.01 ; N 9.54 ; Expérimentales: C 59.43 ; H 6.05 ; N 9.56Calculated: C 59.33; H 6.01; N 9.54; Experimental: C 59.43; H 6.05; No. 9.56
Masse (DCI/NH3) : 47 1 (MH+), 437, 339, 219, 1 36Mass (DCI / NH3): 47 1 (MH +), 437, 339, 219, 1 36
IR (KBr) : 3450,3009,2927,2853 , 1 698, 1 646, 1428, 1242IR (KBr): 3450.3009.2927.2853, 1 698, 1 646, 1428, 1242
RMN IH (DMSO) : 2.21 (s,3H); 2.33 (s,3H); 2.63 (M,4H); 3.01 (M,4H); 3.45 (M,2H); 3.60 (M,6H); 3.74 (s,2H); 6.60 (s,2H); 6.85 (dd, 2.7 et 8.7 Hz, l H); 6.95 (d,2.6 Hz, l H); 7.07-7. 1 6 (m,4H); 7.41 (d,8.6 Hz, l H).1 H NMR (DMSO): 2.21 (s, 3H); 2.33 (s, 3H); 2.63 (M, 4H); 3.01 (M, 4H); 3.45 (M, 2H); 3.60 (M, 6H); 3.74 (s, 2H); 6.60 (s, 2H); 6.85 (dd, 2.7 and 8.7 Hz, l H); 6.95 (d, 2.6 Hz, 1 H); 7.07-7. 16 (m, 4H); 7.41 (d, 8.6 Hz, l H).
Point de fusion : 189°C EXEMPLE 6Melting point: 189 ° C EXAMPLE 6
Hcmifumarate du 4-(4-nitrophénéthyl)pipérazin-l-yloate de (4- chloro-3-(4-méthyIpipérazin-l-yl)] phényle4- (4-nitrophenethyl) piperazin-1-yloate (4-chloro-3- (4-methylpiperazin-1-yl)] phenyl hcmifumarate
Figure imgf000039_0001
X £
Figure imgf000039_0001
X £
Composé 6a : l-(4-nitrophénéthyl)pipérazineCompound 6a: 1- (4-nitrophenethyl) piperazine
Une solution de bromure de 4-nitrophénéthyle (1.58g;6.52mmol) est agitée pendant deux heures à température ambiante en présence de pipérazine (2.81g; 32.6mmol) et de carbonate de césium (3.19g;9.8mmol) dans le DMF (60ml) . Le mélange réactionnel est ensuite concentré, puis repris dans l'eau et extrait trois fois à l'acétate d'éthyle. Les phases organiques sont réunies, lavées avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium, filtrées et concentrées. Le brut réactionnel est purifié par chromatographie-éclair avec un gradient de (95/5/1) à (85/15/1) de dichlorométhane/méthanol/ammoniaqueA solution of 4-nitrophenethyl bromide (1.58g; 6.52mmol) is stirred for two hours at room temperature in the presence of piperazine (2.81g; 32.6mmol) and cesium carbonate (3.19g; 9.8mmol) in DMF ( 60ml). The reaction mixture is then concentrated, then taken up in water and extracted three times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude reaction product is purified by flash chromatography with a gradient from (95/5/1) to (85/15/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 1.046 g (Rdt : 68 %)Mass obtained: 1.046 g (Yield: 68%)
Analyse Elémentaire pour: C12H17N3O2Elementary Analysis for: C12H17N3O2
Calculées: C 61.26 ; H 7.28 ; N 17.86 ; Expérimentales: C 61.10 ; H 7.27 ; N 17.53Calculated: C 61.26; H 7.28; N 17.86; Experimental: C 61.10; H 7.27; N 17.53
IR (KBr) : 3266,2950,2815,1516,1344IR (KBr): 3266,2950,2815,1516,1344
RMN IH (CDCI3) : 1.85 (s, IH), 2.47 (m, 4H), 2.56 (m, 2H), 2.87 (m, 6H, ), 7.33 (d, 8.6Hz, 2H), 8.11 (d, 8.7Hz, 2H). Composé 6b : l-chlorocarbonyl-4-(/?-nitrophénéthyl)pipérazine1 H NMR (CDCI3): 1.85 (s, IH), 2.47 (m, 4H), 2.56 (m, 2H), 2.87 (m, 6H,), 7.33 (d, 8.6Hz, 2H), 8.11 (d, 8.7 Hz, 2H). Compound 6b: l-chlorocarbonyl-4 - (/? - nitrophenethyl) piperazine
Le composé 6b est préparé suivant la procédure décrite pour le composé 5c à partir des produits suivants l-(4- nitrophénéthyl)pipérazine (397mg,1.69 mmol), triphosgeneCompound 6b is prepared according to the procedure described for compound 5c from the following products 1- (4-nitrophenethyl) piperazine (397 mg, 1.69 mmol), triphosgene
(168 mg, 0.57 mmol), pyridine (137ml, 1.69mmol), dichloromethane (30ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (100/1) de dichlorométhane/ammoniaque puis (95/5/1) de dichlorométhane/méthanol/ammoniaque .(168 mg, 0.57 mmol), pyridine (137ml, 1.69mmol), dichloromethane (30ml). The crude reaction product is purified by flash chromatography with a mixture (100/1) of dichloromethane / ammonia and then (95/5/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 216mg (Rdt : 43%)Mass obtained: 216 mg (Yield: 43%)
IR (KBr) : 2940,2810,1730,1508,1340IR (KBr): 2940,2810,1730,1508,1340
Masse : 298 (MH+).Mass: 298 (MH +).
RMN ]H (CDCl3) : 2.57 (M, 4H), 2.69 (t,7.4Hz, 2H), 2.93 (t,7.4Hz,2H), 3.67 (M, 2H), 3.76 (M, 2H), 7.37 (d,8.6Hz, 2H,), 8.16 (d,8.6Hz, 2H).NMR ] H (CDCl 3 ): 2.57 (M, 4H), 2.69 (t, 7.4Hz, 2H), 2.93 (t, 7.4Hz, 2H), 3.67 (M, 2H), 3.76 (M, 2H), 7.37 (d, 8.6Hz, 2H,), 8.16 (d, 8.6Hz, 2H).
Composé 6 :Compound 6:
Le composé 6 est préparé suivant la procédure décrite pour le composé 5 à partir des réactifs suivants 4-chloro-3-(4-méthylpipérazin-l- yl)phénol (148 mg,0.66mmol), composé 6b (195mg,0.66mmol), hydrure de sodium (50%, 34.6mg,0.72mmol), THF (17ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque .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.
Masse obtenue : 273 mg (Rdt : 85%).Mass obtained: 273 mg (Yield: 85%).
Analyse élémentaire pour C24H30CIN5O4-O.5C4H4O4-O.2H2O calculée C 56.78 H 5.94 N 12.73 Cl 6.45 ; expérimentale C 56.79 H 5.89 N 12.28 Cl 6.22. Masse (DCI/NH3) : 488 (MH+).Elemental analysis for C24H30CIN5O4-O.5C4H4O4-O.2H2O calculated C 56.78 H 5.94 N 12.73 Cl 6.45; experimental C 56.79 H 5.89 N 12.28 Cl 6.22. Mass (DCI / NH3): 488 (MH +).
IR (KBr) : 2924,2834,1789,1518,1342.IR (KBr): 2924.2834,1789,1518,1342.
RMN lH (DMSO) : 2.28 (s,3H), 2.5 (m,8H), 2.63 (t,7.7Hz,2H), 2.92 (t,7.6Hz,2H), 2.96 (M,4H), 3.42 (M,2H), 3.55 (M,2H), 6.60 (s,lH), 6.82 (dd,2.6 et 8.6Hz,lH), 6.90 (d,2.6Hz,lH), 7.39 (d,8.5Hz,lH), 7.55 (d, 8.7Hz, 2H), 8.16 (d, 8.7Hz, 2H).1 H NMR (DMSO): 2.28 (s, 3H), 2.5 (m, 8H), 2.63 (t, 7.7Hz, 2H), 2.92 (t, 7.6Hz, 2H), 2.96 (M, 4H), 3.42 (M , 2H), 3.55 (M, 2H), 6.60 (s, lH), 6.82 (dd, 2.6 and 8.6Hz, lH), 6.90 (d, 2.6Hz, lH), 7.39 (d, 8.5Hz, lH), 7.55 (d, 8.7Hz, 2H), 8.16 (d, 8.7Hz, 2H).
Point de fusion : 184 °C.Melting point: 184 ° C.
EXEMPLE 7EXAMPLE 7
Fumarate du N- [4-méthoxy-3-(4-méthylpipérazin-l -y I) phenyl] -4-(3- phénylpropan-l-yl)pipérazin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-y I) phenyl] -4- (3-phenylpropan-1-yl) piperazin-1-ylamide fumarate
Figure imgf000041_0001
Figure imgf000041_0001
Composé 7a : N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl|-4- /erf-butyloxycarbonylpipérazin-l-ylamideCompound 7a: N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl | -4- / erf-butyloxycarbonylpiperazin-1-ylamide
Le composé 7a est préparé suivant la procédure décrite dans l'exemple 1 à partir des réactifs suivants : triphosgene (2.21g,7.75mmol) ; 4- méthoxy-3-(4-méthylpipérazin-l-yl)aniline (4.94g,22.36mmol) ; pyridine (1.81mlx2,22.36mmolx2) ; l-(/er/-butyloxycarbonyl) pipérazine (4.16g, 22.36mmol) ; dichloromethane (200ml).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).
Masse obtenue : 9.55g (Rdt brut : 99%) RMN IH (CDCI3) : 1.43 (s,9H); 2.55 (s,3H); 2.90 (M,4H); 3.16 (M,4H); 3.42 (M,8H); 3.77 (s,3H); 6.71 (d,10.1Hz,lH); 6.93 (d,2.3Hz,lH); 7.18 (m,lH); 7.44 (s,lH).Mass obtained: 9.55g (gross yield: 99%) 1 H NMR (CDCI3): 1.43 (s, 9H); 2.55 (s, 3H); 2.90 (M, 4H); 3.16 (M, 4H); 3.42 (M, 8H); 3.77 (s, 3H); 6.71 (d, 10.1Hz, 1H); 6.93 (d, 2.3Hz, 1H); 7.18 (m, 1H); 7.44 (s, 1H).
Composé 7b: N-[4-méthoxy-3-(4-méthylpipérazin-l-yI)phényl]-4- pipérazin-1-ylamideCompound 7b: N- [4-methoxy-3- (4-methylpiperazin-1-yI) phenyl] -4- piperazin-1-ylamide
Le composé 7b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 7a (9.55g,22mmol); acide trifluoroacétique (15ml), dichloromethane (150ml). Après la neutralisation de l'acide trifluoroacétique, les deux phases sont évaporées sous pression réduite puis le brut obtenu est filtré sur silice avec un mélange (60/40/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 6.06g (Rdt: 83%)Mass obtained: 6.06g (Yield: 83%)
RMN IH (DMSO): 2.22 (s,3H); 2.45 (M,4H); 2.67 (M,4H); 2.93 (M,4H); 3.32 (M,4H); 3.72 (s,3H); 6.78 (d,8.6Hz,lH); 7.01-7.09 (m,2H); 8.18 (s,lH).1 H NMR (DMSO): 2.22 (s, 3H); 2.45 (M, 4H); 2.67 (M, 4H); 2.93 (M, 4H); 3.32 (M, 4H); 3.72 (s, 3H); 6.78 (d, 8.6Hz, 1H); 7.01-7.09 (m, 2H); 8.18 (s, 1H).
Composé 7 : Le composé 7 est préparé suivant la procédure décrite pour le composé 6a à partir des réactifs suivants : composé 7b (587mg,1.76mmol); l-bromo-3-phénylpropane (330ml, 2.1 lmmol); carbonate de césium (860mg,2.64mmol); diméthylformamide (20ml). le brut est purifié par chromatographie-éclair avec un mélange (91/9/1) de (dichlorométhane/méthanol/ammoniaque). Deux produits sont isolés.Compound 7: 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.
* Composé le moins polaire : N-[4-méthoxy-3-(4-méthylpipérazin-l- yl)phényl]-4-(3-phénylpropan-l-yloxycarbonyl)pipérazin-l-ylamide* Less polar compound: N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- (3-phenylpropan-1-yloxycarbonyl) piperazin-1-ylamide
Masse obtenue : 187mg (Rdt : 24%) RMN IH (CDCI3) : 1.99 (m,2H); 2.41 (M,3H); 2.71 (M,6H); 3.14 (M,4H); 3.48 (M,8H); 3.83 (s,3H); 4.14 (t,6.5Hz,2H); 6.33 (s,lH); 6.77 (d,8.6Hz,lH); 6.93-7.01 (m,2H); 7.16-7.28 (m,5H).Mass obtained: 187mg (Yield: 24%) 1 H NMR (CDCI3): 1.99 (m, 2H); 2.41 (M, 3H); 2.71 (M, 6H); 3.14 (M, 4H); 3.48 (M, 8H); 3.83 (s, 3H); 4.14 (t, 6.5Hz, 2H); 6.33 (s, 1H); 6.77 (d, 8.6Hz, 1H); 6.93-7.01 (m, 2H); 7.16-7.28 (m, 5H).
* Composé le plus polaire : composé 7* Most polar compound: compound 7
Masse obtenue : 300mg (Rdt : 38%)Mass obtained: 300mg (Yield: 38%)
Analyse Elémentaire pour: C26H37N5O2-l.2C4H4O4-O.5H2O Calculées: C 61.67 ; H 7.19 ; N 11.67 ; Expérimentales: C 61.54 ; H 7.57 ; N 11.69Elemental Analysis for: C26H37N5O2-1.2C4H4O4-O.5H2O Calculated: C 61.67; H 7.19; N 11.67; Experimental: C 61.54; H 7.57; N 11.69
IR (KBr): 3435,3026,2938,2838,1649,1508IR (KBr): 3435,3026,2938,2838,1649,1508
RMN IH (DMSO) : 1.76 (m,2H); 2.37 (M,9H); 2.56-2.68 (M,6H); 2.99 (M,4H); 3.42 (M,4H); 3.73 (s,3H); 6.58 (s,2.4H); 6.79 (d,8.7Hz,lH); 7.04-7.09 (m,2H); 7.20-7.32 (m,5H); 8.08 (s,lH).1 H NMR (DMSO): 1.76 (m, 2H); 2.37 (M, 9H); 2.56-2.68 (M, 6H); 2.99 (M, 4H); 3.42 (M, 4H); 3.73 (s, 3H); 6.58 (s, 2.4H); 6.79 (d, 8.7Hz, 1H); 7.04-7.09 (m, 2H); 7.20-7.32 (m, 5H); 8.08 (s, 1H).
Point de fusion : 164°CMelting point: 164 ° C
EXEMPLE 8EXAMPLE 8
Dif uma rate du 4-[2-(2,3-diméthylphényloxy)éthane-l-yl)pipérazin-Diff uma rate of 4- [2- (2,3-dimethylphenyloxy) ethane-1-yl) piperazin-
1-yloate de [4-chloro-3-(4-méthylpipérazin-l-yl)]phényIe[4-chloro-3- (4-methylpiperazin-1-yl)] phenyl 1-yloate
Figure imgf000043_0001
Composé 8a : 2-chloro- l-(4-ι'er/-butyloxycarbonylpipérazin-l -yl) éthanonc
Figure imgf000043_0001
Compound 8a: 2-chloro- l- (4-ι'er / -butyloxycarbonylpiperazin-l -yl) ethanonc
Le chlorure de chloroacetyle (2.42ml,30.4mmol) est ajouté goutte à goutte à une solution de l -/ert-butyloxycarbonylpipérazine (5. 1 5g,27.6mmol) et de carbonate de calcium (8.34g,83.4mmol) dans la méthyléthylcétone (60ml) refroidie à 0°C. Le mélange réactionnel est agité à cette température pendant 1 h 30 puis il est filtré sur Célite. La Célite est rincée plusieurs fois avec de l'acétate d'éthyle et une solution de soude 3M . Les deux phases du filtrat sont ensuite séparées et la phase organique est séchée sur sulfate de magnésium, filtrée et concentrée pour donner le produit attendu.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.
Masse obtenue : 4.07g (Rdt : 56%)Mass obtained: 4.07g (Yield: 56%)
RMN 1 H (DMSO) : 1 .41 (s,9H); 3.36-3.64 (M,8H); 4.03 (s,2H).1 H NMR (DMSO): 1.41 (s, 9H); 3.36-3.64 (M, 8H); 4.03 (s, 2H).
Composé 8b : 2-(2,3-diméthyIphényloxy)-l-(4-/er/'-butyloxy carbonyl pipérazin-l-yl)éthanoneCompound 8b: 2- (2,3-dimethylphenyloxy) -1- (4- / er / '- butyloxy carbonyl piperazin-1-yl) ethanone
Le composé 8b est préparé suivant la procédure décrite pour le composé 6a à partir des réactifs suivants composé 8aCompound 8b is prepared according to the procedure described for compound 6a from the following reagents compound 8a
( 1 .33 g,5.07mmol); 2,3-diméthylphénol (620mg,5.07mmol); carbonate de césium (3.3g, 1 0.1 mmol); diméthylformamide (20ml). Le mélange est agité pendant 12h. Le brut est purifié par chromatographie-éclair avec un mélange (91 /9/1 ) de (dichlorométhane/méthanol/ammoniaque) . Masse obtenue : 1 .95g (Rdt quantitatif)(1.33 g, 5.07mmol); 2,3-dimethylphenol (620mg, 5.07mmol); cesium carbonate (3.3g, 1 0.1 mmol); dimethylformamide (20ml). The mixture is stirred for 12 hours. The crude is purified by flash chromatography with a mixture (91/9/1) of (dichloromethane / methanol / ammonia). Mass obtained: 1.95g (quantitative yield)
RMN I H (CDCl3) : 1 .41 (s,9H); 2. 1 1 (s,3H); 2.21 (s,3 H); 3.37 (M,4H); 3.52 (M,4H); 4.62 (s,2H); 6.62 (d,7.6Hz, l H); 6.75 (d,7.4Hz, l H); 6.98 (t,7.8Hz, l H). Composé 8c: 2-(2,3-diméthyIphényloxy)-l-(pipérazin-l-yl)éthanone1 H NMR (CDCl 3 ): 1.41 (s, 9H); 2. 1 1 (s, 3H); 2.21 (s, 3H); 3.37 (M, 4H); 3.52 (M, 4H); 4.62 (s, 2H); 6.62 (d, 7.6 Hz, 1 H); 6.75 (d, 7.4Hz, 1H); 6.98 (t, 7.8Hz, l H). Compound 8c: 2- (2,3-dimethylphenyloxy) -1- (piperazin-1-yl) ethanone
Le composé 8c est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants composé 8b (1.95g,5.07mmol); acide trifluoroacétique (5.0ml), dichloromethane (25ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 991mg (Rdt : 79%)Mass obtained: 991 mg (YId: 79%)
RMN IH (CDCl3) : 2.18 (s,3H); 2.27 (s,3H); 2.85 (t,5. lHz,4H); 3.60 (M,4H); 4.67 (s,2H); 6.73 (d,8.2Hz,lH); 6.81 (d,7.5Hz,lH); 7.05 (t,7.9Hz,lH).1 H NMR (CDCl 3 ): 2.18 (s, 3H); 2.27 (s, 3H); 2.85 (t, 5.lHz, 4H); 3.60 (M, 4H); 4.67 (s, 2H); 6.73 (d, 8.2Hz, 1H); 6.81 (d, 7.5Hz, 1H); 7.05 (t, 7.9Hz, 1H).
Composé 8d : l-(2,3-diméthylphényloxyéthan-l-yl)pipérazineCompound 8d: 1- (2,3-dimethylphenyloxyethan-1-yl) piperazine
Le composé 8d est préparé suivant la procédure décrite pour le composé 3a à partir des réactifs suivants : composé 8c (515mg,2.08mmol); hydrure de lithium et d'aluminium (3.1ml d'une solution 1M dans le tétrahydrofurane, 3. lmmol); éther éthylique (10ml). La réaction dure 3h. Le brut réactionnel est engagé tel quel dans l'étape suivante.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.
Masse obtenue : 354mg (Rdt : 73%)Mass obtained: 354 mg (YId: 73%)
Composé 8e : l-chIorocarbonyI-4-(2,3-dimcthylphényloxyéthan-l- yl)pipérazineCompound 8e: l-chIorocarbonyI-4- (2,3-dimcthylphenyloxyéthan-l-yl) piperazine
Le composé 8e est préparé suivant la procédure décrite pour le composé 5c à partir des réactifs suivants : composé 8dCompound 8e is prepared according to the procedure described for compound 5c from the following reagents: compound 8d
(354mg,1.51mmol); triphosgene (150mg,0.50mmol); pyridine(354mg, 1.51mmol); triphosgene (150mg, 0.50mmol); pyridine
(125ml, 1.51mmoI); dichloromethane (40ml). Le brut réactionnel est purifié avec un gradient de (99.5/0.5/0.5) à (95/5/1) de dichlorométhane/méthanol/ammoniaque.(125ml, 1.51mmoI); dichloromethane (40ml). The reaction crude is purified with a gradient from (99.5 / 0.5 / 0.5) to (95/5/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 336mg (Rdt : 75%)Mass obtained: 336 mg (Yield: 75%)
RMN IH (CDCl3) : 2.14 (s,3H); 2.27 (s,3H); 2.66 (t,5.2Hz,4H); 2.88 (t,5.4Hz,2H); 3.64-3.77 (M,4H); 4.09 (t,5.4Hz,2H); 6.68 (d,8.1HZ,1H); 6.79 (d,7.5Hz,lH); 7.04 (t,7.8Hz,lH).1 H NMR (CDCl 3 ): 2.14 (s, 3H); 2.27 (s, 3H); 2.66 (t, 5.2Hz, 4H); 2.88 (t, 5.4Hz, 2H); 3.64-3.77 (M, 4H); 4.09 (t, 5.4Hz, 2H); 6.68 (d, 8.1HZ, 1H); 6.79 (d, 7.5Hz, 1H); 7.04 (t, 7.8Hz, 1H).
composé 8 :compound 8:
Le composé 8 est préparé suivant la procédure décrite pour le composé 5 à partir des réactifs suivants composé 8eCompound 8 is prepared according to the procedure described for compound 5 from the following reagents compound 8e
(333mg,1.12mmol); 4-chloro-3-(4-méthylpipérazin-l-yl)phénol(333mg, 1.12mmol); 4-chloro-3- (4-methylpiperazin-l-yl) phenol
(255mg,1.12mmol); hydrure de sodium (50%,50mg,l .12mmol); tétrahydrofuranne (20ml). Le brut réactionnel est purifié avec un mélange (95/5/1) puis (90/9/1) de dichlorométhane/méthanol/ammoniaque.(255mg, 1.12mmol); sodium hydride (50%, 50mg, 1.12mmol); tetrahydrofuran (20ml). The crude reaction product is purified with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 379mg (Rdt : 70%)Mass obtained: 379 mg (YId: 70%)
Analyse Elémentaire pour: C26H35CIN4O3-2C4H4O4-O.65H2O Calculées: C 55.87 ; H 6.11 ; N 7.67 ; Expérimentales: C 55.63 ; H 6.10 ; N 7.58Elemental Analysis for: C26H35CIN4O3-2C4H4O4-O.65H2O Calculated: C 55.87; H 6.11; N 7.67; Experimental: C 55.63; H 6.10; N 7.58
IR (KBr): 3434,2940,1722,1591,1255IR (KBr): 3434,2940,1722,1591,1255
RMN IH (DMSO) : 2.09 (s,3H); 2.2 (s,3H); 2.37 (s,3H); 2.2.60 (M,4H); 2.67 (M,4H); 2.81 (t,5.5Hz,2H); 3.03 (M,4H); 3.45 (M,2H); 3.59 (M,2H); 4.08 (t,5.6Hz,2H); 6.62 (s,4H); 6.74-7.07 (m,5H); 7.40 (d,8.5Hz,lH).1 H NMR (DMSO): 2.09 (s, 3H); 2.2 (s, 3H); 2.37 (s, 3H); 2.2.60 (M, 4H); 2.67 (M, 4H); 2.81 (t, 5.5Hz, 2H); 3.03 (M, 4H); 3.45 (M, 2H); 3.59 (M, 2H); 4.08 (t, 5.6Hz, 2H); 6.62 (s, 4H); 6.74-7.07 (m, 5H); 7.40 (d, 8.5Hz, 1H).
Point de fusion : 85 °C EXEMPLE 9Melting point: 85 ° C EXAMPLE 9
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-[3-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- [3- fumarate
(4-fluorophényl)-3-oxopropan-l-yl)pipérazin-l-yiamidc(4-fluorophenyl) -3-oxopropan-1-yl) piperazin-1-yiamidc
Figure imgf000047_0001
Figure imgf000047_0001
Une solution de 3-chloro-4-fluoropropiophénone (340mg;1.8mmol) est agitée pendant 5h à température ambiante en présence de N-[4- méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-pipérazin-l-ylamide (7b) (500mg; 1.5mmol), carbonate de potassium (310mg;2.25mmol) et d'iodure de potassium (une pointe de spatule) dans la méthyléthylcétone (20ml) . Le mélange réactionnel est ensuite versé dans l'eau et extrait trois fois à l'acétate d'éthyle. Les phases organiques sont réunies, lavées avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium, filtrées et concentrées. Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.A solution of 3-chloro-4-fluoropropiophenone (340 mg; 1.8 mmol) is stirred for 5 h at room temperature in the presence of N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4-piperazine -l-ylamide (7b) (500mg; 1.5mmol), potassium carbonate (310mg; 2.25mmol) and potassium iodide (a tip of a spatula) in methyl ethyl ketone (20ml). The reaction mixture is then poured into water and extracted three times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 440mg (Rdt : 76%)Mass obtained: 440mg (YId: 76%)
Analyse Elémentaire pour: C26H34FN5O3-C4H4O4-O.45H2O Calculées: C 59.29 ; H 6.45 ; N 11.52 ; Expérimentales: C 59.16 ; H 6.42 ; N 11.34Elemental Analysis for: C26H34FN5O3-C4H4O4-O.45H2O Calculated: C 59.29; H 6.45; N 11.52; Experimental: C 59.16; H 6.42; N 11.34
IR (KBr): 3435,3314,2838,1689,1602,1508IR (KBr): 3435,3314,2838,1689,1602,1508
RMN IH (DMSO) : 2.33 (s,3H); 2.43 (M,4H); 2.62 (M,4H); 2.70 (t,7.0Hz,2H); 2.96 (M,4H); 3.23 (t,7.1Hz,2H); 3.39 (M,4H); 3.71 (s,3H); 6.57 (s,2H); 6.78 (d,8.7Hz,lH); 7.02-7.08 (m,2H); 7.35 (t,8.8Hz,2H); 8.07 (dd,5.5 et 8.8Hz,2H); 8.27 (s,lH).1 H NMR (DMSO): 2.33 (s, 3H); 2.43 (M, 4H); 2.62 (M, 4H); 2.70 (t, 7.0Hz, 2H); 2.96 (M, 4H); 3.23 (t, 7.1Hz, 2H); 3.39 (M, 4H); 3.71 (s, 3H); 6.57 (s, 2H); 6.78 (d, 8.7Hz, 1H); 7.02-7.08 (m, 2H); 7.35 (t, 8.8Hz, 2H); 8.07 (dd, 5.5 and 8.8Hz, 2H); 8.27 (s, 1H).
Point de fusion : 132°CMelting point: 132 ° C
EXEMPLE 10EXAMPLE 10
Fumarate du N-[4-méthoxy-3-(4-méthyIpipcrazin-l-yl)phényl]-4-N- [4-methoxy-3- (4-methyIpipcrazin-1-yl) phenyl] -4- fumarate
[(E)-styrylcarbonyl]pipérazin-l-ylamidc[(E) -styrylcarbonyl] piperazin-l-ylamidc
Figure imgf000048_0001
10
Figure imgf000048_0001
10
Le composé 10 est préparé suivant la procédure décrite pour le composé 2a à partir des réactifs suivants composé 7bCompound 10 is prepared according to the procedure described for compound 2a from the following reagents compound 7b
(500mg,1.5mmol); acide cinnamique (220mg,l .5mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3-éthylcarbodiimide (290mg, 1.5mmol); 4-diméthylaminopyridine (une pointe de spatule); dichloromethane (15ml). La réaction dure 5h. Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.(500mg, 1.5mmol); cinnamic acid (220mg, 1.5mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (290mg, 1.5mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (15ml). The reaction lasts 5 hours. The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 414mg (Rdt : 60%)Mass obtained: 414 mg (yield: 60%)
Analyse Elémentaire pour: C26H33N5O3-C4H4O4-O.27H2O Calculées: C 61.65 ; H 6.47 ; N 11.98 ; Expérimentales: C 61.56 ; H 6.65 ; N 11.80Elemental Analysis for: C26H33N5O3-C4H4O4-O.27H2O Calculated: C 61.65; H 6.47; N 11.98; Experimental: C 61.56; H 6.65; No. 11.80
IR (KBr) : 3395,3005,2831,1702,1642IR (KBr): 3395,3005,2831,1702,1642
RMN IH (DMSO) : 2.39 (s,3H); 2.70 (M,4H); 3.02 (M,4H); 3.41 (M,4H); 3.63 (M,2H); 3.75 (M,5H); 6.59 (s,2H); 6.83(d,8.6Hz,lH); 7.07-7.12 (M,2H); 7.28-7.59 (M,5H); 7.77 (M,2H); 8.43 (s,lH). Point de fusion : 180°C1 H NMR (DMSO): 2.39 (s, 3H); 2.70 (M, 4H); 3.02 (M, 4H); 3.41 (M, 4H); 3.63 (M, 2H); 3.75 (M, 5H); 6.59 (s, 2H); 6.83 (d, 8.6Hz, 1H); 7.07-7.12 (M, 2H); 7.28-7.59 (M, 5H); 7.77 (M, 2H); 8.43 (s, 1H). Melting point: 180 ° C
EXEMPLE 11EXAMPLE 11
Fumarate du N-[4-méthoxy-3-(4-méthyIpipérazin-l-yl)phényI]-4- (2,3-diméthylphénylcarbonyl]pipérazin-l-yIamideN- [4-methoxy-3- (4-methyIpiperazin-1-yl) phenyI] -4- (2,3-dimethylphenylcarbonyl] piperazin-l-yIamide fumarate
Figure imgf000049_0001
Figure imgf000049_0001
1111
Le composé 11 est préparé suivant la procédure décrite pour le composé 2a à partir des réactifs suivants : composé 7b (500mg,l .5mmol); acide 2,3-diméthylbenzoïque (220mg,1.5mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3-éthylcarbodiimide (290mg, 1.5mmol); 4-diméthylaminopyridine (une pointe de spatule); dichloromethane (20ml). La réaction dure 2h. Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 479mg (Rdt : 68%)Mass obtained: 479 mg (Yield: 68%)
Analyse Elémentaire pour: C26H35N5O3-C4H4O4-O.3H2O Calculées: C 61.38 ; H 6.80 ; N 11.93 ; Expérimentales: C 61.31 ; H 6.97 ; N 11.58 IR (KBr) : 3422,2918,2838,1709,1635,1508Elemental Analysis for: C26H35N5O3-C4H4O4-O.3H2O Calculated: C 61.38; H 6.80; N 11.93; Experimental: C 61.31; H 6.97; N 11.58 IR (KBr): 3422,2918,2838,1709,1635,1508
RMN IH (DMSO) : 2.10 (s,3H); 2.25 (s,3H); 2.38 (s,3H); 2.70 (M,4H); 2.98 (M,4H); 3.11 (M,2H); 3.31 (M,2H); 3.51 (M,2H); 3.68 (M,2H); 3.71 (s,3H); 6.55 (s,2H); 6.78 (d,8.7Hz,lH); 6.98-7.21 (m,5H); 8.38 (s,lH). Point de fusion : 185°C1 H NMR (DMSO): 2.10 (s, 3H); 2.25 (s, 3H); 2.38 (s, 3H); 2.70 (M, 4H); 2.98 (M, 4H); 3.11 (M, 2H); 3.31 (M, 2H); 3.51 (M, 2H); 3.68 (M, 2H); 3.71 (s, 3H); 6.55 (s, 2H); 6.78 (d, 8.7Hz, 1H); 6.98-7.21 (m, 5H); 8.38 (s, 1H). Melting point: 185 ° C
EXEMPLE 12EXAMPLE 12
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- fumarate
(2,4,5-triméthylphénylaminocarbonyl]pipérazin-l-ylamide(2,4,5-trimethylphenylaminocarbonyl] piperazin-1-ylamide
Figure imgf000050_0001
Figure imgf000050_0001
1212
Le composé 12 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants composé 7bCompound 12 is prepared according to the procedure described for compound 1 from the following reagents compound 7b
(500mg,1.5mmol); 2,4,5-triméthylaniline (200mg,l .5mmoI); triphosgene (160mg,0.55mmol); pyridine (130mlx2,1.65mmolx2); dichloromethane (30ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.(500mg, 1.5mmol); 2,4,5-trimethylaniline (200mg, 1.5mmoI); triphosgene (160mg, 0.55mmol); pyridine (130mlx2,1.65mmolx2); dichloromethane (30ml). The crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 376mg (Rdt : 51%)Mass obtained: 376 mg (Yield: 51%)
Analyse Elémentaire pour: C27H38N6O3-C4H4O4Elementary Analysis for: C27H38N6O3-C4H4O4
Calculées: C 60.97 ; H 6.93 ; N 13.76 ; Expérimentales: C 60.86 ; H 7.06 ; N 13.75Calculated: C 60.97; H 6.93; N 13.76; Experimental: C 60.86; H 7.06; N 13.75
IR (KBr) : 3301,2918,2838,1635,1510IR (KBr): 3301,2918,2838,1635,1510
RMN IH (DMSO) : 2.10 (s,6H); 2.22 (s,3H); 2.36 (s,3H); 2.67 (M,4H); 2.99 (M,4H); 3.46 (M,8H); 3.73 (s,3H); 6.58 (s,2H); 6.81 (d,8.7Hz,lH); 6.85 (s,2H); 7.05-7.11 (m,2H); 7.86 (s,lH); 8.36 (s,lH).1 H NMR (DMSO): 2.10 (s, 6H); 2.22 (s, 3H); 2.36 (s, 3H); 2.67 (M, 4H); 2.99 (M, 4H); 3.46 (M, 8H); 3.73 (s, 3H); 6.58 (s, 2H); 6.81 (d, 8.7Hz, 1H); 6.85 (s, 2H); 7.05-7.11 (m, 2H); 7.86 (s, 1H); 8.36 (s, 1H).
Point de fusion : 245°C EXEMPLE 13Melting point: 245 ° C EXAMPLE 13
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényI]-4-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) fumarate] -4-
(5,6,7,8-tétrahydronaphtylaminocarbonyljpipérazin-l-ylamide(5,6,7,8-tetrahydronaphthylaminocarbonyljpiperazin-l-ylamide
H
Figure imgf000051_0001
13 H
Figure imgf000051_0001
13
Le composé 13 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : composé 7b (604mg, 1.81 mmol); 5,6,7,8-tétrahydronaphtylamine (301mg,2.0mmol); triphosgene (202mg,0.68mmol); pyridine (162mlx2,1.81mmolx2); dichloromethane (60ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 678mg (Rdt : 74%)Mass obtained: 678 mg (Yield: 74%)
Analyse Elémentaire pour: C28H38N6O3-C4H4O4-O.55H2O-Elementary Analysis for: C28H38N6O3-C4H4O4-O.55H2O-
0.4C4HιoO0.4C 4 HιoO
Calculées: C 60.94 ; H 7.17 ; N 12.69 ; Expérimentales: C 60.97 ; HCalculated: C 60.94; H 7.17; N 12.69; Experimental: C 60.97; H
7.44 ; N 12.597.44; N 12.59
IR (KBr) : 3295,2932,2851,1642,1508IR (KBr): 3295,2932,2851,1642,1508
RMN IH (DMSO) : 1.67 (M,4H); 2.30 (s,3H); 2.59 (M,6H); 2.70 (M,2H); 2.95 (M,4H); 3.43 (M,8H); 3.71 (s,3H); 6.56 (s,2H); 6.79 (d,8.7Hz,lH); 6.87 (m,lH); 6.98-7.08 (m,4H); 7.95 (s,lH); 8.33 (s,lH).1 H NMR (DMSO): 1.67 (M, 4H); 2.30 (s, 3H); 2.59 (M, 6H); 2.70 (M, 2H); 2.95 (M, 4H); 3.43 (M, 8H); 3.71 (s, 3H); 6.56 (s, 2H); 6.79 (d, 8.7Hz, 1H); 6.87 (m, 1H); 6.98-7.08 (m, 4H); 7.95 (s, 1H); 8.33 (s, 1H).
Point de fusion : 144°C EXEMPLE 14Melting point: 144 ° C EXAMPLE 14
Fumarate du N-[4-méthoxy-3-(4-mέthylpipérazin-l-yl)phcnyI]-4-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phcnyI fumarate] -4-
(2,4,6-triméthylbenzènesuIfonyl)pipérazin-l-ylamidc(2,4,6-trimethylbenzenesuIfonyl) piperazin-1-ylamidc
Figure imgf000052_0001
14
Figure imgf000052_0001
14
Une solution de chlorure de mésytilènesulfonyle (650mg,2.97mmol) dans le dichloromethane (5ml) est ajoutée à une solution du composé 7b (500mg,1.50mmol) dans la soude 1M (1.1ml) à 0°C. Le mélange biphasique est ensuite ramené à température ambiante et agité pendant 5h. Après ce temps, les deux phases sont séparées et la phase aqueuse est extraite trois fois avec du dichloromethane. Les phases organiques réunies sont lavées avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium, filtrées et concentrées. Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (95/5/1) puis (90/9/1) de dichlorométhane/méthanol/ammoniaque.A solution of mesytilenesulfonyl chloride (650mg, 2.97mmol) in dichloromethane (5ml) is added to a solution of compound 7b (500mg, 1.50mmol) in 1M sodium hydroxide (1.1ml) at 0 ° C. The two-phase mixture is then brought to room temperature and stirred for 5 h. After this time, the two phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude reaction product is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 330mg (Rdt : 43%)Mass obtained: 330mg (Yield: 43%)
Analyse Elémentaire pour: C26H37N5O4S-C4H4O4 Calculées: C 57.04 ; H 6.54 ; N 11.09 ; Expérimentales: C 56.85 ; H 6.69 ; N 10.91Elemental Analysis for: C26H37N5O4S-C4H4O4 Calculated: C 57.04; H 6.54; N 11.09; Experimental: C 56.85; H 6.69; N 10.91
IR (KBr) : 3402,2938,2851,1642,1508IR (KBr): 3402.2938,2851,1642,1508
RMN IH (DMSO) : 2.28 (s,3H); 2.35 (s,3H); 2.56 (s,6H); 2.62 (M,4H); 3.01 (M,8H); 3.45 (M,4H); 3.71 (s,3H); 6.57 (s,2H); 6.79 (d,8.7Hz,lH); 6.98-7.16 (2H); 7.10 (s,2H); 8.40 (s,lH).1 H NMR (DMSO): 2.28 (s, 3H); 2.35 (s, 3H); 2.56 (s, 6H); 2.62 (M, 4H); 3.01 (M, 8H); 3.45 (M, 4H); 3.71 (s, 3H); 6.57 (s, 2H); 6.79 (d, 8.7Hz, 1H); 6.98-7.16 (2H); 7.10 (s, 2H); 8.40 (s, 1H).
Point de fusion : 175°C EXEMPLE 15Melting point: 175 ° C EXAMPLE 15
Fumarate du N-[4-méthoxy-3-(4-méthylpipcrazin- l-yI)phényl]-4-(2- naphtyl-2-oxoéthan-l-yl)pipérazin- l-ylamideN- [4-methoxy-3- (4-methylpipcrazin-1-yI) phenyl] -4- (2-naphthyl-2-oxoethan-1-yl) piperazin-1-ylamide fumarate
Figure imgf000053_0001
15
Figure imgf000053_0001
15
Composé 15a : (pipérazin- l-yl)méthyl-2-naphtylcétoneCompound 15a: (piperazin-1-yl) methyl-2-naphthylketone
Le composé 15a est préparé suivant la procédure décrite pour le composé 6a à partir des réactifs suivants : bromométhyl-2- naphtylcétone (5g,20mmol); pipérazine (8.6g,2.100mmol); carbonate de césium (9.8g,30mmol); diméthylformamide (200ml). le brut est purifié par chromatographie-éclair avec un mélange (85/ 1 5/ 1 ) puis (80/1 8/2) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 1 .03g (Rdt : 20.2%)Mass obtained: 1.03g (Yield: 20.2%)
RMN I H (CDCl3) : 2.64 (M,4H); 2.97 (M,4H); 3.92 (s,2H); 7.58 (m,2H); 7.83-8.03 (m,4H); 8.52 (s, l H).1 H NMR (CDCl 3 ): 2.64 (M, 4H); 2.97 (M, 4H); 3.92 (s, 2H); 7.58 (m, 2H); 7.83-8.03 (m, 4H); 8.52 (s, l H).
Composé 15 :Compound 15:
Le composé 15 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : composé 15a (588mg, 2.3 1 mmol); 4-méthoxy-3-(4-méthylpipérazin- l -yl)aniline (490mg,2.31mmol); triphosgene (250mg, 0.84mmol); pyridine (200mlx2,2.53mmolx2); dichloromethane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (95/5/ 1 ) de dichlorométhane/méthanol/ammoniaque. Masse obtenue : 248mg (Rdt : 21%)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%)
Analyse Elémentaire pour: C29H35N5O3-C4H4O4-H2O Calculées: C 62.35 ; H 6.50 ; N 11.02 ; Expérimentales: C 63.03 ; H 6.47 ; N 11.19Elemental Analysis for: C29H35N5O3-C4H4O4-H2O Calculated: C 62.35; H 6.50; N 11.02; Experimental: C 63.03; H 6.47; N 11.19
IR (KBr) : 3395,2925,2838,1514,1232IR (KBr): 3395,2925,2838,1514,1232
RMN IH (DMSO) : 2.33 (s,3H); 2.60 (M,8H); 2.96 (M,4H); 3.44 (M,4H); 3.70 (s,3H); 4.05 (s,2H); 6.56 (s,2H); 6.78 (d,8.7Hz,lH); 7.04 (m,2H); 7.64 (m,2H); 7.99 (m,2H); 8.10 (m,lH);8.27 (s,lH); 8.70 (s,lH).1 H NMR (DMSO): 2.33 (s, 3H); 2.60 (M, 8H); 2.96 (M, 4H); 3.44 (M, 4H); 3.70 (s, 3H); 4.05 (s, 2H); 6.56 (s, 2H); 6.78 (d, 8.7Hz, 1H); 7.04 (m, 2H); 7.64 (m, 2H); 7.99 (m, 2H); 8.10 (m, 1H); 8.27 (s, 1H); 8.70 (s, 1H).
Point de fusion : 123°CMelting point: 123 ° C
EXEMPLE 16EXAMPLE 16
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4- benzylpipérazin-1-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- benzylpiperazin-1-ylamide fumarate
Figure imgf000054_0001
Figure imgf000054_0001
1616
Le composé 16 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : 4-méthoxy-3-(4- méthylpipérazin-l-yl)aniline (457mg,2.07mmol); 1-benzylpipérazine (364mg,2.07mmol); triphosgene (205mg, 0.69mmol); triéthylamine (290mlx2,2.07mmolx2); dichloromethane (40ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (95/5/1) puis (90/9/1) de dichlorométhane/méthanol/ammoniaque. Masse obtenue : 776mg (Rdt : 89%)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%)
Analyse Elémentaire pour: C24H33N5O2-C4H4O4-O.25H2O Calculées: C 61.81 ; H 6.95 ; N 12.87 ; Expérimentales: C 62.17 ; H 7.04 ; N 12.81Elemental Analysis for: C24H33N5O2-C4H4O4-O.25H2O Calculated: C 61.81; H 6.95; N 12.87; Experimental: C 62.17; H 7.04; N 12.81
Masse (DCI/NH3) : 424 (MH+), 248,177,137,120Mass (DCI / NH3): 424 (MH +), 248,177,137,120
IR (KBr) : 3414,2833,1637,1604,1508,1234IR (KBr): 3414,2833,1637,1604,1508,1234
RMN IH (DMSO) : 2.35 (M,7H); 2.65 (M,4H); 2.97 (M,4H); 3.35 (M,4H); 3.49 (s,2H); 3.71 (s,3H); 6.56 (s,2H); 6.77 (d,lH); 7.04 (m,2H); 7.30 (m,5H); 8.26 (s,lH).1 H NMR (DMSO): 2.35 (M, 7H); 2.65 (M, 4H); 2.97 (M, 4H); 3.35 (M, 4H); 3.49 (s, 2H); 3.71 (s, 3H); 6.56 (s, 2H); 6.77 (d, 1H); 7.04 (m, 2H); 7.30 (m, 5H); 8.26 (s, 1H).
Point de fusion : 145°CMelting point: 145 ° C
EXEMPLE 17EXAMPLE 17
Fumarate du N- [4-méthoxy-3-(4-méthylpipérazin-l -y I) phέnyl] -4-(4- fluorobenzyl)oxopipέridin-l-ylamidεN- [4-methoxy-3- (4-methylpiperazin-l -y I) phέnyl] -4- (4-fluorobenzyl) oxopipέridin-l-ylamidε fumarate
Figure imgf000055_0001
Figure imgf000055_0001
1717
Le composé 17 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : 4-méthoxy-3-(4- méthylpipérazin-l-yl)aniline (398mg,1.80mmol); 4-fluorobenzyloxo- pipéridine (608mg,2.93mmol); triphosgene (180mg, 0.60mmol); pyridine (150mlx2,l .80mmolx2); dichloromethane (40ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (95/5/1) puis (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 646mg (Rdt : 79%)Mass obtained: 646 mg (YId: 79%)
Analyse Elémentaire pour: C25H31FN4O3-C4H4O4-O.45H2O Calculées: C 60.19 ; H 6.25 ; N 9.68 ; Expérimentales: C 60.39 ; H 6.24 ; N 9.63Elemental Analysis for: C25H31FN4O3-C4H4O4-O.45H2O Calculated: C 60.19; H 6.25; N 9.68; Experimental: C 60.39; H 6.24; N 9.63
Masse (DCI/NH3) : 455(MH+),248,208Mass (DCI / NH3): 455 (MH +), 248.208
IR (KBr) : 3400,2952,2838,1678,1638,1597,1233IR (KBr): 3400,2952,2838,1678,1638,1597,1233
RMN IH (DMSO) : 1.10 (m,2H); 1.46 (m,2H); 2.35 (s,3H); 2.74 (M,4H); 2.98 (M,6H); 3.74 (M,4H); 4.15 (de, 13 Hz,2H); 6.60 (s,2H); 6.81 (d,8.6 Hz,lH); 7.06 (m,2H); 7.39 (t,8.8 Hz,2H); 8.13 (m,2H); 8.30 (s,lH).1 H NMR (DMSO): 1.10 (m, 2H); 1.46 (m, 2H); 2.35 (s, 3H); 2.74 (M, 4H); 2.98 (M, 6H); 3.74 (M, 4H); 4.15 (de, 13 Hz, 2H); 6.60 (s, 2H); 6.81 (d, 8.6 Hz, 1H); 7.06 (m, 2H); 7.39 (t, 8.8 Hz, 2H); 8.13 (m, 2H); 8.30 (s, 1H).
Point de fusion : 118°CMelting point: 118 ° C
EXEMPLE 18EXAMPLE 18
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yI)phényl]-4- benzylpipéridin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yI) phenyl] -4-benzylpiperidin-1-ylamide fumarate
Figure imgf000056_0001
Figure imgf000056_0001
1818
Le composé 18 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants 4-méthoxy-3-(4- méthylpipérazin-l-yl)aniline (480mg,2.17mmol); benzylpipéridine (382ml,2.17mmol); triphosgene (215mg, 0.72mmol); triéthylamine (300mlx2,2.17mmolx2); dichloromethane (40ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 780mg (Rdt : 85%)Mass obtained: 780 mg (Yield: 85%)
Analyse Elémentaire pour: C25H34N4O2-C4H4O4 Calculées: C 64.67 ; H 7.11 ; N 10.40 ; Expérimentales: C 65.03 ; H 7.41 ; N 10.61Elemental Analysis for: C25H34N4O2-C4H4O4 Calculated: C 64.67; H 7.11; N 10.40; Experimental: C 65.03; H 7.41; N 10.61
Masse (DCI/NH3) : 423 (MH+),248,176Mass (DCI / NH3): 423 (MH +), 248.176
IR (KBr) : 3408,2934,2841,1707,1637,1500IR (KBr): 3408.2934.2841,1707,1637,1500
RMN IH (DMSO) : 1.07 (m,2H); 1.61 (m,3H); 2.34 (s,3H); 2.53 (M,2H); 2.63 (M, 6H); 2.98 (M,4H); 3.73 (s,3H); 4.06 (M,2H); 6.59 (s,2H); 6.79 (d,8.7 Hz,lH); 7.02-7.34 (m,7H); 8.22 (s,lH).1 H NMR (DMSO): 1.07 (m, 2H); 1.61 (m, 3H); 2.34 (s, 3H); 2.53 (M, 2H); 2.63 (M, 6H); 2.98 (M, 4H); 3.73 (s, 3H); 4.06 (M, 2H); 6.59 (s, 2H); 6.79 (d, 8.7 Hz, 1H); 7.02-7.34 (m, 7H); 8.22 (s, 1H).
Point de fusion : 160°CMelting point: 160 ° C
EXEMPLE 19EXAMPLE 19
Fumarate du N- [4-méthoxy-3-(4-méthyipipérazin-l -y 1) phenyl] -4-(3 • phénylpropan-l-yl)pipéridin-l-ylamideN- [4-methoxy-3- (4-methyipiperazin-l -y 1) phenyl] -4- (3 • phenylpropan-l-yl) piperidin-l-ylamide fumarate
Figure imgf000057_0001
Figure imgf000057_0001
1919
Le composé 19 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants 4-méthoxy-3-(4- méthylpipérazin-l-yl)aniline (516mg,2.33mmol); 4-(3-phénylpropan-l - yl)pipéridine (473mg,2.33mmol); triphosgene (231mg, 0.78mmol); triéthylamine (330mlx2,2.33mmolx2); dichloromethane (40ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (94/6/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 712mg (Rdt : 68%)Mass obtained: 712 mg (Yield: 68%)
Analyse Elémentaire pour: C27H38N4O2-2C4H4O4Elementary Analysis for: C27H38N4O2-2C4H4O4
Calculées: C 61.57 ; H 6.79 ; N 8.21 ; Expérimentales: C 61.65 ; H 6.90 ; N 8.37Calculated: C 61.57; H 6.79; N 8.21; Experimental: C 61.65; H 6.90; N 8.37
Masse (DCI/NH3) : 451 (MH+),248,204,136Mass (DCI / NH3): 451 (MH +), 248,204,136
IR (KBr) : 3384,3025,2930,2849,1709,1504IR (KBr): 3384,3025,2930,2849,1709,1504
RMN IH (DMSO) : 0.88-1.65 (m,9H); 2.38 (s,3H); 2.50 (m,2H); 2.72 (M,6H); 2.98 (M,4H); 3.69 (s,3H); 4.00 (M,1H); 4.07 (M,1H); 6.55 (s,4H); 6.75 (d,8.6 Hz,lH); 7.01-7.28 (m,7H); 8.17 (s,lH).1 H NMR (DMSO): 0.88-1.65 (m, 9H); 2.38 (s, 3H); 2.50 (m, 2H); 2.72 (M, 6H); 2.98 (M, 4H); 3.69 (s, 3H); 4.00 (M, 1H); 4.07 (M, 1H); 6.55 (s, 4H); 6.75 (d, 8.6 Hz, 1H); 7.01-7.28 (m, 7H); 8.17 (s, 1H).
EXEMPLE 20EXAMPLE 20
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4- (l,2,3,4-tétrahydronaphtyl-l)pipérazin-l-ylamidcN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- (1,2,3,4-tetrahydronaphthyl-1) piperazin-1-ylamidc fumarate
&&
Figure imgf000058_0001
Figure imgf000058_0001
20 Composé 20a : l-(l,2,3,4-tétrahydroπaphtyl)pipérazine20 Compound 20a: l- (1,2,3,4-tetrahydroπaphthyl) piperazine
Une solution de 1,2,3,4-tétrahydronaphtylamine (6ml, 41.8mmol) et du chlorhydrate de la bis(2-chloroéthyl)amine (7.44g, 41.8mmol) en présence de carbonate de sodium (2.22g,20.9mmol) dans le butanol-1 est portée au reflux pendant 48h. Après ce temps le butanol- 1 est évaporé sous pression réduite et le brut réactionnel est imprégné sur silice puis purifié par chromatographie-éclair avec un gradient de (98/2/1) à (80/20/1) de dichlorométhane/méthanol/ammoniaque.A solution of 1,2,3,4-tetrahydronaphthylamine (6ml, 41.8mmol) and bis (2-chloroethyl) amine hydrochloride (7.44g, 41.8mmol) in the presence of sodium carbonate (2.22g, 20.9mmol) in butanol-1 is brought to reflux for 48 hours. After this time the butanol-1 is evaporated under reduced pressure and the reaction crude is impregnated on silica and then purified by flash chromatography with a gradient from (98/2/1) to (80/20/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 386mg (Rdt : 4.3%)Mass obtained: 386 mg (Yield: 4.3%)
RMN IH (CDCl3) : 1.66 (m,2H); 1.93 (m,2H); 2.40-2.97 (M.10H); 3.74 (M.1H); 6.99-7.17 (m,3H); 7.68 (M,1H).1 H NMR (CDCl 3 ): 1.66 (m, 2H); 1.93 (m, 2H); 2.40-2.97 (M.10H); 3.74 (M.1H); 6.99-7.17 (m, 3H); 7.68 (M, 1H).
Composé 20 :Compound 20:
Le composé 20 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : 4-méthoxy-3-(4- méthylpipérazin-l-yl)aniline (375mg,1.70mmol); composé 20a (380mg,1.76mmol); triphosgene (168mg, 00.57mmol); triéthylamine (235mlx2,1.70mmolx2); dichloromethane (40ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (95/5/1) puis (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 470mg (Rdt : 60%)Mass obtained: 470 mg (Yield: 60%)
Analyse Elémentaire pour: C27H37N5O2-C4H4O4-O.35H2O Calculées: C 63.54 ; H 7.17 ; N 11.95 ; Expérimentales: C 63.64 ; H 7.23 ; N 12.09Elemental Analysis for: C27H37N5O2-C4H4O4-O.35H2O Calculated: C 63.54; H 7.17; N 11.95; Experimental: C 63.64; H 7.23; N 12.09
Masse (DCI/NH3) : 464 (MH+),248,217,136Mass (DCI / NH3): 464 (MH +), 248,217,136
IR (KBr) : 3395,2932,2835,1707,1637,1604,1506,1232 RMN IH (DMSO) : 1.62 (m,2H); 1.91 (m,2H); 2.35 (s,3H); 2.51 (M,4H); 2.67 (M,6H); 2.98 (M,4H); 3.44 (M,4H); 3.73 (s,3H); 3.84 (M,1H); 6.59 (s,2H); 6.80(d,8.6Hz,lH); 7.12 (m, 5H); 7.63 (m,lH); 8.27 (s,lH).IR (KBr): 3395,2932,2835,1707,1637,1604,1506,1232 1 H NMR (DMSO): 1.62 (m, 2H); 1.91 (m, 2H); 2.35 (s, 3H); 2.51 (M, 4H); 2.67 (M, 6H); 2.98 (M, 4H); 3.44 (M, 4H); 3.73 (s, 3H); 3.84 (M, 1H); 6.59 (s, 2H); 6.80 (d, 8.6Hz, 1H); 7.12 (m, 5H); 7.63 (m, 1H); 8.27 (s, 1H).
Point de fusion : 110-111°CMelting point: 110-111 ° C
EXEMPLE 21EXAMPLE 21
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phénylJ-4- (l,2,3,4-tétrahydronaphtyl-2)pipérazin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenylJ-4- (1,2,3,4-tetrahydronaphthyl-2) piperazin-1-ylamide fumarate
Figure imgf000060_0001
21
Figure imgf000060_0001
21
Composé 21a : 2-(l,2,3,4-tétrahydronaphtyl)pipérazineCompound 21a: 2- (1,2,3,4-tetrahydronaphthyl) piperazine
Une solution de b-tétralone (970mg,6.6mmol) et de pipérazine (2.85mg,33.0mmol) dans le toluène (30ml) est porté au reflux en présence d'acide para-toluènesulfonique (pointe de spatule) avec entraînement azéotropique de l'eau. Après 48h, le mélange réactionnel est refroidi et dilué avec de l'éthanol (30ml). Il est ensuite placé sous pression d'hydrogène (45 PSI) en présence d'oxyde de platine (116mg). Au bout de 7h, le mélange est filtré sur Célite, concentré sous pression réduite et purifié par chromatographie-éclair avec un mélange (95/5/1) à (90/9/1) de dichlorométhane/méthanol/ammoniaque.A solution of b-tetralone (970mg, 6.6mmol) and piperazine (2.85mg, 33.0mmol) in toluene (30ml) is brought to reflux in the presence of para-toluenesulfonic acid (tip of spatula) with azeotropic entrainment of l 'water. After 48 hours, the reaction mixture is cooled and diluted with ethanol (30 ml). It is then placed under hydrogen pressure (45 PSI) in the presence of platinum oxide (116 mg). After 7 hours, the mixture is filtered through Celite, concentrated under reduced pressure and purified by flash chromatography with a mixture (95/5/1) to (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 970mg (Rdt : 68%)Mass obtained: 970 mg (Yield: 68%)
Masse (DCI/NH3) : 217 (MH+), 177, 148, 132,110 RMN IH (CDCI3) : 1.65 (m,lH); 2.10 (M,2H); 2.63-2.97 (M,13H); 7.09 (s,4H).Mass (DCI / NH3): 217 (MH +), 177, 148, 132,110 1 H NMR (CDCI3): 1.65 (m, 1H); 2.10 (M, 2H); 2.63-2.97 (M, 13H); 7.09 (s, 4H).
Composé 21 : Le composé 21 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants 4-méthoxy-3-(4- méthylpipérazin-l-yl)aniline (665mg,3.00mmol); composé 21a (680mg,3.15mmol); triphosgene (297mg, 3.00mmol); triéthylamine (243mlx2,3.00mmolx2); dichloromethane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.Compound 21: 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.
Masse obtenue : 931mg (Rdt : 67%)Mass obtained: 931 mg (Yield: 67%)
Analyse Elémentaire pour: C27H37N5O2-I.2C4H4O4-H2OElemental Analysis for: C27H37N5O2-I.2C4H4O4-H2O
Calculées: C 61.51 ; H 7.11 ; N 11.28 ; Expérimentales: C 61.45 ; H 6.79 ;N 10.94Calculated: C 61.51; H 7.11; N 11.28; Experimental: C 61.45; H 6.79; N 10.94
Masse (DCI/NH3) : 464 (MH+),248,217,180,136Mass (DCI / NH3): 464 (MH +), 248,217,180,136
IR (KBr) : 3301,2932,2844,1663,1508,1239IR (KBr): 3301,2932,2844,1663,1508,1239
RMN IH (DMSO) : 1.60 (M,1H); 1.99 (M,1H); 2.35 (s,3H); 2.56-2.67 (M.13H); 2.97 (M,4H); 3.40 (M,4H); 3.70 (s,3H); 6.56 (s,2.4H); 6.78 (d,8.7Hz,lH); 7.05 (M,6H); 8.27 (s,lH).1 H NMR (DMSO): 1.60 (M, 1H); 1.99 (M, 1H); 2.35 (s, 3H); 2.56-2.67 (M.13H); 2.97 (M, 4H); 3.40 (M, 4H); 3.70 (s, 3H); 6.56 (s, 2.4H); 6.78 (d, 8.7Hz, 1H); 7.05 (M, 6H); 8.27 (s, 1H).
Point de fusion : 168-170°C Melting point: 168-170 ° C
EXEMPLE 22EXAMPLE 22
N-[4-méthoxy-3-(4-méthylpipérazin- l-yl)phényl]-4-phénylcarboxami dopipéridin-1-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4-phenylcarboxami dopiperidin-1-ylamide
Figure imgf000062_0001
Figure imgf000062_0001
2222
Composé 22a : l-benzyl-4-phénylcarboxamidopipéridineCompound 22a: l-benzyl-4-phenylcarboxamidopiperidine
Le dichlorhydrate monohydraté de la l -benzyl-4-aminopipéridine (9g,34mmol) est dessalifié puis mis en solution dans le dichloromethane (70ml) en présence de triéthylamine (7.13ml,51mmol). Celle-ci est refroidie dans un bain de glace puis le chlorure de benzoyle (3.74ml,40mmol) est additionné lentement. Le mélange réactionnel est ensuite ramené à température ambiante, agité l Omn puis versé sur un bain de glace. Le pH de la phase aqueuse est ramené à ~ 1 1 avec une solution de soude diluée puis les phases sont séparées. La phase organique est lavée avec une solution saturée en chlorure de sodium avant d'être séchée sur sulfate de magnésium, filtrée et concentrée.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.
Masse obtenue : 8.8g (Rdt brut : 88%)Mass obtained: 8.8g (gross yield: 88%)
RMN IH (CDCI3) : 1 .46 (m,2H); 2.01 (M,2H); 2.1 7 (td,2.3 et 1 1 .6Hz,2H); 2.85 (M,2H); 3.5 1 (s,2H); 4.012 (m, l H); 6.00 (de, l H); 7.3 1 (M,6H); 7.48 (M,2H); 7.73 (dd, 1 .4 et 5.6Hz,2H). Composé 22b : 4-phénylcarboxamidopipéridine1 H NMR (CDCI3): 1.46 (m, 2H); 2.01 (M, 2H); 2.1 7 (td, 2.3 and 11.6 Hz, 2H); 2.85 (M, 2H); 3.5 1 (s, 2H); 4.012 (m, 1H); 6.00 (de, l H); 7.3 1 (M, 6H); 7.48 (M, 2H); 7.73 (dd, 1 .4 and 5.6Hz, 2H). Compound 22b: 4-phenylcarboxamidopiperidine
Le composé 22a (3.55g, 12mmol) dissous dans le méthanol (160ml) est placé sous pression d'hydrogène (40 PSI) en présence d'hydroxyde de palladium et d'acide acétique (20ml) pendant 4h. Le mélange réactionnel est ensuite filtré sur Célite et concentré. L'huile obtenue est dissoute dans le dichloromethane et lavée trois fois avec une solution de soude 4M. La phase organique est séchée sur sulfate de magnésium, filtrée et concentrée.Compound 22a (3.55g, 12mmol) dissolved in methanol (160ml) is placed under hydrogen pressure (40 PSI) in the presence of palladium hydroxide and acetic acid (20ml) for 4h. The reaction mixture is then filtered through Celite and concentrated. The oil obtained is dissolved in dichloromethane and washed three times with a 4M sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and concentrated.
Masse obtenue : 1.13g (Rdt brut : 46%)Mass obtained: 1.13g (gross yield: 46%)
RMN IH (CDCI3) : 1.46 (m,2H); 2.05 (M,2H); 2.76 (td.2.4^ et 12.1Hz,2H); 3.17 (M.2H); 4.10 (m,lH); 6.17 (de,lH); 7.44 (M,3H); 7.75 (dd,1.5 et 7.5Hz,2H).1 H NMR (CDCI3): 1.46 (m, 2H); 2.05 (M, 2H); 2.76 (td.2.4 ^ and 12.1Hz, 2H); 3.17 (M.2H); 4.10 (m, 1H); 6.17 (from, 1H); 7.44 (M, 3H); 7.75 (dd, 1.5 and 7.5Hz, 2H).
Composé 22 :Compound 22:
Le composé 22 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants 4-méthoxy-3-(4- méthylpipérazin-l-yl)aniline (433mg,l .96mmol); composé 22b (400mg,1.96mmol); triphosgene (210mg, 0.72mmol); pyridine (170mlx2,2.15mmolx2); dichloromethane (60ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 353mg (Rdt : 40%)Mass obtained: 353 mg (Yield: 40%)
RMN IH (CDCI3) : 1.46 (m,2H); 2.10 (m,2H); 2.34 (s,3H); 2.611 H NMR (CDCI3): 1.46 (m, 2H); 2.10 (m, 2H); 2.34 (s, 3H); 2.61
(M,4H); 3.12 (M,6H); 3.82 (s,3H); 4.18 (de,2H); 4.22 (M,1H); 6.03 (d,7.7Hz,lH); 6.28 (s,lH); 6.75 (d,9.4Hz,lH); 6.95 (m,2H); 7.45 (m,3H); 7.75 (dd,1.8 et 6.0Hz,2H). EXEMPLE 23(M, 4H); 3.12 (M, 6H); 3.82 (s, 3H); 4.18 (from, 2H); 4.22 (M, 1H); 6.03 (d, 7.7Hz, 1H); 6.28 (s, 1H); 6.75 (d, 9.4Hz, 1H); 6.95 (m, 2H); 7.45 (m, 3H); 7.75 (dd, 1.8 and 6.0Hz, 2H). EXAMPLE 23
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-(2- fluorophénéthyl)pipérazin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- (2-fluorophenethyl) piperazin-1-ylamide fumarate
Figure imgf000064_0001
23
Figure imgf000064_0001
23
Composé 23a : l-(2-fluorobenzyIcarbonyl)-4-(/er/-butyloxycarbonyl) pipérazineCompound 23a: 1- (2-fluorobenzycarbonyl) -4 - (/ er / -butyloxycarbonyl) piperazine
Le composé 23a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide (2-fluorophényl)acétiqueCompound 23a is prepared according to the same procedure as that described for compound 2a from the following reagents: (2-fluorophenyl) acetic acid
(5.50g,35.7mmol); l-/ert-butyloxycarbonylpipérazine (6.65g,35.7mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3-éthylcarbodiimide(5.50g, 35.7mmol); 1- / ert-butyloxycarbonylpiperazine (6.65g, 35.7mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
(6.84g,35.7mmol); 4-diméthylaminopyridine (une pointe de spatule); dichloromethane (100ml). Le brut réactionnel est purifié par chromatographie- éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque.(6.84g, 35.7mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (100ml). The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 9.50g (Rdt : 83%)Mass obtained: 9.50g (Yield: 83%)
RMN IH (CDCI3) : 1.47 (s,9H); 3.31-3.47 (M,6H); 3.62 (M,2H); 3.75 (s,2H); 7.02-7.34 (m,4H).1 H NMR (CDCI3): 1.47 (s, 9H); 3.31-3.47 (M, 6H); 3.62 (M, 2H); 3.75 (s, 2H); 7.02-7.34 (m, 4H).
Composé 23b: l-(2-fluorobenzylcarbonyl)pipérazineCompound 23b: 1- (2-fluorobenzylcarbonyl) piperazine
Le composé 23b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 23a (9.49g,29.5mmol); acide trifluoroacétique (20ml),dichlorométhane (200ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1 ) de dichlorométhane/méthanol/ammoniaque. Masse obtenue : 4.63g (Rdt : 71%)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%)
RMN IH (CDCI3) : 2.69-2.82 (m,4H); 3.43 (t,5.1Hz,2H); 3.59 (t,5.1Hz,2H); 3.69 (s,2H); 6.97-7.31 (m,4H).1 H NMR (CDCI3): 2.69-2.82 (m, 4H); 3.43 (t, 5.1Hz, 2H); 3.59 (t, 5.1Hz, 2H); 3.69 (s, 2H); 6.97-7.31 (m, 4H).
Composé 23c : l-(2-fluorophénéthyl)pipérazineCompound 23c: 1- (2-fluorophenethyl) piperazine
Le composé 23c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 23b (3.53g, 15.9mmol); hydrure de lithium et d'aluminium (25ml d'une solution IM dans l'éther éthylique,25mmol); éther éthylique (50ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1 ) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 2.43g (Rdt : 73%)Mass obtained: 2.43g (YId: 73%)
RMN IH (CDCI3) : 1.86 (se,lH); 2.55 (M,6H); 2.90 (M,6H); 6.94-7.22(m,4H).1 H NMR (CDCI3): 1.86 (sc, 1H); 2.55 (M, 6H); 2.90 (M, 6H); 6.94-7.22 (m, 4H).
Composé 23 : Le composé 23 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : triphosgene (371mg,1.25mmol) ; 4- méthoxy-3-(4-méthylpipérazin-l-yl)aniline (828mg,3.75mmoI) ; pyridineCompound 23: 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
(305μlx2,3.75mmolx2) ; l-(2-fluorophénéthyl)pipérazine (23c) (780mg,(305μlx2.3.75mmolx2); l- (2-fluorophenethyl) piperazine (23c) (780mg,
3.75mmol) ; dichloromethane (70ml).3.75mmol); dichloromethane (70ml).
Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1 ) de dichlorométhane/méthanol/ammoniaque.The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 1.49g (Rdt : 87 %)Mass obtained: 1.49g (Yield: 87%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H34FN5O2-C4H4O4-O.3H2O Calculées: C 60.36 ; H 6.74 ; N 12.014 ; Expérimentales: C 60.77 ; H 6.93 ; N 12.31Elementary Analysis for: C25H34FN5O2-C4H4O4-O.3H2O Calculated: C 60.36; H 6.74; N 12,014; Experimental: C 60.77; H 6.93; N 12.31
Masse (DCI/NH3) : 456(MH+),248,209Mass (DCI / NH3): 456 (MH +), 248.209
IR (KBr) : 3395,2952,2831, 1642,1595, 1508,1232,977IR (KBr): 3395,2952,2831, 1642,1595, 1508,1232,977
RMN IH (DMSO) : 2.33 (s,3H); 2.45 (M,4H); 2.51 (m,2H); 2.63 (M,4H); 2.77 (te,2H); 2.96 (M,4H); 3.39 (M,4H); 3.70 (s,3H); 6.55 (s,2H); 6.77 (d,8.7Hz,lH); 7.01-7.36 (m,6H); 8.25 (s,lH).1 H NMR (DMSO): 2.33 (s, 3H); 2.45 (M, 4H); 2.51 (m, 2H); 2.63 (M, 4H); 2.77 (te, 2H); 2.96 (M, 4H); 3.39 (M, 4H); 3.70 (s, 3H); 6.55 (s, 2H); 6.77 (d, 8.7Hz, 1H); 7.01-7.36 (m, 6H); 8.25 (s, 1H).
Point de fusion : 102- 105°CMelting point: 102-105 ° C
EXEMPLE 24 Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yI)phényI]-4- phénoxypipéridin-1-ylamideEXAMPLE 24 N- [4-methoxy-3- (4-methylpiperazin-1-yI) phenyl] fumarate -4- phenoxypiperidin-1-ylamide
o
Figure imgf000066_0001
o 24 ^> o
Figure imgf000066_0001
o 24 ^>
Composé 24a : l-benzyl-4-phénoxypipéridineCompound 24a: l-benzyl-4-phenoxypiperidine
Une solution de diéthylazodicarboxylate (8.7ml; 20.91mmol; 40% dans le toluène) diluée dans le tétrahydrofurane (20ml) est ajoutée goutte à goutte à une solution de l-benzyl-4-hydroxypipéridine (4.0g,20.92mmol) , phénol (1.95g,20.92mmol) et triphénylphosphine (5.48g,20.89mmol) dans le tétrahydrofurane (50ml). Le mélange réactionnel est agité pendant 43h puis il est versé sur de la glace et extrait trois fois avec de l'acétate d'éthyle. Les phases organiques réunies sont ensuite lavées avec une solution saturée en chlorure de sodium, séchées sur sulfate de sodium, filtrées et concentrées. Le brut réactionnnel est imprégné sur silice puis purifié par chromatographie-éclair avec un mélange (50/50/0) puis (50/50/5) d 'éther de pétrole/acétate d'éthyle/éthanol.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.
Masse obtenue : 4.15g (Rdt : 74%)Mass obtained: 4.15g (Yield: 74%)
RMN IH (CDCI3) : 1.80 (m,2H); 1.95 (M,2H); 2.27 (M,2H); 2.72 (M,2H); 3.52 (s,2H); 4.30 (m,lH); 6.91 (M,3H); 7.28 (M,7H).1 H NMR (CDCI3): 1.80 (m, 2H); 1.95 (M, 2H); 2.27 (M, 2H); 2.72 (M, 2H); 3.52 (s, 2H); 4.30 (m, 1H); 6.91 (M, 3H); 7.28 (M, 7H).
Composé 24b : 4-phénoxypipéridineCompound 24b: 4-phenoxypiperidine
1010
Le composé 24b est préparé suivant la procédure décrite pour le composé 22b à partir des réactifs suivants : composé 24a (4.14g, 15.5mmol); hydroxyde de palladium (300mg); acide acétique (50ml); méthanol (160ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (70/30/1) puis (60/40/1) d'éther !5 de pétrole/éthanol/ammoniaque.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.
Masse obtenue : 1.35g (Rdt : 49%)Mass obtained: 1.35g (Yield: 49%)
RMN IH (CDCI3) ; 1.69 (m,3H); 2.00 (M,2H); 2.73 (m,2H); 3.16 (m,2H); 0 4.37 (m, IH); 6.94 (M,3H); 7.28 (M,2H).1 H NMR (CDCI3); 1.69 (m, 3H); 2.00 (M, 2H); 2.73 (m, 2H); 3.16 (m, 2H); 0 4.37 (m, 1H); 6.94 (M, 3H); 7.28 (M, 2H).
Composé 24 :Compound 24:
Le composé 24 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : 4-méthoxy-3-(4-méthylpipérazin- l-yl)aniline 5 (500mg,2.26mmol); composé 24b (400mg,2.26mmol); triphosgene (225mg, 0.76mmol); pyridine (175mlx2,2.26mmolx2); dichloromethane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
30 Masse obtenue : 592mg (Rdt : 62%)30 Mass obtained: 592 mg (Yield: 62%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther. Analyse Elémentaire pour: C24H32N4O3- 1.1 C4H4O4-O.2H2O-0.1 C4H 1 QO Calculées: C 61.42 ; H 6.76 ; N 9.95 ; Expérimentales: C 61.24 ; H 7.10 ; N 9.64This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether. Elemental Analysis for: C24H32N4O3- 1.1 C4H4O4-O.2H2O-0.1 C4H 1 QO Calculated: C 61.42; H 6.76; N 9.95; Experimental: C 61.24; H 7.10; N 9.64
Masse (DCI/NH3) : 425 (MH+),280,248, 192Mass (DCI / NH3): 425 (MH +), 280.248, 192
IR (KBr) : 3408,2945,2838, 1642,1602,1508, 1232IR (KBr): 3408.2945.2838, 1642.1602.1508, 1232
RMN IH (DMSO) : 1.55 (M,2H); 1.93 (M,2H); 2.34 (s,3H); 2.63 (M,4H); 2.98 (M,4H); 3.24 (M,2H); 3.72 (s,3H); 3.84 (m,2H); 4.58 (m, lH); 6.58 (s, 1.8H); 6.80 (d,8.6Hz,lH); 6.89-7.05 (m,5H); 2.29 (m,2H); 8.33 (s,lH).1 H NMR (DMSO): 1.55 (M, 2H); 1.93 (M, 2H); 2.34 (s, 3H); 2.63 (M, 4H); 2.98 (M, 4H); 3.24 (M, 2H); 3.72 (s, 3H); 3.84 (m, 2H); 4.58 (m, 1H); 6.58 (s, 1.8H); 6.80 (d, 8.6Hz, 1H); 6.89-7.05 (m, 5H); 2.29 (m, 2H); 8.33 (s, 1H).
Point de fusion : 104°C (amoφhe)Melting point: 104 ° C (amoφhe)
EXEMPLE 25 fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4- anilinopipéridin-l-ylamideEXAMPLE 25 N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4-anilinopiperidin-1-ylamide fumarate
&
Figure imgf000068_0001
^ \< y &
Figure imgf000068_0001
^ \ <y
Composé 25a : l-benzyl-4-anilinopipéridineCompound 25a: l-benzyl-4-anilinopiperidine
Une solution de cyanoborohydrure de sodium (1.45g,23.0mmol) dans l'éthanol (30ml) est ajoutée goutte à goutte à une solution de l-benzyl-4-pipéridone (3.2ml, 15.2mmol), aniline (1.5ml, 15.8mmol) et acide acétique ( 1.9ml,25.5mmol) dans l'éthanol (45ml) à température ambiante. Après 5h, le mélange réactionnel est versé sur un bain de glace puis il est basifié avec de la soude IN (15ml) et extrait trois fois avec de l'acétate d'éthyle. Les phases organiques réunies sont alors lavées avec de l'eau, séchées sur sulfate de magnésium et concentrées. Le brut réactionnel est imprégné sur silice et purifié par chromatagraphie-éclair avec un mélange (70/50/5/1) puis (70/50/10/1 ) d'éther de pétrole/acétate d'éthyle/éthanol/ ammoniaque.A solution of sodium cyanoborohydride (1.45g, 23.0mmol) in ethanol (30ml) is added dropwise to a solution of l-benzyl-4-piperidone (3.2ml, 15.2mmol), aniline (1.5ml, 15.8 mmol) and acetic acid (1.9ml, 25.5mmol) in ethanol (45ml) at room temperature. After 5 h, the reaction mixture is poured onto an ice bath and then it is basified with IN sodium hydroxide solution (15 ml) and extracted three times with ethyl acetate. The combined organic phases are then washed with water, dried over magnesium sulfate and concentrated. 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.
Masse obtenue : 3.45g (Rdt : 76%)Mass obtained: 3.45g (Yield: 76%)
RMN IH (CDCI3) : 1.47 (M,2H); 2.03-2.23 (M,4H); 2.85 (M,2H); 3.32 (m, lH); 4.54 (s,2H); 6.65 (M,3H); 7.13-7.36 (M,7H).1 H NMR (CDCl3): 1.47 (M, 2H); 2.03-2.23 (M, 4H); 2.85 (M, 2H); 3.32 (m, 1H); 4.54 (s, 2H); 6.65 (M, 3H); 7.13-7.36 (M, 7H).
Composé 25b : 4-anilinopipéridineCompound 25b: 4-anilinopiperidine
Le composé 25b est préparé suivant la procédure décrite pour le composé 22b à partir des réactifs suivants : composé 25a (3.43g,12.0mmol); hydroxyde de palladium (440mg); acide acétique (40ml); méthanol (160ml). Le brut réactionnel est purifié par chromatographie-éclair avec un gradient de (90/10) à (100/0) de (dichloroméfhane/méthanol).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).
Masse obtenue : 1.04g (Rdt : 49%)Mass obtained: 1.04g (Yield: 49%)
RMN IH (CDCI3) : 1.33 (M,2H); 1.74 (M,1H); 2.05 (M,2H); 2.72 (m,2H); 3.1 1 (m,2H); 3.37 (m,lH); 3.40 M, 1H); 6.63 (M,3H); 7.17 (M,2H).1 H NMR (CDCl3): 1.33 (M, 2H); 1.74 (M, 1H); 2.05 (M, 2H); 2.72 (m, 2H); 3.1 1 (m, 2H); 3.37 (m, 1H); 3.40 M, 1H); 6.63 (M, 3H); 7.17 (M, 2H).
Composé 25 :Compound 25:
Le composé 25 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : 4-méthoxy-3-(4-méthylpipérazin-l-yl)aniline (500mg,2.26mmol); composé 25b (400mg,2.26mmol); triphosgene (225mg, 0.76mmol); pyridine (315mlx2,4.01mmolx2); dichloromethane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 120mg (Rdt : 12%)Mass obtained: 120mg (Yield: 12%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther. Analyse Elémentaire pour: C24H33N5O2- 1.6C4H4O4-O.5H2O-O.4C4H \ QO Calculées: C 59.32 ; H 6.91 ; N 10.81 ; Expérimentales: C 59.35 ; H 7.16 ; N 1 1.03This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether. Elementary Analysis for: C24H33N5O2- 1.6C4H4O4-O.5H2O-O.4C4H \ QO Calculated: C 59.32; H 6.91; N 10.81; Experimental: C 59.35; H 7.16; N 1 1.03
Masse (DCI/NH3) : 424 (MH+),280,248,222, 177Mass (DCI / NH3): 424 (MH +), 280,248,222, 177
IR (KBr) : 3415,2938,2838, 1602, 1508,1226IR (KBr): 3415.2938.2838, 1602, 1508.1226
RMN IH (DMSO) : 1.25 (M,2H); 1.90 (M,2H); 2.35 (s,3H); 2.66 (M,4H); 2.89 (M,2H); 2.96 (M,4H); 3.42 (M, 1H); 3.71 (s,3H); 3.98 (M, 1H); 4.06 (m,lH); 6.49 (m,2H); 6.57 (s,3.2H); 6.60 (se,lH); 6.78 (d,8.6Hz,lH); 7.01-7.09 (m,4H); 8.28 (s, lH).1 H NMR (DMSO): 1.25 (M, 2H); 1.90 (M, 2H); 2.35 (s, 3H); 2.66 (M, 4H); 2.89 (M, 2H); 2.96 (M, 4H); 3.42 (M, 1H); 3.71 (s, 3H); 3.98 (M, 1H); 4.06 (m, 1H); 6.49 (m, 2H); 6.57 (s, 3.2H); 6.60 (sc, 1H); 6.78 (d, 8.6Hz, 1H); 7.01-7.09 (m, 4H); 8.28 (s, 1H).
Point de fusion : 120°C (amoφhe)Melting point: 120 ° C (amoφhe)
EXEMPLE 26EXAMPLE 26
Fumarate du N-[4-méthoxy-3-(4-méthyIpipérazin-l-yl)phényl]-4-N- [4-methoxy-3- (4-methyIpiperazin-1-yl) phenyl] fumarate -4-
(benzylcarbonyl)pipérazin-l-ylamide(benzylcarbonyl) piperazin-l-ylamide
Figure imgf000070_0001
Figure imgf000070_0001
Une solution du composé 7b (630mg,1.89mmol) et d'acide phénylacétique (257mg,1.89mmol) dans le dichloromethane (30ml) est agitée pendant 12h à température ambiante en présence du chlorhydrate de la l-(3- diméthylaminopropyl)-3-éthylcarbodiimide (362mg, 1.89mmo!) et de 4- diméthylaminopyridine (une pointe de spatule). Le mélange réactionnel est ensuite dilué avec de l'eau puis les phases sont séparées. La phase organique est lavée avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium, filtrée et concentrée. Le brut est purifié par chromatographie- éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.A solution of compound 7b (630mg, 1.89mmol) and phenylacetic acid (257mg, 1.89mmol) in dichloromethane (30ml) is stirred for 12 h at room temperature in the presence of 1- (3- dimethylaminopropyl) -3 hydrochloride -ethylcarbodiimide (362mg, 1.89mmo!) and 4-dimethylaminopyridine (a tip of a spatula). The reaction mixture is then diluted with water and then the phases are separated. The organic phase is washed with saturated sodium chloride solution, dried over sulfate magnesium, filtered and concentrated. The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 640 mg (Rdt : 75 %)Mass obtained: 640 mg (Yield: 75%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H35N5O3-C4H4O4-O.35H2OElementary Analysis for: C25H35N5O3-C4H4O4-O.35H2O
Calculées: C 60.69 ; H 6.62 ; N 12.20 ; Expérimentales: C 60.21 ; H 6.73 ; N 11.92Calculated: C 60.69; H 6.62; N 12.20; Experimental: C 60.21; H 6.73; N 11.92
Masse (DCI/NH3) : 452 (MH+),248,205Mass (DCI / NH3): 452 (MH +), 248.205
IR (KBr) : 3395,3012,2925,2838,1709,1635,1508, 1232,984IR (KBr): 3395,3012,2925,2838,1709,1635,1508, 1232,984
RMN IH (DMSO) : 2.35 (s,3H); 2.65 (M,4H); 2.98 (M,4H); 3.37 (M,4H); 3.52 (M,4H); 3.73 (s,3H); 3.77 (s,2H); 6.59 (s,2H); 6.80 (d,8.7Hz,lH); 7.03-7.09 (m,2H); 7.23-7.36 (m,5H); 8.35 (s,lH).1 H NMR (DMSO): 2.35 (s, 3H); 2.65 (M, 4H); 2.98 (M, 4H); 3.37 (M, 4H); 3.52 (M, 4H); 3.73 (s, 3H); 3.77 (s, 2H); 6.59 (s, 2H); 6.80 (d, 8.7Hz, 1H); 7.03-7.09 (m, 2H); 7.23-7.36 (m, 5H); 8.35 (s, 1H).
Point de fusion : 118- 120°CMelting point: 118-120 ° C
EXEMPLE 27 Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-EXAMPLE 27 N- [4-Methoxy-3- (4-methylpiperazin-1-yl) phenyl] fumarate -4-
(benzylsulfonyl)pipérazin-l-yiamide(benzylsulfonyl) piperazin-1-yiamide
Figure imgf000071_0001
Figure imgf000071_0001
27 Une solution de chlorure de benzylsulfonyle (605mg,3.17mmol) dans le dichloromethane (5ml) est ajoutée à une solution du composé 7b (528mg, 1.59mmol) dans la soude IM (1.6ml) à 0°C. Le mélange biphasique est ensuite ramené à température ambiante et agité pendant 5h. Après ce temps, les deux phases sont séparées et la phase aqueuse est extraite trois fois avec du dichloromethane. Les phases organiques réunies sont lavées avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium, filtrées et concentrées. Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (95/5/1) puis (90/9/1) de dichlorométhane/méthanol/ammoniaque.27 A solution of benzylsulfonyl chloride (605mg, 3.17mmol) in dichloromethane (5ml) is added to a solution of compound 7b (528mg, 1.59mmol) in IM soda (1.6ml) at 0 ° C. The two-phase mixture is then brought to room temperature and stirred for 5 h. After this time, the two phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude reaction product is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 550mg (Rdt : 71%)Mass obtained: 550mg (Yield: 71%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C24H33N5O4S-O.85C4H4O4-O.2H2O- 0.2Elementary Analysis for: C24H33N5O4S-O.85C4H4O4-O.2H2O- 0.2
C4H10OC 4 H 10 O
Calculées: C 56.01 ; H 6.47 ; N 1 1.58 ; Expérimentales: C 56.28 ; H 6.56 ; NCalculated: C 56.01; H 6.47; N 1 1.58; Experimental: C 56.28; H 6.56; NOT
10.9910.99
Masse (DCI/NH3) : 488(MH+),248Mass (DCI / NH3): 488 (MH +), 248
IR (KBr) : 3395,2965,2925,2858, 1709,1642, 1508, 1246, 1 146,984IR (KBr): 3395,2965,2925,2858, 1709,1642, 1508, 1246, 1 146.984
RMN IH (DMSO) : 2.36 (s,3H); 2.67 (M,4H); 2.99 (M,4H); 3.12 (M,4H); 3.43 (M,4H); 3.73 (s,3H); 4.46 (s,2H); 6.57 (s,1.7H); 6.81 (d,8.8Hz,lH); 7.01-7.08 (m,2H); 7.40 (M,5H); 8.40 (s,lH).1 H NMR (DMSO): 2.36 (s, 3H); 2.67 (M, 4H); 2.99 (M, 4H); 3.12 (M, 4H); 3.43 (M, 4H); 3.73 (s, 3H); 4.46 (s, 2H); 6.57 (s, 1.7H); 6.81 (d, 8.8Hz, 1H); 7.01-7.08 (m, 2H); 7.40 (M, 5H); 8.40 (s, 1H).
Point de fusion : 121-125°C EXEMPLE 28Melting point: 121-125 ° C EXAMPLE 28
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-(l- naphty!sulfonyl)pipérazin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- (l- naphthy! Sulfonyl) piperazin-1-ylamide fumarate
Figure imgf000073_0001
28
Figure imgf000073_0001
28
Le composé 28 est préparé suivant la procédure utilisée pour le composé 27 à partir des réactifs suivants : chlorure de 1-naphtylsulfonyle ( 671mg,296mmol); composé 7b ( 493mg,1.48mmol); solution de soude IN ( 1.5ml); dichloromethane (5ml). Le brut réactionnel est purifié par chromatographie- éclair avec un mélange (95/5/1) puis (90/9/1 ) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 756mg (Rdt : 98%)Mass obtained: 756 mg (Yield: 98%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C27H33N5O4S-C4H4O4-O.2H2O-O. I 5C4H10OElemental Analysis for: C27H33N5O4S-C4H4O4-O.2H2O-O. I 5C4H10O
Calculées: C 57.99 ; H 5.99 ; N 10.70 ; Expérimentales: C 58.14 ; H 5.83 ; N 10.82Calculated: C 57.99; H 5.99; N 10.70; Experimental: C 58.14; H 5.83; N 10.82
Masse (DCI/NH3) : 524 (MH+),277,248Mass (DCI / NH3): 524 (MH +), 277.248
IR (KBr) : 3402,2925,2844, 1702,1635,1602,1508,1239,977 RMN IH (DMSO) : 2.31 (s,3H); 2.60 (M,4H); 2.92 (M,4H); 3.08 (M,4H); 3.44 (M,4H); 3.69 (s,3H); 6.57 (s,2H); 6.75 (d,8.7Hz,lH); 6.91-6.99 (m,2H); 7.64-7.79 (m,3H); 8.1 1-8.18 (m,2H); 8.29-8.33 (m,2H); 8.70 (d,8.2Hz, lH).IR (KBr): 3402.2925,2844, 1702,1635,1602,1508,1239,977 1 H NMR (DMSO): 2.31 (s, 3H); 2.60 (M, 4H); 2.92 (M, 4H); 3.08 (M, 4H); 3.44 (M, 4H); 3.69 (s, 3H); 6.57 (s, 2H); 6.75 (d, 8.7Hz, 1H); 6.91-6.99 (m, 2H); 7.64-7.79 (m, 3H); 8.1 1-8.18 (m, 2H); 8.29-8.33 (m, 2H); 8.70 (d, 8.2Hz, 1H).
Point de fusion : 1 10°C (amorphe)Melting point: 1 10 ° C (amorphous)
EXEMPLE 29EXAMPLE 29
Hémifumarate du N-[4-méthoxy-3-(4-méthyIpipérazin-l-yl)phényI]-4- phénoxyméthylpipéridin-1-ylamideN- [4-methoxy-3- (4-methyIpiperazin-1-yl) phenyl) hemifumarate -4- phenoxymethylpiperidin-1-ylamide
^ o
Figure imgf000074_0001
C Λ O ^ o
Figure imgf000074_0001
C Λ O
2929
Composé 29a :4-phénoxyméthvlpipéridineCompound 29a: 4-phenoxymethvlpiperidine
Le composé 29a est préparé suivant la procédure décrite pour le composé 24a à partir des réactifs suivants phénol (2.28g,24.25mmol); 4- hydroxyméthylpipéridine (2.5g,24.25mmol); diéthylazodicarboxylate (1 1ml; 24.25mmol; 40% dans le toluène) ; triphénylphosphine (6.36g,24.25mmol); tétrahydrofurane (70ml). Le brut réactionnel est purifié par chromatographie- éclair avec un mélange (95/5/1) puis (50/50/5) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 220mg (4.7%)Mass obtained: 220mg (4.7%)
RMN IH (CDC13) : 1.30 (m,2H); 1.80-2.01 (M,4H); 2.65 (te, 1 1.2Hz,2H); 3.13 (de, 11.9Hz,2H); 3.77 (d,6.2Hz,2H); 6.85-6.95 (m,3H); 7.22-7.30 (m,2H). Composé 29 :1 H NMR (CDCl3): 1.30 (m, 2H); 1.80-2.01 (M, 4H); 2.65 (te, 1 1.2Hz, 2H); 3.13 (de, 11.9Hz, 2H); 3.77 (d, 6.2Hz, 2H); 6.85-6.95 (m, 3H); 7.22-7.30 (m, 2H). Compound 29:
Le composé 29 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : 4-méthoxy-3-(4-méthyIpipérazin- l-yl)aniline (255mg,1.15mmol); composé 29a (220mg,1.15mmol); triphosgene (114mg, 0.76mmol); pyridine (90mlx2,1.15mmolx2); dichloromethane (40ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 225mg (Rdt : 34%)Mass obtained: 225mg (Yield: 34%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H34N4O3-O.9C4H4O4-O.35H2OElementary Analysis for: C25H34N4O3-O.9C4H4O4-O.35H2O
Calculées: C 62.53 ; H 7.03 ; N 10.20 ; Expérimentales: C 62.61 ; H 6.96 ; N 10.1 1Calculated: C 62.53; H 7.03; N 10.20; Experimental: C 62.61; H 6.96; N 10.1 1
Masse (DCI/NH3) : 439(MH+),248, 192Mass (DCI / NH3): 439 (MH +), 248, 192
IR (KBr) : 3388,2925,2838,1702, 1649,1602, 1508,1230IR (KBr): 3388,2925,2838,1702, 1649,1602, 1508,1230
RMN IH (DMSO) : 1.20 (M,2H); 1.78 (de, 13.2Hz,2H); 1.96 (M, 1 H); 2.33 (s,3H); 2.63 (M,4H); 2.77 (te,11.8Hz,2H); 2.97 (M,4H); 3.71 (s,3H); 3.83 (d,6.2Hz,2H); 4.14 (de,13.1Hz,2H); 6.57 (s,1.8H); 6.78 (d,8.6Hz, l H); 6.91 (m,3H); 7.05 (m,2H); 7.29 (dd,7.9 et 8.9Hz,2H); 8.25 (s,lH).1 H NMR (DMSO): 1.20 (M, 2H); 1.78 (de, 13.2Hz, 2H); 1.96 (M, 1H); 2.33 (s, 3H); 2.63 (M, 4H); 2.77 (te, 11.8Hz, 2H); 2.97 (M, 4H); 3.71 (s, 3H); 3.83 (d, 6.2Hz, 2H); 4.14 (de, 13.1Hz, 2H); 6.57 (s, 1.8H); 6.78 (d, 8.6Hz, 1H); 6.91 (m, 3H); 7.05 (m, 2H); 7.29 (dd, 7.9 and 8.9Hz, 2H); 8.25 (s, 1H).
Point de fusion : 120°C (amorphe) EXEMPLE 30Melting point: 120 ° C (amorphous) EXAMPLE 30
Fumarate du 4-phényléthynyl-l,2,3,6-tétrahydropyridin-l-yloate de [4- chloro-3-(4-méthylpipéridin-l-yl)]phényle4-Phenylethynyl-1,2,3,6-tetrahydropyridin-1-yloate [4-chloro-3- (4-methylpiperidin-1-yl)] phenyl fumarate
Figure imgf000076_0001
Figure imgf000076_0001
3030
Composé 30a : l-benzyl-4-trifluorométhvlsulfonvloxy-1.2.3.6-tétrahydro- pyridineCompound 30a: l-benzyl-4-trifluorométhvlsulfonvloxy-1.2.3.6-tétrahydro-pyridine
Une solution de N-benzylpipéridone (9.45ml,53.0mmol) dans le tétrahydrofurane (50ml) est additionnée goutte à goutte sur une solution de LDA (préparée à partir de diisopropylamine (7.95ml,58.3mmol) et de butyllithium (36.5ml d'une solution 1.6M dans l'hexane,58.3mmmmol)) dans le tétrahydrofurane (50ml) à -78°C. Le mélange réactionnel est agité 30mn à - 78°C puis une solution de N-phényltrifluorométhanesulfonimide (20g,56mmol) dans le tétrahydrofurane (50ml) est canulée. Le mélange est ensuite ramené à température ambiante et agité pendant 3h avant d'être concentré. Finalement, il est purifié par chromatographie rapide sur une colonne d'alumine neutre avec un mélange (90/10) d'éther de pétrole/acétate d'éthyle.A solution of 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. The reaction mixture is stirred for 30 minutes at -78 ° C. and then a solution of N-phenyltrifluoromethanesulfonimide (20g, 56mmol) in tetrahydrofuran (50ml) is cannulated. The mixture is then brought to room temperature and stirred for 3 hours before being concentrated. Finally, it is purified by rapid chromatography on a neutral alumina column with a mixture (90/10) of petroleum ether / ethyl acetate.
Masse obtenue : 14.2g (83%)Mass obtained: 14.2g (83%)
RMN IH (CDC13) : 2.45 (M,2H); 2.73 (t,5.7Hz,2H); 3.13 (m,2H); 3.63 (s,2H); 5.73 (M,1H); 7.32 (M,5H).1 H NMR (CDCl3): 2.45 (M, 2H); 2.73 (t, 5.7Hz, 2H); 3.13 (m, 2H); 3.63 (s, 2H); 5.73 (M, 1H); 7.32 (M, 5H).
Composé 30b :l-benzyl-4-phénvléthvnyI-l,2,3,6-tétrahydropyridine Une solution du composé 30a (6g,18.7mmol); de phénylacétylène (3.1ml,28.05mmol); de triéthylamine (5.1ml,36.9mmol) et de dichloro-bw- triphénylphosphinepalladium (300mg) dans le diméthylformamide (75ml) est chauffée à 75°C pendant lh30 sous atmosphère d'argon. Après ce temps, le diméthylformamide est évaporé sous vide puis le brut réactionnel est repris à l'eau et extrait trois fois à l'acétate d'éthyle. Les phases organiques réunies sont alors lavées plusieurs fois avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium, filtrées et concentrées. Le brut obtenu est purifié par chromatographie-éclair avec un mélange (95/5) d'éther de pétrole/acétate d'éthyle.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. The combined organic phases are then washed several times with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product obtained is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.
Masse obtenue : 3.38g (Rdt : 66%)Mass obtained: 3.38g (Yield: 66%)
RMN IH (CDC13) : 2.40 (M,2H); 2.71 (t,5.8Hz,2H); 3.17 (m,2H); 3.71 (s,2H); 6.09 (M,1H); 7.24-7.45 (M,10H).1 H NMR (CDCl3): 2.40 (M, 2H); 2.71 (t, 5.8Hz, 2H); 3.17 (m, 2H); 3.71 (s, 2H); 6.09 (M, 1H); 7.24-7.45 (M, 10H).
Composé 30c : l-chlorocarbonyl-4-phényléthynvl-l,2,3,6-tétrahydro- pyridineCompound 30c: l-chlorocarbonyl-4-phenylethynvl-1,2,3,6-tetrahydropyridine
Une solution du composé 30b (2g,7.32mmol) dans le dichloromethane (15ml) est ajoutée goutte à goutte sur une solution de triphosgene (726mg,2.44mmol) dans le dichloromethane (15ml) à 0°C sous atmosphère d'azote. Le mélange réactionnel est ensuite ramené à température ambiante puis agité pendant 12h.Il est concentré puis purifié directement par chromatographie-éclair avec du dichloromethane pur puis un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaqueA solution of compound 30b (2g, 7.32mmol) in dichloromethane (15ml) is added dropwise to a solution of triphosgene (726mg, 2.44mmol) in dichloromethane (15ml) at 0 ° C under nitrogen atmosphere. The reaction mixture is then brought to ambient temperature and then stirred for 12 h. It is concentrated and then purified directly by flash chromatography with pure dichloromethane then a mixture (95/5/1) of dichloromethane / methanol / ammonia
Masse obtenue : 633mg (Rdt : 36%)Mass obtained: 633 mg (Yield: 36%)
RMN IH (CDC13) : 2.46 (M,2H); 3.75 (t,5.7Hz,lH); 3.84 (t,5.7Hz,lH); 4.21 (m,lH); 4.29 (m,lH); 6.07 (M, 1H); 7.34 (M,3H); 7.42 (M,2H). Composé 30 :1 H NMR (CDCl3): 2.46 (M, 2H); 3.75 (t, 5.7Hz, 1H); 3.84 (t, 5.7Hz, 1H); 4.21 (m, 1H); 4.29 (m, 1H); 6.07 (M, 1H); 7.34 (M, 3H); 7.42 (M, 2H). Compound 30:
Le composé 30 est préparé suivant la procédure décrite pour le composé 5 à partir des réactifs suivants : 4-chloro-3-(4-méthylpipérazin-l-yl)phénol (720mg,3.17mmol); composé 30c (780mg,3.17mmol); hydrure de sodium (50%,167mg, 3.48mmol); tétrahydrofurane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/10/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 1.1 g (Rdt : 80%)Mass obtained: 1.1 g (Yield: 80%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H26CIN3O2-C4H4O4 Calculées: C 63.10 ; H 5.48 ; N 7.61 ; Expérimentales: C 62.84 ; H 5.57 ; N 7.44Elemental Analysis for: C25H26CIN3O2-C4H4O4 Calculated: C 63.10; H 5.48; N 7.61; Experimental: C 62.84; H 5.57; N 7.44
Masse (DCI/NH3) : 436 (MH+),298,227,180,136Mass (DCI / NH3): 436 (MH +), 298,227,180,136
IR (KBr) : 3442,2844,1723,1407IR (KBr): 3442,2844,1723,1407
RMN IH (DMSO) : 2.33 (M,5H); 2.62 (M,4H); 3.01 (M,4H); 3.57(M,1H); 3.71 (M, 1H); 4.06 (M,1H); 4.24 (M, 1H); 6.23 (se,lH); 6.59 (s,2H); 6.85 (dd,2.5 et 8.6Hz,lH); 6.96 (d,2.4Hz,lH); 7.40 (M,6H).1 H NMR (DMSO): 2.33 (M, 5H); 2.62 (M, 4H); 3.01 (M, 4H); 3.57 (M, 1H); 3.71 (M, 1H); 4.06 (M, 1H); 4.24 (M, 1H); 6.23 (sc, 1H); 6.59 (s, 2H); 6.85 (dd, 2.5 and 8.6Hz, 1H); 6.96 (d, 2.4Hz, 1H); 7.40 (M, 6H).
Point de fusion : 198°C Melting point: 198 ° C
EXEMPLE 31EXAMPLE 31
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4- phénéthylpipéridin-1-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- phenethylpiperidin-1-ylamide fumarate
Figure imgf000079_0001
31
Figure imgf000079_0001
31
Composé 31a : l-terf-butyloxycarbonyl-4-trifluorométhylsuIfonyloxy- 1,2,3,6-tétrahydropyridineCompound 31a: l-terf-butyloxycarbonyl-4-trifluoromethylsuIfonyloxy- 1,2,3,6-tetrahydropyridine
Le composé 31a est préparé suivant la procédure décrite pour le composé 30a à partir des réactifs suivants : l-/ert-butoxycarbonylpipéridone (20.0g, 100.4mmol); diisopropylamine (8.08ml, HOmmol); butyllithium (68.8ml d'une solution 1.6M dans l'hexane,1 10mmol); N- phényltrifluorométhanesulfonimide (38.2g, 107mmol) ; tétrahydrofurane (300ml). Le brut réactionnel est purifié par chromatographie rapide sur une colonne d'alumine neutre avec un mélange (90/10) d'éther de pétrole/acétate d'éthyle.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.
Masse obtenue : 19.7g (51%)Mass obtained: 19.7g (51%)
RMN IH (CDC13) : 1.46 (s,9H); 2.43 (M,2H); 3.62 (t,5.7Hz,2H); 4.05 (m,2H); 5.75 (M, IH).1 H NMR (CDCl3): 1.46 (s, 9H); 2.43 (M, 2H); 3.62 (t, 5.7Hz, 2H); 4.05 (m, 2H); 5.75 (M, 1H).
Composé 31b : l-/er/-butyloxycarbonyl-4-phényléthynyl-l,2,3,6- tétrahydro- pyridineCompound 31b: l- / er / -butyloxycarbonyl-4-phenylethynyl-1,2,3,6- tetrahydropyridine
Le composé 31b est préparé suivant la procédure décrite pour le composé 30b à partir des réactifs suivants : composé 31a (4g,10.3mmol); phénylacétylène (1.73ml,15.7mmol); triéthylamine (5.0ml,36.1mmol); dichloro-b/s- triphénylphosphinepalladium (170mg); diméthylformamide (40ml). Le brut obtenu est purifié par chromatographie-éclair avec un mélange (95/5) d'éther de pétrole/acétate d'éthyle.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). The crude product obtained is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.
Masse obtenue : 2.18g (Rdt : 75%)Mass obtained: 2.18g (Yield: 75%)
RMN IH (CDC13) : 1.45 (s,9H); 2.32 (M,2H); 2.52 (t,5.7Hz,2H); 4.01 (m,2H); 6.08 (M, 1H); 7.24-7.32 (m,3H); 7.38-7.43 (m,2H)..1 H NMR (CDCl3): 1.45 (s, 9H); 2.32 (M, 2H); 2.52 (t, 5.7Hz, 2H); 4.01 (m, 2H); 6.08 (M, 1H); 7.24-7.32 (m, 3H); 7.38-7.43 (m, 2H) ..
Composé 31c : l-/gr/-butvloxycarbonvl-4-phénéthylpipéridineCompound 31c: l- / gr / -butvloxycarbonvl-4-phenethylpiperidine
Le composé 31b (1.09g,3.85mmol) en solution dans le méthanol (50ml) est hydrogéné (35 PSI) sur charbon actif. Après lh30,le mélange réactionnel est filtré , concentré puis purifié par chromatographie-éclair un mélange (90/10) d'éther de pétrole/acétate d'éthyle.Compound 31b (1.09g, 3.85mmol) dissolved in methanol (50ml) is hydrogenated (35 PSI) on activated carbon. After 1.5 hours, the reaction mixture is filtered, concentrated and then purified by flash chromatography a mixture (90/10) of petroleum ether / ethyl acetate.
Masse obtenue : 845mg (Rdt : 76%)Mass obtained: 845mg (YId: 76%)
RMN IH (CDC13) : 1.03-1.26 (m,2H); 1.46 (s,9H); 1.55- 1.75 (m,5H); 2.64 (m,4H); 4.07 (M,2H); 7.16-7.37 (m,5H).1 H NMR (CDCl3): 1.03-1.26 (m, 2H); 1.46 (s, 9H); 1.55-1.75 (m, 5H); 2.64 (m, 4H); 4.07 (M, 2H); 7.16-7.37 (m, 5H).
Composé 31d : 4-phénéthvlpipéridineCompound 31d: 4-phenethvlpiperidine
Le composé 31d est préparé suivant la procédure employée pour le composé 2b à partir des réactifs suivants ; composé 31c (830mg,2.87mmol); acide trifluoroacétique (2.8ml); dichloromethane (15ml). Le brut réactionnel est purifié par chromatographie-éclair avec un gradient de (90/10/1) à (0/100/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 340mg (Rdt : 62%) RMN IH (CDC13) : 1.12- 1.44 (m,4H); 1.55 (m,2H); 1.75 (de,2H); 2.53-2.66 (m,4H); 3.10 (de,2H); 7.15-7.31 (m,5H).Mass obtained: 340mg (Yield: 62%) 1 H NMR (CDCl3): 1.12-1.44 (m, 4H); 1.55 (m, 2H); 1.75 (from, 2H); 2.53-2.66 (m, 4H); 3.10 (from, 2H); 7.15-7.31 (m, 5H).
Composé 31:Compound 31:
5 Le composé 31 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : 4-méthoxy-3-(4-méthylpipérazin-l-yl)aniline (515mg,2.33mmol); composé 31d (440mg,2.33mmol); triphosgene (230mg, 0.77mmol); pyridine (180mlx2,2.33mmolx2); dichloromethane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1 ) de i o dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 520mg (Rdt : 51%)Mass obtained: 520mg (Yield: 51%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique 15 pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C26H36N4O2- 1.1 C4H4O4-0.15H2O Calculées: C 64.40 ; H 7.24 ; N 9.88 ; Expérimentales: C 64.16 ; H 7.21 ; N 10.02 20Elemental Analysis for: C26H36N4O2- 1.1 C4H4O4-0.15H2O Calculated: C 64.40; H 7.24; N 9.88; Experimental: C 64.16; H 7.21; N 10.02 20
Masse (DCI/NH3) : 437 (MH+),294,248, 190Mass (DCI / NH3): 437 (MH +), 294.248, 190
IR (KBr) : 3408,3026,2925,2844,1716,1649, 1508, 1232IR (KBr): 3408,3026,2925,2844,1716,1649, 1508, 1232
25 RMN IH (DMSO) : 1.06 (M,2H); 1.45-1.55 (M,3H); 1.68 (de,2H); 2.30 (s,3H); 2.59 (M,6H), 2.66 (m,2H), 2.94 (M,4H); 3.69 (s,3H); 4.04 (de,2H); 6.55 (s,2.2H); 6.75 (d,8.5Hz,lH); 7.00-7.29 (m,7H); 8.18 (s, lH).1 H NMR (DMSO): 1.06 (M, 2H); 1.45-1.55 (M, 3H); 1.68 (from, 2H); 2.30 (s, 3H); 2.59 (M, 6H), 2.66 (m, 2H), 2.94 (M, 4H); 3.69 (s, 3H); 4.04 (de, 2H); 6.55 (s, 2.2H); 6.75 (d, 8.5Hz, 1H); 7.00-7.29 (m, 7H); 8.18 (s, 1H).
Point de fusion : 120°CMelting point: 120 ° C
30 EXEMPLE 3230 EXAMPLE 32
Fumarate de N-[4-méthoxy-3-(4-méthyipipérazin-l-yl)phényl]-4-(N- phénylcarbamoyl)pipéridin-l-ylamideN- [4-methoxy-3- (4-methyipiperazin-1-yl) phenyl] -4- (N- phenylcarbamoyl) piperidin-1-ylamide fumarate
Figure imgf000082_0001
Figure imgf000082_0001
3232
Composé 32a : l-/er/-butyloxycarbonyl-4-(phénylcarbamoyl)pipéridineCompound 32a: l- / er / -butyloxycarbonyl-4- (phenylcarbamoyl) piperidine
Le composé 32a est préparé suivant la procédure utilisée pour le composé 2a à partir des réactifs suivants : aniline (2ml,21.8mmol); acide \-tert- butyloxycarbonylpipéridine-4-carboxylique (5g,21.8mmol); triéthylamineCompound 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
(3.1ml,21.8mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3- éthylcarbodiimide (4.2g,21.8mmol); 4-diméthylaminopyridine (une pointe de spatule); dichloromethane (100ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichloromethane/ méthanol/ammoniaque.(3.1ml, 21.8mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.2g, 21.8mmol); 4-dimethylaminopyridine (a tip of a spatula); dichloromethane (100ml). The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 6.05g (Rdt : 91%)Mass obtained: 6.05g (Yield: 91%)
RMN IH (CDC13) : 1.44 (s,9H); 1.61-1.90 (m,4H); 2.36 (m, lH); 2.76 (m,2H); 4.13 (M,1H); 4.19 (M,1H); 7.09 (t,7.3Hz,lH); 7.30 (t,7.5Hz,2H); 7.48 (d,7.9Hz,2H).1 H NMR (CDCl3): 1.44 (s, 9H); 1.61-1.90 (m, 4H); 2.36 (m, 1H); 2.76 (m, 2H); 4.13 (M, 1H); 4.19 (M, 1H); 7.09 (t, 7.3Hz, 1H); 7.30 (t, 7.5Hz, 2H); 7.48 (d, 7.9Hz, 2H).
Composé 32b : 4-(phénylcarbamoyl)pipéridineCompound 32b: 4- (phenylcarbamoyl) piperidine
Le composé 32b est préparé suivant la procédure utilisée pour le composé 2b à partir des réactifs suivants : composé 32a (6.05g, 19.9mmol); acide trifluoroacétique (20ml); dichloromethane (100ml). Le brut réactionnel est directement engagé dans l'étape suivante.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.
Masse obtenue : 3.5g (Rdt : 85%)Mass obtained: 3.5g (Yield: 85%)
RMN IH (CDC13) : 1.61-1.93 (m,5H); 2.37 (tt,3.9 et 1 1.5Hz,lH); 2.66 (td,3.9 et 1 1.5 Hz,2H); 3.19 (m,2H); 7.09 (t,7.4Hz, lH); 7.31 (m,2H); 7.51 (d,7.9Hz,2H).1 H NMR (CDCl3): 1.61-1.93 (m, 5H); 2.37 (tt, 3.9 and 1 1.5Hz, 1H); 2.66 (td, 3.9 and 1 1.5 Hz, 2H); 3.19 (m, 2H); 7.09 (t, 7.4Hz, 1H); 7.31 (m, 2H); 7.51 (d, 7.9Hz, 2H).
Composé 32:Compound 32:
Le composé 32 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : 4-méthoxy-3-(4-méthylpipérazin- l-yl)aniline (2.67 g, 12.1 mmol); composé 32b (2.47g,12.1mmol); triphosgene (1.2g, 4.05mmol); pyridine (935mlx2,12.1mmolx2); dichloromethane (135ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 2.97g (Rdt : 55%)Mass obtained: 2.97g (Yield: 55%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H33N5O3-C4H4O4-O.2H2O Calculées: C 60.98 ; H 6.60 ; N 12.26 ; Expérimentales: C 61.00 ; H 6.69 ; N 12.28Elemental Analysis for: C25H33N5O3-C4H4O4-O.2H2O Calculated: C 60.98; H 6.60; N 12.26; Experimental: C 61.00; H 6.69; N 12.28
Masse (DCI/NH3) : 452 (MH+),248,205Mass (DCI / NH3): 452 (MH +), 248.205
IR (KBr) : 3395,2945,2838, 1635, 1602,1508, 1232IR (KBr): 3395,2945,2838, 1635, 1602,1508, 1232
RMN IH (DMSO) : 1.55 (M,2H); 1.78 (M,2H); 2.32 (s,3H); 2.62 (M,5H); 2.78 (te,2H); 2.96 (M,4H); 3.70 (s,3H); 4.14 (de,2H); 6.56 (s,2H); 6.77 (d,8.7Hz,lH); 6.96-7.08 (M,3H); 7.26 (t,7.8Hz,2H); 7.58 (d,7.7Hz,2H); 8.27 (S,1H); 9.91 (S,1H). Point de fusion : 135°C (amorphe)1 H NMR (DMSO): 1.55 (M, 2H); 1.78 (M, 2H); 2.32 (s, 3H); 2.62 (M, 5H); 2.78 (te, 2H); 2.96 (M, 4H); 3.70 (s, 3H); 4.14 (de, 2H); 6.56 (s, 2H); 6.77 (d, 8.7Hz, 1H); 6.96-7.08 (M, 3H); 7.26 (t, 7.8Hz, 2H); 7.58 (d, 7.7Hz, 2H); 8.27 (S, 1H); 9.91 (S, 1H). Melting point: 135 ° C (amorphous)
EXEMPLE 33EXAMPLE 33
Fumarate de N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-(phényI- aminométhyI)pipéridin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- (phenyI- aminomethyI) piperidin-1-ylamide fumarate
Figure imgf000084_0001
Figure imgf000084_0001
3333
Le composé 33 est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 32 (500mg, 1.1 mmol); hydrure de lithium et d'aluminium (1.8ml d'une solution IM dans le tétrahydrofurane, l .δmmol); tétrahydrofurane (10ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.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 .δmmol); tetrahydrofuran (10ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 120mg (Rdt : 25%)Mass obtained: 120mg (Yield: 25%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H35N5O2-l .2C4H4O4-O.3H2OElemental Analysis for: C25H35N5O2-l .2C4H4O4-O.3H2O
Calculées: C 61.47 ; H 6.99 ; N 12.03 ; Expérimentales: C 61.34 ; H 7.06 ; NCalculated: C 61.47; H 6.99; N 12.03; Experimental: C 61.34; H 7.06; NOT
12.0012.00
Masse (DCI/NH3) : 438 (MH+), 248,191Mass (DCI / NH3): 438 (MH +), 248.191
IR (KBr) : 3435,2925,2844, 1642, 1602, 1508 RMN IH (DMSO) : 1.22 (M,2H); 1.75 (M,3H); 2.33 (s,3H); 2.63 (M,4H); 2.72 (te,2H); 2.92 (M,6H); 3.72 (s,3H); 4.08 (se,lH); 4.18 (se, lH); 6.44-6.54 (m,3H); 6.58 (s,2.4H); 6.78 (d,8.66Hz, lH); 7.01-7.09 (m,4H); 8.22 (s, lH).IR (KBr): 3435,2925,2844, 1642, 1602, 1508 1 H NMR (DMSO): 1.22 (M, 2H); 1.75 (M, 3H); 2.33 (s, 3H); 2.63 (M, 4H); 2.72 (te, 2H); 2.92 (M, 6H); 3.72 (s, 3H); 4.08 (sc, 1H); 4.18 (sc, 1H); 6.44-6.54 (m, 3H); 6.58 (s, 2.4H); 6.78 (d, 8.66Hz, 1H); 7.01-7.09 (m, 4H); 8.22 (s, 1H).
Point de fusion : 105°CMelting point: 105 ° C
EXEMPLE 34EXAMPLE 34
Fumarate du 4-phényIéthylpipéridin-l-yIoate de 3-(4-méthylpiperazin-l- yl)phényle3- (4-methylpiperazin-1-yl) phenyl 4-phenylethylpiperidin-1-yl fumate
Figure imgf000085_0001
Figure imgf000085_0001
3434
Le composé 30 (540mg,1.24mmol) est hydrogéné (31 PSI) sur palladium de Lindlar (130mg) en solution dans l'éthanol (25ml) et en présence de quinoline (520ml). Après 24h, le mélange réactionnel est filtré sur célite puis purifié par chromatographie-éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 31 Omg (Rdt : 61 %)Mass obtained: 31 Omg (Yield: 61%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H33N3O2- l.2C4H4O4-O.lH2OElementary Analysis for: C25H33N3O2- l.2C4H4O4-O.lH2O
Calculées: C 64.24 ; H 6.18 ; N 7.66 ; Expérimentales: C 65.25 ; H 7.06 ; N 7.97Calculated: C 64.24; H 6.18; N 7.66; Experimental: C 65.25; H 7.06; N 7.97
Masse (DCI/NH3) : 408(MH+),251 IR (KBr) : 3415,2931,2844,2354, 1702,1601,1 185Mass (DCI / NH3): 408 (MH +), 251 IR (KBr): 3415.2931.2844.2354, 1702.1601.1 185
RMN I H (DMSO) : 1.10 (M,2H); 1.55 (M,3H); 1.77 (M.2H); 2.30 (s,3H); 2.53 (M,6H); 2.88 (M,2H); 3.17 (M,4H); 4.05 (M,2H); 6.50 (dd, 1.7 et 7.8Hz, l H); 6.60 (S.2.4H); 6.64 (m, lH); 6.80 (dd,2.1 et 8.1Hz, lH); 7.23 (M,6H).1 H NMR (DMSO): 1.10 (M, 2H); 1.55 (M, 3H); 1.77 (M.2H); 2.30 (s, 3H); 2.53 (M, 6H); 2.88 (M, 2H); 3.17 (M, 4H); 4.05 (M, 2H); 6.50 (dd, 1.7 and 7.8Hz, l H); 6.60 (S.2.4H); 6.64 (m, 1H); 6.80 (dd, 2.1 and 8.1Hz, 1H); 7.23 (M, 6H).
Point de fusion : 125°CMelting point: 125 ° C
EXEMPLE 35 Fumarate du N-[4-méthoxy-3-(4-méthyIpipérazin-l-yl)phényI]-4-(2- méthoxyphénéthyl)pipérazin-l-ylamideEXAMPLE 35 N- [4-methoxy-3- (4-methyIpiperazin-1-yl) phenyl) fumarate -4- (2-methoxyphenethyl) piperazin-1-ylamide
Figure imgf000086_0001
Figure imgf000086_0001
3535
Composé 35a l-(2-méthoxybenzyIcarbonyl)-4-(ter/-butyIoxycarbonyl) pipérazineCompound 35a l- (2-methoxybenzyIcarbonyl) -4- (ter / -butyIoxycarbonyl) piperazine
Le composé 35a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide (2-méthoxyphényl)acétique (3.0g,l8.05mmol); l-/e/7-butyloxycarbonylpipérazine (3.36g,18.05mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3-éthylcarbodiimide (3.46g,18.05mmol); triéthylamine (1.32ml,18.05mmol); 4- diméthylaminopyridine (une pointe de spatule); dichloromethane (60ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (5/5) d'acétate d'éthyle/éther de pétrole. Masse obtenue : 4.78g (Rdt : 79%)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%)
RMN IH (CDCI3) : 1.43 (s,9H); 3.20-3.41 (M,6H); 3.68 (m,4H); 3.81 (s,3H); 6.82-7.26 (M,4H).1 H NMR (CDCI3): 1.43 (s, 9H); 3.20-3.41 (M, 6H); 3.68 (m, 4H); 3.81 (s, 3H); 6.82-7.26 (M, 4H).
Composé 35b: l-(2-méthoxybenzylcarbonyl)pipérazineCompound 35b: 1- (2-methoxybenzylcarbonyl) piperazine
Le composé 35b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 35a (2.0g,5.08mmol); acide trifluoroacétique (5ml); dichloromethane (30ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1 ) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 1.46g (Rdt : 98%)Mass obtained: 1.46g (Yield: 98%)
RMN IH (CDCl3) : 2.67-2.82 (M,4H); 3.44 (t,4.9Hz,2H); 3.63 (t,4.9Hz,2H); 3.68 (s,2H); 3.82 (s,3H); 6.83-7.26 (M,4H).1 H NMR (CDCl 3 ): 2.67-2.82 (M, 4H); 3.44 (t, 4.9Hz, 2H); 3.63 (t, 4.9Hz, 2H); 3.68 (s, 2H); 3.82 (s, 3H); 6.83-7.26 (M, 4H).
Composé 35c : l-(2-méthoxyphénéthyI)pipérazineCompound 35c: l- (2-methoxyphenethyI) piperazine
Le composé 35c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 35b ( 1.40g,5.98mmol); hydrure de lithium et d'aluminium (9ml d'une solution IM dans le tétrahydrofurane,9mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 0.67g (Rdt : 51%)Mass obtained: 0.67g (Yield: 51%)
RMN IH (CDCl3) : 1.89 (se, lH); 2.53 (m,6H); 2.83 (m,2H); 2.93 (m,4H); 3.82 (s,3H); 6.83-7.26 (M,4H). Composé 35 : Le composé 35 est préparé suivant la procédure décrite pour le composé 1 à partir des réactifs suivants : triphosgene (225mg,0.76mmol) ; 4- méthoxy-3-(4-méthylpipérazin- l-yl)aniline (500mg,2.26mmol) ; pyridine (180μlx2,2.26mmolx2) ; l-(2-méthoxyphénéthyi)pipérazine (35c) (497mg, 2.26mmol) ; dichloromethane (50ml).1 H NMR (CDCl 3 ): 1.89 (sc, 1H); 2.53 (m, 6H); 2.83 (m, 2H); 2.93 (m, 4H); 3.82 (s, 3H); 6.83-7.26 (M, 4H). Compound 35: 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 (180μlx2,2.26mmolx2); l- (2-methoxyphenethyi) piperazine (35c) (497mg, 2.26mmol); dichloromethane (50ml).
Le brut est purifié par chromatographie-éclair avec un mélange (90/9/1) de dichlorométhane/méthanol/ammoniaque.The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 0.23g (Rdt : 22 %)Mass obtained: 0.23g (Yield: 22%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C26H37N5O3-C4H4O4-I .6H2OElemental Analysis for: C26H37N5O3-C4H4O4-I .6H2O
Calculées: C 58.83 ; H 7.27 ; N 1 1.43 ; Expérimentales: C 59.15 ; H 7.22 ; N 11.07Calculated: C 58.83; H 7.27; N 1 1.43; Experimental: C 59.15; H 7.22; N 11.07
Masse (DCI/NH3) : 468 (MH+),248,222Mass (DCI / NH3): 468 (MH +), 248.222
IR (KBr) : 3420,2926,1607,1542, 1242IR (KBr): 3420,2926,1607,1542, 1242
RMN IH (DMSO) : 2.17 (s,3H); 2.26 (M,4H); 2.30 (M,4H); 2.54 (M,4H); 2.79 (M,4H); 3.22 (M,4H); 3.52 (s,3H); 3.58 (s,3H); 6.38 (s,2H); 6.60 (d,8.8Hz, lH); 6.66 (t,7.3Hz,lH); 6.74 (d,7.9Hz,lH); 6.83-6.89 (m,2H); 6.95-7.06 (m,2H); 8.09 (s,lH).1 H NMR (DMSO): 2.17 (s, 3H); 2.26 (M, 4H); 2.30 (M, 4H); 2.54 (M, 4H); 2.79 (M, 4H); 3.22 (M, 4H); 3.52 (s, 3H); 3.58 (s, 3H); 6.38 (s, 2H); 6.60 (d, 8.8Hz, 1H); 6.66 (t, 7.3Hz, 1H); 6.74 (d, 7.9Hz, 1H); 6.83-6.89 (m, 2H); 6.95-7.06 (m, 2H); 8.09 (s, 1H).
Point de fusion : 1 15°C o EXEMPLE 36Melting point: 1 15 ° C o EXAMPLE 36
Fumarate du N-[4-méthoxy-3-(4-méthyIpipérazin-l-yl)phényI]-4-(3,4,5- triméthoxyphénéthyl)pipérazin-l-ylamideN- [4-methoxy-3- (4-methyIpiperazin-1-yl) phenyl) fumarate -4- (3,4,5- trimethoxyphenethyl) piperazin-1-ylamide
Figure imgf000089_0001
36
Figure imgf000089_0001
36
Composé 36a : l-(3,4,5-triméthoxybenzylcarbonyl)-4-(/ι?r/-butyloxycarbonyl) pipérazineCompound 36a: 1- (3,4,5-trimethoxybenzylcarbonyl) -4 - (/ ι? R / -butyloxycarbonyl) piperazine
Le composé 36a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide (3,4,5- triméthoxyphényl)acétique (2.0g,8.88mmol); l-/er/-butyloxycarbonyl- pipérazine (1.65g,8.88mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3- éthylcarbodiimide ( 1.70g,8.88mmol); triéthylamine (0.65ml,8.88mmol);4- diméthylaminopyridine (une pointe de spatule); dichloromethane (60ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (5/5) d'acétate d'éthyle/éther de pétrole.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.
Masse obtenue : 3.44g (Rdt : 99%)Mass obtained: 3.44g (Yield: 99%)
RMN IH (CDCI3) : 1.45 (s,9H); 3.27-3.42 (M,6H); 3.59-3.68 (M,4H); 3.84 (M,9H); 6.45 (s,2H).1 H NMR (CDCI3): 1.45 (s, 9H); 3.27-3.42 (M, 6H); 3.59-3.68 (M, 4H); 3.84 (M, 9H); 6.45 (s, 2H).
Composé 36b : l-(3,4,5-triméthoxybenzylcarbonyI)pipérazineCompound 36b: 1- (3,4,5-trimethoxybenzylcarbonyI) piperazine
Le composé 36b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 36a (3.40g,8.63mmol); acide trifluoroacétique (9ml); dichloromethane (50ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 2.31 g (Rdt : 91 %)Mass obtained: 2.31 g (Yield: 91%)
RMN IH (CDCI3) : 2.33-2.45 (m,lH); 2.80-2.94 (M,3H); 3.42-3.72 (M,8H); 3.83 (m,9H); 6.45 (s,2H).1 H NMR (CDCI3): 2.33-2.45 (m, 1H); 2.80-2.94 (M, 3H); 3.42-3.72 (M, 8H); 3.83 (m, 9H); 6.45 (s, 2H).
Composé 36c : l-(3,4,5-triméthoxyphénéthyI)pipérazineCompound 36c: 1- (3,4,5-trimethoxyphenethyI) piperazine
Le composé 36c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 36b (2.30g,7.82mmol); hydrure de lithium et d'aluminium (12ml d'une solution IM dans le tétrahydrofurane, 12mmol); tétrahydrofurane (30ml). Le brut est purifié par chromatographie-éclair avec un mélange (92/8/1) de dichloromethane/ méthanol/ammoni aque .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.
Masse obtenue : 0.98g (Rdt : 45%)Mass obtained: 0.98g (Yield: 45%)
RMN 1H (CDC13) : 2.49-2.58 (M,6H); 2.68-2.74 (M,2H); 2.89-2.94 (M,4H); 3.83 (m,9H); 6.35 (s,2H).1H NMR (CDCl3): 2.49-2.58 (M, 6H); 2.68-2.74 (M, 2H); 2.89-2.94 (M, 4H); 3.83 (m, 9H); 6.35 (s, 2H).
Composé 36d : 4-méthoxy-3-(4-méthyIpipérazin-l-yl)-l-(/-?rf- butyloxycarbonyl)anilineCompound 36d: 4-methoxy-3- (4-methyIpiperazin-l-yl) -l - (/ -? Rf- butyloxycarbonyl) aniline
Une solution de 4-méthoxy-3-(4-méthylpipérazin-l-yl)aniline pouvant être préparée selon la méthode décrite dans le brevet européen 0533266-1 1 (5.0g,22.62mmol) et de di-tert-butyl dicarbonate (5.42g,24.88mmol) dans le toluène ( 100ml) est chauffée pendant 3 h au reflux sous atmosphère d'azote. Le mélange réactionnel est ensuite ramené à température ambiante pendant la nuit. Celui-ci est concentré sous pression réduite, dilué avec de l'eau puis extrait trois fois avec du dichloromethane. Les phases organiques sont rassemblées, lavées une fois avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium et concentrées. Le brut est purifié par chromatographie- éclair avec un mélange (92/8/1) de dichlorométhane/méthanol/ammoniaque.A solution of 4-methoxy-3- (4-methylpiperazin-1-yl) aniline which can be prepared according to the method described in European patent 0533266-1 1 (5.0g, 22.62mmol) and di-tert-butyl dicarbonate ( 5.42g, 24.88mmol) in toluene (100ml) is heated for 3 h at reflux under a nitrogen atmosphere. The reaction mixture is then brought to ambient temperature overnight. This is concentrated under reduced pressure, diluted with water and then extracted three times with dichloromethane. The organic phases are combined, washed once with a saturated sodium chloride solution, dried over magnesium sulfate and concentrates. The crude product is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 6.39g (Rdt : 88%)Mass obtained: 6.39g (Yield: 88%)
RMN IH (CDCI3) : 1.46 (s,9H); 2.35 (s,3H); 2.61 (se,4H); 3.09 (se,4H); 3.83 (s,3H); 6.41 (se,lH); 6.75 (d,8.6Hz, lH); 6.95 (m,2H).1 H NMR (CDCI3): 1.46 (s, 9H); 2.35 (s, 3H); 2.61 (se, 4H); 3.09 (sc, 4H); 3.83 (s, 3H); 6.41 (sc, 1H); 6.75 (d, 8.6Hz, 1H); 6.95 (m, 2H).
Composé 36 : A une suspension du composé 36c (0.80g,2.86mmol) dans le tétrahydrofurane (10ml) est ajoutée lentement une solution de butyllithiumCompound 36: To a suspension of compound 36c (0.80g, 2.86mmol) in tetrahydrofuran (10ml) is slowly added a solution of butyllithium
(2.2ml d'une solution 1.6M dans l'hexane,3.43mmol). Pendant cette opération, le mélange réactionnel est refroidi avec un bain de glace. Après lOmn, celui-ci est cannulé sur une solution du composé 36d (0.91g,2.86mmol) dans le tétrahydrofurane (10ml) à température ambiante. Le mélange réactionnel est ensuite porté au reflux pendant 4h et laissé à température ambiante pendant la nuit. Le mélange est dilué avec de l'eau puis extrait trois fois avec de l'acétate d'éthyle. Les phases organiques sont rassemblées, lavées une fois avec une solution saturée en chlorure de sodium, séchées sur sulfate de magnésium et concentrées. Le brut est purifié par chromatographie-éclair avec un mélange (92/8/1) de dichlorométhane/méthanol/ammoniaque.(2.2ml of a 1.6M solution in hexane, 3.43mmol). During this operation, the reaction mixture is cooled with an ice bath. After 10 minutes, this is cannulated on a solution of compound 36d (0.91g, 2.86mmol) in tetrahydrofuran (10ml) at room temperature. The reaction mixture is then brought to reflux for 4 h and left at room temperature overnight. The mixture is diluted with water and then extracted three times with ethyl acetate. The organic phases are combined, washed once with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
Masse obtenue : 1.03 g (Rdt : 69%)Mass obtained: 1.03 g (Yield: 69%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C28H41N5O5-C4H4O4-O.2H2OElementary Analysis for: C28H41N5O5-C4H4O4-O.2H2O
Calculées: C 59.71 ; H 7.05 ; N 10.88 ; Expérimentales: C 59.38 ; H 7.20 ; N 10.77Calculated: C 59.71; H 7.05; N 10.88; Experimental: C 59.38; H 7.20; N 10.77
Masse (DCI/NH3) : 528 (MH+),281,248Mass (DCI / NH3): 528 (MH +), 281.248
IR (KBr) : 3409,2936,2824,1581, 1508,1232 RMN IH (DMSO) : 2.33 (s,3H); 2.47 (m,4H); 2.56-2.69 (M,8H); 2.97 (se,4H); 3.39 (se,4H); 3.62 (s,3H); 3.73 (s,3H); 3.76 (se,6H); 6.55 (s,2H); 6.57 (s,2H); 6.80 (d,8.8Hz,lH); 7.03(se, lH); 7.07 (d,8.7Hz, lH); 8.28 (s, lH).IR (KBr): 3409.2936.2824.1581, 1508.1232 1 H NMR (DMSO): 2.33 (s, 3H); 2.47 (m, 4H); 2.56-2.69 (M, 8H); 2.97 (se, 4H); 3.39 (sc, 4H); 3.62 (s, 3H); 3.73 (s, 3H); 3.76 (sc, 6H); 6.55 (s, 2H); 6.57 (s, 2H); 6.80 (d, 8.8Hz, 1H); 7.03 (sc, 1H); 7.07 (d, 8.7Hz, 1H); 8.28 (s, 1H).
Point de fusion : 1 19°CMelting point: 1 19 ° C
EXEMPLE 37EXAMPLE 37
Fumarate du N-[4-méthoxy-3-(4-méthyIpipérazin-l-yl)phényl]-4-(2- naphtalen-2-yI-éthyl)pipérazin-l-ylamideN- [4-methoxy-3- (4-methyIpiperazin-1-yl) phenyl] -4- (2- naphthalen-2-yI-ethyl) piperazin-1-ylamide fumarate
Figure imgf000092_0001
Figure imgf000092_0001
3737
Composé 37a : l-(naphtalen-2-yl-acétyl)-4-(/er/-butyloxycarbonyl) pipérazineCompound 37a: 1- (naphthalen-2-yl-acetyl) -4 - (/ er / -butyloxycarbonyl) piperazine
Le composé 37a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide 2-naphtylacétique ( 1.0g,5.37mmol); l-/er/-butyloxycarbonylpipérazine (1.0g,5.37mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3-éthylcarbodiimide (1.03g,5.37mmol); triéthylamine (0.39ml,5.37mmol); 4-diméthylaminopyridine (une pointe de spatule); dichloromethane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (5/5/0.1) d'acétate d'éthyle/éther de pétrole/ammoniaque.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.
Masse obtenue : 1.63g (Rdt : 86%)Mass obtained: 1.63g (Yield: 86%)
RMN IH (CDCI3) : 1.40 (s,9H); 3.16 (m,2H); 3.56 (M,4H); 3.60 (m,2H); 3.89 (s,2H); 7.23-7.81 (M,7H). Composé 37b: 2-naphtaIen-2-yl-pipérazin-l-yl-éthanone1 H NMR (CDCI3): 1.40 (s, 9H); 3.16 (m, 2H); 3.56 (M, 4H); 3.60 (m, 2H); 3.89 (s, 2H); 7.23-7.81 (M, 7H). Compound 37b: 2-naphthaIen-2-yl-piperazin-l-yl-ethanone
Le composé 37b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 37a (1.63g,4.60mmol); acide trifluoroacétique (5ml); dichloromethane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichloromethane/ méthanol/ammoniaque. Masse obtenue : 1.15g (Rdt : 98%)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%)
RMN IH (CDCl3) : 2.63 (t,4.8Hz,2H); 2.83 (t,4.9Hz,2H); 3.45 (t,4.9Hz,2H); 3.65 (t,4.9Hz,2H); 3.90 (s,2H); 7.26-7.51 (M,3H); 7.68 (se, lH); 7.76-7.83 (M,3H).1 H NMR (CDCl 3 ): 2.63 (t, 4.8Hz, 2H); 2.83 (t, 4.9Hz, 2H); 3.45 (t, 4.9Hz, 2H); 3.65 (t, 4.9Hz, 2H); 3.90 (s, 2H); 7.26-7.51 (M, 3H); 7.68 (sc, 1H); 7.76-7.83 (M, 3H).
Composé 37c : l-(2-naphtalen-2-yI-éthyl)pipérazineCompound 37c: 1- (2-naphthalen-2-yI-ethyl) piperazine
Le composé 37c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 37b (1.15g,4.52mmol); hydrure de lithium et d'aluminium (7ml d'une solution IM dans le tétrahydrofurane,7mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/10/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 0.62g (Rdt : 57%)Mass obtained: 0.62g (Yield: 57%)
RMN IH (CDCl3) : 1.95 (se,lH); 2.54 (se,4H); 2.68 (m,2H); 2.95 (m,6H); 7.13-7.46 (M,3H); 7.64 (se,lH); 7.75-7.97 (M,3H).1 H NMR (CDCl 3 ): 1.95 (sc, 1H); 2.54 (sc, 4H); 2.68 (m, 2H); 2.95 (m, 6H); 7.13-7.46 (M, 3H); 7.64 (sc, 1H); 7.75-7.97 (M, 3H).
Composé 37: Le composé 37 est préparé suivant la même procédure que celle décrite pour le composé 36 à partir des réactifs suivants : composé 37c (0.50g,2.08mmol); butyllithium (1.6ml d'une solution 1.6M dans l'hexane,2.50mmol); composé 36d (0.67g,2.08mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque. Masse obtenue : 0.67g (Rdt : 66%)Compound 37: 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%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C29H37N5O2-C4H4O4- I .5H2OElemental Analysis for: C29H37N5O2-C4H4O4- I .5H2O
Calculées: C 65.65 ; H 6.84 ; N 1 1.60 ; Expérimentales: C 66.36 ; H 6.92 ; NCalculated: C 65.65; H 6.84; N 1 1.60; Experimental: C 66.36; H 6.92; NOT
1 1.551 1.55
Masse (DCI/NH3) : 488 (MH+),241Mass (DCI / NH3): 488 (MH +), 241
IR (KBr) : 3373,1600,1505,1363,1226IR (KBr): 3373,1600,1505,1363,1226
RMN IH (DMSO) : 2.33 (s,3H); 2.50 (M,4H); 2.66 (M,6H); 2.94 (M,6H); 3.43 (se,4H); 3.72 (s,3H); 6.58 (s,2H); 6.80 (d,8.8Hz,lH); 7.03(se,lH); 7.07(d,8.7Hz, lH); 7.42-7.50 (M,3H); 7.74 (s,lH); 7.85 (m,3H); 8.29 (s,lH).1 H NMR (DMSO): 2.33 (s, 3H); 2.50 (M, 4H); 2.66 (M, 6H); 2.94 (M, 6H); 3.43 (se, 4H); 3.72 (s, 3H); 6.58 (s, 2H); 6.80 (d, 8.8Hz, 1H); 7.03 (sc, 1H); 7.07 (d, 8.7Hz, 1H); 7.42-7.50 (M, 3H); 7.74 (s, 1H); 7.85 (m, 3H); 8.29 (s, 1H).
Point de fusion : 141°CMelting point: 141 ° C
EXEMPLE 38EXAMPLE 38
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yI)phényl]-4-(2- naphtalen-l-yl-éthyl)pipérazin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yI) phenyl] -4- (2- naphthalen-1-yl-ethyl) piperazin-1-ylamide fumarate
Figure imgf000094_0001
38 Composé 38a : l-(naphtalen-l-yl-acétyl)-4-(ι'er/'-buty.oxycarbonyl) pipérazine
Figure imgf000094_0001
38 Compound 38a: l- (naphthalen-l-yl-acetyl) -4- (ι'er / '- buty.oxycarbonyl) piperazine
Le composé 38a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide 1-naphtylacétique (1.0g,5.37mmol); l-ter/-butyloxycarbonylpipérazine ( 1.0g,5.37mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3-éthylcarbodiimide (1.03g,5.37mmol); triéthylamine (0.39ml,5.37mmol); 4-diméthylaminopyridine (une pointe de spatule); dichloromethane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (5/5/0.1) d'acétate d'éthyle/éther de pétrole/ammoniaque .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.
Masse obtenue : 1.58g (Rdt : 83%)Mass obtained: 1.58g (Yield: 83%)
RMN IH (CDCI3) : 1.44 (s,9H); 3.23 (m,2H); 3.41 (m,4H); 3.67 (m,2H); 4.17 (s,2H); 7.25-7.99 (M,7H).1 H NMR (CDCI3): 1.44 (s, 9H); 3.23 (m, 2H); 3.41 (m, 4H); 3.67 (m, 2H); 4.17 (s, 2H); 7.25-7.99 (M, 7H).
Composé 38b: 2-naphtalen-l-yl-pipérazin-l-yl-éthanoneCompound 38b: 2-naphthalen-l-yl-piperazin-l-yl-ethanone
Le composé 38b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 38a (1.58g,4.46mmol); acide trifluoroacétique (4.5ml); dichloromethane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 1.09g (Rdt : 96%)Mass obtained: 1.09g (Yield: 96%)
RMN IH (CDCI3) : 2.68 (t,5.0Hz,2H); 2.86 (t,5.1Hz,2H); 3.41 (t,5.0Hz,2H); 3.68 (t,5.1Hz,2H); 4.15 (s,2H); 7.26-7.58 (M,4H); 7.75-7.99 (M,3H).1 H NMR (CDCI3): 2.68 (t, 5.0Hz, 2H); 2.86 (t, 5.1Hz, 2H); 3.41 (t, 5.0Hz, 2H); 3.68 (t, 5.1Hz, 2H); 4.15 (s, 2H); 7.26-7.58 (M, 4H); 7.75-7.99 (M, 3H).
Composé 38c : l-(2-naphtalen-l-yl-éthyl)pipéraziπeCompound 38c: l- (2-naphthalen-l-yl-ethyl) pipéraziπe
Le composé 38c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 38b (0.92g,3.62mmol); hydrure de lithium et d'aluminium (5.5ml d'une solution I M dans le tétrahydrofurane,5.5mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (92/8/1) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 0.22g (Rdt : 25%)Mass obtained: 0.22g (Yield: 25%)
RMN IH (CDCI3) : 2.52 (se,4H); 2.64 (m,2H); 2.90 (se,4H); 3.21 (m,2H); 7.27-7.46 (M,4H); 7.64 (d,7.9Hz,lH); 7.77 (d,7.8Hz,lH); 8.09 (d,7.8Hz, lH).1 H NMR (CDCI3): 2.52 (sc, 4H); 2.64 (m, 2H); 2.90 (se, 4H); 3.21 (m, 2H); 7.27-7.46 (M, 4H); 7.64 (d, 7.9Hz, 1H); 7.77 (d, 7.8Hz, 1H); 8.09 (d, 7.8Hz, 1H).
Composé 38: Le composé 38 est préparé suivant la même procédure que celle décrite pour le composé 36 à partir des réactifs suivants : composé 38c (0.21g,0.88mmol); butyllithium (0.7ml d'une solution 1.6M dans l'hexane,1.06mmol); composé 36d (0.28g,0.88mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (93/7/1 ) de dichlorométhane/méthanol/ammoniaque.Compound 38: 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.
Masse obtenue : 0.29g (Rdt : 68%)Mass obtained: 0.29g (Yield: 68%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C29H37N5O2- 1.1 C4H4O4-O.5H2OElementary Analysis for: C29H37N5O2- 1.1 C4H4O4-O.5H2O
Calculées: C 65.65 ; H 6.84 ; N 1 1.60 ; Expérimentales: C 65.06 ; H 7.08 ; N 1 1.47Calculated: C 65.65; H 6.84; N 1 1.60; Experimental: C 65.06; H 7.08; No. 1 1.47
Masse (DCI/NH3) : 488 (MH+),248Mass (DCI / NH3): 488 (MH +), 248
IR (KBr) : 3373,1600,1505,1363,1226IR (KBr): 3373,1600,1505,1363,1226
RMN IH (DMSO) : 2.33 (s,3H); 2.50 (M,10H); 2.97 (se,4H); 3.27 (m,2H); 3.46 (se,4H); 3.73 (s,3H); 6.58 (s,2H); 6.80 (d,8.6Hz,lH); 7.07 (se,lH); 7.09 (d,8.5Hz,lH); 7.42 (se,2H); 7.51-7.58 (M,2H); 7.78 (d,6.3Hz,lH); 7.92 (d,7.8Hz,lH); 8.08 (d,8.2Hz,lH); 8.30 (s,lH). Point de fusion : 143°C1 H NMR (DMSO): 2.33 (s, 3H); 2.50 (M, 10H); 2.97 (se, 4H); 3.27 (m, 2H); 3.46 (se, 4H); 3.73 (s, 3H); 6.58 (s, 2H); 6.80 (d, 8.6Hz, 1H); 7.07 (sc, 1H); 7.09 (d, 8.5Hz, 1H); 7.42 (sc, 2H); 7.51-7.58 (M, 2H); 7.78 (d, 6.3Hz, 1H); 7.92 (d, 7.8Hz, 1H); 8.08 (d, 8.2Hz, 1H); 8.30 (s, 1H). Melting point: 143 ° C
EXEMPLE 39EXAMPLE 39
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényI]-4-(2,3- difluorophénéthyl)pipérazin-l-ylamideN- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl) fumarate -4- (2,3-difluorophenethyl) piperazin-1-ylamide
Figure imgf000097_0001
Figure imgf000097_0001
3939
Composé 39a : l-(2,3-difluorobenzylcarbonyl)-4-(/er/-butyloxycarbonyl) pipérazineCompound 39a: l- (2,3-difluorobenzylcarbonyl) -4 - (/ er / -butyloxycarbonyl) piperazine
Le composé 39a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide (2,3-difluorophényI)acétique (1.0g,5.81mmol); l-/ert-butyloxycarbonylpipérazine ( 1.08g,5.81mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3-éthylcarbodiimide (1.1 lg,5.81mmoι); triéthylamine (0.43ml,5.81mmol); 4-diméthylaminopyridine (une pointe de spatule); dichloromethane (25ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (5/5/0.1 ) d'acétate d'éthyle/éther de pétrole/ammoniaque .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, 5.81mmoι); 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.
Masse obtenue : 1.51g (Rdt : 76%)Mass obtained: 1.51g (YId: 76%)
RMN IH (CDCI3) : 1.44 (s,9H); 3.42 (M,6H); 3.61 (m,2H); 3.74 (s,2H); 7.03- 7.13 (M,3H). Composé 39b: l-(2,3-diflurobenzylcarbonyl)pipérazine1 H NMR (CDCI3): 1.44 (s, 9H); 3.42 (M, 6H); 3.61 (m, 2H); 3.74 (s, 2H); 7.03- 7.13 (M, 3H). Compound 39b: 1- (2,3-diflurobenzylcarbonyl) piperazine
Le composé 39b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 39a (1.51g,4.44mmol); acide trifluoroacétique (5ml); dichloromethane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/10/1 ) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 0.88g (Rdt : 83%)Mass obtained: 0.88g (Yield: 83%)
RMN IH (CDCI3) : 1.76 (m,4H); 3.45 (t,5.1Hz,2H); 3.59 (t,5.1Hz,2H); 3.71 (se,2H); 7.00-7.05 (M,3H).1 H NMR (CDCI3): 1.76 (m, 4H); 3.45 (t, 5.1Hz, 2H); 3.59 (t, 5.1Hz, 2H); 3.71 (sc, 2H); 7.00-7.05 (M, 3H).
Composé 39c : l-(2,3-difluorophénéthyl)pipérazineCompound 39c: 1- (2,3-difluorophenethyl) piperazine
Le composé 39c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 39b (0.88g,3.66mmol); hydrure de lithium et d'aluminium (5.5ml d'une solution IM dans le tétrahydrofurane,5.5mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (94/6/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 0.33g (Rdt : 40%)Mass obtained: 0.33g (Yield: 40%)
RMN IH (CDCI3) : 2.51-2.62 (M,6H); 2.83-2.95 (M,6H); 6.97-7.03 (M,3H).1 H NMR (CDCI3): 2.51-2.62 (M, 6H); 2.83-2.95 (M, 6H); 6.97-7.03 (M, 3H).
Composé 39: Le composé 39 est préparé suivant la même procédure que celle décrite pour le composé 36 à partir des réactifs suivants : composé 39c (0.14g,0.62mmol); butyllithium (0.5ml d'une solution 1.6M dans l'hexane,0.74mmol); composé 36d (0.20g,0.62mmol); tétrahydrofurane (10ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque. Masse obtenue : 0.1 l g (Rdt : 38%)Compound 39: 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%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C25H33N5O2F2-C4H4O4-2H2OElementary Analysis for: C25H33N5O2F2-C4H4O4-2H2O
Calculées: C 59.07 ; H 6.32 ; N 1 1.88 ; Expérimentales: C 57.94 ; H 6.44 ; N 1 1.44Calculated: C 59.07; H 6.32; N 1 1.88; Experimental: C 57.94; H 6.44; # 1 1.44
Masse (DCI/NH3) : 474 (MH+),248,227Mass (DCI / NH3): 474 (MH +), 248.227
IR (KBr) : 3420,2948,1638,1511,1239IR (KBr): 3420,2948,1638,1511,1239
RMN IH (DMSO) : 2.33 (s,3H); 2.50-2.61 (M.10H); 2.87 (m,2H); 2.97 (se,4H); 3.40 (se,4H); 3.72 (s,3H); 6.58 (s,2H); 6.79 (d,8.7Hz, lH); 7.06-7.29 (M,5H); 8.27 (s,lH).1 H NMR (DMSO): 2.33 (s, 3H); 2.50-2.61 (M.10H); 2.87 (m, 2H); 2.97 (se, 4H); 3.40 (se, 4H); 3.72 (s, 3H); 6.58 (s, 2H); 6.79 (d, 8.7Hz, 1H); 7.06-7.29 (M, 5H); 8.27 (s, 1H).
Point de fusion : 1 10°CMelting point: 1 10 ° C
EXEMPLE 40EXAMPLE 40
Fumarate du N-|4-méthoxy-3-(4-méthyIpipérazin-l-yl)phényl]-4-(4- trifluorométhyIphénéthyI)pipérazin-l-ylamideN- | 4-methoxy-3- (4-methyIpiperazin-1-yl) phenyl] -4- (4-trifluoromethyIphenethyI) piperazin-1-ylamide fumarate
K lK l
Figure imgf000099_0001
40 Composé 40a : l-(4-trifluorométhylbenzylcarbonyl)-4-(/ι2/-i<-butyloxycarbonyl) pipérazine
Figure imgf000099_0001
40 Compound 40a: l- (4-trifluoromethylbenzylcarbonyl) -4 - (/ ι2 / -i < -butyloxycarbonyl) piperazine
Le composé 40a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants acide (4- trifluorométhylphényl)acétique (1.0g,4.90mmol); l-ter/-butyloxycarbonyl- pipérazine (0.91g,4.90mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3- éthylcarbodiimide (0.94g,4.90mmol); triéthylamine (0.34ml,4.90mmol); 4- diméthylaminopyridine (une pointe de spatule); dichloromethane (50ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (5/5/0.1) d'acétate d'éthyle/éther de pétrole/ammoniaque .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.
Masse obtenue : 1.44g (Rdt : 79%)Mass obtained: 1.44g (YId: 79%)
RMN IH (CDCI3) : 1.45 (s,9H); 3.30 (m,2H); 3.38 (m,4H); 3.61 (m,2H); 3.79 (s,2H); 7.33-7.60 (M,4H).1 H NMR (CDCI3): 1.45 (s, 9H); 3.30 (m, 2H); 3.38 (m, 4H); 3.61 (m, 2H); 3.79 (s, 2H); 7.33-7.60 (M, 4H).
Composé 40b: l-(4-trifluorométhylbenzylcarbonyI)pipérazineCompound 40b: 1- (4-trifluoromethylbenzylcarbonyI) piperazine
Le composé 40b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 40a (1.44g,3.87mmol); acide trifluoroacétique (4ml); dichloromethane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/10/1) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 1.0g (Rdt : 95%)Mass obtained: 1.0g (Yield: 95%)
RMN IH (CDCl3) : 2.72 (t,4.9Hz,2H); 2.82 (t,5.2Hz,2H); 3.42 (t,4.9Hz,2H); 3.62 (t,5.0Hz,2H); 3.76 (se,2H); 7.33 (m,2H); 7.57 (m,2H).1 H NMR (CDCl 3 ): 2.72 (t, 4.9Hz, 2H); 2.82 (t, 5.2Hz, 2H); 3.42 (t, 4.9Hz, 2H); 3.62 (t, 5.0Hz, 2H); 3.76 (sc, 2H); 7.33 (m, 2H); 7.57 (m, 2H).
Composé 40c : l-(4-trifluorométhylphénéthyl)pipérazineCompound 40c: 1- (4-trifluoromethylphenethyl) piperazine
Le composé 40c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 40b (1.0g,3.68mmol); hydrure de lithium et d'aluminium (5.5ml d'une solution IM dans le tétrahydrofurane,5.5mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (94/6/1) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 0.38g (Rdt : 40%)Mass obtained: 0.38g (Yield: 40%)
RMN IH (CDCI3) : 1.65 (se,4H); 2.50 (se,4H); 2.59 (m,2H); 2.86 (m,2H); 2.92 (M,4H); 7.31 (m,2H); 7.53 (m,2H).1 H NMR (CDCI3): 1.65 (sc, 4H); 2.50 (sc, 4H); 2.59 (m, 2H); 2.86 (m, 2H); 2.92 (M, 4H); 7.31 (m, 2H); 7.53 (m, 2H).
Composé 40: Le composé 40 est préparé suivant la même procédure que celle décrite pour le composé 36 à partir des réactifs suivants : composé 40c (0.37g, 1.43mmol); butyllithium (1.08ml d'une solution 1.6M dans rhexane,1.72mmol); composé 36d (0.46g, 1.43mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (92/8/1) de dichiorométhane/méthanol/ammoniaque.Compound 40: 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.
Masse obtenue : 0.17g (Rdt : 24%)Mass obtained: 0.17g (Yield: 24%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C26H34N5O2F3-C4H4O4-I .IH2OElemental Analysis for: C26H34N5O2F3-C4H4O4-I .IH2O
Calculées: C 57.96 ; H 6.16 ; N 1 1.27 ; Expérimentales: C 57.44 ; H 6.09 ; N 11.07Calculated: C 57.96; H 6.16; N 1 1.27; Experimental: C 57.44; H 6.09; N 11.07
Masse (DCI/NH3) : 506 (MH+),259,222Mass (DCI / NH3): 506 (MH +), 259.222
IR (KBr) : 3426,2917,1619, 1502,1326IR (KBr): 3426,2917,1619, 1502,1326
RMN IH (DMSO) : 2.33 (s,3H); 2.45 (m,4H); 2.61 (M,6H); 2.86 (t,7.5Hz,2H); 2.97 (se,4H); 3.41 (se,4H); 3.73 (s,3H); 6.58 (s,2H); 6.79 (d,8.7Hz, lH); 7.00 (se,lH); 7.07 (d,8.7Hz,lH); 7.48 (d,7.9Hz,2H); 7.64 (d,7.9Hz,2H); 8.28 (s, lH).1 H NMR (DMSO): 2.33 (s, 3H); 2.45 (m, 4H); 2.61 (M, 6H); 2.86 (t, 7.5Hz, 2H); 2.97 (se, 4H); 3.41 (se, 4H); 3.73 (s, 3H); 6.58 (s, 2H); 6.79 (d, 8.7Hz, 1H); 7.00 (se, 1H); 7.07 (d, 8.7Hz, 1H); 7.48 (d, 7.9Hz, 2H); 7.64 (d, 7.9Hz, 2H); 8.28 (s, 1H).
Point de fusion : 126°C EXEMPLE 41Melting point: 126 ° C EXAMPLE 41
Fumarate du N-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4-(2-fluoro-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- (2-fluoro-
3-trifluorométhylphénéthyl)pipérazin-l-ylamide3-trifluoromethylphenethyl) piperazin-1-ylamide
Figure imgf000102_0001
Figure imgf000102_0001
4141
Composé 41a : l-(2-fluoro-3-trifluorométhylbenzylcarbonyl)-4-(/eriy- butyloxycarbonyl) pipérazineCompound 41a: l- (2-fluoro-3-trifluoromethylbenzylcarbonyl) -4 - (/ eri y - butyloxycarbonyl) piperazine
Le composé 41a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide (2-fluoro-3- trifluorométhylphényl)acétique (3.0g, 13.51 mmol); 1 -/er/-buty loxycarbonyl- pipérazine (2.52g, 13.51 mmol); chlorhydrate de la l-(3-diméthylaminopropyl)- 3-éthylcarbodiimide (2.59g,13.51mmol); triéthylamine (1.80ml,13.51mmol); 4- diméthylaminopyridine (une pointe de spatule); dichloromethane (60ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (4/6) d'acétate d'éthyle/éther de pétrole.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.
Masse obtenue : 4.70g (Rdt : 89%)Mass obtained: 4.70g (Yield: 89%)
RMN IH (CDCI3) : 1.47 (s,9H); 3.43 (M,4H); 3.51 (Mm,2H); 3.62 (m,2H); 3.77 (s,2H); 7.20-7.22 (M,1H); 7.45-7.55 (M,2H). Composé 41b: l-(2-fluoro-3-trifluorométhylbenzylcarbonyI)pipérazine1 H NMR (CDCI 3 ): 1.47 (s, 9H); 3.43 (M, 4H); 3.51 (Mm, 2H); 3.62 (m, 2H); 3.77 (s, 2H); 7.20-7.22 (M, 1H); 7.45-7.55 (M, 2H). Compound 41b: 1- (2-fluoro-3-trifluoromethylbenzylcarbonyI) piperazine
Le composé 41b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 41a (4.69g, 12.02mmol); acide trifluoroacétique (13ml); dichloromethane (50ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/10/1 ) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 3.33g (Rdt : 96%)Mass obtained: 3.33g (Yield: 96%)
RMN IH (CDCI3) : 2.85 (M,4H); 3.52 (t,4.6Hz,2H); 3.64 (m,2H); 3.76 (s,2H); 7.20-7.26 (m,lH); 7.51-7.55 (m,2H).1 H NMR (CDCl3): 2.85 (M, 4H); 3.52 (t, 4.6Hz, 2H); 3.64 (m, 2H); 3.76 (s, 2H); 7.20-7.26 (m, 1H); 7.51-7.55 (m, 2H).
Composé 41c : l-(2-fluoro-3-trifluorométhylphénéthyI)pipérazineCompound 41c: 1- (2-fluoro-3-trifluoromethylphenethyl) piperazine
Le composé 41c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 41b (2.71g,9.36mmol); hydrure de lithium et d'aluminium (14ml d'une solution IM dans l'éther, 14mmol); éther (50ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque.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.
Masse obtenue : 1.67g (Rdt : 65%)Mass obtained: 1.67g (Yield: 65%)
RMN IH (DMSO) : 2.34 (M,4H); 2.65 (M,4H); 2.83 (M,2H); 3.06 (m,2H); 7.31-7.35 (m,lH); 7.61-7.81 (m,2H).1 H NMR (DMSO): 2.34 (M, 4H); 2.65 (M, 4H); 2.83 (M, 2H); 3.06 (m, 2H); 7.31-7.35 (m, 1H); 7.61-7.81 (m, 2H).
Composé 41: Le composé 41 est préparé suivant la même procédure que celle décrite pour le composé 36 à partir des réactifs suivants : composé 41c (1.16g,3.62mmol); butyllithium (2.7ml d'une solution 1.6M dans l'hexane,4.34mmol); composé 36d (1.0g,3.62mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque. Masse obtenue : 1.1 1g (Rdt : 59%)Compound 41: 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%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C26H33N5O2F4-C4H4O4-O.29H2OElementary Analysis for: C26H33N5O2F4-C4H4O4-O.29H2O
Calculées: C 56.33 ; H 5.83 ; N 10.95 ; Expérimentales: C 56.42 ; H 6.00 ; N 10.76Calculated: C 56.33; H 5.83; N 10.95; Experimental: C 56.42; H 6.00; N 10.76
Masse (DCI/NH3) : 524 (MH+),277,248Mass (DCI / NH3): 524 (MH +), 277.248
IR (KBr) : 3386,2953,2830,1648,1508,1333IR (KBr): 3386.2953,2830,1648,1508,1333
RMN IH (DMSO) : 2.36 (s, 3H), 2.44 (t,4.40 Hz, 4H), 2.50 (m, 2H), 2.59 (t,7.40, 2H), 2.67 (se,- 3H), 2.88 (t,7.4 Hz, 2H), 2.98 (se, 3H), 3.39 (se, 4H), 3.72 (s, 3H), 6.58 (s, 2H), 6.79 (d,8.8 Hz, IH), 7.02-7.09 (M, 2H), 7.34 (t,7.7 Hz,lH), 7.60 (t,7.2 Hz, IH), 7.70 (t,7.2 Hz, IH), 8.28 (s, IH).1 H NMR (DMSO): 2.36 (s, 3H), 2.44 (t, 4.40 Hz, 4H), 2.50 (m, 2H), 2.59 (t, 7.40, 2H), 2.67 (se, - 3H), 2.88 (t , 7.4 Hz, 2H), 2.98 (se, 3H), 3.39 (se, 4H), 3.72 (s, 3H), 6.58 (s, 2H), 6.79 (d, 8.8 Hz, IH), 7.02-7.09 (M , 2H), 7.34 (t, 7.7 Hz, 1H), 7.60 (t, 7.2 Hz, IH), 7.70 (t, 7.2 Hz, IH), 8.28 (s, IH).
Point de fusion : 124°CMelting point: 124 ° C
EXEMPLE 42EXAMPLE 42
Fumarate du Ν-[4-méthoxy-3-(4-méthylpipérazin-l-yl)phényl]-4- phénéthylhomopipérazin-1-ylamideΝ- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4- phenethylhomopiperazin-1-ylamide fumarate
Figure imgf000104_0001
Figure imgf000104_0001
42 Composé 42a : l-benzylcarbonyl-4-(terι'-butyloxycarbonyl) homopipérazine42 Compound 42a: l-benzylcarbonyl-4- (terι'-butyloxycarbonyl) homopiperazine
Le composé 42a est préparé suivant la même procédure que celle décrite pour le composé 2a à partir des réactifs suivants : acide phénylacétique (1.0g,7.35mmol); 1-tert-butyloxycarbonylhomopipérazine ( 1.47g,7.35mmol); chlorhydrate de la l-(3-diméthylaminopropyl)-3-éthylcarbodiimide (1.41g,13.51mmol); triéthylamine (0.54ml,7.35mmol); 4-diméthylamino- pyridine (une pointe de spatule); dichloromethane (60ml). Le brut réactionnel est purifié par chromatographie-éclair avec un mélange (5/5/0.1) d'acétate d'éthyle/éther de pétrole/ammoniaque.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.
Masse obtenue : 1.79g (Rdt : 77%)Mass obtained: 1.79g (YId: 77%)
RMN IH (CDCI3) : 1.45 (s,9H); 1.72 (m,2H); 3.27 (m,3H); 3.47-3.53 (M,4H); 3.65 (se,lH); 3.73 (s,2H); 7.24-7.33 (M,5H).1 H NMR (CDCI3): 1.45 (s, 9H); 1.72 (m, 2H); 3.27 (m, 3H); 3.47-3.53 (M, 4H); 3.65 (sc, 1H); 3.73 (s, 2H); 7.24-7.33 (M, 5H).
Composé 42b: 1-benzyicarbonyl-homopipérazineCompound 42b: 1-benzyicarbonyl-homopiperazine
Le composé 42b est préparé suivant la même procédure que celle décrite pour le composé 2b à partir des réactifs suivants : composé 42a (1.76g,5.53mmol); acide trifluoroacétique (6ml); dichloromethane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/10/1) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 1.04g (Rdt : 87%)Mass obtained: 1.04g (Yield: 87%)
RMN IH (CDCI3) : 1.71 (t,6.0Hz,lH); 1.81 (t,6.0Hz, lH); 2.80 (m,3H); 2.95 (t,5.4Hz, lH); 7.22-7.34(M,5H).1 H NMR (CDCI3): 1.71 (t, 6.0 Hz, 1 H); 1.81 (t, 6.0Hz, 1H); 2.80 (m, 3H); 2.95 (t, 5.4Hz, 1H); 7.22-7.34 (M, 5H).
Composé 42c : l-phénéthyl-homopipérazineCompound 42c: l-phenethyl-homopiperazine
Le composé 42c est préparé suivant la même procédure que celle décrite pour le composé 3a à partir des réactifs suivants : composé 42b (1.01g,2.63mmol); hydrure de lithium et d'aluminium (7ml d'une solution IM dans le tétrahydrofurane, 14mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (90/10/1) de dichloromethane/ méthanol/ammoniaque.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.
Masse obtenue : 0.43g (Rdt : 46%)Mass obtained: 0.43g (Yield: 46%)
RMN IH (DMSO) : 1.84 (m,2H); 2.66 (se,8H); 2.85 (se,lH); 2.98 (M,4H); 7.07-7.37 (M,5H).1 H NMR (DMSO): 1.84 (m, 2H); 2.66 (sc, 8H); 2.85 (sc, 1H); 2.98 (M, 4H); 7.07-7.37 (M, 5H).
Composé 42: Le composé 42 est préparé suivant la même procédure que celle décrite pour le composé 36 à partir des réactifs suivants : composé 42c (0.40g, 1.56mmol); butyllithium (1.2ml d'une solution 1.6M dans l'hexane,1.87mmol); composé 36d (0.63g,1.56mmol); tétrahydrofurane (20ml). Le brut est purifié par chromatographie-éclair avec un mélange (95/5/1) de dichlorométhane/méthanol/ammoniaque.Compound 42: 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.
Masse obtenue : 0.63g (Rdt : 90%)Mass obtained: 0.63g (Yield: 90%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. Celui-ci est cristallisé dans l'éther.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. This is crystallized from ether.
Analyse Elémentaire pour: C26H37N5O2-C4H4O4-O.6H2OElemental Analysis for: C26H37N5O2-C4H4O4-O.6H2O
Calculées: C 63.47 ; H 7.28 ; N 12.34 ; Expérimentales: C 63.63 ; H 7.50 ; N 12.34Calculated: C 63.47; H 7.28; N 12.34; Experimental: C 63.63; H 7.50; N 12.34
Masse (DCI/NH3) : 452 (MH+),248,205Mass (DCI / NH3): 452 (MH +), 248.205
IR (KBr) : 3408,1645,1497,1355,1230IR (KBr): 3408,1645,1497,1355,1230
RMN IH (DMSO) : 1.83 (se, 2H), 2.33 (s,3H); 2.63 (se, 4H), 2.75 (se, 6H), 2.79 (se, 2H), 2.98 (se 4H), 3.50 (t,5.9 Hz, 2H), 3.55 (se, 2H), 3.73 (s, 3H), 6.57 (s, 2H), 6.79 (d,8.8 Hz, IH), 7.06 (se,lH); 7.10 (d,8.8Hz,lH); 7.15-7.28 (M, 5H), 8.00 (s, IH).1 H NMR (DMSO): 1.83 (sc, 2H), 2.33 (s, 3H); 2.63 (se, 4H), 2.75 (se, 6H), 2.79 (se, 2H), 2.98 (se 4H), 3.50 (t, 5.9 Hz, 2H), 3.55 (se, 2H), 3.73 (s, 3H) , 6.57 (s, 2H), 6.79 (d, 8.8 Hz, 1H), 7.06 (sc, 1H); 7.10 (d, 8.8Hz, 1H); 7.15-7.28 (M, 5H), 8.00 (s, IH).
Point de fusion : 131°CMelting point: 131 ° C
Les dérivés de la présente invention sont des antagonistes puissants des récepteurs 5HTi£> comme le montrent les études de liaison et les études d'antagonisme de l'inhibition de l'adénylate cyclase (stimulée par la forskoline) par un agoniste 5HTi£> tel que la sérotonine, le sumatriptan ou la 5-CT, études qui ont été réalisées au niveau des récepteurs humains clones 5HT]£)α et 5HTiDβ.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] £) α and 5HTiDβ.
Les récepteurs humains 5HTιrja et 5HTi£)b ont été clones selon les séquences publiées par M. Hamblin et M. Metcalf, Mol. Pharmacol., 40,143 (1991) et Weinshenk et coll., Proc. Natl. Acad. Sci.89,3630 (1992). La transfection transitoire et la transfection permanente des gènes de ces récepteurs a été réalisée dans des lignées cellulaires Cos-7 et CHO-Kj en utilisant un électroporateur.The human receptors 5HTιrj 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.
La lignée cellulaire HeLa HA7 exprimant le récepteur 5HTj^ humain a été obtenue de Tulco (Duke Univ., Durham, N.C., USA) et cultivée selon la méthode de Fargin et coll., J. Biol. Chem.264.14848 (1989).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).
L'étude de la liaison des dérivés de la présente invention avec les récepteurs 5HTiQa, 5HTiDb et 5HTIA humains a été réalisée selon la méthode décrite par P. Pauwels et C. Palmier (Neuropharmacology, 33,67,1994).The study of the binding of the derivatives of the present invention with human 5HTiQ a , 5HTiDb and 5HTIA receptors was carried out according to the method described by P. Pauwels and C. Palmier (Neuropharmacology, 33,67,1994).
Les milieux d'incubation pour ces mesures de liaison comprennent 0.4 ml de préparation de membrane cellulaire, 0.05ml d'un ligand tritié [3H]-5CT (concentration finale : 2nM) pour les récepteurs 5HTi£>a et 5HTiDb et [3H] -80H-DPAT (concentration finale : 1 nM) pour le récepteur SHTIA et 0.05 ml de la molécule à tester (concentrations finales de 0.1 nM à 1000 nM) ou 10 μM (concentration finale) de sérétonine (5HT i Da e t HT i Db) O U 1 UM (concentration finale) de spiroxatrine ( 5 HT I A) .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 μM (final concentration) of seretonin (5HT i D a and HT i Db) OR 1 U M (final concentration) of spiroxatrine (5 HT IA).
L'étude de l'inhibition de la formation d'AMP cyclique (stimulée par la forskoline) médiée par les récepteurs 5HT] Da et 5HT i £)b humains a été réalisée dans des cellules transfectées par le récepteur selon une technique décrite préalablement (P. Pauwels et C. Palmier, Neuropharmacology, 32,67, 1994; Cell. Pharmacol. 2, 183 , 1 995 ; Cell. Pharmacol. 2,49, 1 995 ; Eur. J. of Pharmacol. (Mol . Pharm.) 290, 95, 1995).The study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by human 5HT] D a and 5HT i £) b receptors was carried out in cells transfected by the receptor according to a technique described previously. (P. Pauwels and C. Palmier, Neuropharmacology, 32.67, 1994; Cell. Pharmacol. 2, 183, 1 995; Cell. Pharmacol. 2.49, 1 995; Eur. J. of Pharmacol. (Mol. Pharm .) 290, 95, 1995).
Les nouveaux composés dérivés d'aryl piperazines faisant partie de la présente invention sont des antagonistes puissants et sélectifs des récepteurs 5HT ι o et présentent l'avantage d'être particulièrement sélectifs pour les récepteurs 5HT i £) humains en particulier par rapport aux récepteurs 5HT j ^,The new compounds derived from aryl piperazines which are part of the present invention are powerful and selective antagonists of the 5HT receptors ι o and have the advantage of being particularly selective for the 5HT receptors i £) human in particular compared to the 5HT receptors j ^,
5HTι C, 5HT2, 04 , 0:2 et D2.5HTι C , 5HT 2 , 04, 0: 2 and D 2 .
Les dérivés de la présente invention sont en outre capables d'inhiber la contraction induite par la 5-hydroxytryptamine dans les anneaux de veine saphène de lapin et d'antagoniser l'inhibition induite par la 5- carboxamidotryptamine (5CT) au niveau de la libération de sérotonine dans les tranches de cerveau de cobaye. Ces deux modèles pharmacologiques sont généralement reconnus comme particulièrement pertinents dans la caractérisation fonctionnelle des récepteurs 5HT i £) et, dans le cas des produits de la présente invention, permettent de mettre en évidence leur activité antagoniste au niveau de ces récepteurs.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. These two pharmacological models are generally recognized as particularly relevant in the functional characterization of the 5HT receptors ((in the case of the products of the present invention, they make it possible to demonstrate their antagonistic activity at the level of these receptors.
Les dérivés de la présente invention se distinguent sans ambiguïté de l'art antérieur par leur structure chimique originale mais également par leur profil biologique. En effet, la comparaison des produits de la présente invention avec l'art antérieur le plus proche (demande de brevet FR 9408981 ) met en évidence, de façon inattendue, la supériorité des produits de la présente invention, comme l'illustre l'étude comparative suivante (table 1 ). Table 1The derivatives of the present invention are unambiguously distinguished from the prior art by their original chemical structure but also by their biological profile. Indeed, the comparison of the products of the present invention with the closest prior art (patent application FR 9408981) unexpectedly highlights the superiority of the products of the present invention, as illustrated by the study following comparison (table 1). Table 1
Figure imgf000109_0001
Figure imgf000109_0001
Ki (nM) l Dα l Dβ I AKi (nM) l Dα l Dβ I A
Z \ est omis* 340 1 8 450Z \ is omitted * 340 1 8 450
Z \ = CH2-CH2* * 2. 1 1 .9 3500Z \ = CH2-CH2 * * 2. 1 1 .9 3500
"" Composé revendiqué dans la demande de brevet FR 940898 1 * * Composé revendiqué dans la présente invention (exemple 1 )"" Compound claimed in patent application FR 940898 1 * * Compound claimed in the present invention (example 1)
La comparaison décrite ci-dessus démontre, à titre illustratif, que les produits de la présente invention présentent l'avantage d'avoir une meilleure affinité et une meilleure sélectivité en particulier vis-à-vis du récepteur 5 HT I A , au niveau des récepteurs 5 HT I Q et en particulier au niveau du récepteur 5HT i Da. Ces propriétés nouvelles et inattendues des antagonistes 5HT i £) revendiqués dans la présente invention les rendent particulièrement intéressants et utiles pour le traitement des patients souffrant de désordres au niveau du système nerveux central. De ce fait, la présente invention comprend également une méthode pour traiter de tels patients, méthode qui met en oeuvre l'administration d'une dose active d'un composé répondant à la formule générale (I). Les études d'activité antagoniste au niveau de la cyclase médiée par les récepteurs 5HT i £>a et 5HT i £)b démontrent par ailleurs que l'exemple illustratif de la présente invention repris dans la table 1 ci-dessus est un antagoniste puissant et silencieux, à la fois du récepteur 5HTi Db mais aussi 5HTi Da. Ces propriétés mettent bien en évidence les caractéristiques biologiques uniques des dérivés de la présente invention, en particulier si l'on compare ces données avec les données obtenues avec le dérivé GR- I 27935 qui, dans les mêmes conditions apparaît comme un agoniste du récepteur 5HT ι r_)a humain (cf. Pauwels et Colpaert, Neuropharmacol.,34,235 , 1995).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. These new and unexpected properties of the antagonists 5HT i £) claimed in the present invention make them particularly interesting and useful for the treatment of patients suffering from disorders in the central nervous system. Therefore, the present invention also includes a method for treating such patients, which method involves the administration of an active dose of a compound of general formula (I). The studies of antagonist activity at the level of the cyclase mediated by the receptors 5HT i £> a and 5HT i £) b further demonstrate that the illustrative example of the present invention set out in table 1 above is a powerful antagonist and silent, both from the 5HTi Db receiver and also 5HTi D a . These properties clearly highlight the unique biological characteristics of the derivatives of the present invention, in particular if we compare these data with the data obtained with the derivative GR-I 27935 which, under the same conditions appears as an agonist of the receptor 5HT ι r_) a human (cf. Pauwels and Colpaert, Neuropharmacol., 34,235, 1995).
Par ailleurs, les dérivés de la présente invention sont également capables de contrôler la croissance et la prolifération de cellules gliales de type Cβ transfectées par le gène du récepteur 5HT i £>β et par le gène du récepteur 5HT ι rja stimulées par un médiateur hormonal tel que la sérotonine. A titre d'exemple, les exemples de la présente invention inhibent l'incorporation de thymidine marquée (stimulée par 0. 1 μM de sumatriptan) avec une CI 50 de 10 à 100 nM (méthode décrite par P. Pauwels et coll ., J. of Neurochemistry, sous presse). A ce titre, les dérivés de la présente invention trouvent donc également leur utilité dans le traitement de cancers et autres désordres liés à la prolifération cellulaire.Furthermore, the derivatives of the present invention are also capable of controlling the growth and proliferation of type C β glial cells transfected by the 5HT i £> β receptor gene and by the 5HT ι rj a receptor gene stimulated by a hormonal mediator such as serotonin. By way of example, the examples of the present invention inhibit the incorporation of labeled thymidine (stimulated with 0.1 μM sumatriptan) with an IC 50 of 10 to 100 nM (method described by P. Pauwels et al., J . of Neurochemistry, in press). As such, the derivatives of the present invention therefore also find their utility in the treatment of cancers and other disorders linked to cell proliferation.
Doivent également être considérée comme faisant partie de la présente invention les compositions pharmaceutiques contenant à titre d'ingrédients actifs, un composé de formule générale (I) ou un sel physiologiquement acceptable d'un composé de formule (I) associé à un ou plusieurs agents thérapeutiques, tels que, par exemple des agents antidépresseurs comme les antidépresseurs tricycliques (par exemple amitryptyline, clomipramine, desipramine, imipramine), les inhibiteurs de mono-amine oxydase (par exemple isocarboxazide, moclobemide, phenelzine ou tranylcyclopramine), les inhibiteurs de re-uptake de sérotonine (par exemple fluvoxamine, sertraline, fluoxetine, paroxetine ou citalopram), les inhibiteurs de re-uptake de sérotonine et nor-adrénaline (par exemple le milnacipran), ou les antagonistes 0:2 (mianserine, mirtazapine, setiptiline, idazoxan, effaroxan, fluparoxan par exemple).Also to be considered as forming part of the present invention are the pharmaceutical 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. fluvoxamine, sertraline, fluoxetine, paroxetine or citalopram), serotonin and norepinephrine re-uptake inhibitors (e.g. milnacipran), or 0: 2 antagonists (mianserine, mirtazapine, setiptiline, idazoxan , effaroxan, fluparoxan for example).
Les dérivés de la présente invention ou leurs sels physiologiquement acceptables peuvent également être administrés sous forme de compositions pharmaceutiques, en association avec un antagoniste du récepteur 5 -HT J A (tel que, par exemple le pindolol, le WAY 1001 35 , le UH-30 1 ou le WAY 100635). Cette association fait également partie de la présente invention.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. (such as, for example, pindolol, WAY 1001 35, UH-30 1 or WAY 100635). This association is also part of the present invention.
La présente invention a également pour objet les compositions pharmaceutiques contenant comme principe actif un composé de formule générale I ou un de ses sels acceptables pour l'usage pharmaceutique, mélangé ou associé à un excipient approprié. Ces compositions peuvent revêtir, par exemple, la forme de compositions solides, liquides, d'émulsions, lotions ou crèmes.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.
Comme compositions solides pour administration orale, peuvent être utilisés des comprimés, des pilules, des poudres (capsules de gélatine, cachets) ou des granulés. Dans ces compositions, le principe actif selon l'invention est mélangé à un ou plusieurs diluants inertes, tels que amidon, cellulose, saccharose, lactose ou silice, sous courant d'argon. Ces compositions peuvent également comprendre des substances autres que les diluants, par exemple un ou plusieurs lubrifiants tels que le stéarate de magnésium ou le talc, un colorant, un enrobage (dragées) ou un vernis.As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, 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. 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.
Comme compositions liquides pour administration orale, on peut utiliser des solutions, des suspensions, des emulsions, des sirops et des elixirs pharmaceutiquement acceptables contenant des diluants inertes tels que l'eau, l'éthanol, le glycérol, les huiles végétales ou l'huile de paraffine. Ces compositions peuvent comprendre des substances autres que les diluants, par exemple des produits mouillants, édulcorants, épaississants, aromatisants ou stabilisants.As liquid 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. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
Les compositions stériles pour administration parenterale, peuvent être de préférence des solutions aqueuses ou non aqueuses, des suspensions ou des emulsions. Comme solvant ou véhicule, on peut employer l'eau, le propylèneglycol, un polyéthylèneglycol, des huiles végétales, en particulier l'hui le d'olive, des esters organiques injectables, par exemple l'oleate d'éthyle ou autres solvants organiques convenables. Ces compositions peuvent également contenir des adjuvants, en particulier des agents mouillants, isotonisants, émulsifiants, dispersants et stabilisants. La stérilisation peut se faire de plusieurs façons, par exemple par filtration aseptisante, en incorporant à la composition des agents stérilisants, par irradiation ou par chauffage. Elles peuvent également être préparées sous forme de compositions solides stériles qui peuvent être dissoutes au moment de l'emploi dans de l'eau stérile ou tout autre milieu stérile injectable.The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As 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.
Les compositions pour administration rectale sont les suppositoires ou les capsules rectales qui contiennent, outre le produit actif, des excipients tels que le beurre de cacao, des glycérides semi-synthétiques ou des polyéthylèneglycols.The 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.
Les compositions pour administration topique peuvent être par exemple des crèmes, lotions, collyres, collutoires, gouttes nasales ou aérosols .The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
Les doses dépendent de l'effet recherché, de la durée du traitement et de la voie d'administration utilisée ; elles sont généralement comprises entre 0,001 g et 1 g (de préférence comprises entre 0,005 g et 0,25 g) par jour de préférence par voie orale pour un adulte avec des doses unitaires al lant de 0, 1 mg à 500 mg de substance active, de préférence de 1 mg à 50 mg. D'une façon générale, le médecin déterminera la posologie appropriée en fonction de l'âge, du poids et de tous les autres facteurs propres au sujet à traiter. Les exemples suivants illustrent des compositions selon l'invention [dans ces exemples, le terme "composant actif" désigne un ou plusieurs (généralement un) des composés de formule (I) selon la présente invention] :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]:
ComprimésTablets
On peut les préparer par compression directe ou en passant par une granulation au mouillé. Le mode opératoire par compression directe est préféré mais il peut ne pas convenir dans tous les cas selon les doses et les propriétés physiques du composant actif.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.
A - Par compression directeA - By direct compression
mg pour 1 comprimé composant actif 1 0,0 cellulose microcristalline B .P.C. 89,5 stéarate de magnésium 0,5mg for 1 tablet active component 1 0.0 microcrystalline cellulose B .P.C. 89.5 magnesium stearate 0.5
1 00,01 00.0
On passe le composant actif au travers d'un tamis à ouverture de maille de 250 μm de côté, on mélange avec les excipients et on comprime à l'aide de poinçons de 6,0 mm. On peut préparer des comprimés présentant d'autres résistances mécaniques en modifiant le poids de compression avec utilisation de poinçons appropriés. The active component is passed through a sieve with a mesh opening of 250 μm 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.
B - Granulation au mouillé mg pour un comprimé composant actif 1 0,0 lactose Codex 74,5 amidon Codex 1 0,0 amidon de maïs prégélatinisé Codex 5 ,0 stéarate de magnésium 0,5B - Wet granulation mg for one tablet active component 1 0.0 lactose Codex 74.5 codex starch 1 0.0 pregelatinized corn starch Codex 5.0 magnesium stearate 0.5
Poids à la compression 100,0Compression weight 100.0
On fait passer le composant actif au travers d'un tamis à ouverture de maille de 250 μm et on mélange avec le lactose, l'amidon et l'amidon prégélatinisé. On humidifie les poudres mélangées par de l'eau purifiée, on met à l'état de granulés, on sèche, on tamise et on mélange avec le stéarate de magnésium. Les granulés lubrifiés sont mis en comprimés comme pour les formules par compression directe. On peut appliquer sur les comprimés une pellicule de revêtement au moyen de matières filmogènes appropriées, par exemple la méthylcellulose ou I'hydroxy-propyl-méthyl-cellulose, selon des techniques classiques. On peut également revêtir les comprimés de sucre.The active component is passed through a sieve with a mesh opening of 250 μm 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.
CapsulesCapsules
mg pour une capsule composant actif 10,0mg for one active ingredient capsule 10.0
*amidon 1500 89,5 stéarate de magnésium Codex 0,5* starch 1500 89.5 magnesium stearate Codex 0.5
Poids de remplissage 1 00,0Filling weight 1 00.0
* une forme d'amidon directement compressible provenant de la firme Colorcon Ltd, Orpington, Kent, Royaume Uni .* a form of directly compressible starch from the firm Colorcon Ltd, Orpington, Kent, United Kingdom.
On fait passer le composant actif au travers d'un tamis à ouverture de mail le de 250 μm et on mélange avec les autres substances. On introduit le mélange dans des capsules de gélatine dure n°2 sur une machine à remplir appropriée. On peut préparer d'autres unités de dosage en modifiant le poids de remplissage et, lorsque c'est nécessaire, en changeant la dimension de la capsule.The active component is passed through a 250 μm 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.
Sirop mg par dose de 5 ml composant actif 1 0,0 saccharose Codex 2750,0 glycérine Codex 500,0 tampon ) arôme ) colorant ) q.s. préservateur ) eau distillée 5,0Syrup mg per 5 ml dose active ingredient 1 0.0 sucrose Codex 2750.0 glycerin Codex 500.0 buffer) flavor) color) q.s. preservative) distilled water 5.0
On dissout le composant actif, le tampon, l'arôme, le colorant et le préservateur dans une partie de l'eau et on ajoute la glycérine. On chauffe le restant de l'eau à 80°C et on y dissout le saccharose puis on refroidit. On combine les deux solutions, on règle le volume et on mélange. Le sirop obtenu est clarifié par filtration.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.
SuppositoiresSuppositories
Composant actif 10,0 mg *Witepsol H 1 5 complément à 1 ,0 gActive ingredient 10.0 mg * Witepsol H 1 5 supplement to 1.0 g
^ Marque commercialisée pour Adeps Solidus de la Pharmacopée Européenne.^ Brand sold for Adeps Solidus of the European Pharmacopoeia.
On prépare une suspension du composant actif dans le Witepsol H 1 5 et on l'introduit dans une machine appropriée avec moules à suppositoires de 1 g. Liquide pour administration par injection intraveineuseA 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
g/1 composant actif 2,0 eau pour injection Codex complément à 1000,0g / 1 active component 2.0 water for injection Codex complement to 1000.0
On peut ajouter du chlorure de sodium pour régler la tonicité de la solution et régler le pH à la stabilité maximale et/ou pour faciliter la dissolution du composant actif au moyen d'un acide ou d'un alcali dilué ou en ajoutant des sels tampons appropriés. On prépare la solution, on la clarifie et on l'introduit dans des ampoules de dimension appropriée qu'on scelle par fusion du verre. On peut également stériliser le liquide pour inj ection par chauffage à l'autoclave selon l'un des cycles acceptables. On peut également stériliser la solution par filtration et introduire en ampoule stérile dans des conditions aseptiques. La solution peut être introduite dans les ampoules en atmosphère gazeuse.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.
Cartouches pour inhalationInhalation cartridges
g/cartouche composant actif micronisé 1 ,0 lactose Codex 39,0g / cartridge active ingredient micronized 1, 0 lactose Codex 39.0
Le composant actif est micronisé dans un broyeur à énergie de fluide et mis à l'état de fines particules avant mélange avec du lactose pour comprimés dans un mélangeur à haute énergie. Le mélange pulvérulent est introduit en capsules de gélatine dure n°3 sur une machine à encapsuler appropriée. Le contenu des cartouches est administré à l'aide d'un inhalateur à poudre. Aérosol sous pression à valve doseuseThe 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 pour 1 boite composant actif micronisé 0,500 120 mg acide oléique Codex 0,050 12 mg trichlorofluorométhane pour usage pharmaceutique 22,25 5 ,34 g dichlorodifluorométhane pour usage pharmaceutique 60,90 14,62 gmg / 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
Le composant actif est micronisé dans un broyeur à énergie de fluide et mis à l'état de fines particules. On mélange l'acide oléique avec le trichlorofluorométhane à une température de 10- 1 5 °C et on introduit dans la solution à l'aide d'un mélangeur à haut effet de cisaillement le médicament micronisé. La suspension est introduite en quantité mesurée dans des boîtes aérosol en aluminium sur lesquelles on fixe des valves doseuses appropriées délivrant une dose de 85 mg de la suspension ; le dichlorodifluorométhane est introduit dans les boites par injection au travers des valves. 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.

Claims

REVENDICATIONS
1. Composés répondant à la formule générale (I)1. Compounds corresponding to the general formula (I)
Figure imgf000118_0001
Figure imgf000118_0001
dans laquellein which
R\ représente un hydrogène ou un alkyle linéaire ou ramifié comprenant deR \ represents a hydrogen or a linear or branched alkyl comprising
1 à 6 atomes de carbone, Z2 représente O, NH, CH2O ou CH2NH,1 to 6 carbon atoms, Z2 represents O, NH, CH2O or CH2NH,
R2 et R3 identiques ou différents représentent un hydrogène ou un groupe choisi parmi un alkyle linéaire ou ramifié, un alcoxy, thioether, nitrile, trifluoromethyle ou halogène (F, Cl, Br, I), ou, R2 et R3 , lorsqu'ils sont adjacents, pris ensemble, forment un cycle à 5 ou 6 chaînons de façon à constituer par exemple un naphtyle, un tétrahydronaphtyle, un benzopyrane ou un benzodioxane,R2 and R3, which are 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,
X-Y représente NCH2, CH-CH2, C=CH, N ou NCH2CH2,X-Y represents NCH2, CH-CH2, C = CH, N or NCH2CH2,
Z ] représente -(CH2)n-. "(CH2)n CO-, -CO-, -CO(CH2)n-, -SO2-, -Z] represents - (CH2) n -. "(CH2) n CO-, -CO-, -CO (CH 2 ) n -, -SO2-, -
S02(CH2)n-, -O(CH2)n-, -O(CH2)nCO-, -OCO-, -NH(CH2)n-, - NH(CH2)nCO-, -NHCO-, -NHCO(CH2)n-, -NH(CH2)nSθ2-, -NHSO2-, -S0 2 (CH 2 ) n -, -O (CH2) n -, -O (CH 2 ) n CO-, -OCO-, -NH (CH 2 ) n -, - NH (CH2) n CO-, - NHCO-, -NHCO (CH2) n -, -NH (CH2) n Sθ2-, -NHSO2-, -
NHS02(CH2)n-, -CH=CHCO-,-CCCO- -(CH2)nSθ2-, -O(CH2)nSθ2-.NHS02 (CH2) n -, -CH = CHCO -, - CCCO- - (CH2) n Sθ2-, -O (CH2) n Sθ2-.
Dans le cas particulier où X-Y représente CH-CH2, Z i peut également représenter -O-,In the particular case where X-Y represents CH-CH2, Z i can also represent -O-,
-NH- , -CONH-, -SO2NH-, -OCONH-, -NHCOO-, -NHCONH-, -(CH2)nNH-, -(CH2)nO-, -CO(CH2)nNH-, -NH(CH2)nO-, -NH(CH2)nNH-, -0(CH2)nNH-,-NH-, -CONH-, -SO2NH-, -OCONH-, -NHCOO-, -NHCONH-, - (CH2) n NH-, - (CH2) n O-, -CO (CH 2 ) n NH-, -NH (CH2) n O-, -NH (CH2) n NH-, -0 (CH 2 ) n NH-,
-0(CH2)nO-, -CO(CH2)nO-, -Sθ2(CH2)nNH-, -Sθ2(CH2)nO- , - (CH2)nS02NH-, -(CH2)nCONH-, -0(CH2)nS02NH-, -0(CH2)nCONH-, - NH(CH2)nS02NH-, -NH(CH2)nCONH-, -NHCO(CH2)nNH-,-0 (CH 2 ) n O-, -CO (CH 2 ) n O-, -Sθ2 (CH 2 ) n NH-, -Sθ2 (CH 2 ) n O-, - (CH 2 ) nS0 2 NH-, - (CH 2 ) n CONH-, -0 (CH 2 ) n S0 2 NH-, -0 (CH 2 ) n CONH-, - NH (CH 2 ) nS0 2 NH- , -NH (CH 2 ) n CONH-, -NHCO (CH 2 ) n NH-,
NHSθ2(CH2)nNH- dans lesquels n représente un nombre entier compris entre 1 et 6, Dans le cas particulier où X-Y représente CH-CH2 ou C=CH. Z l peut également représenter -CH=CH-, -CC-,NHSθ2 (CH2) n NH- in which n represents an integer between 1 and 6, In the particular case where XY represents CH-CH2 or C = CH. Z l can also represent -CH = CH-, -CC-,
Ari représente un reste aromatique (phenyl, naphtyl ou pyridyl) pouvant être diversement substitué par exemple par un ou plusieurs groupes choisis parmi un alkyle linéaire ou ramifié comprenant de 1 à 6 atomes de carbone, un trifluoromethyle, un trifluorométhoxy, un 2,2,2-trifluoroéthyle, un phényle, un benzyle, un cycloalkyle comprenant de 3 à 7 atomes de carbone, un hydroxyle, un thiol, un alcoxy (OR4), thioether (SR4), un nitro (NO2), un nitrile (CN), une amine (NH2 ou NR4R4'), un dérivé d'aminé (NHCOR4, NHSO2R4, NHCONR4R'4, NHCO2R4, NHS02NR4R'4), un halogène (fluor, chlore, brome ou iode), un carbonyle (COH, COR4, COOR4, CONR4R'4) ou un hétérocycle pouvant éventuellement être substitué tel qu'un hétérocycle à 5 membres pouvant contenir de 1 à 4 héteroatomes choisis parmi l'oxygène, le soufre ou l'azote ou par deux substituants sur des carbones voisins pouvant former un cycle avec le reste aromatique auquel ils sont attachés, ou encore, le reste Ar-Z i représente un tétrahydronaphtyle dont la liaison avec X met en oeuvre un carbone saturé,Ari 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, a hydroxyl, a thiol, an alkoxy (OR4), thioether (SR4), a nitro (NO2), a 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) or a heterocycle which can optionally be substituted such as a 5-membered heterocycle which can contain from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen or by two substituents on neighboring carbons which can form a cycle with the aromatic remainder to which they are attached, or again, the remainder Ar-Z i repr has a tetrahydronaphthyl whose bond with X implements a saturated carbon,
R4 représente un reste alkyle, linéaire ou ramifié, comprenant de 1 à 6 atomes de carbone, R'4 représente un hydrogène ou un reste alkyle, linéaire ou ramifié, comprenant de 1 à 6 atomes de carbone et leurs sels, hydrates, solvates et bioprécurseurs physiologiquement acceptables pour l'usage thérapeutique, les composés de formule générale (I) se présentant sous forme isomères géométriques et optiques ainsi que sous forme racémique.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 salts, hydrates, solvates and physiologically acceptable bioprecursors for therapeutic use, the compounds of general formula (I) being in the form of geometric and optical isomers as well as in racemic form.
2. Composés selon la revendication 1 caractérisés en ce qu'ils correspondent à la formule générale la : R.2. Compounds according to Claim 1, characterized in that they correspond to the general formula la: R.
//
Figure imgf000120_0001
Figure imgf000120_0001
dans laquelle Ar i , Z \ , X-Y, Z2 et R i sont définis comme dans la revendication 1 et R2 représente un hydrogène, un méthyle, un méthoxy ou un chlore.in which Ar i, Z \, X-Y, Z2 and R i are defined as in claim 1 and R2 represents hydrogen, methyl, methoxy or chlorine.
3. Composés selon la revendication 1 caractérisés en ce que Z2 représente O ou NH.3. Compounds according to claim 1 characterized in that Z2 represents O or NH.
4. Composés selon la revendication 1 caractérisés en ce que Z2 représente CH2O ou CH2NH.4. Compounds according to claim 1 characterized in that Z2 represents CH 2 O or CH 2 NH.
5. Composés selon la revendication 1 caractérisés en ce que X-Y représente N-CH2.5. Compounds according to claim 1 characterized in that XY represents N-CH 2 .
6. Composés selon la revendication 1 caractérisés en ce que X-Y représente CH-CH2 ou C=CH.6. Compounds according to claim 1 characterized in that XY represents CH-CH 2 or C = CH.
7. Composés selon la revendication 1 caractérisés en ce que Z i représente (CH2)n, CO(CH2)n, SO2(CH2)n, O(CH2)n, NH(CH2)n ou NHCO(CH2)n-7. Compounds according to Claim 1, characterized in that Z i represents (CH 2 ) n, CO (CH 2 ) n , SO 2 (CH 2 ) n , O (CH 2 ) n , NH (CH 2 ) n or NHCO (CH 2 ) n -
8. Composés selon la revendication 1 caractérisé en ce que Z j représente (CH2)nCO, CO, O(CH2)nCO, NH(CH2)nCO ou CH=CHCO. 8. Compounds according to claim 1 characterized in that Z j represents (CH 2 ) n CO, CO, O (CH 2 ) nCO, NH (CH 2 ) n CO or CH = CHCO.
9. Composés selon la revendication 1 caractérisés en ce que Z \ représente S02, (CH2)nSO2, 0(CH2)nS02 ou NH(CH2)nS02.9. Compounds according to claim 1, characterized in that Z \ represents S0 2 , (CH 2 ) n SO 2 , 0 (CH 2 ) nS0 2 or NH (CH 2 ) n S0 2 .
10. Composés selon la revendication 1 caractérisés en ce que X-Y représente CH-CH2 et Z ] représente O, NH, CONH, S02NH, OCONH, NHCOO,10. Compounds according to claim 1, characterized in that XY represents CH-CH 2 and Z] represents O, NH, CONH, SO 2 NH, OCONH, NHCOO,
NHCONH, (CH2)nNH, (CH2)nO, NH(CH2)nO, 0(CH2)nNH, NH(CH2)nNH, CO(CH2)nNH ou CO(CH2)nO.NHCONH, (CH 2 ) n NH, (CH 2 ) n O, NH (CH 2 ) n O, 0 (CH 2 ) n NH, NH (CH 2 ) n NH, CO (CH 2 ) n NH or CO ( CH 2 ) n O.
11. Procédé de préparation des composés de formule (I) dans laquelle Ar i , Z i , X-Y, R \ , R2 et R3 sont définis comme précédemment et Z2 représente CH2O ou CH2NH caractérisé en ce que l'on condense un intermédiaire de formule (II)11. Method for preparing the compounds of formula (I) in which Ar i, Z i, XY, R \, R2 and R3 are defined as above and Z2 represents CH2O or CH2NH characterized in that an intermediate of formula is condensed (II)
Figure imgf000121_0001
Figure imgf000121_0001
dans laquelle Ar i , Z \ et X-Y so nt définis comme précédemment et Y' représente un groupe partant tel qu'un halogène (chlore ou brome), un tosylate, un mesylate ou un triflate, avec une aryl pipérazine de formule générale IIIwherein Ar i, Z \ and XY n t n as defined above and Y 'represents a leaving group such as halogen (chlorine or bromine), tosylate, mesylate or triflate, with an aryl piperazine of general formula III
Figure imgf000121_0002
dans laquelle X' représente O ou NH, et R j , R2 ou R3 sont définis comme précédemment en présence d'une base organique ou inorganique.
Figure imgf000121_0002
in which X 'represents O or NH, and R j, R2 or R3 are defined as above in the presence of an organic or inorganic base.
12. Procédé de préparation des composés de formule (I) dans lesquels Ar j , Z i , X-Y sont définis comme précédemment et Z2 représente O ou NH caractérisé en ce que l'on condense un intermédiaire de formule (III) défini comme dans la revendication 1 1 , et une aryl pipérazine de formule (IV)12. Method for preparing the compounds of formula (I) in which Ar j , Z i, XY are defined as above and Z2 represents O or NH characterized in that an intermediate of formula (III) defined as in the claim 1 1, and an aryl piperazine of formula (IV)
Arj-Z — X r^ NH ( IV )Ar j -Z - X r ^ NH (IV)
\\
YY
dans laquelle Ar j , Z i et X-Y sont définis comme précédemment avec un électrophile de formule (XII)in which Ar j, Z i and X-Y are defined as above with an electrophile of formula (XII)
x
Figure imgf000122_0001
 x
Figure imgf000122_0001
dans laquelle X j et X2 représentent un groupe partant tel qu'un halogène (en particulier le chlore), un groupe o-alkyle (en particulier le groupein which X j and X2 represent a leaving group such as a halogen (in particular chlorine), an o-alkyl group (in particular the group
OCCI3), un succinimyle, phtalyle ou imidiazolyle.OCCI3), a succinimyl, phtalyl or imidiazolyle.
13. Procédé de préparation des composés de formule (I) dans laquelle X représente un azote, caractérisé en ce que l'on condense un intermédiaire de formule (XXXI)13. Process for preparing the compounds of formula (I) in which X represents a nitrogen, characterized in that an intermediate of formula (XXXI) is condensed
Figure imgf000122_0002
dans laquelle R \ , R2, R3 et Z2 sont définis comme précédemment et X-Y représente N, N-CH2 ou NCH2CH2 avec un électrophile de formule (XVII)
Figure imgf000122_0002
in which R \, R2, R3 and Z2 are defined as above and XY represents N, N-CH2 or NCH2CH2 with an electrophile of formula (XVII)
Ar i - Z i - L (XVII)Ar i - Z i - L (XVII)
dans laquelle Ar j et Z \ sont définis comme précédemment et L représente un groupe partant dont le choix ainsi que le choix des conditions expérimentales (pour réaliser la condensation) dépendront de la nature de Z \ .in which Ar j and Z \ are defined as above and L represents a leaving group whose choice as well as the choice of experimental conditions (to achieve the condensation) will depend on the nature of Z \.
14. Procédé de préparation des produits de formule (I) dans laquelle Ar j , X- Y, Z j , Z2 sont définis comme précédemment et R \ représente un hydrogène caractérisé en ce que l'on hydrolyse en milieu acide un composé de formule (I) dans lequel R \ représente un t-butoxycarbonyle.14. Process for the preparation of products of formula (I) in which Ar j, X- Y, Z j, Z2 are defined as above and R \ represents a hydrogen characterized in that a compound of formula is hydrolyzed in acid medium (I) in which R \ represents a t-butoxycarbonyl.
15. Compositions pharmaceutiques contenant à titre d'ingrédients actifs, un composé selon l'une des revendications 1 à 10, en combinaison avec un véhicule pharmaceutique acceptable comme médicaments.15. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 10, in combination with a pharmaceutical vehicle acceptable as medicaments.
16. Compositions pharmaceutiques contenant, à titre d'ingrédients actifs, un composé selon l'une des revendications 1 à 1 0, en combinaison avec un véhicule pharmaceutique acceptable, pour le traitement tant curatif que préventif de la dépression et des désordres ou troubles compulsifs obsessionnels.16. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 1 0, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of depression and compulsive disorders or disorders obsessive.
17. Compositions pharmaceutiques contenant, à titre d'ingrédients actifs, un composé selon l'une des revendications 1 à 1 0, en combinaison avec un véhicule pharmaceutique acceptable, pour le traitement tant curatif que préventif de l'anxiété et des attaques de panique, de la schizophrénie, de l'agressivité, de la boulimie, de l'alcoolisme, de la douleur et des maladies neurodégénératives comme les maladies de Parkinson ou d'Alzheimer. 17. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 1 0, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of anxiety and panic attacks , schizophrenia, aggression, bulimia, alcoholism, pain and neurodegenerative diseases like Parkinson's or Alzheimer's.
18. Compositions pharmaceutiques contenant, à titre d'ingrédients actifs, un composé selon l'une des revendications 1 à 1 0, en combinaison avec un véhicule pharmaceutique acceptable, pour le traitement tant curatif que préventif des cancers.18. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 1 0, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of cancers.
19. Compositions pharmaceutiques selon l ' une des revendications 1 3 à 16, caractérisées en ce qu' elles contiennent, en outre, au moins un second principe actif associé, doté de propriétés antidépressives, en particulier, le MILNACIPRAN et/ou un antagoniste 5HT I A. 19. Pharmaceutical compositions according to one of claims 1 3 to 16, characterized in that they contain, in addition, at least one second associated active principle, endowed with antidepressant properties, in particular, MILNACIPRAN and / or a 5HT antagonist I A.
PCT/FR1997/000203 1996-02-02 1997-02-03 Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs WO1997028141A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU16074/97A AU1607497A (en) 1996-02-02 1997-02-03 Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs
EP97902427A EP0880512A1 (en) 1996-02-02 1997-02-03 Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs
CA 2245718 CA2245718A1 (en) 1996-02-02 1997-02-03 Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs
BR9707251A BR9707251A (en) 1996-02-02 1997-02-03 Process compounds for their preparation and pharmaceutical compositions
JP9527377A JP2000505795A (en) 1996-02-02 1997-02-03 Novel aromatic piperazines derived from substituted cycloazane, their preparation, pharmaceutical compositions and use as medicaments

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR96/01273 1996-02-02
FR9601273A FR2744449B1 (en) 1996-02-02 1996-02-02 NOVEL AROMATIC PIPERAZINES DERIVED FROM SUBSTITUTED CYCLOAZANES, AS WELL AS THEIR PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND THEIR USE AS MEDICAMENTS

Publications (1)

Publication Number Publication Date
WO1997028141A1 true WO1997028141A1 (en) 1997-08-07

Family

ID=9488768

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1997/000203 WO1997028141A1 (en) 1996-02-02 1997-02-03 Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs

Country Status (8)

Country Link
EP (1) EP0880512A1 (en)
JP (1) JP2000505795A (en)
CN (1) CN1214047A (en)
AU (1) AU1607497A (en)
BR (1) BR9707251A (en)
FR (1) FR2744449B1 (en)
MX (1) MX9806255A (en)
WO (1) WO1997028141A1 (en)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047885A1 (en) * 1997-04-18 1998-10-29 Smithkline Beecham Plc A bicyclic aryl or a bicyclic heterocyclic ring containing compounds having a combined 5ht1a, 5ht1b and 5ht1d receptor antagonistic activity
EP0899270A1 (en) * 1997-08-27 1999-03-03 Solvay Pharmaceuticals GmbH Indolylmethyl-N,N'-bisacylpiperazines as neurokinine receptor antagonists
US6001833A (en) * 1997-08-27 1999-12-14 Solvay Pharmaceuticals Gmbh Urea derivatives
WO2000009480A1 (en) * 1998-08-11 2000-02-24 Daiichi Pharmaceutical Co., Ltd. Novel sulfonyl derivatives
WO2000042011A1 (en) * 1999-01-14 2000-07-20 Fujisawa Pharmaceutical Co., Ltd. Amide compounds
US6169087B1 (en) 1997-09-23 2001-01-02 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (PTPases)
US6339154B1 (en) 1999-02-04 2002-01-15 Shiseido Co, Ltd. (2-Substituted oxyphenyl) alkanamide derivative, hair growth promoter and external composition for skin using the same
WO2003092695A1 (en) * 2002-05-01 2003-11-13 Bristol-Myers Squibb Company Bicyclo 4.4.0 antiviral derivatives
WO2005002562A1 (en) 2003-07-04 2005-01-13 H. Lundbeck A/S The combination of a serotonin reuptake inhibitors and agomelatine
US7053089B2 (en) 2001-02-23 2006-05-30 Merck & Co., Inc. N-substituted nonaryl-heterocyclic NMDA/NR2B antagonists
US7259157B2 (en) 2001-04-03 2007-08-21 Merck & Co., Inc. N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists
US7485646B2 (en) 2004-09-09 2009-02-03 Research Foundation Itsuu Laboratory Serotonin 5-HT3 receptor agonist
EP2036564A1 (en) 1999-12-06 2009-03-18 H.Lundbeck A/S The combination of a serotonin reuptake inhibitor and a 5-HT2C antagonist, inverse agonist or partial agonist
EP2060564A1 (en) * 2007-11-19 2009-05-20 Ludwig-Maximilians-Universität München Non-peptidic promoters of apoptosis
EP2065369A1 (en) * 2006-08-23 2009-06-03 Astellas Pharma Inc. Urea compound or salt thereof
US7696379B2 (en) 2005-04-25 2010-04-13 Novartis Ag Acetylene derivatives
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
EP2204368A1 (en) * 2007-09-21 2010-07-07 Banyu Pharmaceutical Co., Ltd. 4-sulfonylpiperidine derivatives
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
EP2448581A1 (en) * 2009-06-29 2012-05-09 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US8742119B2 (en) 2009-04-06 2014-06-03 Agios Pharmaceuticals, Inc. Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
US8877791B2 (en) 2006-08-04 2014-11-04 Beth Israel Deaconess Medical Center, Inc. Inhibitors of pyruvate kinase and methods of treating disease
US8889667B2 (en) 2010-12-29 2014-11-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US9181231B2 (en) 2011-05-03 2015-11-10 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia
US9221792B2 (en) 2010-12-17 2015-12-29 Agios Pharmaceuticals, Inc N-(4-(azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase M2 (PMK2) modulators
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
US9365545B2 (en) 2013-03-15 2016-06-14 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US10029987B2 (en) 2009-06-29 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US11530184B2 (en) 2020-06-30 2022-12-20 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11780811B2 (en) 2020-06-30 2023-10-10 Imbria Pharmaceuticals, Inc. Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11883396B2 (en) 2021-05-03 2024-01-30 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020049211A1 (en) * 2000-09-06 2002-04-25 Sobolov-Jaynes Susan Beth Combination treatment for depression and anxiety
US20020183316A1 (en) * 2000-10-27 2002-12-05 Kevin Pan Amidoalkyl-piperidine and amidoalkyl-piperazine derivatives useful for the treatment of nervous system disorders
GB0030710D0 (en) 2000-12-15 2001-01-31 Hoffmann La Roche Piperazine derivatives
WO2006062110A1 (en) * 2004-12-06 2006-06-15 Banyu Pharmaceutical Co., Ltd. Piperazine derivative
GB0503646D0 (en) * 2005-02-22 2005-03-30 Novartis Ag Organic compounds
TW200738701A (en) 2005-07-26 2007-10-16 Du Pont Fungicidal carboxamides

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0524146A1 (en) * 1991-07-19 1993-01-20 Ciba-Geigy Ag Aminosubstituted Piperazinederivatives
EP0533266A1 (en) * 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0533267A1 (en) * 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0533268A1 (en) * 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
GB2273930A (en) * 1992-12-30 1994-07-06 Glaxo Group Ltd Benzanilide derivatives
EP0606824A1 (en) * 1993-01-15 1994-07-20 Ciba-Geigy Ag Substituted dialkylthioethers
WO1994015920A1 (en) * 1992-12-30 1994-07-21 Glaxo Group Limited Benzanilide derivatives as 5-ht1d-antagonists
WO1995004729A1 (en) * 1993-08-06 1995-02-16 Smithkline Beecham Plc Amide derivatives as 5ht1d receptor antagonists
WO1995006044A1 (en) * 1993-08-20 1995-03-02 Smithkline Beecham Plc Amide and urea derivatives as 5ht1d receptor antagonists
WO1996002525A1 (en) * 1994-07-20 1996-02-01 Pierre Fabre Medicament Novel aryl piperazine-derived piperazide derivatives, methods for their preparation, their use as drugs and pharmaceutical compositions comprising same

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0524146A1 (en) * 1991-07-19 1993-01-20 Ciba-Geigy Ag Aminosubstituted Piperazinederivatives
EP0533266A1 (en) * 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0533267A1 (en) * 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0533268A1 (en) * 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
GB2273930A (en) * 1992-12-30 1994-07-06 Glaxo Group Ltd Benzanilide derivatives
WO1994015920A1 (en) * 1992-12-30 1994-07-21 Glaxo Group Limited Benzanilide derivatives as 5-ht1d-antagonists
EP0606824A1 (en) * 1993-01-15 1994-07-20 Ciba-Geigy Ag Substituted dialkylthioethers
WO1995004729A1 (en) * 1993-08-06 1995-02-16 Smithkline Beecham Plc Amide derivatives as 5ht1d receptor antagonists
WO1995006044A1 (en) * 1993-08-20 1995-03-02 Smithkline Beecham Plc Amide and urea derivatives as 5ht1d receptor antagonists
WO1996002525A1 (en) * 1994-07-20 1996-02-01 Pierre Fabre Medicament Novel aryl piperazine-derived piperazide derivatives, methods for their preparation, their use as drugs and pharmaceutical compositions comprising same

Cited By (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6159979A (en) * 1997-04-18 2000-12-12 Smithkline Beecham P.L.C. Bicyclic aryl or a bicyclic heterocyclic ring containing compounds having a combined 5HT1A, 5HT1B and 5HT1D receptor antagonistic activity
WO1998047885A1 (en) * 1997-04-18 1998-10-29 Smithkline Beecham Plc A bicyclic aryl or a bicyclic heterocyclic ring containing compounds having a combined 5ht1a, 5ht1b and 5ht1d receptor antagonistic activity
CN1108290C (en) * 1997-08-27 2003-05-14 索尔瓦药物有限公司 Urea derivatives
US6001833A (en) * 1997-08-27 1999-12-14 Solvay Pharmaceuticals Gmbh Urea derivatives
EP0899270A1 (en) * 1997-08-27 1999-03-03 Solvay Pharmaceuticals GmbH Indolylmethyl-N,N'-bisacylpiperazines as neurokinine receptor antagonists
US6169087B1 (en) 1997-09-23 2001-01-02 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (PTPases)
WO2000009480A1 (en) * 1998-08-11 2000-02-24 Daiichi Pharmaceutical Co., Ltd. Novel sulfonyl derivatives
US6710043B1 (en) 1999-01-14 2004-03-23 Fujisawa Pharmaceutical Co., Ltd. Amide compounds
WO2000042011A1 (en) * 1999-01-14 2000-07-20 Fujisawa Pharmaceutical Co., Ltd. Amide compounds
KR100525809B1 (en) * 1999-01-14 2005-11-03 후지사와 야꾸힝 고교 가부시키가이샤 Amide compounds
US6339154B1 (en) 1999-02-04 2002-01-15 Shiseido Co, Ltd. (2-Substituted oxyphenyl) alkanamide derivative, hair growth promoter and external composition for skin using the same
US6573297B2 (en) 1999-02-04 2003-06-03 Shiseido Co., Ltd. (2-substituted oxyphenyl)alkanamide derivative, hair growth promoter and external composition for skin using the same
EP2036564A1 (en) 1999-12-06 2009-03-18 H.Lundbeck A/S The combination of a serotonin reuptake inhibitor and a 5-HT2C antagonist, inverse agonist or partial agonist
US8536184B2 (en) 2000-11-01 2013-09-17 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
USRE43098E1 (en) 2000-11-01 2012-01-10 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7053089B2 (en) 2001-02-23 2006-05-30 Merck & Co., Inc. N-substituted nonaryl-heterocyclic NMDA/NR2B antagonists
US7259157B2 (en) 2001-04-03 2007-08-21 Merck & Co., Inc. N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists
WO2003092695A1 (en) * 2002-05-01 2003-11-13 Bristol-Myers Squibb Company Bicyclo 4.4.0 antiviral derivatives
US7037913B2 (en) 2002-05-01 2006-05-02 Bristol-Myers Squibb Company Bicyclo 4.4.0 antiviral derivatives
WO2005002562A1 (en) 2003-07-04 2005-01-13 H. Lundbeck A/S The combination of a serotonin reuptake inhibitors and agomelatine
US7485646B2 (en) 2004-09-09 2009-02-03 Research Foundation Itsuu Laboratory Serotonin 5-HT3 receptor agonist
US7696379B2 (en) 2005-04-25 2010-04-13 Novartis Ag Acetylene derivatives
US8877791B2 (en) 2006-08-04 2014-11-04 Beth Israel Deaconess Medical Center, Inc. Inhibitors of pyruvate kinase and methods of treating disease
EP2065369A4 (en) * 2006-08-23 2011-12-28 Astellas Pharma Inc Urea compound or salt thereof
EP2065369A1 (en) * 2006-08-23 2009-06-03 Astellas Pharma Inc. Urea compound or salt thereof
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
EP2204368A1 (en) * 2007-09-21 2010-07-07 Banyu Pharmaceutical Co., Ltd. 4-sulfonylpiperidine derivatives
EP2204368A4 (en) * 2007-09-21 2012-02-15 Msd Kk 4-sulfonylpiperidine derivatives
US8163898B2 (en) 2007-09-21 2012-04-24 Msd K. K. 4-sulfonylpiperidine derivatives
WO2009065570A1 (en) * 2007-11-19 2009-05-28 Ludwig-Maximilians-Universität München Non-peptidic promoters of apoptosis
EP2060564A1 (en) * 2007-11-19 2009-05-20 Ludwig-Maximilians-Universität München Non-peptidic promoters of apoptosis
US9657004B2 (en) 2009-04-06 2017-05-23 Agios Pharmaceuticals, Inc Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
US9938259B2 (en) 2009-04-06 2018-04-10 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US8742119B2 (en) 2009-04-06 2014-06-03 Agios Pharmaceuticals, Inc. Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
EP2448581A1 (en) * 2009-06-29 2012-05-09 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US9115086B2 (en) 2009-06-29 2015-08-25 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US11866411B2 (en) 2009-06-29 2024-01-09 Agios Pharmaceutical, Inc. Therapeutic compounds and compositions
USRE49582E1 (en) 2009-06-29 2023-07-18 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
EP2448581A4 (en) * 2009-06-29 2013-02-20 Agios Pharmaceuticals Inc Therapeutic compositions and related methods of use
US10988448B2 (en) 2009-06-29 2021-04-27 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10029987B2 (en) 2009-06-29 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US9221792B2 (en) 2010-12-17 2015-12-29 Agios Pharmaceuticals, Inc N-(4-(azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase M2 (PMK2) modulators
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
US10087169B2 (en) 2010-12-21 2018-10-02 Agios Pharmaceuticals, Inc. Bicyclic PKM2 activators
US9199968B2 (en) 2010-12-29 2015-12-01 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US8889667B2 (en) 2010-12-29 2014-11-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US10632114B2 (en) 2011-05-03 2020-04-28 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US11793806B2 (en) 2011-05-03 2023-10-24 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9181231B2 (en) 2011-05-03 2015-11-10 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia
US9365545B2 (en) 2013-03-15 2016-06-14 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US10918728B2 (en) 2017-06-20 2021-02-16 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10953102B2 (en) 2017-06-20 2021-03-23 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11376330B2 (en) 2017-06-20 2022-07-05 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11844840B2 (en) 2017-06-20 2023-12-19 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11530184B2 (en) 2020-06-30 2022-12-20 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11780811B2 (en) 2020-06-30 2023-10-10 Imbria Pharmaceuticals, Inc. Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11746090B2 (en) 2020-06-30 2023-09-05 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11883396B2 (en) 2021-05-03 2024-01-30 Imbria Pharmaceuticals, Inc. Methods of treating kidney conditions using modified forms of trimetazidine

Also Published As

Publication number Publication date
JP2000505795A (en) 2000-05-16
AU1607497A (en) 1997-08-22
FR2744449B1 (en) 1998-04-24
CN1214047A (en) 1999-04-14
EP0880512A1 (en) 1998-12-02
BR9707251A (en) 1999-04-06
MX9806255A (en) 1998-11-29
FR2744449A1 (en) 1997-08-08

Similar Documents

Publication Publication Date Title
EP0880512A1 (en) Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs
US5874447A (en) 4-Phenylpiperidine compounds for treating depression
US5789412A (en) Piperazides derived from arylpiperazine, processes for their preparation, their use as medicaments and pharmaceutical compositions comprising them
US6498168B2 (en) Muscarinic antagonists
WO1996041802A1 (en) Novel heteroaromatic piperazines for use as drugs
FR2744448A1 (en) NOVEL PIPERIDINES DERIVED FROM ARYL PIPERAZINE, AND PROCESS FOR PREPARING THEM, PHARMACEUTICAL COMPOSITIONS AND THEIR USE AS MEDICAMENTS
WO1998031677A1 (en) Novel aromatic amines derived from cyclic amines useful as medicines
WO1997014689A1 (en) Aryl-piperazine cyclic amine derivatives, preparation thereof and pharmaceutical compositions containing same
US4426386A (en) Substituted phenyl piperidines
WO1998031669A1 (en) Novel arylpiperazine derived from piperidine as antidepressant medicines
WO1997028139A1 (en) Novel naphthylpiperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions and use thereof as drugs
EP0782568B1 (en) Aromatic ethers derived from indols such as 5ht1-like ligands
WO1998042692A1 (en) Piperazines derived from cyclic amines, preparation and application thereof as medicines
US4719219A (en) Phenyl-azacycloalkanes and use thereof in treatment of central nervous system disorders
CA2245718A1 (en) Novel aromatic piperazines derived from substituted cycloazanes, method for preparing same, pharmaceutical compositions, and use thereof as drugs
FR2761069A1 (en) Di:hydro benzo furan spiro:amine derivatives
US4937346A (en) Phenyl-azacykloalkanes
WO1995026336A1 (en) N-(benzhydryloxyalkyl)-4-(carboxy/carbamoyl-methyl)-piperidine derivatives as antidepressants
US4124719A (en) -4-Phenylhexahydro-4-indolinol derivatives
WO1998023586A1 (en) Aromatic aminoalcohols as 5ht1a antagonists and as serotonin reabsorption inhibitors
WO1996026922A1 (en) Novel sulphonamide bi-tryptamine derivatives, method for preparing same, and use of said derivatives as drugs
WO1996012713A1 (en) Novel naphthylpiperazine-derived aromatic ethers for use as drugs
FR2663329A1 (en) Aminated aromatic compounds, process for their preparation, and pharmaceutical compositions containing them

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 97193122.4

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA CN JP KR MX NZ US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2245718

Country of ref document: CA

Ref document number: 2245718

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/1998/006255

Country of ref document: MX

Ref document number: 331222

Country of ref document: NZ

Ref document number: 1997902427

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1997902427

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997902427

Country of ref document: EP