WO1997014689A1 - Aryl-piperazine cyclic amine derivatives, preparation thereof and pharmaceutical compositions containing same - Google Patents

Aryl-piperazine cyclic amine derivatives, preparation thereof and pharmaceutical compositions containing same Download PDF

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WO1997014689A1
WO1997014689A1 PCT/FR1996/001626 FR9601626W WO9714689A1 WO 1997014689 A1 WO1997014689 A1 WO 1997014689A1 FR 9601626 W FR9601626 W FR 9601626W WO 9714689 A1 WO9714689 A1 WO 9714689A1
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mmol
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derivative
fumarate
meoh
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PCT/FR1996/001626
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French (fr)
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Serge Halazy
Marie Lamothe
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Pierre Fabre Medicament
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    • 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
    • C07D295/18—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 carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • 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
    • C07D211/30—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
    • 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
    • C07D295/18—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 carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • 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 aryl-piperazines derived from cyclic amines, 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. central, serotonin controls functions as varied as sleep, locomotion, food intake, learning and memory, endocrine modulations, sexual behavior, thermoregulation In the marrow, serotonin plays an important role in control systems for peripheral nociceptive afferents (see A Mouhgnier, Rev Neurol (Paris), 150.3-15.1994)
  • Serotonin can play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggressiveness, 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, strokes, pain, migraine, or various headaches (R Glennon, Neurosci. Biobehavioral Reviews, 14.35, 1990)
  • the 5HT] rj receptors themselves contain several receptor subtypes; thus the 5HT ] £) ⁇ and 5HTi £> ⁇ receptors were cloned and then identified in humans (cf. for example E Hamel et al., Mol. Pharmacol., 44,242, 1993; GW Rebeck et coil , Proc NatI Acad. Sci. USA, 91.3666, 1994). Furthermore, it has recently been demonstrated that the 5HT j ⁇ auto-receptors in rodents and 5HTj r_) in other species are capable of controlling the release of serotonin in nerve endings (cf. M B ⁇ ley, C Moret, Cl. Neuropharm, 16,387, 1993; BE Léonard, Int. Clin. Psychopharmacol, 9,7, 1994) as well as the release of other neuro transmitters such as norepinephrine, dopamine or acetylcholine (M. Harrrington, J. Clin. Psychiatry, 53, 10, 1992).
  • Compounds having a selective antagonist activity at the level of the central 5HT ID 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 antagonists 5HTj £) also find their utility in the treatment of endocrine disorders such as hyperprolactinemia, the treatment of vasospasms, hypertension and gastrointestinal disorders in which there are changes in motility and secretion .
  • the compounds according to the present invention are potent and selective antagonists of the 5HTifj) receptors and more particularly receptors recently identified as 5HT] D ⁇ and 5HT j rj> ⁇ in humans and therefore find their utility, alone or in combination with other molecules, as drugs 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 for the subtypes of serotonin receptors (5HT ⁇ rj) ⁇ and ⁇ ) and their antagonistic activity
  • the present invention relates to derivatives of general formula (I)
  • R] H, Cj-Cg alkyl
  • R2 represents an alkyl residue, linear or branched comprising from 1 to 8 carbon atoms, a cycloalkyl (comprising from 3 to 8 carbon atoms), an aryl, an arylalkyl, an aryl carbonyl or even an aryl ether when X is different from d 'a nitrogen in which the aromatic ring may be a phenyl, a naphthyl, a tetrahydronaphthyl, a benzothienyl, a benzofuryl, an indole, a benzodioxane or a benzodioxine which may be variously substituted by one or more groups chosen from R 1, OH, OR ⁇ , SR ⁇ , NO2, CN, COR ⁇ , CO 2 R6, CONHR 6 , NH 2 , NHR 6 , NHCOR ⁇ , NHCO 2 R6, NHCONHRg, OCONHR 6 , SO 2 R 6
  • R3 and R4 identical or different, represent a hydrogen or a group chosen from a linear or branched alkyl (R7), an alkoxy (OR7), thioether (SR7), nitrile, trifluoromethyl or halogen (Cl, F, BR or I) in which R7 represents an alkyl residue comprising from 1 to 5 carbon atoms, or, R3 and R4 when they are adjacent, taken together, form a 5 or 6-membered ring with the aromatic residue to which they are attached so as to constitute, by example, a naphthylE or a tetrahydronaphthyl, it being understood that the substituents -Z, R3 and R4 can be located in various relative positions on the aromatic ring to which they are attached;
  • Z Z 1 - (CH 2 ) m -Z 2 , Z ⁇ -Ar- (CH 2 ) nZ 2 , Z 1 - (CH 2 ) m . 1 -CONH-, Z ⁇ CH ⁇ ! -
  • NH im represents an integer between 2 and 8
  • n represents an integer between 1 and 6
  • R5 represents a hydrogen, a linear or branched alkyl comprising from 1 to 5 carbon atoms, an aryl (such as a phenyl) or an arylalkyl (such as a benzyl) which can be variously substituted by a hydroxyl, an amine, a thiol or thiomethyl
  • Ar represents an aromatic residue (such as phenyl) to which the substituents are attached to different carbons and can be in various relative positions, and their physiologically acceptable salts, hydrates, solvates and bioprecursors for their therapeutic use.
  • geometric and optical isomers of the compounds of general formula (I) also form part of the present invention as well as their mixtures in all proportions and in racemic form.
  • (I) are included the salts obtained by addition of organic or inorganic acids such as the hydrochlorides, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoate, p-toluenesulfonates, methanesulfonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates , salicylates, fumarates, succinates, lactates, glutarates, glutaconates.
  • organic or inorganic acids such as the hydrochlorides, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoate, p-toluenesulfonates, methanesulfonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates , salicylates, fumarates, succinates, lactates,
  • 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).
  • * XY represents N-CH 2 or CH-CH 2 and / or, * Ri represents a methyl and / or
  • R 3 represents a hydrogen and R "a chlorine atom or a methoxy group and / or,
  • R 3 and Rj are adjacent and, taken as a whole, form a 6-membered ring with the aromatic residue to which they are attached and / or, * Z represents -Z ⁇ - (CH 2 ) m -Z 2 or Zi- (CH 2 ) m- ⁇ -CONH, or else
  • a general method for preparing the compounds of general formula (I) consists in condensing a cyclic amine of general formula (II)
  • R ⁇ , R3, R4 and Z are defined as above and X represents a leaving group such as, for example, chlorine.
  • the method consists in condensing an amine of formula (II) with a carboxylic acid derivative of formula (III) in which Z is defined as above and X represents OH, O-alkyl, CI, or, the group "XCO” represents any activated form derived from a carboxylic acid suitable for the preparation of an amide by the methods and techniques well known to those skilled in the art for preparing an amide by condensation of an amine with a carboxylic acid derivative. The experimental conditions for carrying out this condensation will be determined as a function of the nature of Z and especially of the nature of X.
  • this condensation can be carried out starting from a carboxylic ester of formula (III) (in 1 which X represents an O-alkyl such as for example an ethyloxy) with an amine of formula (II) in the presence of trimethylaluminium in an anhydrous aprotic solvent such as dichloromethane or toluene.
  • a carboxylic ester of formula (III) in 1 which X represents an O-alkyl such as for example an ethyloxy
  • an amine of formula (II) in the presence of trimethylaluminium in an anhydrous aprotic solvent such as dichloromethane or toluene.
  • an organic base or inorganic such as pyridine, DiPEA, DMAP, DBU, K 2 C03, Cs 2 C ⁇ 3 or Na 2 C ⁇ 3 in an anhydrous polar aprotic solvent such as THF, DME, dichloromethane, at a temperature between - 20 ° C and 40 ° C.
  • the preparation of the compounds of the present invention of general formula (I) in which Z is described as above can also be carried out by condensation of an amine of formula (II) with an activated ester of
  • a tertiary amine such as triethylamine, diisipropylethylamine, pyridine, DiPEA, DMAP, N-methylmorpholine
  • a polar aprotic solvent such as THF, dichloromethane, DCE, ethyl acetate, chloroform, DMF, for
  • Rj, R3 and R4 are defined as above, Zj represents O or NH, and Y represents (CH 2 ) m -Z 2 , Ar- (CH 2 ) n -Z 2 , (CH 2 ) m _ j-CONH or Ar- (CH 2 ) n . j -CONH by reaction with a derivative of general formula (V)
  • X and X ′ which are identical or different, each represent a leaving group such as a halogen (in particular chlorine), an O-alkyl group (in particular the group OCCI3), an O-aryl group (in particular the group O -pyridyl), a succinimyl, phthalyl or imidazolyl group.
  • the method of the present invention also comprises the use of precursors or analogues well known to the reagents of general formula (V). It is thus and by way of example that the condensation of intermediates (IV) with phosgene can be advantageously carried out using diphosgene or triphosgene according to a procedure well known to those skilled in the art.
  • R 2 , XY and Z ⁇ are defined as in formula (I), Z "represents (CH 2 ) m _] or Ar (CH 2 ) n . ⁇ and X represents a leaving group or the remainder" COX "represents any form derived from a carboxylic acid conducive to condensation with an amine to form an amide by methods and techniques well known to those skilled in the art.
  • R ⁇ , R3 and R4 are defined as above and X represents a leaving group (for example a chlorine) or, the group "XCO” represents any form derived from a carboxylic acid (for example an activated ester) suitable for condensation with an amine to form an amide by methods and techniques well known to those skilled in the art.
  • X represents a leaving group (for example a chlorine) or, the group "XCO” represents any form derived from a carboxylic acid (for example an activated ester) suitable for condensation with an amine to form an amide by methods and techniques well known to those skilled in the art.
  • Z ′ 2 represents OH or NH-P in which P represents a group such as butyloxycarbonyl or trifluoroacetyl with an electrophile of general formula (XI)
  • R 2 XY are defined as above
  • Z '" represents Z ] - (CH 2 ) m or Z ⁇ -Ar- (CH 2 ) n
  • L represents a leaving group such as a halogen (preferably bromine or iodine ), a tosylate, a mesylate or a triflate.
  • This condensation is carried out in basic medium in the presence of a base such as NaH, KH or Cs 2 C ⁇ 3 in a polar aprotic solvent such as DMF, THF, dioxane, DME or DMSO, at a temperature of between ⁇ 10 ° and 60 ° C.
  • condensation using an aromatic amine derivative of formula (X) in which Z ′ 2 represents NHBOC or NHCOCF3
  • the condensation will be followed by a step of deprotection of the aromatic amine (for example by using acidic conditions such as the use of hydrochloric or trifluoroacetic acid in the case of the tbutoxycarbonyl derivative or by using basic conditions such as sodium or potassium hydroxide or reducing conditions s (basic aluminum hydrides) in the case of N-trifluoroacetyl derivatives).
  • acidic conditions such as the use of hydrochloric or trifluoroacetic acid in the case of the tbutoxycarbonyl derivative
  • basic conditions such as sodium or potassium hydroxide or reducing conditions s (basic aluminum hydrides) in the case of N-trifluoroacetyl derivatives.
  • an alternative but particularly preferred method of preparation consists in condensing a derivative of amino acid of general formula (VIII) in which R 2 , XY and R5 are defined as above and an intermediate of formula (XII) ⁇
  • R] R3 R4 are defined as above and Z 2 represents O or NH with a reagent of formula (V) in which X and X 'are defined as previously
  • Z represents CH (R5) -NHC0 2 or CH (R5) -NH- CONH by condensation of the derivatives of formula (VIII) and derivatives of formula (XII) with a reagent of formula (V ) such as the choice of the order of the reactants, 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-reactants (such as an organic or inorganic base, for example a tertiary amine) or catalysts will be determined essentially by the nature of the reactant (V) (choice of X and X ").
  • the intermediate esters of formula (III) in which X represents O-alkyl or O-alkylaryl and Z represents (CH 2 ) m -O, or Ar- (CH 2 ) n -O or CH (R5) - NHCO 2 - are respectively prepared by condensation of an arylpiperazine of formula (XII) in which Z 2 represents an oxygen with an electrophile of formula (XIII), (XIV) or (XV)
  • L represents a leaving group such as a halogen (chlorine, bromine or iodine), a tosylate, a mesylate and a triflate and L 'represents a halogen or a residue of activated carbamoyl such as OCCI3 O-succinimyl or O-pyridyl.
  • the condensation of phenols of formula (XII) in which Z 2 represents oxygen with an electrophile of formula (XIII) or (XIV) is preferably carried out in the presence of a base (for example NaH, KH, CS2CO3, DiPEA or l ⁇ BuOK) in a polar aprotic solvent such as DMF, DMSO or diethyl ketone, at a temperature between 20 and 100 ° C.
  • a base for example NaH, KH, CS2CO3, DiPEA or l ⁇ BuOK
  • a polar aprotic solvent such as DMF, DMSO or diethyl ketone
  • the intermediate esters of formula (III) in which X represents O-alkyl or O-arylalkyl and Z represents (CH 2 ) m -NH, Ar- (CH 2 ) n -NH, CH (R5) -NH-CONH, ( CH 2 ) m - j-CONH or Ar (CH 2 ) n _ ⁇ CONH are prepared by condensation of an intermediate of formula (XII) in which Z 2 represents NH or NBOC or NCOCF3 with respectively an electrophilic of formula (XIII), (XIV), (XV), (XVI) or (XVII)
  • L represents a leaving group (such as chlorine) or also the group COL" represents an activated ester, a carboxylic acid or any form derived from a suitable carboxylic acid to the formation of an amide by condensation with an amine.
  • the electrophiles of formula (XIII) and (XIV) will be condensed preferably with an aniline derivative of formula (XII) in which Z 2 represents NBOC or NCOCF3 in a polar aprotic solvent such as THF or DMSO or DMF in the presence of a strong base such as NaH, KH or t_ BuOK at a temperature between 20 and 80 ° C and will be followed by deprotection of aromatic nitrogen (in an acid medium if the starting product is a derivative t_ butoxycarbonyl , in basic or reducing medium if the starting product is a trifluoroacetyl derivative).
  • a polar aprotic solvent such as THF or DMSO or DMF
  • a strong base such as NaH, KH or t_ BuOK
  • the derivatives of formula (III) of urea type are obtained by condensation of an aromatic amine of formula (XII) in which Z 2 represents NH with an electrophile of formula (XV) in which L 'represents for example a chlorine (intermediate derived of the reaction of XCO-CH (R5) NH 2 with triphosgene) in an aprotic anhydrous solvent such as dichloromethane in the presence of triethylamine.
  • the amide type intermediates of formula (III) are prepared by condensation of an aromatic amine of formula (XII) in which Z 2 represents NH with a carboxylic acid derivative (conducive to condensation with an amine) of formula (XVI) or (XVII) in which L "is defined as above, by the methods and techniques well known to those skilled in the art for preparing an amide from an amine and an acid derivative carboxylic.
  • esters derived from formula (III) in which Z represents (CH 2 ) m or Ar (CH 2 ) n are prepared by condensation of a triflate of general formula (XVIII)
  • X represents O-alkyl or O-aryl and m and n are greater than or equal to 2, according to a described method (cf. J. Org. Chem. 58, 2201, 1993).
  • M represents Li, MgBr or ZnBr with an appropriate electrophile such as for example a compound corresponding to formula (XIII) or (XIV)
  • organometallic structures (XXI) are accessible by metal halogen exchange from the aromatic bromines of formula (XXII).
  • an alternative but particularly appreciated method consists in condensing by the methods and techniques well known under the Heck reaction name, an ⁇ , ⁇ unsaturated ester with an aromatic bromine derivative of formula (XXII), in the presence of a palladium derivative, followed by the reduction of the double bond of the intermediate thus formed by catalytic hydrogenation (in the presence of palladium on carbon for example).
  • intermediates of formula (IV) are in turn prepared according to the methods described above for the preparation of intermediates (III), which will be determined essentially as a function of the nature of Zj and which of course will use precursor synthons from the group " HZ] -Y "appropriate.
  • intermediates of formulas (VI), (X), (XII) or (XXI) will be carried out with electrophiles of general formula (XXIII)
  • Z ⁇ represents O or NH
  • Y ' represents either (CH 2 ) m , Ar- (CH 2 ) n , (CH 2 ) m _ ⁇ -CO or Ar- (CH 2 ) n .
  • ⁇ -CO and L represents a leaving group such as a halogen (bromine, chlorine or iodine), a tosylate, a mesylate or a triflate, by the structures described above for the preparation of intermediates of formula (III) for the same type reaction, followed by deprotection of Z ⁇ by the appropriate methods chosen according to the nature of P such as catalytic hydrogenation in the presence of palladium on carbon if P represents a benzyl residue, treatment with fluorides (such as CsF or Bu 4 NF) if P is a silyl radical or acid hydrolysis if P is the "butoxycarboxyle.
  • halogen bromine, chlorine or iodine
  • a tosylate a mesylate or a triflate
  • An alternative but appreciated method for preparing the derivatives of formula (IV) in which Z ⁇ represents oxygen consists in reducing an appropriate precursor of general formula (III) in which X represents an O-alkyl (for example OEt or OMe) by a aluminum hydride (such as for example LiAlPLt;) in an anhydrous solvent such as ethyl ether or THF at a temperature between 0 ° and 60 ° C, it being understood that the residue Y in the final product of formula ( IV) will contain one CH 2 more than the residue Z in the precursor of formula (III).
  • represents NH can be prepared by reduction of nitriles of formula XXIV ⁇ $)
  • X represents O-alkyl or O-alkylaryl and X 'represents a leaving group such as chlorine, or alternatively, the group X'CO represents an activated form of carboxylic acid suitable for condensation with an amine by methods and techniques well known to those skilled in the art.
  • the intermediates of formula (XI) are prepared by condensation of a cyclic amine of formula (II) with an electrophile of formula (XXVI) in which X 'is described as in formula (XXV), Z'"is defined as in formula (XI) and P represents a temporary protected form which will be transformed into a remainder L as defined in formula (XI), after the condensation reaction between the derivatives (II) and (XXVI).
  • L represents a mesylate will be prepared by condensation of a cyclic amine of formula (II) with an activated carboxylic acid derivative of formula (XXVI)
  • X ' represents a chlorine
  • a base for example triethylamine or pyridine
  • the intermediates of formula (VIII) are prepared by condensation of an amino acid derivative of formula HOOC-CH (R5) -NH-Boc with a cyclic amine of formula (II) by the methods and techniques well known in the art. one skilled in the art.
  • piperazines of formula (II) (in which XY represents N-CH 2 ), (VI), (IX), (X), (XII) and (XXII) are prepared by various methods and techniques well known to man of art and the choice of which will essentially depend on the nature of R 2 in the case of piperazines of formula (II) and of the substituents linked to the aromatic residue in the case of piperazines (VI), (IX), (X), (XII) and (XXII).
  • R'i represents R ⁇ or a protective group such as a t_ butoxycarbonyl or a tosyle and X represents a chlorine, a bromine, an iodine, a tosylate or a mesylate.
  • a polar anhydrous solvent such as DMF, acetonitrile, THF, n-butanol, t-butanol or DMSO, usually at O 97/14689 PC17FR96 / 01626
  • a particularly preferred preparation method consists in condensing the piperazine (which will then be used in excess) or the N-BOC-piperazine with an electrophile corresponding to the formula R 2 -L in which L represents a leaving group such as a halogen (Cl, Br or I), a tosylate, a mesylate or a triflate, optionally in the presence of an organic base such as 'a tertiary or inorganic amine such as Cs 2 C ⁇ 3 in an anhydrous solvent such as DMF, THF or DMSO at a temperature between 20 and 80 ° C.
  • an organic base such as 'a tertiary or inorganic amine
  • an anhydrous solvent such as DMF, THF or DMSO at a temperature between 20 and 80 ° C.
  • An alternative but particularly appreciated method consists in condensing N-BOC-piperazine with a carboxylic acid derivative of formula (in which R ′ 2 is defined so that R ′ 2 CH 2 are equivalent to R 2 ) such that '' an acid chloride, in the presence of a base such as a tertiary amine, in a solvent such as dichloromethane followed by reduction (for example using lithium aluminum hydride in ether at 25 ° C) of the amide thus formed
  • 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.
  • an appropriate acid preferably in equivalent quantity
  • 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 the acid (-) - di-p-toluoyl-l-tartaric, acid (+) - di-p-toluoyl-l-tartaric, acid (+) - camphorsulfonic, acid (-) - camphorsulfonic, l (+) - phenylpropionic acid, (-) - phenylpropionic acid, followed by fractional crystallization and regeneration of the free base.
  • RI is a hydrogen comprising at
  • the 2,3-xylylpiperazine hydrochloride (B) (2 g; 8.8 mmol) is dissolved in dichloromethane (20 ml) in the presence of triethylamine (3 ml; 22 mmol) under a nitrogen atmosphere. The solution is cooled to 0 ° C. and then 4-chlorobutanoyl chloride (1.2 ml; 11 mmol) is added. The reaction is immediate. The solution is diluted in dichloromethane washed with a semi-saturated sodium bicarbonate solution and dried over magnesium sulfate. The LA derivative is purified by flash chromatography with a 25-75 mixture (EtOAc-EDP).
  • Derivative A (1 g; 5.2 mmol) is dissolved in dimethylformamide (35 ml) in the presence of derivative IA (1.5 g; 5.2 mmol) and cesium carbonate (3.3 g; 10 mmol) under a nitrogen atmosphere .
  • the suspension is stirred for 1 day at room temperature then heated 1 day to 63 ° C LA derivative (0 5 g; 1 5 mmol) and cesium carbonate (3 3 g; 10 mmol) are added, then the suspension is heated to 80 ° C for 3 days The reaction no longer evolves.
  • the derivative 2A is prepared according to the same procedure described for LA from the following reagents: B (5 g; 22 mmol); 5-bromopentanoyl chloride (3.6 ml; 27 mmol); triethylamine (7.6 ml; 54 mmol) in dichloromethane (50 ml).
  • Derivative A (684 mg; 3.5 mmol) is dissolved in DMF (16 ml) in the presence of 2A (1.25 g; 3.5 mmol) and cesium carbonate (1.1 g; 3.5 mmol) under an atmosphere of nitrogen. The mixture is stirred for 24 hours at room temperature, then diluted in ethyl acetate, washed twice with water, dried over magnesium sulfate and concentrated.
  • the derivative 3A is prepared according to the same method described for _LA from the following reagents: B (5 g; 25 mmol); 1-bromo-hexanoyl chloride (4.1 ml; 27 mmol); triethylamine (7.6 ml; 54 mmol) in dichloromethane (50 ml).
  • the derivative 3 is prepared according to the same method described for 2 from the following reagents: A (700 mg; 3.6 mmol); 3A (1.13 g; 3.1 mmol); cesium carbonate (2 g; 6 mmol) in DMF (16 ml).
  • ⁇ -RMN (200 MHz, dmso-d 6 ) ⁇ : 7.00 (t, IH, 7.6Hz); 6.90-6.70 (m, 6H); 3.91 (t, 2H, 6Hz); 3.56 (brs, 4H); 2.93 (brs, 4H); 2.70 (brs, 4H); 2.55-2.30 (m, 6H); 2.17 (s, 6H); 2.15 (s, 3H); 1.85-1.40 (m, 6H).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • ⁇ -RMN 200 MHz, dmso-d 6 ) ⁇ : 7.15-6.8 (m, 7H); 6.60 (s, fumarate); 3.96 (t, 2H, 6Hz); 3.61 (brs, 4H); 3.05 (brs, 4H); 2.73 (brs, 8H); 2.39 (brs, 5H); 2.22 (s, 3H); 2.19 (s, 3H); 1.9-1.4 (m, 6H)
  • the derivative 4A is prepared according to the same procedure as LA from the following reagents: N-phenethyl-piperazine (2 g; 10.5 mmol); 5-bromo-pentanoyl chloride (1.7 ml; 12.6 mmol); triethylamine (2.2 ml; 15.7 mmol) in dichloromethane (21 ml).
  • the derivative 4 is prepared according to the same method described for 2 from the following reagents: 4A (3.58 g; 10 mmol); A (1.94 g; 10 mmol); cesium carbonate (6.6 g; 20 mmol) in DMF (60 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • IR flCBr 3300, 3031, 2958, 1709, 1654, 1246.
  • CJ 4-Chloro-2- (4-methyl-piperazin-1-yl) -phenol
  • Derivative 5 is prepared according to the same method described for 2 from the following reagents: ⁇ (1 g; 4.4 mmol); 2A (1.5 g; 4.4 mmol); cesium carbonate (1.4 g; 4.4 mmol) in DMF (30 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 6A is prepared according to the same method described for LA from the following reagents: 4-phenylpiperidine (1 g; 6.2 mmol); 5-bromo-pentanoyl chloride (913 ⁇ l; 6.8 mmol); triethylamine (950 ⁇ l; 6.8 mmol) in dichloromethane (12 ml).
  • the derivative 6 is prepared according to the same method described for 2 from the following reagents: A (500 mg; 2.6 mmol); 6A (1.44 g; 4.4 mmol); cesium carbonate (1.7 g; 5.2 mmol) in DMF (10 ml).
  • ⁇ -RMN (200 MHz, dmso-d 6 ) ⁇ : 7.4-7.1 (m, 5H); 7.0-6.75 (m, 4H); 4.55 (brd, 1H, 13Hz); 4.1-3.85 (m, 3H); 3.33 (brs, 1H); 3.2-2.85 (m, 5H); 2.75 (brt, IH, 12.5 and 3Hz); 2.65-2.35 (m, 6H); 2.25 (s, 3H); 1.9-1.3 (m, 8H).
  • IR fKBr 3440, 2940, 1722, 1617, 1459, 1255
  • the derivative 2A (2.8 g; 8 mmol) diluted in DMF (20 ml) is added dropwise to the reaction mixture. The solution is stirred for 24 hours then neutralized with a few drops of water and then the solvent is evaporated. The oily residue is diluted in ethyl acetate and washed twice with water. The solution is dried over magnesium sulfate and concentrated.
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • JH-RiMN (200 MHz, dmso-d 6 ) ⁇ : 7.1-6.7 (m, 5H); 6.7-6.41 (m, 2H + fumarate); 5.3-4.3 (brs, 1H, NH); 3.57 (brs, 4H); 3.06 (brs, 2H); 2.9-2.5 (m, 12H); 2.5-2.25 (m, 5H); 2.18 (s, 3H); 2.15 (s, 3H); 1.59 (brs, 4H).
  • the derivative 8A is prepared according to the same method described for 7 ⁇ _ from the following reagents 4-methoxy-3- (4-methyl-piperazin-1-yl) -an ⁇ l ⁇ ne (1 5 g, 7 0 mmol), di-tert- butyldicarbonate
  • the derivative 8 is prepared according to the same method described for 7 from the following reagents: crude 8B, trifluoroacetic acid (1.8 ml) in dichloromethane (10 ml).
  • the derivative 9 is prepared according to the same method described for 2 from the following reagents: 4-chloro-3- (4-methyl-piperazin-1-yl) -phenol (500 mg, 2.2 mmol); 2A (779 mg; 2.2 mmol); cesium carbonate (718 mg; 2.2 mmol) in DMF (10 ml). ⁇
  • ⁇ -RMN 200 MHz, dmso-d 6 ) ⁇ 7 97 (d, 2H, 7 3 Hz), 7 75-7 30 (m, 7H), 6 95 (t, IH, 7 6Hz), 6 84 ( d, IH, 7 2Hz), 6 60 (d, IH, 7 9Hz), 5 6-5 2 (m, 2H), 3 70 (brs, 2H), 3 30 (brs, 2H), 2 62 (brs , 4H), 2 16 (s, 3H), 2 09 (s, 3H)
  • the 1QA derivative (361 g, 85 mmol) is dissolved in 17 ml of a methanol solution containing 1% (by mass) of sodium hydroxide
  • the residual oil is diluted in dichloromethane and neutralized with acid hydrochloric (pH about 7-8)
  • the aqueous phase is extracted three times with dichloromethane
  • the organic phases are combined, dried over magnesium sulfate and concentrated
  • iH-RMN 200 MHz, dmso-d 6 ) ⁇ 7 53 (d, IH, 7 2Hz), 7 40 (td, IH, 1 5 and 7 2Hz), 7 32 (td, IH, 1 5 and 7 2Hz ), 7 22 (dd, IH, 1 5 and 7 4Hz), 7 04 (t, IH, 7 6Hz), 6 88 (d, 2H, 7 6Hz), 5 23 (t, IH, OH, 5 4Hz) , 4 49 (d, 2H, 5 4Hz), 3 80 (brs, 2H), 3 29 (brs, 2H), 2 84 (brs, 2H), 2 72 (brs, 2H), 2 21 (s, 3H ), 2 17 (s, 3H)
  • lithium chloride 98 mg; 2.3 mmol
  • methane sulfonyl chloride 179 ⁇ l; 2.3 mmol
  • the derivative 1J) is prepared according to the same method described for 2 from the following reagents: A (347 mg; 1.8 mmol); 10C (619 mg; 1.8 mmol); cesium carbonate (1.2 g; 3.6 mmol); in DMF (16 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • 11A [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl
  • the derivative 11A is prepared according to the same method described for LA from the following reagents: B (3 g; 13.2 mmol); 3-chioromethyl-benzoyl chloride (2.3 ml; 16.3 mmol); pyridine (2.6 ml; 32.7 mmol) in dichloromethane (30 ml).
  • the derivative L1 is prepared according to the same method described for 2 from the following reagents: A (1 g; 5.2 mmol); 11A (1.78 g; 5.2 mmol), cesium carbonate (1.69 g; 5.2 mmol) in DMF (30 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 12A is prepared according to the same method described for LA from the following reagents: B (3 g; 13 mmol); 4-chloromethylbenzoyl chloride (3.1 g; 16 mmol); pyridine (2.6 ml; 33 mmol) in dichloromethane (30 ml).
  • the L2 derivative is prepared according to the same method described for 2 from the following reagents: A (800 mg; 4.2 mmol); 12A (1.4 g; 4.2 mmol); cesium carbonate (2.7 g; 8.3 mmol) in DMF (20 ml).
  • the derivative 14A is prepared according to the same method described for LA from the following reagents: N-phenethyl-piperazine (2 g; 10.5 mmol), 3-chloromethylbenzoyl chloride (1.8 ml; 12.6 mmol); triethylamine (22 ml; 15.8 mmol) in dichloromethane (21 ml).
  • L4 derivative is prepared according to the same method described for 7_D from the following reagents: A (372 mg; 1.9 mmol); 14A (1 g; 2.9 mmol); NaH (139 mg; 2.9 mmol) in DMF (12 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 15A is prepared according to the same method described for 7D from the following reagents: A (1.5 g; 7.8 mmol); 3-chloromethyl-1-nitrobenzene (2 g; 1 1.7 mmol); NaH (561 mg; 11.7 mmol) in DMF (16 ml).
  • the derivative 15B is prepared according to the same method described for 7B from the following reagents 15A (1 19 g, 36 mmol), hydrated hydrazine (907 ⁇ l), Raney nickel (cat) in ethanol (12 ml)
  • the derivative 16A is purified by flash chromatography with a mixture of eluents (20% EtOH in EDP).
  • 16B (2S) 2-amino-1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] -propan-1-derivative 16B is prepared according to the method used for 7 from of the following reagents. 16A (3.28 g; 9.07 mmol); trifluoroacetic acid (42 ml) in dichloromethane (250 ml).
  • ⁇ -RMN 200 MHz, dmso-d ⁇
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • 2-hydroxy-1- (4-methyl-piperazin-1-yl) -naphthalene is prepared according to the procedure described in French patent No. 9408981.
  • the derivative 17 is prepared according to the same method described for 2 from the following reagents: 2A (780 mg; 2.3 mmol); 2-hydroxy-1- (4-methyl-piperazin-1-yl) -naphthalene (468 mg; 1.9 mmol); cesium carbonate (1.26 g, 3.9 mmol) in DMF (30 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • IR OCBr 3600-2300, 1722, 1620, 1590, 1550.
  • the derivative 19B is prepared according to the method used for 7 from the following reagents: 19A (1.86 g; 5.1 mmol); trifluoroacetic acid (24 ml) in dichloromethane (140 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 20A is prepared according to the same method described for 7D from the following reagents: A (1.5 g; 7.8 mmol); 2-chloromethyl-1-nitrobenzene (2 g; 1 1.7 mmol); NaH (561 mg; 11.7 mmol) in DMF (16 ml).
  • the derivative 20B is prepared according to the same method described for 7B from the following reagents: 20A (1.41 g; 4.33 mmol); hydrazine hydrate (1.08 ml); Raney nickel (cat) in ethanol (15 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • ⁇ -RMN (200 MHz, dmso-d 6 ) ⁇ : 8.33 (s, 1H); 7.52 (d, 1H); 7.45-6.8 (m, 10H); 6.58 (s, fumarate); 5.07 (s, 2H); 3.57 (brs, 4H); 3.04 (brs, 4H); 2.74 (brs, 4H); 2.61 (brs, 4H); 2.33 (s, 3H); 2.21 (s, 3H); 2.17 (s, 3H).
  • the derivative 21A is prepared according to the same method described for 7D from the following reagents A (1 8 g, 9 4 mmol), 4-chloromethyl-1-nitrobenzene (2 42 g, 14 1 mmol), NaH (677 mg, 14 1 mmol) in DMF (20 ml)
  • the derivative 21B is prepared according to the same method described for 7B from the following reagents 21A (1 56 g, 4 8 mmol), hydrazine hydrate (1 2 ml), Raney nickel (cat) in ethanol (16 ml)
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 22A is prepared according to the same procedure described for LA from the following reagents: 1 -phenethylpiperazine (700 mg; 3.7 mmol); 4-chlorobutanoyl chloride (493 ml; 4.4 mmol); triethylamine (767 ml; 5.5 mmol) in dichloromethane (7.3 ml).
  • Derivative A (554 mg; 2.9 mmol) is dissolved in dimethylformamide (20 ml) in the presence of bromoacetonitrile (220 ml; 3.2 mmol) and potassium carbonate (1.2 g; 8.4 mmol) under a nitrogen atmosphere. The suspension is stirred for 4 days at room temperature and then heated for 1 day at 60 ° C. The reaction no longer evolves. The solvent is evaporated, the oily residue is dissolved in ethyl acetate, washed twice with water and dried over magnesium sulfate. The derivative 23A is purified in the form of the free base by flash chromatography with a gradient of NH4 ⁇ H-MeOH-CH 2 Cl 2 (0.5-2 to 5-98 to 95). Mass obtained: 179 mg (27%)
  • the derivative 23A (560 mg; 2.4 mmol) is dissolved in THF (17 ml) under a nitrogen atmosphere and the lithium aluminum hydride (IM in THF, 7.5 ml, 7.5 mmol) is added dropwise. drop at 0 ° C.
  • the reaction mixture is stirred for 1 hour at room temperature, then neutralized by successive addition of 190 ml of water, 190 ml of 10% NaOH in water and 570 ml of water.
  • the precipitate is removed by filtration and the filtrate is concentrated.
  • Derivative 23 is purified in the form of the base free by flash chromatography with a gradient of NH4 ⁇ H-MeOH-CH 2 Cl 2 (0.5-2 to 5-98 to 95).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • N- / e / 7-butoxycarbonylhomogIycin (2 g; 10.5 mmol) is dissolved in dichloromethane (35 ml) under a nitrogen atmosphere in the presence of B (2.87 g; 12.7 mmol), of triethylamine (1.62 ml; 11.6 mmol ), 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride (2.22 g; 11.6 mmol) and 4-N, N-dimethylaminopyridine (30 mg).
  • the reaction mixture is stirred for 24 hours at room temperature, then diluted in dichloromethane, washed once with water and once with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated.
  • the derivative 27A is dissolved in dichloromethane (377 ml) under a nitrogen atmosphere and trifluoroacetic acid (65 ml) is added. The solution is stirred for 3 hours at room temperature, then the solvent and the acid are evaporated. The oily residue is taken up in dichloromethane and washed with water. The aqueous phase is extracted 3 times with dichloromethane. The organic phases are combined, dried over MgS ⁇ 4 and concentrated. Derivative 27B is used without further purification.
  • the derivative 27 is prepared according to the same method described for day 6 from the following reagents: 7B (500 mg; 2.6 mmol); triphosgene (309 mg, 1 mmol), pyridine (422ml; 5.22 mmol); 27B (774 mg; 3.1 mmol) in dichloromethane (18 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 28A is prepared according to the same method described for 26C from the following reagents: N-teri'-butoxycarbonylgiycin (1.69 g; 9.7 mmol); 1- (2,3-dimethylphenyl) piperidine hydrochloride (2 g; 8.8 mmol); triethylamine (2.58 ml; 18.5 mmol); the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.85 g; 9.7 mmol); 4- NN-dimethylaminopyridine (30 mg) in dichloromethane (30 ml).
  • the derivative 30 is prepared according to the same method described for 16 from the following reagents: 26B (500 mg; 2.21 mmol); triphosgene (216 mg; 0.72 mmol); pyridine (356 ml; 4.4 mmol); 27B (819 mg; 3.3 mmol) in dichloromethane (15 ml). 5
  • IR flCBr 3600-2300, 1650, 1580, 1500, 1450.
  • the derivative 31A is prepared according to the same method described for 26C from the following reagents: N- / er / -butoxycarbonylg ⁇ ycine (891 mg; 5.1 mmol); 4- (4-fluorobenzoyl) piperidine tosylate (2.32 g; 6.1 mmol); triethylamine (780 ml; 5.6 mmol); the -i 9
  • the product 31B is prepared according to the same method for 27B using the following reagents 31A (1 7 g; 4 7 mmol), dichloromethane (129 ml), torofluoroacetic (22 ml)
  • the derivative 32A is prepared according to the same method described for 26C from the following reagents N-fert-butoxycarbonylglycine (2 g, 11 4 mmol), l- (2-methoxyphenyl) pizzame -4 Hr
  • JH-RiMN (200 MHz, dmso-d 6 ) ⁇ : 7.0-6.65 (m, 5H), 3.90-3.70 (m, 5H); 3.52 (brs, 4H); 2.89 (brs, 4H); 1.35 (s, 9H).
  • the derivative 32B is prepared according to the same method described for 27B from the following reagents: 32A (2.7 g; 7.7 mmol); dichloromethane (214 ml); trifluoroacetic (36 ml).
  • 32A 2.7 g; 7.7 mmol
  • dichloromethane 214 ml
  • trifluoroacetic 36 ml
  • ⁇ -RMN (200 MHz, dmso-d 6 ) ⁇ : 7.1-6.8 (m, 4H); 3.78 (s, 3H); 3.59 (brs, 2H); 3.47 (brs, 2H); 3.36 (brs, 2H); 2.90 (brs, 4H).
  • Derivative 32 is prepared according to the same method described for .16 from the following reagents: 26B (500 mg; 2.21 mmol); triphosgene (216 mg; 0.72 mmol); pyridine (356 ml; 4.4 mmol); 32B (826 mg; 3.3 mmol) in dichloromethane (15 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 33A is prepared according to the same method described for 26C from the following reagents: N- / er / -butoxycarbonylglycine (1.8 g; 10.3 mmol), 4-phenylpiperidine (1.98 g; 12.3 mmol); triethylamine (1.57 ml; 1 1.3 mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.16 g; 1 1.3 mmol); 4-N, N- dimethylaminopyridine (40 mg) in dichloromethane (35 ml). 1 ⁇
  • ⁇ -RMN 200 MHz, dmso-d 6 ) ⁇ : 7.24 (brs, 5H); 6.74 (brt, 1H); 4.47 (brd, 1H); 3.88 (brd, 1H); 3.80 (d, 2H, 5.7Hz); 3.07 (brt, 1H); 2.76 (brtt, 1H); 2.63 (brt, 1H); 1.8-1.3 (m, 4H); 1.39 (s, 9H).
  • the derivative 33B is prepared according to the same method described for 27B from the following reagents: 33A (2.76 g; 8.7 mmol); dichloromethane (240 ml); trifluoroacetic (40 ml).
  • the derivative 33B is purified by flash chromatography with a mixture of eluents (1-7-93 ⁇ NH4 ⁇ H-MeOH-CH 2 Cl 2 ).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • ⁇ -RMN 200 MHz, dmso-d 6 ) ⁇ : 8.33 (s, 1H); 8.04 (dd, IH, 1.4 and 8Hz); 7.64 (brs, 1H); 7.4-7.0 (m, 6H); 6.89 (dd, IH, 1.4 and 8Hz); 6.57 (s, fumarate), 4.52 (brd, 1H); 4.1-3.8 (m, 3H); 3.55 (brt, 2H); 3.12 (brt, 1H), 2.9-2.5 (m, 8H); 2.38 (s, 3H); 2.0-1.3 (m, 4H).
  • the derivative 34A is prepared according to the same method described for 18B from the following reagents: D18A (900 mg; 2.76 mmol); NaH (60% in oil; 264 mg; 6.6 mmol); 6A (1.07 g; 3.3 mmol); DMF (25 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 35A is prepared according to the same method described for 1_A from the following reagents: 1- (2-methoxyphenyl) piperazine (3.45 g; 18 mmol); 5-bromopentanoyl chloride (2.88 ml; 21.5 mmol); triethylamine (375 ml; 27 mmol) in dichloromethane (35 ml).
  • 35B 5- [N-terf-butoxycarbonyI-3-chIoro-2- (4-methylpiperazin-I-yl) phenylamino] -l- [4- (2-methoxyphenyl) piperazin-1-yIJpentan-1-Le derivative 35B is prepared according to the same method described for 18B from the following reagents:! 8A (900 mg; 2.76 mmol); NaH (60% in oil, 264 mg; 6.6 mmol); 35A (1.17 g; 3.3 mmol); DMF (25 ml).
  • the derivative 35 is prepared according to the same method described for .18 from the following reagents: 35B (1.454 g; 2.4 mmol); TFA (1 1.4 ml); dichloromethane (67 ml).
  • the 2-amino meta cresol (7 g; 56.8 mmol) is dissolved in 1-butanol (1 13 ml) in the presence of mechloethamine hydrochloride (1 1.5 g, 59.7 mmol) and sodium carbonate (3 g; 28.4 mmol) under a nitrogen atmosphere.
  • the reaction is heated to 123 ° C for 3 days.
  • the solvent is evaporated.
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • IR flCBr 3100-2700, 1716, 1649, 1582, 1454.
  • the derivative 37 is prepared according to the same method described for 36 from the following reagents.
  • 36A 500 mg; 2.4 mmol
  • NaH 60% in oil; 145 mg; 3.6 mmol
  • 4A (1.28 g, 3.6 mmol
  • DMF 15 ml
  • This compound is dissolved in methanol and treated with fumaric acid to give the co ⁇ espondant fumarate.
  • the derivative 38 is prepared according to the same method described for 36 from the following reagents: 36A (500 mg; 2.4 mmol); NaH (60% in oil; 145 mg; 3.6 mmol); 6A (1.17 g, 3.6 mmol); DMF (20 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • DKKBr 3600-3200, 3000, 2932, 2864, 1642, 1600, 1461
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • IR ftCBr 3700-2400, 1716, 1700, 1642, 1610.
  • the derivative 40A is prepared according to the same method described for 1_A from the following reagents: 1- (2,4-dimethylphenyl) piperazine (2.73 g; 14.3 mmol); 5-bromopentanoyl chloride (2.3 ml; 17.2 mmol); triethylamine (3 ml; 21.5 mmol) in dichloromethane (28 ml).
  • ⁇ -RMN (200 MHz, dmso-d 6 ) ⁇ : 7.1-6.8 (m, 3H); 3.53 (brs, 6H); 2.74 (brs, 4H); 2.40 (t, 2H, 7.2 Hz); 2.20 (s, 3H); 2.18 (s, 3H); 1.83 (p, 2H, 7.4 Hz); 1.68 (p, 2H, 7.4 Hz).
  • the derivative 40 is prepared according to the same method described for 36 from the following reagents: 36A (500 mg; 2.4 mmol); NaH (60% in oil; 145 mg; 3.6 mmol); 40A (1.28 g, 3.6 mmol); DMF (20 ml).
  • the 41A derivative is prepared according to the same method described for IA from the following reagents: 1 - (4-fluorobenzoyl) piperidine (2.36 g, 1 15 mmol), 5-bromopentanoyl chloride (1.84 ml; 13.7 mmol ); triethylamine (239 ml, 17.2 mmol) in dichloromethane (25 ml)
  • the derivative 4J. is prepared according to the same method described for 36 from the following reagents: A (500 mg; 2.6 mmol); NaH (50% in oil; 187 mg; 3.9 mmol); 41A (1.44 g, 3.9 mmol); DMF (20 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • ⁇ -RMN (200 MHz, dmso-d 6 ) ⁇ : 8.2-8.0 (m, 2H); 7.37 (t, 2H); 7.0-6.8 (m, 4H); 6.59 (s, fumarate); 4.42 (brd, 1H); 4.05-3.9 (m, 3H); 3.72 (tt, 1H); 3.20 (brt, 1H); 3.03 (brs, 4H); 2.75 (brt, 1H); 2.65 (brs, 4H); 2.42 (brt, 2H); 2.35 (s, 3H); 2.0-1.2 (m, 8H).
  • the derivative A (5.25 g, 27.1 mmol) is dissolved in DMF (100 ml) at 0 ° C under a nitrogen atmosphere in the presence of sodium hydride (50% in oil; 1.960g; 41 mmol).
  • the ethyl 5-bromo-pentanoate diluted in DMF (70 ml) is added dropwise at 0 ° C.
  • the cold bath is removed and the reaction is stirred for 15 hours at room temperature.
  • the suspension is neutralized with a few drops of water, then diluted in ethyl acetate, washed twice with water, dried over magnesium sulfate, filtered and concentrated.
  • the 42A derivative (5.08 g, 15.8 mmol) is dissolved in THF (18 ml). A sodium hydroxide solution (IM in water, 17.43 ml, 17.43 mmol) is added and the solution is heated at 50 ° C for 6 hours. The reaction is cooled to room temperature and then neutralized by adding hydrochloric acid (IN in water, 17.43 ml, 17.43 mmol). The solvents are evaporated. The semi-solid residue is triturated in a little ethanol and filtered. The filtrate is concentrated to give a foam. The 42B derivative is used without further purification for the rest of the syntheses. Mass obtained: 5 g
  • reaction mixture is diluted in dichloromethane, washed once with IM soda and once with IN HCl, then dried over magnesium sulfate, filtered and concentrated.
  • the derivative 42 is prepared according to the same method described for 26C from the following reagents: 42D (389 mg; 1.5 mmol); 42B (400 mg, 1.25 mmol); triethylamine go
  • This compound is dissolved in methanol and treated with fumaric acid to give 0 the corresponding fumarate.
  • DKKBr 3441, 2934, 1610, 1480.
  • the derivative 43 is prepared according to the same method described for 26C from the following reagents: 4-benzoylpiperidine (371 mg; 1.96 mmol); 42B (403 mg; 1.29 mmol); triethylamine (210 ml; 1.5 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288 mg; 1.5 mmol); 4-NJV-dimethylaminopyridine (8 mg) in dichloromethane (17 ml).
  • the derivative 44 is prepared according to the same method described for 26C from the following reagents: 4-hydroxydiphenylmethyl hydrochloride) piperidine (499 mg; 1.64 mmol); 42B (403 mg; 1.29 mmol); triethylamine (210 ml; 1.5 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288 mg; 1.5 mmol); 4-NN- dimethylaminopyridine (8 mg) in dichloromethane (20 ml).
  • 4-hydroxydiphenylmethyl hydrochloride piperidine (499 mg; 1.64 mmol); 42B (403 mg; 1.29 mmol); triethylamine (210 ml; 1.5 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288 mg; 1.5 mmol); 4-NN- dimethylaminopyridine (8 mg) in dichloromethane (20 ml
  • the derivative 45 is prepared according to the same method described for 26C from the following reagents: 1- (2-methoxyphenyl) piperazine (708 mg; 3.7 mmol); 42B (900 mg; 2.9 mmol); triethylamine (470 ml; 3.4 mmol); 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride (647 mg; 3.4 mmol); 4-N, ⁇ r -dimethylaminopyridine (15 mg) in dichloromethane (25 ml).
  • ⁇ -RMN (200 MHz, dmso-d ⁇ ) ⁇ : 7.1-6.8 (m, 8H), 659 (s, fumarate), 3.97 (brt, 2H); 3.79 (s, 3H); 3.60 (brs, 4H); 3.02 (brs, 4H), 2.91 (brs, 4H); 2.64 (brs, 4H); 2.43 (brt, 2H); 2.34 (s, 3H); 1.75 (brs, 4H).
  • the derivative 46 is prepared according to the same method described for 26C from the following reagents: 1-benzhydryloxypiperidine (446 mg; 147 mmol); 42B (394 mg; 1.23 mmol); triethylamine (188 ml, 1.35 mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (259 mg, 1.35 mmol); 4-N.N- dimethylaminopyridine (8 mg) in dichloromethane (17 ml).
  • the derivative 47 is prepared according to the same method described for 26C from the following reagents: 1-phenoxypiperidine hydrochloride (329 mg; 1.54 mmol); 42B (41 1 mg; 1.29 mmol); triethylamine (197 ml; 1.41 mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (272 mg; 1.41 mmol); 4-N, N- dimethylaminopyridine (8 mg) in dichloromethane (18 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 48 is prepared according to the same method described for 26C from the following reagents: 1-benzylpiperidine (280 ml; 1.59 mmol); 42 B (423 mg; 1.33 mmol); triethylamine (203 ml; 1.46 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (280 mg; 1.46 mmol); 4-N, N-dimethylaminopyridine (10 mg) in dichloromethane (22 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 50A is prepared according to the same method described for .LA from the following reagents: 4-phenylpiperidine (1.1 g; 6.8 mmol); 6-bromo-hexanoyl chloride (1.02 ml; 6.7 mmol); triethylamine (1.16 ml; 8.38 mmol) in dichloromethane (11 ml).
  • the derivative 50 is prepared according to the same method described for 36 from the following reagents: A (576 mg; 2.99 mmol); NaH (50% in oil; 215 mg; 4.5 mmol); 50A (1.67 g, 4.9 mmol); DMF (20 ml).
  • the derivative 51A is prepared according to the same method described for .LA from the following reagents: 1 - (2-methoxyphenyl) piperazine (1.2 g; 6.24 mmol), 6-bromo-hexanoyl chloride (1.14 ml; 7.48 mmol); triethylamine (1.3 ml; 9.36 mmol) in dichloromethane (15 ml). Mass obtained: 2.3 g (100%)
  • the derivative 5_1 is prepared according to the same method described for 36 from the following reagents: A (845 mg; 4.4 mmol); NaH (50% in oil, 316 mg; 6.6 mmol); 5LA (2.3 g, 6.2 mmol); DMF (28 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 52A is prepared according to the same method described for 42A from the following reagents: A (5.07 g; 26.4 mmol); NaH (50% in oil; 1.89 g; 39.6 mmol); 7- ethyl bromoheptanoate (8.2 g, 34.3 mmol); DMF (164 ml).
  • the derivative 52A (4.87 g, 14 mmol) is dissolved in THF (15 ml). A sodium hydroxide solution (IM in water, 15.4 ml, 15.4 mmol) is added and the solution is heated at 50 ° C for 6 hours. The reaction is cooled to room temperature and then neutralized by adding hydrochloric acid (IN in water, 15.4 ml, 15.4 mmol). The solvents are evaporated. The semi-solid residue is triturated in a little ethanol and filtered. The filtrate is O 97/14689 PC17FR96 / 01626
  • the derivative 52 is prepared according to the same method described for 26C from the following reagents l- (2,3-dimethylphenyl) p ⁇ peraz ⁇ ne hydrochloride (1 18 g, 5 2 mmol), 52B (1 5 g, 4 3 mmol), triethylamine (668 ml, 4 8 mmol), l - (3- dimethylam ⁇ nopropyl) -3-ethylcarbod ⁇ imide hydrochloride (919 mg, 4 8 mmol), 4-NN- dimethylaminopyridine (10 mg) in dichloromethane (15 ml)
  • the derivative 53 is prepared according to the same method described for 26C from the following reagents: 1- (2-methoxyphenyl) piperazine (1.12 g, 4 88 mmol); 52B (1.68 g; 4.88 mmol); triethylamine (748 ml; 5.36 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.02 g, 5.36 mmol); 4-N.N- dimethylaminopyridine (10 mg) in dichloromethane (20 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 54 is prepared according to the same method described for 26C from the following reagents: 4-phenylpiperidine (1.02 g; 6.3 mmol); 52 B (1.5 g; 4.36 mmol); triethylamine (667 ml; 4.79 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (919 mg; 4.79 mmol); 4-N, N-dimethylaminopyridine (10 mg) in dichloromethane (15 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • the derivative 55A is prepared according to the same method described for 26C from the following reagents: 1- (2,3-dimethylphenyl) piperazine hydrochloride (1.82 g; 8 mmol); 8-bromooctanoic acid (1.5 g; 6.72 mmol); triethylamine (1.03 ml; 7.4 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.41 g; 7.4 mmol); 4- N, N-dimethylaminopyridine (15 mg) in dichloromethane (22 ml).
  • the derivative 55 is prepared according to the same method described for 36 from the following reagents: A (766 mg; 4 mmol); NaH (50% in oil; 286 mg; 6 mmol); 55A (2.05 g, 5.2 mmol); DMF (25 ml).
  • the derivative 56A is prepared according to the same method described for 26C from the following reagents: 1- (2-methoxyphenyl) piperazine (1 55 g, 8 mmol); 8-bromooctanoic acid (1.5 g; 6.72 mmol); triethylamine (103 ml, 744 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1441 g, 7.4 mmol); 4-N, N- dimethylaminopyridine (15 mg) in dichloromethane (22 ml)
  • the derivative 56 is prepared according to the same method described for 36 from the following reagents: A (297 mg; 1.54 mmol); NaH (50% in oil, 1 10 mg; 2.31 mmol); 56A (799 mg, 2 mmol); DMF (10 ml).
  • This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
  • DKKBr 3700-2300, 1629, 1501, 1246
  • the derivatives of the present invention are potent antagonists of 5HT receptors £) as evidenced by binding studies and antagonism of study of the inhibition of adenylate cyclase (forskolin-stimulated) by a 5HT agonist j £> such as serotonin, sumatriptan or 5-CT, studies which have been carried out at the level of human receptors cloned 5HTiQ ⁇ and 5HTi £) ⁇ .
  • the human receptors 5HTj £) a and SHTjDt j were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40, 143 (1991) and Weinshenk et al., Proc. NatI. Acad. Sci. 89.3630 (1992).
  • the incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand [[3HJ-5CT (final concentration: 2nM) for the 5HT] D a and 5HTID D and [3HJ -8OH-DPAT (final concentration: 1 nM) for the 5HT] ⁇ J receptor and 0.05 ml of the test molecule (final concentrations of 0.1 nM to 1000 nM) or 10 ⁇ M (final concentration) of seretonin (5HT] rj a and 5HTi £) v, ⁇ or 1 ⁇ M (final concentration) of spiroxatrine (5HT IA).
  • the study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by the human 5HTij) b receptor was carried out in CHO-K1 cells transfected by the receptor according to the technique described previously for the 5HTJB receptor (P. Pauwels and C. Palmier, Neuropharmacology, 33.67, 1994).
  • the new compounds derived from aryl piperazines forming part of the present invention are potent and selective antagonists of the 5HT] () receptors) and have the advantage of being particularly selective for the human 5HTu) ⁇ and ⁇ receptors in particular with respect to 5HTj j ⁇ , 5HT ⁇ c 5HT 2 , cq, ⁇ 2 and D 2 receptors.
  • the derivatives of the present invention are, in addition, capable of inhibiting the contraction induced by 5-hydroxy-tryptamine in the rabbit saphenous vein rings and of antagonizing the inhibition induced by 5-carboxamido-tryptamine (5CT ) at the level of serotonin release in guinea pig brain slices.
  • 5-carboxamido-tryptamine 5CT
  • These two pharmacological models are generally recognized as particularly relevant in the functional characterization of the 5HTJD receptors and, in the case of the products of the present invention, make it possible to demonstrate their antagonistic activity at the level of these receptors.
  • the present invention also comprises a method for treating such patients, a method which involves the administration of an active dose of a compound corresponding to the general formula (I).
  • the derivatives of the present invention are also capable of controlling the growth and proliferation of glial cells of the Cg type transfected by the gene for the receptor 5HT j £) ⁇ , stimulated by a hormonal mediator such as serotonin.
  • 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 IC50 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.
  • 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 colorant, 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, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents.
  • These compositions can 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.
  • compositions according to the invention 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.
  • the active component is passed through a sieve with a mesh opening of 250 ⁇ m and mixed with the lactose, ramidon 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 hydroxy-propyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated.
  • the active component is passed through a sieve with a mesh opening of 250 ⁇ m and mixed with the other substances.
  • the mixture is introduced into hard gelatin capsules No. 2 on an appropriate filling machine. We can prepare other units by changing the filling weight and, when necessary, by 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 H15 is prepared and introduced into a suitable machine with 1 g suppository molds.
  • 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 ⁇ ⁇ Uf
  • the solution is prepared, clarified and introduced into suitable size vials which are sealed by melting the glass.
  • the liquid for injection can also be sterilized 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.

Abstract

Derivatives of general formula (I), wherein R1 = H or C1-6 alkyl; R2 is a straight or branched C1-8 alkyl residue, C3-8 cycloalkyl, aryl, arylalkyl, arylcarbonyl or, when X is not nitrogen, arylether; each of R3 and R4, which are the same or different, is hydrogen or a group selected from straight or branched alkyl, alkoxy, trifluoromethyl or halogen; X-Y is CH, CH-CH2, C=CH, NCH2 or NCH2CH2; Z = Z1-(CH2)m-Z2, Z1-Ar-(CH2)n-Z2, Z1-(CH2)m-1-CONH-, Z1-Ar-(CH2)n-1-CONH-, -CH(R5)-NHCO-Z2 wherein Z1 and Z2, which are the same or different, may be absent or are O or NH; m is an integer from 2 to 8; and n is an integer from 1 to 6.

Description

DERIVES D'AMINES CYCLIQUES D'ARYL-PEPERAZINES, LEUR PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES CYCLIC AMINE DERIVATIVES OF ARYL-PEPERAZINES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS
LES CONTENANTCONTAINING THEM
La présente invention se rapporte à de nouvelles aryl-pipérazines dérivées d'aminés cycliques, ainsi qu'à leur procédé de préparation, les compositions pharmaceutiques les contenant et leur utilisation comme médicamentsThe present invention relates to new aryl-piperazines derived from cyclic amines, 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-instestinaux 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 Mouhgnier, Rev Neurol (Paris), 150,3-15,1994)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. central, serotonin controls functions as varied as sleep, locomotion, food intake, learning and memory, endocrine modulations, sexual behavior, thermoregulation In the marrow, serotonin plays an important role in control systems for peripheral nociceptive afferents (see A Mouhgnier, Rev Neurol (Paris), 150.3-15.1994)
La sérotonine peut jouer un rôle important dans divers types de conditions pathologiques tels que certains désordres psychiatriques (anxiété, dépression, aggressivité, 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, 1990)Serotonin can play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggressiveness, 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, strokes, 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> 40ι> 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 lMany recent pharmacological studies have highlighted the diversity of serotonin receptors and their respective involvement in its various modes of action (see E. Zifa, G. Fillion, Pharm Reviews, 44> 4 0ι> 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 l
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 5HT_ι) qui comportent elles-mêmes des sous-classes telles que les récepteurs 5HTι qui sont divisés principalement en 5HT I A, 5HT J B, 5HTj £) (cf. G.R. Martin, P.A. Humphrey, Neuropharmacol., 33,261 , 1994 ; P.R. Saxena, Exp. Opin. Invest. Drugs, 3(5), 513, 1994). Les récepteurs 5HT] rj renferment eux-mêmes plusieurs sous-types de récepteurs ; c'est ainsi que les récepteurs 5HT ] £)α et 5HTi £>β ont été clones puis identifiés chez l'homme (cf. par exemple E Hamel et coll., Mol. Pharmacol.,44,242, 1993 ; G.W. Rebeck et coil , Proc NatI Acad. Sci. USA, 91,3666, 1994). Par ailleurs, il a été démontré récemment que les auto-récepteurs 5HTj β chez les rongeurs et 5HTj r_) chez les autres espèces étaient capables de contrôler la libération de sérotonine dans les terminaisons nerveuses (cf. M Bπley, C Moret, Cl. Neuropharm. 16,387, 1993 ; B.E. Léonard, Int. Clin. Psychopharmacol , 9,7, 1994) ainsi que la libération d'autres neuro transmetteurs tels que la norepinéphrine, la dopamine ou l'acétylcholine (M. Harrrington, J. Clin. Psychiatry, 53, 10, 1992).Psychiatry, 53, 36-45 (1992); DG Grahame-Smith, Int. Clin. Psychopharmacology, 6, suppl. 4, 6-13, (1992). These receivers are mainly divided into 4 main classes (5HTι, 5HT2, 5HT3 and 5HT_ι) which themselves include subclasses such as the 5HTι receivers which are mainly divided into 5HT IA, 5HT JB, 5HT j £ ) (cf. GR Martin, PA Humphrey, Neuropharmacol., 33,261, 1994; PR Saxena, Exp. Opin. Invest. Drugs, 3 (5), 513, 1994). The 5HT] rj receptors themselves contain several receptor subtypes; thus the 5HT ] £) α and 5HTi £> β receptors were cloned and then identified in humans (cf. for example E Hamel et al., Mol. Pharmacol., 44,242, 1993; GW Rebeck et coil , Proc NatI Acad. Sci. USA, 91.3666, 1994). Furthermore, it has recently been demonstrated that the 5HT j β auto-receptors in rodents and 5HTj r_) in other species are capable of controlling the release of serotonin in nerve endings (cf. M Bπley, C Moret, Cl. Neuropharm, 16,387, 1993; BE Léonard, Int. Clin. Psychopharmacol, 9,7, 1994) as well as the release of other neuro transmitters 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 5HT ID 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 5HTj£) 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 5HT ID 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 antagonists 5HTj £) also find their utility in the treatment of endocrine disorders such as hyperprolactinemia, the treatment of vasospasms, hypertension and gastrointestinal disorders in which there are changes in motility and secretion .
Les composés selon la présente invention sont des antagonistes puissants et sélectifs des récepteurs 5HTifj) et plus particulièrement des récepteurs récemment identifiés comme 5HT]Dα et 5HTj rj>β 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 5HTifj) receptors and more particularly receptors recently identified as 5HT] D α and 5HT j rj> β in humans and therefore find their utility, alone or in combination with other molecules, as drugs 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-2276161, GB-2276162, GB-2276163, GB-2276164, GB-2276165, WO- 9504729, WO-9506044, WO-9506637, WO-951 1243 et F 9408981 qui décrivent des dérivés aromatiques comme antagonistes 5HTj£), et les publications récentes qui décrivent le GR 127,935 comme antagoniste 5HTifj (cf. M. Skingle et coll., J. of Psychopharm. 8(1), 14, 1994 ; S. Starkey, M. Skingle, Neuropharmacol.,33,393, 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-2276161, GB-2276162, GB- 2276163, GB-2276164, GB-2276165, WO-9504729, WO-9506044, WO-9506637, WO-951 1243 and F 9408981 which describe aromatic derivatives as antagonists 5HTj £), and recent publications which describe GR 127,935 as 5HTifj antagonist (cf. M. Skingle et al., J. of Psychopharm. 8 (1), 14, 1994; S. Starkey, M. Skingle, Neuropharmacol., 33,393, 1994).
Les dérivés de la présente invention se distinguent de l'art antérieur non seulement par leur structure chimique nouvelle qui les distingue sans ambiguité des dérivés précédemment décrits mais également par leur profil biologique original, en particulier en ce qui concerne leur sélectivité pour les sous-types de récepteurs de la sérotonine (5HTιrj)α et β) et leur activité antagoniste 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 for the subtypes of serotonin receptors (5HTιrj) α and β) and their antagonistic activity
La présente invention concerne des dérivés de formule générale (I)The present invention relates to derivatives of general formula (I)
Figure imgf000006_0001
Figure imgf000006_0001
dans laquelle,in which,
R] = H, Cj-Cg alkyle;R] = H, Cj-Cg alkyl;
R2 représente un résidu alkyle, linéaire ou ramifié comprenant de 1 à 8 atomes de carbone, un cycloalkyle (comprenant de 3 à 8 atomes de carbone), un aryle, un arylalkyle, un aryl carbonyl ou encore un aryl éther lorsque X est différent d'un azote dans lesquels le cycle aromatique peut-être un phényle, un naphtyle, un tétrahydronaphtyle, un benzothiényle, un benzofuryle, un indole, un benzodioxanne ou une benzodioxine pouvant être diversement substitués par un ou plusieurs groupes choisis parmi R^, OH, OR^, SR^, NÛ2, CN, COR^, CO2R6, CONHR6, NH2, NHR6, NHCOR^, NHCO2R6, NHCONHRg, OCONHR6, SO2R6, SO2NHR6, CF3, CH=CH2, C = C - H ou un halogène (F, Cl, Br ou I) dans lesquels R5 représente un reste alkyle comprenant de 1 à 5 atomes de carbone ou un phényl ;R2 represents an alkyl residue, linear or branched comprising from 1 to 8 carbon atoms, a cycloalkyl (comprising from 3 to 8 carbon atoms), an aryl, an arylalkyl, an aryl carbonyl or even an aryl ether when X is different from d 'a nitrogen in which the aromatic ring may be a phenyl, a naphthyl, a tetrahydronaphthyl, a benzothienyl, a benzofuryl, an indole, a benzodioxane or a benzodioxine which may be variously substituted by one or more groups chosen from R 1, OH, OR ^, SR ^, NO2, CN, COR ^, CO 2 R6, CONHR 6 , NH 2 , NHR 6 , NHCOR ^, NHCO 2 R6, NHCONHRg, OCONHR 6 , SO 2 R 6 , SO 2 NHR 6 , CF3, CH = CH 2 , C = C - H or a halogen (F, Cl, Br or I) in which R5 represents an alkyl residue comprising from 1 to 5 carbon atoms or a phenyl;
R3 et R4 identiques ou différents représentent un hydrogène ou un groupe choisi parmi un alkyle linéaire ou ramifié (R7), un alcoxy (OR7), thioéther (SR7), nitrile, trifluorométhyle ou halogène (Cl, F, BR ou I) dans lesquels R7 représente un reste alkyle comprenant de 1 à 5 atomes de carbone, ou, R3 et R4 lorsqu'ils sont adjacents, pris ensemble, forment un cycle à 5 ou 6 chainons avec le résidu aromatique auxquels ils sont attachés de façon à constituer, par exemple, un naphtylE ou un tétrahydronaphtyle, étant entendu que les substituants -Z, R3 et R4 peuvent être situés en diverses positions relatives sur le cycle aromatique auquel ils sont attachés;R3 and R4, identical or different, represent a hydrogen or a group chosen from a linear or branched alkyl (R7), an alkoxy (OR7), thioether (SR7), nitrile, trifluoromethyl or halogen (Cl, F, BR or I) in which R7 represents an alkyl residue comprising from 1 to 5 carbon atoms, or, R3 and R4 when they are adjacent, taken together, form a 5 or 6-membered ring with the aromatic residue to which they are attached so as to constitute, by example, a naphthylE or a tetrahydronaphthyl, it being understood that the substituents -Z, R3 and R4 can be located in various relative positions on the aromatic ring to which they are attached;
X-Y représente CH, CH-CH2, C=CH, NCH2 ou NCH2CH2;XY represents CH, CH-CH 2 , C = CH, NCH 2 or NCH 2 CH 2 ;
Z = Z1-(CH2)m-Z2, Zι-Ar-(CH2)n-Z2, Z1 -(CH2)m.1-CONH-, Z ^^CH^!-Z = Z 1 - (CH 2 ) m -Z 2 , Zι-Ar- (CH 2 ) nZ 2 , Z 1 - (CH 2 ) m . 1 -CONH-, Z ^^ CH ^! -
CONH-, -CH(R5)-NHCO-Z2 dans lequels Z\ et Z2, identiques ou différents peuvent être omis ou représenter O ouCONH-, -CH (R 5 ) -NHCO-Z 2 in which Z \ and Z 2 , identical or different may be omitted or represent O or
NH, i m représente un nombre entier compris entre 2 et 8, n représente un nombre entier compris entre 1 et 6,NH, im represents an integer between 2 and 8, n represents an integer between 1 and 6,
R5 représente un hydrogène, un alkyle linéaire ou ramifié comprenant de 1 à 5 atomes de carbone, un aryle (tel qu'un phényle) ou un arylalkyle (tel qu'un benzyle) pouvant être diversement substitué par un hydroxyle, une aminé, un thiol ou un thiométhylR5 represents a hydrogen, a linear or branched alkyl comprising from 1 to 5 carbon atoms, an aryl (such as a phenyl) or an arylalkyl (such as a benzyl) which can be variously substituted by a hydroxyl, an amine, a thiol or thiomethyl
Ar représente un reste aromatique (tel qu'un phényle) auquel les substituants sont attachés sur des carbones différents et peuvent être en diverses positions relatives, et leurs sels, hydrates, solvates et bioprécurseurs physiologiquement acceptables pour leur usage thérapeutique.Ar represents an aromatic residue (such as phenyl) to which the substituents are attached to different carbons and can be in various relative positions, and their physiologically acceptable salts, hydrates, solvates and bioprecursors for their therapeutic use.
Les isomères géométriques et optiques des composés de formule générale (I) font également partie de la présente invention ainsi que leurs mélanges en toutes proportions et 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 mixtures in all proportions and in racemic form.
Parmi les sels physiologiquement acceptables des composés de formule généraleAmong the physiologically acceptable salts of the compounds of general formula
(I) sont inclus les sels obtenus par addition d'acides organiques ou inorganiques tels que les chlorohydrates, bromhydrates, sulfates, phosphates, benzoates, acétates, naphtoate, p-toluènesulfonates, méthanesulfonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maléates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates.(I) are included the salts obtained by addition of organic or inorganic acids such as the hydrochlorides, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoate, 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).
Des sous-classes de composés particuliers préférés, objet de la présente invention, sont les composés de formule générale I dans laquelle :Subclasses of preferred particular compounds which are the subject of the present invention are the compounds of general formula I in which:
* X-Y représente N-CH2 ou CH-CH2 et/ou , * Ri représente un méthyle et/ou* XY represents N-CH 2 or CH-CH 2 and / or, * Ri represents a methyl and / or
* R3 représente un hydrogène et R» un atome de chlore ou un groupe méthoxy et/ou,* R 3 represents a hydrogen and R "a chlorine atom or a methoxy group and / or,
* R3 et Rj sont adjacents et, pris dans leur ensemble, forment un cycle à 6 chaînons avec le résidu aromatique auquel ils sont rattachés et/ou, * Z représente -Zι-(CH2)m-Z2 ou Zi- (CH2)m-ι-CONH, ou bien* R 3 and Rj are adjacent and, taken as a whole, form a 6-membered ring with the aromatic residue to which they are attached and / or, * Z represents -Zι- (CH 2 ) m -Z 2 or Zi- (CH 2 ) m- ι-CONH, or else
Zi-ArtCHzV.-CONH-, ou encoreZi-ArtCHzV.-CONH-, or even
CH(R3)-NHCO-Z2. Les composés de la présente invention de formule générale (I) sont préparés par différentes méthodes et techniques qui dépendront de la nature de R1-R4, X-Y mais surtout de Z.CH (R 3 ) -NHCO-Z 2 . The compounds of the present invention of general formula (I) are prepared by different methods and techniques which will depend on the nature of R1-R4, XY but especially on Z.
Une méthode générale de préparation des composés de formule générale (I) consiste à condenser une aminé cyclique de formule générale (II)A general method for preparing the compounds of general formula (I) consists in condensing a cyclic amine of general formula (II)
/ \/ \
Rr 2 -x NH R r 2 -x NH
\\
Y _/Y _ /
( I I I(I I I
dans laquelle R2 et X-Y sont définis comme précédemment avec un carbonyle activé de formule générale (III)in which R 2 and XY are defined as above with an activated carbonyl of general formula (III)
Figure imgf000008_0001
dans laquelle R\, R3, R4 et Z sont définis comme précédemment et X représente un groupe partant tel que par exemple un chlore.
Figure imgf000008_0001
in which R \, R3, R4 and Z are defined as above and X represents a leaving group such as, for example, chlorine.
Le choix de la nature de X et des conditions expérimentales pour réaliser la condensation de l'aminé cyclique (II) avec le dérivé (III) dépendra essentiellement de la nature de Z. C'est ainsi que dans le cas particulier des amides de formule (I) dans laquelle Z représente (CH2)m-Z2, Ar-(CH2)n-Z2-, (CH2)m.1 -CONH, Ar-(CH2)n. j -CONH ou CH(R5)-NH-CO-Z2 la méthode consiste à condenser une aminé de formule (II) avec un dérivé d'acide carboxylique de formule (III) dans laquelle Z est défini comme ci-dessus et X représente OH, O-alkyle, CI, ou encore, le groupe "XCO" représente toute forme activée dérivée d'un acide carboxylique propice à la préparation d'une amide par les méthodes et techniques bien connues de l'homme de métier pour préparer une amide par condensation d'une aminé avec un dérivé d'acide carboxylique. Les conditions expérimentales pour réaliser cette condensation seront déterminées en fonction de la nature de Z et surtout de la nature de X. C'est ainsi, et à titre d'exemple que cette condensation peut être réalisée à partir d'un ester carboxylique de formule (III) (dans 1 laquelle X représente un O-alkyle tel que par exemple un éthyloxy) avec une aminé de formule (II) en présence de triméthylaluminium dans un solvant aprotique anhydre tel que le dichlorométhane ou le toluène.The choice of the nature of X and of the experimental conditions for carrying out the condensation of the cyclic amine (II) with the derivative (III) will depend essentially on the nature of Z. Thus, in the particular case of the amides of formula (I) in which Z represents (CH 2 ) m -Z 2 , Ar- (CH 2 ) n -Z 2 -, (CH 2 ) m .1 -CONH, Ar- (CH 2 ) n . j -CONH or CH (R5) -NH-CO-Z 2 the method consists in condensing an amine of formula (II) with a carboxylic acid derivative of formula (III) in which Z is defined as above and X represents OH, O-alkyl, CI, or, the group "XCO" represents any activated form derived from a carboxylic acid suitable for the preparation of an amide by the methods and techniques well known to those skilled in the art for preparing an amide by condensation of an amine with a carboxylic acid derivative. The experimental conditions for carrying out this condensation will be determined as a function of the nature of Z and especially of the nature of X. It is thus, and by way of example that this condensation can be carried out starting from a carboxylic ester of formula (III) (in 1 which X represents an O-alkyl such as for example an ethyloxy) with an amine of formula (II) in the presence of trimethylaluminium in an anhydrous aprotic solvent such as dichloromethane or toluene.
A titre d'exemple complémentaire, cette condensation peut également être réalisée à partir d'une aminé de formule (II) et d'un chlorure d'acide de formule (III) dans laquelle X = Cl, en présence d'une base organique ou inorganique telle que la pyridine, la DiPEA, la DMAP, le DBU, K2C03, Cs2Cθ3 ou Na2Cθ3 dans un solvant anhydre aprotique polaire tel que le THF, la DME, le dichlorométhane, à une température comprise entre - 20°C et 40°C. La préparation des composés de la présente invention de formule générale (I) dans laquelle Z est décrit comme ci-dessus peut également être réalisée par condensation d'une aminé de formule (II) avec un ester activé de formule (III) selon les méthodes et techniques bien connues pour ce type de transformation. A titre d'exemple complémentaire, cette condensation peut également être réalisée à partir d'une aminé de formule (II) et d'un acide carboxylique de formule (III) dans laquelle X=OH, en présence d'une aminé tertiaire telle que la triéthylamine, la diisipropyléthylamine, la pyridine, la DiPEA, la DMAP, la N-méthylmorpholine, dans un solvant aprotique polaire tel que le THF, le dichlorométhane, le DCE, l'acétate d'ethyle, le chloroforme, le DMF, par réaction avec un agent activant tel que l'EDC, le DCC, le BOP, le PyBOP, à une température comprise entre -10 et 35°C.As a further example, this condensation can also be carried out from an amine of formula (II) and an acid chloride of formula (III) in which X = Cl, in the presence of an organic base or inorganic such as pyridine, DiPEA, DMAP, DBU, K 2 C03, Cs 2 Cθ3 or Na 2 Cθ3 in an anhydrous polar aprotic solvent such as THF, DME, dichloromethane, at a temperature between - 20 ° C and 40 ° C. The preparation of the compounds of the present invention of general formula (I) in which Z is described as above can also be carried out by condensation of an amine of formula (II) with an activated ester of formula (III) according to the methods and techniques well known for this type of transformation. As a further example, this condensation can also be carried out from an amine of formula (II) and a carboxylic acid of formula (III) in which X = OH, in the presence of a tertiary amine such as triethylamine, diisipropylethylamine, pyridine, DiPEA, DMAP, N-methylmorpholine, in a polar aprotic solvent such as THF, dichloromethane, DCE, ethyl acetate, chloroform, DMF, for example reaction with an activating agent such as EDC, DCC, BOP, PyBOP, at a temperature between -10 and 35 ° C.
Dans le cas particulier des composés de formule (I) dans laquelle Z représente Z\ - (CH2)m-Z2,
Figure imgf000009_0001
ou Z x - Ar-(CH2)n. x -CONH dans lesquels Z\ représente O ou NH et qui sont dès lors des carbamates ou des urées, la condensation d'une aminé cyclique de formule (II) sera effectuée avec un intermédiaire de formule (III) dans laquelle X représentera préférentiellement Cl, OCCI3, O-pyridyl, un succinimyle ou un imidiazolyle dans un solvant anhydre aprotique tel que le dichlorométhane, à une température comprise entre 0 et 80°C en présence d'une base telle qu'une aminé tertiaire (par exemple la triéthylamine) ou un carbonate inorganique. Dans ces cas particuliers, les intermédiaires de formule (III) seront préparés et éventuellement utilisés directement sans purification préalable à partir des aminés ou des alcools correspondants (dépendant de la nature de Z\ ) de formule (IV)
Figure imgf000010_0001
In the particular case of the compounds of formula (I) in which Z represents Z \ - (CH 2 ) m -Z 2 ,
Figure imgf000009_0001
or Z x - Ar- (CH 2 ) n . x -CONH in which Z \ represents O or NH and which are therefore carbamates or ureas, the condensation of a cyclic amine of formula (II) will be carried out with an intermediate of formula (III) in which X will preferably represent Cl , OCCI3, O-pyridyl, succinimyl or imidiazolyl in an aprotic anhydrous solvent such as dichloromethane, at a temperature between 0 and 80 ° C in the presence of a base such as a tertiary amine (for example triethylamine) or an inorganic carbonate. In these particular cases, the intermediates of formula (III) will be prepared and optionally used directly without prior purification from the corresponding amines or alcohols (depending on the nature of Z \) of formula (IV)
Figure imgf000010_0001
dans laquelle Rj, R3 et R4 sont définis comme précédemment, Zj représente O ou NH, et Y représente (CH2)m-Z2, Ar-(CH2)n-Z2, (CH2)m_ j-CONH ou Ar-(CH2)n. j -CONH par reaction avec un dérivé de formule générale (V)in which Rj, R3 and R4 are defined as above, Zj represents O or NH, and Y represents (CH 2 ) m -Z 2 , Ar- (CH 2 ) n -Z 2 , (CH 2 ) m _ j-CONH or Ar- (CH 2 ) n . j -CONH by reaction with a derivative of general formula (V)
oo
II x — C — X ' (V)II x - C - X '(V)
dans laquelle X et X' 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 O-aryl (en particulier le groupe O-pyridyl), un groupe succinimyle, phthalyle ou imidazolyle. La méthode de la présente invention comprend également l'utilisation de précurseurs ou analogues bien connus des réactifs de formule générale (V). C'est ainsi et à titre d'exemple que la condensation des intermédiaires (IV) avec le phosgene peut être avantageusement effectuée à l'aide de diphosgène ou de triphosgéne selon une procédure bien connue de l'homme de l'art.in which X and X ′, which are identical or different, each represent a leaving group such as a halogen (in particular chlorine), an O-alkyl group (in particular the group OCCI3), an O-aryl group (in particular the group O -pyridyl), a succinimyl, phthalyl or imidazolyl group. The method of the present invention also comprises the use of precursors or analogues well known to the reagents of general formula (V). It is thus and by way of example that the condensation of intermediates (IV) with phosgene can be advantageously carried out using diphosgene or triphosgene according to a procedure well known to those skilled in the art.
Dans le cas particulier des composés de formule générale (I) dans laquelle le groupe Z représente Zι-(CH2)m_ι-CONH ou Zι-Ar-(CH2)n_ι-CONH une méthode alternative de préparation consiste à condenser une aminé aromatique de formule (VI)In the particular case of the compounds of general formula (I) in which the group Z represents Zι- (CH 2 ) m _ι-CONH or Zι-Ar- (CH 2 ) n _ι-CONH an alternative method of preparation consists in condensing a aromatic amine of formula (VI)
Figure imgf000010_0002
Figure imgf000010_0002
dans laquelle Rj, R3 et R4 sont définis comme précédemment avec un dérivé d'acide carboxylique de formule (VII)in which R j , R3 and R4 are defined as above with a carboxylic acid derivative of formula (VII)
— Z — Z " ~ C — X (VI I )
Figure imgf000010_0003
3- Z - Z "~ C - X (VI I)
Figure imgf000010_0003
3
dans laquelle R2, X-Y et Z\ sont définis comme dans la formule (I), Z" représente (CH2)m_] ou Ar(CH2)n.ι et X représente un groupe partant ou encore le reste "COX" représente toute forme dérivée d'un acide carboxylique propice à la condensation avec une amine pour former une amide par les méthodes et techniques bien connues de l'homme de l'art.in which R 2 , XY and Z \ are defined as in formula (I), Z "represents (CH 2 ) m _] or Ar (CH 2 ) n .ι and X represents a leaving group or the remainder" COX "represents any form derived from a carboxylic acid conducive to condensation with an amine to form an amide by methods and techniques well known to those skilled in the art.
Dans le cas particulier des composés de formule (I) dans laquelle Z représente CH(R5)- NHCO une méthode de synthèse alternative mais particulièrement appréciée consiste à condenser un dérivé d'acide aminé de formule générale (VIII)In the particular case of the compounds of formula (I) in which Z represents CH (R5) - NHCO, an alternative but particularly appreciated method of synthesis consists in condensing an amino acid derivative of general formula (VIII)
Figure imgf000011_0001
Figure imgf000011_0001
dans laquelle R2, X-Y et R5 sont définis comme précédemment avec un dérivé d'acide carboxylique aromatique de formule générale (IX)in which R 2 , XY and R5 are defined as above with an aromatic carboxylic acid derivative of general formula (IX)
Figure imgf000011_0002
Figure imgf000011_0002
dans laquelle R\, R3 et R4 sont définis comme précédemment et X représente un groupe partant (par exemple un chlore) ou encore, le groupe "XCO" représente toute forme dérivée d'un acide carboxylique (par exemple un ester activé) propice à la condensation avec une amine pour former une amide par les méthodes et techniques bien connues de l'homme de l'art.in which R \, R3 and R4 are defined as above and X represents a leaving group (for example a chlorine) or, the group "XCO" represents any form derived from a carboxylic acid (for example an activated ester) suitable for condensation with an amine to form an amide by methods and techniques well known to those skilled in the art.
Dans le cas particulier des composés de formule (I) dans laquelle Z représente Zj- (CH2)m-Z2 ou Z]-Ar-(CH2)n-Z2 dans lesquels Z2 représente O ou NH, une méthode alternative mais particulièrement appréciée faisant partie de la présente invention consiste à condenser un intermédiaire aromatique de formule (X) ΛOIn the particular case of the compounds of formula (I) in which Z represents Zj- (CH 2 ) m -Z 2 or Z ] -Ar- (CH 2 ) n -Z 2 in which Z 2 represents O or NH, a method alternative but particularly appreciated forming part of the present invention consists in condensing an aromatic intermediate of formula (X) ΛO
Figure imgf000012_0001
Figure imgf000012_0001
dans laquelle R], R3 et R4 sont définis comme précédemment, Z'2 représente OH ou NH-P dans laquelle P représente un groupe tel qu'un ^butyloxycarbonyle ou un trifluoroacétyle avec un électrophile de formule générale (XI)in which R], R3 and R4 are defined as above, Z ′ 2 represents OH or NH-P in which P represents a group such as butyloxycarbonyl or trifluoroacetyl with an electrophile of general formula (XI)
Figure imgf000012_0002
Figure imgf000012_0002
dans laquelle R2 X-Y sont définis comme précédemment Z'" représente Z]-(CH2)m ou Zι-Ar-(CH2)n et L représente un groupe partant tel qu'un halogène (de préférence un brome ou un iode), un tosylate, un mésylate ou un triflate. Cette condensation est réalisée en milieu basique en présence d'une base telle que NaH, KH ou Cs2Cθ3 dans un solvant aprotique polaire tel que le DMF, le THF, le dioxane, le DME ou le DMSO, à une température comprise entre - 10° et 60°C. Dans le cas particulier de la condensation mettant en oeuvre un dérivé d'aminé aromatique de formule (X) dans laquelle Z'2 représente NHBOC ou NHCOCF3, la condensation sera suivie d'une étape de déprotection de l'aminé aromatique (par exemple en utilisant des conditions acides telles que l'emploi de l'acide chlorhydrique ou trifluoroacétique dans le cas du dérivé tbutoxycarbonyle ou en utilisant des conditions basiques telles que l'hydroxyde de sodium ou potassium ou des conditions réductrices (hydrures d'aluminium de base) dans le cas de dérivés N- trifluoroacétyle).in which R 2 XY are defined as above Z '"represents Z ] - (CH 2 ) m or Zι-Ar- (CH 2 ) n and L represents a leaving group such as a halogen (preferably bromine or iodine ), a tosylate, a mesylate or a triflate. This condensation is carried out in basic medium in the presence of a base such as NaH, KH or Cs 2 Cθ3 in a polar aprotic solvent such as DMF, THF, dioxane, DME or DMSO, at a temperature of between −10 ° and 60 ° C. In the particular case of condensation using an aromatic amine derivative of formula (X) in which Z ′ 2 represents NHBOC or NHCOCF3, the condensation will be followed by a step of deprotection of the aromatic amine (for example by using acidic conditions such as the use of hydrochloric or trifluoroacetic acid in the case of the tbutoxycarbonyl derivative or by using basic conditions such as sodium or potassium hydroxide or reducing conditions s (basic aluminum hydrides) in the case of N-trifluoroacetyl derivatives).
Dans le cas particulier des composés de formule (I) de la présente invention dans lesquels Z représente CH(R5)NHCO-Z2 où Z2 représente O ou NH, une méthode de préparation alternative mais particulièrement appréciée consiste à condenser un dérivé d'acide aminé de formule générale (VIII) dans laquelle R2, X-Y et R5 sont définis comme précédemment et un intermédiaire de formule (XII) ΛΛIn the particular case of the compounds of formula (I) of the present invention in which Z represents CH (R5) NHCO-Z 2 where Z 2 represents O or NH, an alternative but particularly preferred method of preparation consists in condensing a derivative of amino acid of general formula (VIII) in which R 2 , XY and R5 are defined as above and an intermediate of formula (XII) ΛΛ
Figure imgf000013_0001
Figure imgf000013_0001
dans laquelle R], R3 R4 sont définis comme précédemment et Z2 représente O ou NH avec un réactif de formule (V) dans laquelle X et X' sont définis comme précédemment Les méthodes et techniques choisies pour la mise en oeuvre de la préparation des composés de formule (I) dans laquelle Z représente CH(R5)-NHC02 ou CH(R5)-NH- CONH par condensation des dérivés de formule (VIII) et de dérivés de formule (XII) avec un réactif de formule (V) 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 seront déterminés essentiellement par la nature du réactif (V) (choix de X et X"). C'est ainsi qu'une méthode plus particulièrement appréciée pour la préparation de dérivés de formule (I) dans laquelle Z représente CH(R5)-NHC02 ou CH(R5>NH-CONH consiste à faire réagir le dipyridyl carbonate (préparé selon Tet Lett 32,4251, 1991) ou le triphosgéne avec un dérivé de formule (XII) en présence de triéthylamine dans un solvant tel que le dichlorométhane, puis avec une amine de formule (VIII) en présence de triéthylamine dans le dichlorométhane.in which R], R3 R4 are defined as above and Z 2 represents O or NH with a reagent of formula (V) in which X and X 'are defined as previously The methods and techniques chosen for carrying out the preparation of compounds of formula (I) in which Z represents CH (R5) -NHC0 2 or CH (R5) -NH- CONH by condensation of the derivatives of formula (VIII) and derivatives of formula (XII) with a reagent of formula (V ) such as the choice of the order of the reactants, 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-reactants (such as an organic or inorganic base, for example a tertiary amine) or catalysts will be determined essentially by the nature of the reactant (V) (choice of X and X "). This is how a method more particularly appreciated for the preparation of derivatives of formula (I) in which Z represents CH (R5) -NHC0 2 or CH (R5> NH-CONH consists in reacting the dipyridyl carbonate (prepared according to Tet Lett 32,4251, 1991) or the triphosgene with a derivative of formula ( XII) in the presence of triethylamine in a solvent such as dichloromethane, then with an amine of formula (VIII) in the presence of triethylamine in dichloromethane.
Les intermédiaires de formule générale (III) [propices à la condensation avec une amine de formule (II) pour la préparation des composés de formule (I)] dans lesquels le résidu Z est défini de façon à former une liaison carbone-carbone avec le groupe "XCO" auquel il est attaché sont eux-même préparés à partir des esters (répondant à la formule (III) dans laquelle X représente un O-alkyle ou un O-arylalkyle) ou des acides carboxyliques correspondants (répondant à la formule (III) dans laquelle X représente OH) par les méthodes bien connues de l'homme de l'art pour préparer par exemple un chlorure d'acide ou un ester activé à partir d'un acide carboxylique eux-même issus de l'hydrolyse des esters correspondants (les conditions, par exemple acides ou basiques seront définies en fonction de la nature de Z et des substituants R] , R3 et R4) Ces esters carboxyliques sont obtenus par différentes méthodes et techniques qui dépendront de la nature de Z λ 1Intermediaries of general formula (III) [conducive to condensation with an amine of formula (II) for the preparation of compounds of formula (I)] in which the residue Z is defined so as to form a carbon-carbon bond with the "XCO" group to which it is attached are themselves prepared from esters (corresponding to formula (III) in which X represents an O-alkyl or an O-arylalkyl) or corresponding carboxylic acids (corresponding to formula ( III) in which X represents OH) by methods well known to those skilled in the art for preparing, for example, an acid chloride or an activated ester starting from a carboxylic acid themselves resulting from the hydrolysis of corresponding esters (the conditions, for example acidic or basic will be defined according to the nature of Z and of the substituents R], R3 and R4) These carboxylic esters are obtained by different methods and techniques which will depend on the nature of Z λ 1
C'est ainsi que les esters intermédiaires de formule (III) dans laquelle X représente O- alkyle ou O-alkylaryle et Z représente (CH2)m-O, ou Ar-(CH2)n-O ou CH(R5)- NHCO2- sont préparés respectivement par condensation d'une arylpipérazine de formule (XII) dans laquelle Z2 représente un oxygène avec un électrophile de formule (XIII), (XIV) ou (XV)Thus, the intermediate esters of formula (III) in which X represents O-alkyl or O-alkylaryl and Z represents (CH 2 ) m -O, or Ar- (CH 2 ) n -O or CH (R5) - NHCO 2 - are respectively prepared by condensation of an arylpiperazine of formula (XII) in which Z 2 represents an oxygen with an electrophile of formula (XIII), (XIV) or (XV)
O II X -C -(CH2)m — L (XIII)O II X -C - (CH 2 ) m - L (XIII)
X -C - Ar- (CH2)n - L (χ|V) X -C - Ar- (CH 2 ) n - L (χ | V)
O II X — C — CH(R
Figure imgf000014_0001
O II X - C - CH (R
Figure imgf000014_0001
dans lesquelles X représente O-alkyle ou O-aryle ou O-alkylaryle, L représente un groupe partant tel qu'un halogène (chlore, brome ou iode), un tosylate, un mésylate et un triflate et L' représente un halogène ou un reste de carbamoyl activé tel que OCCI3 O- succinimyle ou O-pyridyle. La condensation des phénols de formule (XII) dans laquelle Z2 représente un oxygène avec un électrophile de formule (XIII) ou (XIV) est réalisée préférentiellement en présence d'une base (par exemple NaH, KH, CS2CO3, DiPEA ou l~ BuOK) dans un solvant aprotique polaire tel que le DMF, le DMSO ou la diéthylcétone, à une température comprise entre 20 et 100°C. La condensation d'un phénol de formule (XII) dans laquelle Z2 = O avec un électrophile de formule (XV) est réalisée de préférence dans un solvant tel que le dichlorométhane en présence d'une base organique telle qu'une amine tertiaire.in which X represents O-alkyl or O-aryl or O-alkylaryl, L represents a leaving group such as a halogen (chlorine, bromine or iodine), a tosylate, a mesylate and a triflate and L 'represents a halogen or a residue of activated carbamoyl such as OCCI3 O-succinimyl or O-pyridyl. The condensation of phenols of formula (XII) in which Z 2 represents oxygen with an electrophile of formula (XIII) or (XIV) is preferably carried out in the presence of a base (for example NaH, KH, CS2CO3, DiPEA or l ~ BuOK) in a polar aprotic solvent such as DMF, DMSO or diethyl ketone, at a temperature between 20 and 100 ° C. The condensation of a phenol of formula (XII) in which Z 2 = O with an electrophile of formula (XV) is preferably carried out in a solvent such as dichloromethane in the presence of an organic base such as a tertiary amine.
Les esters intermédiaires de formule (III) dans laquelle X représente O-alkyle ou O- arylalkyle et Z représente (CH2)m-NH, Ar-(CH2)n-NH, CH(R5)-NH-CONH, (CH2)m- j-CONH ou Ar(CH2)n_ι CONH sont préparés par condensation d'un intermédiaire de formule (XII) dans laquelle Z2 représente NH ou NBOC ou NCOCF3 avec respectivement un életrophile de formule (XIII), (XIV), (XV), (XVI) ou (XVII)The intermediate esters of formula (III) in which X represents O-alkyl or O-arylalkyl and Z represents (CH 2 ) m -NH, Ar- (CH 2 ) n -NH, CH (R5) -NH-CONH, ( CH 2 ) m - j-CONH or Ar (CH 2 ) n _ι CONH are prepared by condensation of an intermediate of formula (XII) in which Z 2 represents NH or NBOC or NCOCF3 with respectively an electrophilic of formula (XIII), (XIV), (XV), (XVI) or (XVII)
Figure imgf000014_0002
o
Figure imgf000014_0002
o
X-C -Ar(CH2) — CO- L" {χv||) A hXC -Ar (CH 2 ) - CO- L " {χv ||) At h
dans lesquels X, L, L' sont définis comme précédemment et L" représente un groupe partant (tel qu'un chlore) ou encore le groupe COL" représente un ester activé, un acide carboxylique ou toute forme dérivée d'un acide carboxylique propice à la formation d'une amide par condensation avec une amine. La condensation des électrophiles de formule (XIII) et (XIV) se fera préférentiellement avec un dérivé d'aniline de formule (XII) dans laquelle Z2 représente NBOC ou NCOCF3 dans un solvant aprotique polaire tel que le THF ou le DMSO ou le DMF en présence d'une base forte tel que NaH, KH ou t_BuOK à une température comprise entre 20 et 80°C et sera suivie de la déprotection de l'azote aromatique (en milieu acide si le produit de départ est un dérivé t_butoxycarbonyle, en milieu basique ou réducteur si le produit de départ est un dérivé trifluoroacétyle). Les dérivés de formule (III) de type urée sont obtenus par condensation d'une amine aromatique de formule (XII) dans laquelle Z2 représente NH avec un électrophile de formule (XV) dans laquelle L' représente par exemple un chlore (intermédiaire issu de la réaction de XCO-CH(R5)NH2 avec du triphosgéne) dans un solvant anhydre aprotique tel que le dichlorométhane en présence de triéthylamine. De même, les intermédiaires de formule (III) de type amides sont préparés par condensation d'une amine aromatique de formule (XII) dans laquelle Z2 représente NH avec un dérivé d'acide carboxylique (propice à la condensation avec une amine) de formule (XVI) ou (XVII) dans lesquels L" est défini comme précédemment, par les méthodes et techniques bien connues de l'homme de l'art pour préparer une amide à partir d'une amine et d'un dérivé d'acide carboxylique.in which X, L, L 'are defined as above and L "represents a leaving group (such as chlorine) or also the group COL" represents an activated ester, a carboxylic acid or any form derived from a suitable carboxylic acid to the formation of an amide by condensation with an amine. The electrophiles of formula (XIII) and (XIV) will be condensed preferably with an aniline derivative of formula (XII) in which Z 2 represents NBOC or NCOCF3 in a polar aprotic solvent such as THF or DMSO or DMF in the presence of a strong base such as NaH, KH or t_ BuOK at a temperature between 20 and 80 ° C and will be followed by deprotection of aromatic nitrogen (in an acid medium if the starting product is a derivative t_ butoxycarbonyl , in basic or reducing medium if the starting product is a trifluoroacetyl derivative). The derivatives of formula (III) of urea type are obtained by condensation of an aromatic amine of formula (XII) in which Z 2 represents NH with an electrophile of formula (XV) in which L 'represents for example a chlorine (intermediate derived of the reaction of XCO-CH (R5) NH 2 with triphosgene) in an aprotic anhydrous solvent such as dichloromethane in the presence of triethylamine. Likewise, the amide type intermediates of formula (III) are prepared by condensation of an aromatic amine of formula (XII) in which Z 2 represents NH with a carboxylic acid derivative (conducive to condensation with an amine) of formula (XVI) or (XVII) in which L "is defined as above, by the methods and techniques well known to those skilled in the art for preparing an amide from an amine and an acid derivative carboxylic.
Les esters dérivés de formule (III) dans lesquelles Z représente (CH2)m ou Ar(CH2)n sont préparés par condensation d'un triflate de formule générale (XVIII)The esters derived from formula (III) in which Z represents (CH 2 ) m or Ar (CH 2 ) n are prepared by condensation of a triflate of general formula (XVIII)
Figure imgf000015_0001
Figure imgf000015_0001
avec un alcène de formule (XIX) ou (XX) A*with an alkene of formula (XIX) or (XX) AT*
oo
I I X - C — (CH2)m.2 — CH = CH, (XIX)IIX - C - (CH 2 ) m . 2 - CH = CH, (XIX)
o x- - C - Ar- (CH2)n.2 - CH = CH, (XX)o x- - C - Ar- (CH 2 ) n . 2 - CH = CH, (XX)
dans lesquelles X représente O-alkyle ou O-aryle et m et n sont supérieur ou égal à 2, selon une méthode décrite (cf. J. Org. Chem. 58, 2201 , 1993). Les aryl triflates de formule générale (XVIII) sont préparés à partir des phénols correspondants (XII) (dans lesquels Z2 = O) par réaction avec l'anhydride triflique ou CF3S02C1.in which X represents O-alkyl or O-aryl and m and n are greater than or equal to 2, according to a described method (cf. J. Org. Chem. 58, 2201, 1993). The aryl triflates of general formula (XVIII) are prepared from the corresponding phenols (XII) (in which Z 2 = O) by reaction with triflic anhydride or CF3SO 2 C1.
Une méthode alternative pour préparer ces mêmes esters (III) consiste à condenser un organométallique de formule (XXI)An alternative method for preparing these same esters (III) consists in condensing an organometallic of formula (XXI)
Figure imgf000016_0001
Figure imgf000016_0001
dans laquelle M représente Li, MgBr ou ZnBr avec un électrophile approprié tel que par exemple un composé répondant à la formule (XIII) ou (XIV)in which M represents Li, MgBr or ZnBr with an appropriate electrophile such as for example a compound corresponding to formula (XIII) or (XIV)
Les organométalliques de structure (XXI) sont accessibles par échange halogène métal à partir des bromes aromatiques de formule (XXII).The organometallic structures (XXI) are accessible by metal halogen exchange from the aromatic bromines of formula (XXII).
Figure imgf000016_0002
Figure imgf000016_0002
Dans le cas particulier des intermédiaires de formule (III) dans laquelle Z représente CH2-CH2 et X représente un reste O-alkyle ou O-alkylaryle, une méthode alternative mais particulièrement appréciée consiste à condenser par les méthodes et techniques bien connues sous le nom de réaction de Heck, un ester α,β insaturé avec un dérivé brome aromatique de formule (XXII), en présence d'un dérivé de palladium, suivi de la réduction de la double liaison de l'intermédiaire ainsi formé par hydrogénation catalytique (en présence de palladium sur charbon par exemple).In the particular case of intermediates of formula (III) in which Z represents CH 2 -CH 2 and X represents an O-alkyl or O-alkylaryl residue, an alternative but particularly appreciated method consists in condensing by the methods and techniques well known under the Heck reaction name, an α, β unsaturated ester with an aromatic bromine derivative of formula (XXII), in the presence of a palladium derivative, followed by the reduction of the double bond of the intermediate thus formed by catalytic hydrogenation (in the presence of palladium on carbon for example).
Les intermédiaires de formule (IV) sont quant à eux préparés selon les méthodes décrites précédemment pour la préparation des intermédiaires (III), qui seront déterminées essentiellement en fonction de la nature de Zj et qui bien entendu feront appel à des synthons précurseurs du groupe "H-Z]-Y" appropriés. Par exemple, la condensation d'intermédiaires de formules (VI), (X), (XII) ou (XXI) sera réalisée avec des électrophiles de formule générale (XXIII)The intermediates of formula (IV) are in turn prepared according to the methods described above for the preparation of intermediates (III), which will be determined essentially as a function of the nature of Zj and which of course will use precursor synthons from the group " HZ] -Y "appropriate. For example, the condensation of intermediates of formulas (VI), (X), (XII) or (XXI) will be carried out with electrophiles of general formula (XXIII)
P-Zi-V-L (XXIII)P-Zi-V-L (XXIII)
dans laquelle Z\ représente O ou NH, P représente un groupe protecteur tel que par exemple un benzyl, un reste silylé lorsque Z\ = O ou plutôt un t_butoxycarbonyle lorsque Z] = NH, Y' représente soit (CH2)m, Ar-(CH2)n, (CH2)m_ι-CO ou Ar-(CH2)n. \ -CO et L représente un groupe partant tel qu'un halogène (brome, chlore ou iode), un tosylate, un mésylate ou un triflate, par les structures décrites précédemment pour la préparation des intermédiaires de formule (III) pour le même type de réaction, suivi de la déprotection de Z\ par les méthodes appropriées choisies en fonction de la nature de P telles que l'hydrogénation catalytique en présence de palladium sur charbon si P représente un reste benzyle, le traitement par des fluorures (tels que CsF ou BU4NF) si P représente un reste silylé ou encore l'hydrolyse acide si P représente un l" butoxycarboxyle.in which Z \ represents O or NH, P represents a protective group such as for example a benzyl, a silylated residue when Z \ = O or rather a t_ butoxycarbonyl when Z] = NH, Y 'represents either (CH 2 ) m , Ar- (CH 2 ) n , (CH 2 ) m _ι-CO or Ar- (CH 2 ) n . \ -CO and L represents a leaving group such as a halogen (bromine, chlorine or iodine), a tosylate, a mesylate or a triflate, by the structures described above for the preparation of intermediates of formula (III) for the same type reaction, followed by deprotection of Z \ by the appropriate methods chosen according to the nature of P such as catalytic hydrogenation in the presence of palladium on carbon if P represents a benzyl residue, treatment with fluorides (such as CsF or Bu 4 NF) if P is a silyl radical or acid hydrolysis if P is the "butoxycarboxyle.
Une méthode alternative mais appréciée de préparation des dérivés de formule (IV) dans laquelle Z \ représente un oxygène consiste à réduire un précurseur approprié de formule générale (III) dans laquelle X représente un O-alkyle (par exemple OEt ou OMe) par un hydrure d'aluminium (tel que par exemple LiAlPLt;) dans un solvant anhydre tel que l'éther éthylique ou le THF à une température comprise entre 0° et 60°C, étant entendu que le résidu Y dans le produit final de formule (IV) comportera un CH2 de plus que le résidu Z dans le précurseur de formule (III).An alternative but appreciated method for preparing the derivatives of formula (IV) in which Z \ represents oxygen consists in reducing an appropriate precursor of general formula (III) in which X represents an O-alkyl (for example OEt or OMe) by a aluminum hydride (such as for example LiAlPLt;) in an anhydrous solvent such as ethyl ether or THF at a temperature between 0 ° and 60 ° C, it being understood that the residue Y in the final product of formula ( IV) will contain one CH 2 more than the residue Z in the precursor of formula (III).
De façon analogue, des aminés de formule (IV) dans laquelle Z | représente NH peuvent être préparées par réduction de nitriles de formule XXIV Λ $)Similarly, amines of formula (IV) in which Z | represents NH can be prepared by reduction of nitriles of formula XXIV Λ $)
Figure imgf000018_0001
Figure imgf000018_0001
dans laquelle Y' représente (CH2)m_ι-Z2, -Ar-(CH2)n. ] -Z2, (CH2)m.2-CONH ou Ar(CH2)n_2-CONH, les nitriles étant eux-mêmes accessibles par les mêmes procédés que décrits précédemment pour la préparation des esters de formule (III) (dans laquelle X représente un reste alkyloxy ou arylalkyloxy) si ce n'est que les produits de départ utilisés sont des nitriles et non des esters.in which Y 'represents (CH 2 ) m _ι-Z 2 , -Ar- (CH 2 ) n . ] -Z 2 , (CH 2 ) m . 2 -CONH or Ar (CH 2 ) n _ 2 -CONH, the nitriles themselves being accessible by the same methods as described above for the preparation of the esters of formula (III) (in which X represents an alkyloxy or arylalkyloxy residue) except that the starting materials used are nitriles and not esters.
Les dérivés de formule générale (VII), que ce soient des acides carboxyliques (X = OH) ou des formes activées de ces produits obtenus à partir des esters correspondants (X = O-alkyle ou O-alkylaryle) par hydrolyse en milieu acide ou basique, suivi de l'activation adéquate de l'acide ainsi formé pour obtenir un intermédiaire propice à la formation d'une liaison amide.The derivatives of general formula (VII), whether they are carboxylic acids (X = OH) or activated forms of these products obtained from the corresponding esters (X = O-alkyl or O-alkylaryl) by hydrolysis in an acid medium or basic, followed by the adequate activation of the acid thus formed to obtain an intermediate suitable for the formation of an amide bond.
Les esters correspondants à la formule (VII) dans laquelle X = O-alkyle ou O-arylalkyle sont préparés par condensation d'une amine cyclique de formule générale (II) avec un ester de formule (XXV)The esters corresponding to formula (VII) in which X = O-alkyl or O-arylalkyl are prepared by condensation of a cyclic amine of general formula (II) with an ester of formula (XXV)
O oO o
II IIII II
X'-C — z,-r-c-x (XXV)X'-C - z, -r-c-x (XXV)
dans laquelle Zi et Z" sont définis comme dans la formule (VII), X représente O-alkyle ou O-alkylaryle et X' représente un groupe partant tel qu'un chlore, ou encore, le groupe X'CO représente une forme activée d'acide carboxylique propice à la condensation avec une amine par les méthodes et techniques bien connues de l'homme de l'art. De la même façon, les intermédiaires de formule (XI) sont préparés par condensation d'une amine cyclique de formule (II) avec un électrophile de formule (XXVI) dans laquelle X' est décrit comme dans la formule (XXV), Z'" est défini comme dans la formule (XI) et P représente une forme protégée temporaire qui sera transformée en reste L tel que défini dans la formule (XI), après la réaction de condensation entre les dérivés (II) et (XXVI). C'est ainsi que par exemple un dérivé de formule (XI) dans lequel Altin which Zi and Z "are defined as in formula (VII), X represents O-alkyl or O-alkylaryl and X 'represents a leaving group such as chlorine, or alternatively, the group X'CO represents an activated form of carboxylic acid suitable for condensation with an amine by methods and techniques well known to those skilled in the art. Similarly, the intermediates of formula (XI) are prepared by condensation of a cyclic amine of formula (II) with an electrophile of formula (XXVI) in which X 'is described as in formula (XXV), Z'"is defined as in formula (XI) and P represents a temporary protected form which will be transformed into a remainder L as defined in formula (XI), after the condensation reaction between the derivatives (II) and (XXVI). Thus, for example, a derivative of formula (XI) in which Alt
L représente un mésylate sera préparé par condensation d'une amine cyclique de formule (II) avec un dérivé d'acide carboxylique activé de formule (XXVI)L represents a mesylate will be prepared by condensation of a cyclic amine of formula (II) with an activated carboxylic acid derivative of formula (XXVI)
oo
II
Figure imgf000019_0001
II
Figure imgf000019_0001
dans laquelle X' représente un chlore, Z'" est défini comme précédemment et P représente O(t-butyldimethylsilyl) en présence d'une amine tertiaire (telle que la triéthylamine) dans un solvant anhydre polaire (tel que le dichlorométhane) suivi de la déprotection de l'éther silylé en alcool (en utilisant un fluorure de tétrabutylammonium dans le THF) et activation de l'alcool en mésylate par réaction avec le chlorure de mésyle en présence d'une base (par exemple la triéthylamine ou la pyridine)in which X 'represents a chlorine, Z' "is defined as above and P represents O (t-butyldimethylsilyl) in the presence of a tertiary amine (such as triethylamine) in a polar anhydrous solvent (such as dichloromethane) followed by deprotection of silylated ether into alcohol (using a tetrabutylammonium fluoride in THF) and activation of the alcohol into mesylate by reaction with mesyl chloride in the presence of a base (for example triethylamine or pyridine)
De même les intermédiaires de formule (VIII) sont préparés par condensation d'un dérivé d'acide aminé de formule HOOC-CH(R5)-NH-Boc avec une amine cyclique de formule (II) par les méthodes et techniques bien connues de l'homme de l'art.Similarly, the intermediates of formula (VIII) are prepared by condensation of an amino acid derivative of formula HOOC-CH (R5) -NH-Boc with a cyclic amine of formula (II) by the methods and techniques well known in the art. one skilled in the art.
Les pipérazines de formule (II) (dans laquelle X-Y représente N-CH2), (VI), (IX), (X), (XII) et (XXII) sont préparées par différentes méthodes et techniques bien connues de l'homme de l'art et dont le choix dépendra essentiellement de la nature de R2 dans le cas de pipérazines de formule (II) et des substituants liés au reste aromatique dans le cas des pipérazines (VI), (IX), (X), (XII) et (XXII).The piperazines of formula (II) (in which XY represents N-CH 2 ), (VI), (IX), (X), (XII) and (XXII) are prepared by various methods and techniques well known to man of art and the choice of which will essentially depend on the nature of R 2 in the case of piperazines of formula (II) and of the substituents linked to the aromatic residue in the case of piperazines (VI), (IX), (X), (XII) and (XXII).
C'est ainsi que de nombreuses arylpipérazines sont préparées par condensation d'une amine aromatique avec un intermédiaire de formules (XXVII) ou (XXVIII):Many arylpiperazines are thus prepared by condensation of an aromatic amine with an intermediate of formulas (XXVII) or (XXVIII):
XVII)
Figure imgf000019_0002
XVII)
Figure imgf000019_0002
dans lesquelles R'i représente R\ ou un groupe protecteur tel que un t_butoxycarbonyle ou un tosyle et X représente un chlore, un brome, un iode, un tosylate ou un mésylate. La préparation d'un pipérazine aromatique par condensation d'une amine aromatique de formule (XXVIII) est préférentiellement réalisée dans un solvant anhydre polaire tel que le DMF, l'acétonitrile, le THF, le n-butanol, le t-butanol ou le DMSO, généralement à O 97/14689 PC17FR96/01626in which R'i represents R \ or a protective group such as a t_ butoxycarbonyl or a tosyle and X represents a chlorine, a bromine, an iodine, a tosylate or a mesylate. The preparation of an aromatic piperazine by condensation of an aromatic amine of formula (XXVIII) is preferably carried out in a polar anhydrous solvent such as DMF, acetonitrile, THF, n-butanol, t-butanol or DMSO, usually at O 97/14689 PC17FR96 / 01626
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 césium de potassium ou de calcium. La condensation d'intermédiaires de formule (XXVIII) avec une amine aromatique peut également être réalisée en milieu acide (l'acide p-toluène sulfonique par exemple) dans un solvant tel que le chlorobenzène. La préparation des pipérazines aromatiques par condensation d'aminés aromatiques avec un dérivé diacide de formule (XXVII) sera réalisée préférentiellement en présence d'anhydride acétique, suivi de la réduction de la dicétopipérazide ainsi formée avec par un exemple un borane.reflux temperature of the solvent used, in the presence of an organic or inorganic base generally used for this type of reaction such as cesium carbonate of potassium or calcium. The condensation of intermediates of formula (XXVIII) with an aromatic amine can also be carried out in an acid medium (p-toluene sulfonic acid for example) in a solvent such as chlorobenzene. The preparation of aromatic piperazines by condensation of aromatic amines with a diacid derivative of formula (XXVII) will preferably be carried out in the presence of acetic anhydride, followed by the reduction of the diketopiperazine thus formed with, for example, a borane.
Dans le cas de la préparation des pipérazines de formule (II) dans laquelle R2 représente un alkyle ou un arylalkyle, une méthode de préparation particulièrement appréciée consiste à condenser la pipérazine (qui sera alors utilisée en excès) ou la N-BOC- pipérazine avec un électrophile répondant à la formule R2-L dans laquelle L représente un groupe partant tel qu'un halogène (Cl, Br ou I), un tosylate, un mésylate ou un triflate, en présence éventuellement d'une base organique telle qu'une amine tertiaire ou inorganique telle que Cs2Cθ3 dans un solvant anhydre tel que le DMF, le THF ou le DMSO à une température comprise entre 20 et 80°C.In the case of the preparation of piperazines of formula (II) in which R 2 represents an alkyl or an arylalkyl, a particularly preferred preparation method consists in condensing the piperazine (which will then be used in excess) or the N-BOC-piperazine with an electrophile corresponding to the formula R 2 -L in which L represents a leaving group such as a halogen (Cl, Br or I), a tosylate, a mesylate or a triflate, optionally in the presence of an organic base such as 'a tertiary or inorganic amine such as Cs 2 Cθ3 in an anhydrous solvent such as DMF, THF or DMSO at a temperature between 20 and 80 ° C.
Une méthode alternative mais particulièrement appréciée consiste à condenser la N- BOC-pipérazine avec un dérivé d'acide carboxylique de formule (dans laquelle R'2 est défini de façon à ce que R'2CH2 sont équivalent à R2) tel qu'un chlorure d'acide, en présence d'une base telle qu'une amine tertiaire, dans un solvant tel que le dichlorométhane suivi de la réduction (par exemple à l'aide de l'hydrure de lithium et aluminium dans l'éther à 25°C) de l'amide ainsi forméeAn alternative but particularly appreciated method consists in condensing N-BOC-piperazine with a carboxylic acid derivative of formula (in which R ′ 2 is defined so that R ′ 2 CH 2 are equivalent to R 2 ) such that '' an acid chloride, in the presence of a base such as a tertiary amine, in a solvent such as dichloromethane followed by reduction (for example using lithium aluminum hydride in ether at 25 ° C) of the amide thus formed
Les pipéridines ou pipéridines insaturées de formule générale (II) (dans laquelle X- Y=CH-CH2 ou C=CH) sont préparées par différentes techniques et méthodes décrites par exemple dans les brevets DE 2801 195, EP 7067 (800123), EP 12643 (800625), FR 2459795 (810116), EP 372776 (900613), FR 2678270 (921231 ), FR 2675801 (921030), EP 580398 (940126), WO 9401403 (940120) ainsi que la publication récente de Shanklin J.R. et collaborateurs (J. Med. Chem. 34, 301 1 , 1991 )The unsaturated piperidines or piperidines of general formula (II) (in which X-Y = CH-CH 2 or C = CH) are prepared by various techniques and methods described for example in patents DE 2801 195, EP 7067 (800123), EP 12643 (800625), FR 2459795 (810116), EP 372776 (900613), FR 2678270 (921231), FR 2675801 (921030), EP 580398 (940126), WO 9401403 (940120) as well as the recent publication of Shanklin JR and collaborators (J. Med. Chem. 34, 301 1, 1991)
De même, les pyrrolidines de formule (II) dans laquelle X-Y=CH2 sont préparées par diverses méthodes et techniques décrites dans la littérature comme par exemple dans J. Chem. Soc. Chem. Commun. 2, 142 (1989); Tetrahedron 47, 5161 (1991) ; Synthesis H, 1023 (1991); Izobretaniya 37, 89 (1992) et Tetrahedron Lett. 35, 973 (1994). 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, 1981 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.Likewise, the pyrrolidines of formula (II) in which XY = CH 2 are prepared by various methods and techniques described in the literature, for example in J. Chem. Soc. Chem. Common. 2, 142 (1989); Tetrahedron 47, 5161 (1991); Synthesis H, 1023 (1991); Izobretaniya 37, 89 (1992) and Tetrahedron Lett. 35, 973 (1994). 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, 1981 and "Protecting Groups", PJ Kocienski, Thieme Verlag , 1994. The appropriate protecting groups will therefore be introduced and removed during the most appropriate step for this and using the methods and techniques described in the references cited above.
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. 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 préparative.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. 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 (+)-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 RI 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 the acid (-) - di-p-toluoyl-l-tartaric, acid (+) - di-p-toluoyl-l-tartaric, acid (+) - camphorsulfonic, acid (-) - camphorsulfonic, l (+) - phenylpropionic acid, (-) - phenylpropionic acid, followed by fractional crystallization and regeneration of the free base. The compounds of formula (I) in which RI 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. SucThe following examples illustrate the invention without, however, limiting its scope. Juice
EXEMPLE 1EXAMPLE 1
Le fumarate de la l-[4-(2,3-diméthyI-phényl)-piperazin-l-yIJ-4-[2-(4-méthyl- pipérazin-l-yl)-phenoxy]-butan-I-one (1)1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yIJ-4- [2- (4-methyl-piperazin-1-yl) -phenoxy] -butan-I-one fumarate (1)
Figure imgf000022_0001
Figure imgf000022_0001
Le 2-(4-méthyl-pipérazin-l-yl)-phénol (A) est préparé selon la procédure décrite dans le brevet français n°9408981.2- (4-methyl-piperazin-1-yl) -phenol (A) is prepared according to the procedure described in French patent No. 9408981.
IA : Le 4-chloro-l-[4-(2,3-diméthyl-phényl)-pipérazin-l-yll-butan-l-oneIA: 4-chloro-1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yll-butan-1-one
L'hydrochlorure de la 2,3-xylylpipérazine (B) (2 g; 8.8 mmol) est dissous dans le dichlorométhane (20 ml) en présence de triéthylamine (3 ml; 22 mmol) sous atmosphère d'azote. La solution est refroidie à 0°C puis le chlorure de 4-chIorobutanoyle (1.2 ml; 1 1 mmol) est ajouté. La réaction est immédiate. La solution est diluée dans du dichlorométhane lavée avec une solution demi-saturée en bicarbonate de sodium et séchée sur sulfate de magnésium. Le dérivé LA est purifié par chromatographie-éclair avec un mélange 25-75 (EtOAc-EDP).The 2,3-xylylpiperazine hydrochloride (B) (2 g; 8.8 mmol) is dissolved in dichloromethane (20 ml) in the presence of triethylamine (3 ml; 22 mmol) under a nitrogen atmosphere. The solution is cooled to 0 ° C. and then 4-chlorobutanoyl chloride (1.2 ml; 11 mmol) is added. The reaction is immediate. The solution is diluted in dichloromethane washed with a semi-saturated sodium bicarbonate solution and dried over magnesium sulfate. The LA derivative is purified by flash chromatography with a 25-75 mixture (EtOAc-EDP).
Masse obtenue: 2.22 g (76 %)Mass obtained: 2.22 g (76%)
1H-RMN (200 MHz ; dmso-d6) δ : 7.05 (t, IH, 7.6Hz) ; 6.95-6.80 (m, 2H) ; 3.70 (t, 2H, 6.5Hz) ; 3.60 (brs, 4H) ; 2.78 (brs, 4H) ; 2.51 (t, 2H, 6.5Hz) ; 2.22 (s, 3H) ; 2.19 (s, 3H) ; 1.98 (p, 2H, 6.5Hz).1H-NMR (200 MHz; dmso-d 6 ) δ: 7.05 (t, IH, 7.6Hz); 6.95-6.80 (m, 2H); 3.70 (t, 2H, 6.5Hz); 3.60 (brs, 4H); 2.78 (brs, 4H); 2.51 (t, 2H, 6.5Hz); 2.22 (s, 3H); 2.19 (s, 3H); 1.98 (p, 2H, 6.5Hz).
l: Le dérivé A (1 g; 5.2 mmol) est dissous dans du diméthylformamide (35 ml) en présence du dérivé IA (1.5 g ; 5.2 mmol) et de carbonate de césium (3.3 g ; 10 mmol) sous atmosphère d'azote. La suspension est agitée 1 jour à température ambiante puis chauffée 1 jour à 63°C Du dérivé LA (0 5 g ; 1 5 mmol) et du carbonate de césium (3 3 g ; 10 mmol) sont ajoutés, puis, la suspension est chauffée à 80°C pendant 3 jours La réaction n'évolue plus. Le solvant est évaporé, le résidu huileux est dissous dans de l'acétate d'ethyle, lavé deux fois avec de l'eau et séché sur sulfate de magnésium Le dérivé i est purifié sous forme de base libre par chromatographie-éclair avec un gradient de NH4OH-MeOH-CH2Cl2 (0 5-2 à 5- 98 à 95)l: Derivative A (1 g; 5.2 mmol) is dissolved in dimethylformamide (35 ml) in the presence of derivative IA (1.5 g; 5.2 mmol) and cesium carbonate (3.3 g; 10 mmol) under a nitrogen atmosphere . The suspension is stirred for 1 day at room temperature then heated 1 day to 63 ° C LA derivative (0 5 g; 1 5 mmol) and cesium carbonate (3 3 g; 10 mmol) are added, then the suspension is heated to 80 ° C for 3 days The reaction no longer evolves. The solvent is evaporated off, the oily residue is dissolved in ethyl acetate, washed twice with water and dried over magnesium sulfate The derivative i is purified in the form of the free base by flash chromatography with a gradient NH 4 OH-MeOH-CH 2 Cl 2 (0 5-2 to 5- 98 to 95)
Masse obtenue : 1 5 g (64 %)Mass obtained: 1 5 g (64%)
iH-RMN (200 MHz, dmso-d6) δ . (t, IH, 7.6Hz) , 6 95-6 75 (m, 6H) , 3 98 (t, 2H, 6Hz) , 3 6 (brs, 4H) , 2 96 (brs, 4H) , 2.72 (brs, 4H) , 2 57 (t, 2H, 6Hz) , 2 45 (brs, 4H) , 2 20 (s, 6H) , 1 17 (s, 3H) , 1 98 (p, 2H, 6Hz)iH-NMR (200 MHz, dmso-d 6 ) δ. (t, IH, 7.6Hz), 6 95-6 75 (m, 6H), 3 98 (t, 2H, 6Hz), 3 6 (brs, 4H), 2 96 (brs, 4H), 2.72 (brs, 4H), 2 57 (t, 2H, 6Hz), 2 45 (brs, 4H), 2 20 (s, 6H), 1 17 (s, 3H), 1 98 (p, 2H, 6Hz)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondantThis compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate
JH-RMN (200 MHz, dmso-dό) δ : 7.15-6.75 (m, 7H) , 6 60 (s, fumarate) ; 4 01 (t, 2H, 6Hz) ; 3.62 (brs, 4H) ; 3 04 (brs, 4H) ; 2.70 (brs, 8H) , 2 58 (t, 2H, 7 4Hz) , 2 37 (s, 3H) ; 2.22 (s, 3H) ; 2 19 (s, 3H) , 2.0 (p, 2H, 6 6Hz)JH-NMR (200 MHz, dmso-dό) δ: 7.15-6.75 (m, 7H), 660 (s, fumarate); 401 (t, 2H, 6Hz); 3.62 (brs, 4H); 304 (brs, 4H); 2.70 (brs, 8H), 258 (t, 2H, 7 4Hz), 237 (s, 3H); 2.22 (s, 3H); 2 19 (s, 3H), 2.0 (p, 2H, 6 6Hz)
IR (KBr) : 3426, 2947, 1709, 1637, 1583, 1502, 1472, 1434, 1246IR (KBr): 3426, 2947, 1709, 1637, 1583, 1502, 1472, 1434, 1246
Analyse élémentaire C27H3gN4θ2 , 1.15 C4H4O4 , 0 5 H20 Calculée . C = 63 99 , H = 7 41 , N = 9 45 ; H2O ≈ 1 52 Irouyée : C = 63.95 ; H = 7.35 ; N = 9.39 ; H2O = 1.40Elementary analysis C 2 7H3gN4θ 2 , 1.15 C4H4O4, 0 5 H 2 0 Calculated. C = 63 99, H = 7 41, N = 9 45; H 2 O ≈ 1 52 Irouyée: C = 63.95; H = 7.35; N = 9.39; H 2 O = 1.40
Masse (DCI, NH3)- 451 (MH+)Mass (DCI, NH 3 ) - 451 (MH +)
Rf : 0.4 (90-10-1 = CH2CI2-MeOH-NH4OH) IIRf: 0.4 (90-10-1 = CH 2 CI 2 -MeOH-NH 4 OH) II
EXEMPLE 2EXAMPLE 2
Le fumarate de la l-[4-(2,3-diméthyl-phényl)-pipérazin-l-yI]-5-[2-(4-méthyl- pipérazin-l-yl)-phénoxyl]-pentaιι-l-one (2)1- [4- (2,3-Dimethyl-phenyl) -piperazin-1-yI] -5- [2- (4-methyl- piperazin-1-yl) -phenoxyl] -pentaιι-l- fumarate one (2)
Figure imgf000024_0001
Figure imgf000024_0001
2A : La 5-bromo-l-[4-(2,3-diméthyI-phényl)-pipérazin-l-yl]-pentan-l-one2A: 5-bromo-1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] -pentan-1-one
Le dérivé 2A est préparé selon la même procédure décrite pour LA à partir des réactifs suivants: B (5 g ; 22 mmol) ; chlorure de 5-bromopentanoyle (3,6 ml ; 27 mmol) ; triéthylamine (7,6 ml ; 54 mmol) dans le dichlorométhane (50 ml).The derivative 2A is prepared according to the same procedure described for LA from the following reagents: B (5 g; 22 mmol); 5-bromopentanoyl chloride (3.6 ml; 27 mmol); triethylamine (7.6 ml; 54 mmol) in dichloromethane (50 ml).
Masse obtenue: 6,75 g (77 %)Mass obtained: 6.75 g (77%)
JH-RMN (200 MHz, dmso-d6) δ : 7.02 (t, IH, 6Hz) , 6.95-6.80 (m, 2H) ; 3.7-3.45 (m, 6H) ; 2.72 (brs, 4H) ; 2.36 (t, 2H, 7.4Hz) ; 2.19 (s, 3H) , 2.16 (s, 3H) ; 1.82 (p, 2H, 7.2Hz) ; 1.60 (p, 2H, 7.2Hz)JH-NMR (200 MHz, dmso-d 6 ) δ: 7.02 (t, 1H, 6Hz), 6.95-6.80 (m, 2H); 3.7-3.45 (m, 6H); 2.72 (brs, 4H); 2.36 (t, 2H, 7.4Hz); 2.19 (s, 3H), 2.16 (s, 3H); 1.82 (p, 2H, 7.2Hz); 1.60 (p, 2H, 7.2Hz)
2 : Le dérivé A (684 mg ; 3.5 mmol) est dissous dans le DMF ( 16 ml) en présence de 2A (1.25 g ; 3.5 mmol) et de carbonate de césium (1. 1 g ; 3.5 mmol) sous atmosphère d'azote. Le mélange est agité 24 heures à température ambiante, puis dilué dans de l'acétate d'ethyle, lavé deux fois avec de l'eau, séché sur sulfate de magnésium et concentré. Le dérivé 2 est isolé sous forme de base libre après purification par chromatographie-éclair avec un mélange d'éluants (1-6-94 = NH4θH-MeOH-CH2Cl2).2: Derivative A (684 mg; 3.5 mmol) is dissolved in DMF (16 ml) in the presence of 2A (1.25 g; 3.5 mmol) and cesium carbonate (1.1 g; 3.5 mmol) under an atmosphere of nitrogen. The mixture is stirred for 24 hours at room temperature, then diluted in ethyl acetate, washed twice with water, dried over magnesium sulfate and concentrated. Derivative 2 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-6-94 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 1.19 g (72 %)Mass obtained: 1.19 g (72%)
iH-RMN (200 MHz, dmso-d6) δ : 7.2-6.7 (m, 7H) ; 3.97 (m, 2H) ; 3.61 (brs, 4H) ; 2.97 (brs, 4H) ; 2.74 (brs, 4H) ; 2.45 (brs, 6H) ; 2.21 (s, 3H) , 2.20 (s, 3H) ; 2.19 (s, 3H) ; 1.76 (brs, 4H). Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.iH-NMR (200 MHz, dmso-d 6 ) δ: 7.2-6.7 (m, 7H); 3.97 (m, 2H); 3.61 (brs, 4H); 2.97 (brs, 4H); 2.74 (brs, 4H); 2.45 (brs, 6H); 2.21 (s, 3H), 2.20 (s, 3H); 2.19 (s, 3H); 1.76 (brs, 4H). This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
]H-RMN (200 MHz, dmso-d6) δ : 7.15-6.7 (m, 7H) ; 6.55 (s, fumarate) ; 3.96 (brs, 2H) s ; 3.59 (brs, 4H) ; 3.01 (brs, 4H) ; 2.85-2.55 (m, 8H) ; 2.55-2.3 (m, 5H) ; 2.19 (s, 3H) ; 2.16 (s, 3H) ; 1.73 (brs, 4H). ] H-NMR (200 MHz, dmso-d 6 ) δ: 7.15-6.7 (m, 7H); 6.55 (s, fumarate); 3.96 (brs, 2H) s; 3.59 (brs, 4H); 3.01 (brs, 4H); 2.85-2.55 (m, 8H); 2.55-2.3 (m, 5H); 2.19 (s, 3H); 2.16 (s, 3H); 1.73 (brs, 4H).
Analyse élémentaire: C28H4QN4O2 ; C4H4O4 ; 0.4 H20 Calculée: C = 65.37 ; H = 7.68 ; N = 9.53 0 Trouvée: C = 65.44 ; H = 7.63 ; N ≈ 9.47Elemental analysis: C 2 8H4QN4O 2 ; C4H4O4; 0.4 H 2 0 Calculated: C = 65.37; H = 7.68; N = 9.53 0 Found: C = 65.44; H = 7.63; N ≈ 9.47
IR (KBr): 2953 ; 1676 ; 1643 ; 1577 ; 1500IR (KBr): 2953; 1676; 1643; 1577; 1500
Masse (DCI, NH3) : 465 (MH+) 5Mass (DCI, NH3): 465 (MH + ) 5
Rf: 0.45 (1-10-90 = NH4θH-MeOH-CH2Cl2)Rf: 0.45 (1-10-90 = NH4θH-MeOH-CH 2 Cl 2 )
EXEMPLE 3EXAMPLE 3
Le fumarate de ia l-[4-(2,3-diméthyI-phéπyl)-pipérazin-l-yl]-6-[2-(4-méthγl- pipérazin-l-yl)-phénoxy|-hexan-l-one (3)Ia l- [4- (2,3-dimethyl-pheπyl) -piperazin-l-yl] -6- [2- (4-methγl- piperazin-l-yl) -phenoxy | -hexan-l- fumarate one (3)
Figure imgf000025_0001
<l r\
Figure imgf000025_0001
<lr \
3A : La 6-bromo-l-[4-(2,3-diméthyl-phényl)-pipérazin-l-yl)-hexan-l-one3A: 6-bromo-1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yl) -hexan-1-one
Le dérivé 3A est préparé selon la même méthode décrite pour _LA à partir des réactifs suivants: B (5 g; 25 mmol) ; chlorure de 1-bromo-hexanoyle (4. 1 ml ; 27 mmol) ; triéthylamine (7.6 ml; 54 mmol) dans le dichlorométhane (50 ml).The derivative 3A is prepared according to the same method described for _LA from the following reagents: B (5 g; 25 mmol); 1-bromo-hexanoyl chloride (4.1 ml; 27 mmol); triethylamine (7.6 ml; 54 mmol) in dichloromethane (50 ml).
Masse obtenue: 7.1 g (78 %)Mass obtained: 7.1 g (78%)
JH-RMN (200 MHz, dmso-d6) δ : 7.03 (t, IH, 7.6Hz) ; 6.95-6.80 (m, 2H) ; 3.7-3.5 (m, 6H) ; 2.73 (brs, 4H) ; 2.34 (t, 2H, 6.8Hz) ; 2.20 (s, 3H) ; 2.17 (s, 3H) ; 1.81 (p, 2H, 7.0Hz) ; 1.65-1.3 (m, 4H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.03 (t, IH, 7.6Hz); 6.95-6.80 (m, 2H); 3.7-3.5 (m, 6H); 2.73 (brs, 4H); 2.34 (t, 2H, 6.8Hz); 2.20 (s, 3H); 2.17 (s, 3H); 1.81 (p, 2H, 7.0Hz); 1.65-1.3 (m, 4H).
3 : Le dérivé 3 est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants: A (700 mg ; 3.6 mmol) ; 3A (1.13 g ; 3.1 mmol) ; carbonate de césium (2 g ; 6 mmol) dans le DMF (16 ml).3: The derivative 3 is prepared according to the same method described for 2 from the following reagents: A (700 mg; 3.6 mmol); 3A (1.13 g; 3.1 mmol); cesium carbonate (2 g; 6 mmol) in DMF (16 ml).
Masse obtenue: 965 mg (65 %)Mass obtained: 965 mg (65%)
^-RMN (200 MHz, dmso-d6) δ : 7.00 (t, IH, 7.6Hz) ; 6.90-6.70 (m, 6H) ; 3.91 (t, 2H, 6Hz) ; 3.56 (brs, 4H) ; 2.93 (brs, 4H) ; 2.70 (brs, 4H) ; 2.55-2.30 (m, 6H) ; 2.17 (s, 6H) ; 2.15 (s, 3H); 1.85-1.40 (m, 6H).^ -RMN (200 MHz, dmso-d 6 ) δ: 7.00 (t, IH, 7.6Hz); 6.90-6.70 (m, 6H); 3.91 (t, 2H, 6Hz); 3.56 (brs, 4H); 2.93 (brs, 4H); 2.70 (brs, 4H); 2.55-2.30 (m, 6H); 2.17 (s, 6H); 2.15 (s, 3H); 1.85-1.40 (m, 6H).
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
^-RMN (200 MHz, dmso-d6) δ : 7.15-6.8 (m, 7H) ; 6.60 (s, fumarate) ; 3.96 (t, 2H, 6Hz) ; 3.61 (brs, 4H) ; 3.05 (brs, 4H) ; 2.73 (brs, 8H) ; 2.39 (brs, 5H) ; 2.22 (s, 3H) ; 2.19 (s, 3H) ; 1.9-1.4 (m, 6H)^ -RMN (200 MHz, dmso-d 6 ) δ: 7.15-6.8 (m, 7H); 6.60 (s, fumarate); 3.96 (t, 2H, 6Hz); 3.61 (brs, 4H); 3.05 (brs, 4H); 2.73 (brs, 8H); 2.39 (brs, 5H); 2.22 (s, 3H); 2.19 (s, 3H); 1.9-1.4 (m, 6H)
Analyse élémentaire: C2<)H42N4θ2 ; 1.25 C4H4O4 ; 0.5 H2O Calculée: C = 64.54 : H = 7.65 ; N = 8.85 : H?O = 1.42 Trouvée: C = 64.54 ; H = 7.70 ; N = 8.92 ; H2O = 1.51Elementary analysis: C 2 <) H4 2 N4θ 2 ; 1.25 C4H4O4; 0.5 H 2 O Calculated: C = 64.54: H = 7.65; N = 8.85: H ? O = 1.42 Found: C = 64.54; H = 7.70; N = 8.92; H 2 O = 1.51
IR (KBr): 3431 ; 2943 ; 1709 ; 1637 ; 1502 ; 1473 , 1434 ; 1246IR (KBr): 3431; 2943; 1709; 1637; 1502; 1473, 1434; 1246
Masse (DCI, NH3) : 479 (MH+) 2, SMass (DCI, NH 3 ): 479 (MH + ) 2 , S
Rf: 0.6 (1-10-90 = NH4OH-MeOH-CH2Cl2)Rf: 0.6 (1-10-90 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 4EXAMPLE 4
Le fumarate de la 5-[2-(4-méthyl-pipérazin-l-yl)-phénoxy)-l-(4-phénéthyl- pipérazin-l-yl)-pentan-l-one (4)5- [2- (4-methyl-piperazin-1-yl) -phenoxy) -l- (4-phenethyl- piperazin-1-yl) -pentan-1-one fumarate (4)
Figure imgf000027_0001
Figure imgf000027_0001
4A : Le 5-bromo-l-[4-phénéthyl-pipérazin-l-yI)-pentan-l-one4A: 5-bromo-1- [4-phenethyl-piperazin-1-yI) -pentan-1-one
Le dérivé 4A est préparé selon la même procédure que LA à partir des réactifs suivants : N-phénéthyl-pipérazine (2 g ; 10.5 mmol) ; chlorure de 5-bromo-pentanoyle (1.7 ml ; 12.6 mmol) ; triéthylamine (2.2 ml ; 15.7 mmol) dans le dichlorométhane (21 ml).The derivative 4A is prepared according to the same procedure as LA from the following reagents: N-phenethyl-piperazine (2 g; 10.5 mmol); 5-bromo-pentanoyl chloride (1.7 ml; 12.6 mmol); triethylamine (2.2 ml; 15.7 mmol) in dichloromethane (21 ml).
Masse obtenue: 3.61 (97 %)Mass obtained: 3.61 (97%)
1H-RMN (200 MHz, dmso-dό) δ : 7.35-7.10 (m, 5H) ; 3.55 (t, 2H, 6.4Hz) ; 3.44 (brs, 4H) ; 2.9-2.2 (m, 10H) ; 1.82 (p, 2H, 6.8Hz) ; 1.59 (p, 2H, 6.8Hz).1H-NMR (200 MHz, dmso-dό) δ: 7.35-7.10 (m, 5H); 3.55 (t, 2H, 6.4Hz); 3.44 (brs, 4H); 2.9-2.2 (m, 10H); 1.82 (p, 2H, 6.8Hz); 1.59 (p, 2H, 6.8Hz).
4 : Le dérivé 4 est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants: 4A (3.58 g ; 10 mmol) ; A (1.94 g ; 10 mmol) ; carbonate de césium (6.6 g ; 20 mmol) dans le DMF (60 ml).4: The derivative 4 is prepared according to the same method described for 2 from the following reagents: 4A (3.58 g; 10 mmol); A (1.94 g; 10 mmol); cesium carbonate (6.6 g; 20 mmol) in DMF (60 ml).
Masse obtenue : 2.66 g (56 %) lbMass obtained: 2.66 g (56%) lb
}H-RMN (200 MHz, dmso-dό) δ : 7.35-7.10 (m, 5H) ; 7.0-6.8 (m, 4H) ; 3.96 (t, 2H, 5.5Hz) ; 3.44 (brs, 4H) ; 2.96 (brs, 4H) ; 2.8-2.65 (m, 2H) ; 2.6-2.3 (m, 12H) ; 2.21 (s, 3H) ; 1.9-1.6 (m, 4H). } H-NMR (200 MHz, dmso-dό) δ: 7.35-7.10 (m, 5H); 7.0-6.8 (m, 4H); 3.96 (t, 2H, 5.5Hz); 3.44 (brs, 4H); 2.96 (brs, 4H); 2.8-2.65 (m, 2H); 2.6-2.3 (m, 12H); 2.21 (s, 3H); 1.9-1.6 (m, 4H).
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 5H), 7 05-6.8 (m, 4H); 6.59 (s, fumarate); 3.98 (bit, 2H); 3.46 (brs, 4H); 3.04 (brs, 4H), 2 S5-2.2 (m, 17H); 1.73 (brs,JH-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 5H), 7 05-6.8 (m, 4H); 6.59 (s, fumarate); 3.98 (bit, 2H); 3.46 (brs, 4H); 3.04 (brs, 4H), 2 S5-2.2 (m, 17H); 1.73 (brs,
4H).4H).
Analyse élémentaire: C2gH4()N4θ2 ; 2.2 C4H4O4 ; 1. 1 5 H20 Calculée: C = 59.67 ; H = 6.95 ; N = 7.56 ; H2O = 2 80 Trouvée: C = 59.77 ; H = 6.89 ; N = 7.29 ; H20 = 2.80Elemental analysis: C 2 gH4 () N4θ 2 ; 2.2 C4H4O4; 1. 1 5 H 2 0 Calculated: C = 59.67; H = 6.95; N = 7.56; H 2 O = 2 80 Found: C = 59.77; H = 6.89; N = 7.29; H 2 0 = 2.80
IR flCBr): 3300, 3031, 2958, 1709, 1654, 1246.IR flCBr): 3300, 3031, 2958, 1709, 1654, 1246.
Rf: 0.4 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.4 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 5EXAMPLE 5
Le fumarate de la 5-[4-chloro-2-(4-méthyl-pipérazin-l-yl)-phénoxy]-l-[4-(2,3- diméthyI-phényl)-pipérazin-l-ylJ-pentan-l-one (5)5- [4-Chloro-2- (4-methyl-piperazin-1-yl) -phenoxy] -l- [4- (2,3-dimethyl-phenyl) -piperazin-1-ylJ-pentan fumarate -l-one (5)
Figure imgf000028_0001
Figure imgf000028_0001
Le 4-chloro-2-(4-méthyl-pipérazin-l-yl)-phénol (ÇJ est préparé selon la procédure décrite dans le brevet français n°9408981. Le dérivé 5 est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants : Ç (1 g ; 4.4 mmol) ; 2A (1.5 g ; 4.4 mmol) ; carbonate de césium (1.4 g ; 4.4 mmol) dans le DMF (30 ml).4-Chloro-2- (4-methyl-piperazin-1-yl) -phenol (CJ is prepared according to the procedure described in French patent No. 9408981. Derivative 5 is prepared according to the same method described for 2 from the following reagents: Ç (1 g; 4.4 mmol); 2A (1.5 g; 4.4 mmol); cesium carbonate (1.4 g; 4.4 mmol) in DMF (30 ml).
Masse obtenue: 1.6 g (73 %)Mass obtained: 1.6 g (73%)
1H-RMN (200 MHz, dmso-d6) δ : 7.01 (t, IH, 7.6Hz) ; 6.95-6.75 (m, 5H) ; 3.94 (brs, 2H) ; 3.57 (brs, 4H) ; 2.94 (brs, 4H); 2.71 (brs, 4H) ; 2.40 (brs, 6H) ; 2.18 (s, 3H) ; 2.17 (s, 3H) ; 2.15 (s, 3H) ; 1.72 (brs, 4H).1H-NMR (200 MHz, dmso-d 6 ) δ: 7.01 (t, IH, 7.6Hz); 6.95-6.75 (m, 5H); 3.94 (brs, 2H); 3.57 (brs, 4H); 2.94 (brs, 4H); 2.71 (brs, 4H); 2.40 (brs, 6H); 2.18 (s, 3H); 2.17 (s, 3H); 2.15 (s, 3H); 1.72 (brs, 4H).
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
!H-RMN (200 MHz, dmso-d6) δ : 7 .15-6.8 (m, 6H) ; 6.58 (s, fumarate) ; 3.97 (brs, 2H) ; 3.59 (brs, 4H) ; 3.02 (brs, 4H) ; 2.74 (brs, 4H) ; 2.58 (brs, 4H) ; 2.46 (bit, 2H) ; 2.30 (s, 3H) ; 2.21 (s, 3H) ; 2.17 (s, 3H) ; 1.74 (brs, 4H).! H-NMR (200 MHz, dmso-d 6 ) δ: 7.15-6.8 (m, 6H); 6.58 (s, fumarate); 3.97 (brs, 2H); 3.59 (brs, 4H); 3.02 (brs, 4H); 2.74 (brs, 4H); 2.58 (brs, 4H); 2.46 (bit, 2H); 2.30 (s, 3H); 2.21 (s, 3H); 2.17 (s, 3H); 1.74 (brs, 4H).
Analyse élémentaire: C2gH3oClN4θ2 ; C4H4O4 Calculée: C = 62.48 ; H = 7.05 ; N = 9.1 1 Trouvée: C = 62.60 ; H = 7.41 ; N = 9.34Elemental analysis: C 2 gH3oClN4θ 2 ; C4H4O4 Calculated: C = 62.48; H = 7.05; N = 9.1 1 Found: C = 62.60; H = 7.41; N = 9.34
DKKBr): 2945, 1631, 1591, 1498, 1473, 1452DKKBr): 2945, 1631, 1591, 1498, 1473, 1452
Masse (DCI, NH3) : 499 (100%, MH+, 35C1) ; 500 (31%) ; 501 (35%) ; 502 (1 1%)Mass (DCI, NH 3 ): 499 (100%, MH +, 35 C1); 500 (31%); 501 (35%); 502 (1 1%)
Rf: 0.6 (1-10-90 = NH4OH-MeOH-CH2Cl2) 2,iRf: 0.6 (1-10-90 = NH 4 OH-MeOH-CH 2 Cl 2 ) 2, i
EXEMPLE 6EXAMPLE 6
Le fumarate de la 5-[2-(4-méthyl-pipérazm-l-yl)-phénoxy]-l-(4-phényl-pipéridin- l-yl)-pentan-l-one (6)5- [2- (4-methyl-piperazm-1-yl) -phenoxy] -l- (4-phenyl-piperidin-1-yl) -pentan-1-one fumarate (6)
Figure imgf000030_0001
Figure imgf000030_0001
6A : Le 5-bromo-l-(4-phényI-pipéridin-l-yI)-pentan-l-one6A: 5-bromo-l- (4-phenyI-piperidin-l-yI) -pentan-l-one
Le dérivé 6A est préparé selon la même méthode décrite pour LA à partir des réactifs suivants: 4-phénylpipéridine (1 g ; 6.2 mmol) ; chlorure de 5-bromo-pentanoyle (913 μl ; 6.8 mmol) ; triéthylamine (950 μl ; 6.8 mmol) dans le dichlorométhane (12 ml).The derivative 6A is prepared according to the same method described for LA from the following reagents: 4-phenylpiperidine (1 g; 6.2 mmol); 5-bromo-pentanoyl chloride (913 μl; 6.8 mmol); triethylamine (950 μl; 6.8 mmol) in dichloromethane (12 ml).
Masse obtenue: 2.0 g (99 %)Mass obtained: 2.0 g (99%)
!H-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 5H) ; 4.52 (brd, IH, 12.7Hz) ; 3.95 (brd, IH, 13.3Hz) ; 3.54 (t, 2H, 6.5Hz) ; 3.05 (brt, IH, 12.5Hz) ; 2.74 (tt, IH, 12Hz et 3.6Hz) ; 2.55 (brd, IH, 12.7Hz) ; 2.36 (t, 2H, 7.4Hz) ; 2.0-1.3 (m, 8H).! H-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 5H); 4.52 (brd, 1H, 12.7Hz); 3.95 (brd, 1H, 13.3Hz); 3.54 (t, 2H, 6.5Hz); 3.05 (brt, 1H, 12.5Hz); 2.74 (tt, 1H, 12Hz and 3.6Hz); 2.55 (brd, 1H, 12.7Hz); 2.36 (t, 2H, 7.4Hz); 2.0-1.3 (m, 8H).
6_: Le dérivé 6 est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants: A (500 mg ; 2.6 mmol) ; 6A (1.44 g ; 4.4 mmol) ; carbonate de césium (1.7 g ; 5.2 mmol) dans le DMF (10 ml).6_: The derivative 6 is prepared according to the same method described for 2 from the following reagents: A (500 mg; 2.6 mmol); 6A (1.44 g; 4.4 mmol); cesium carbonate (1.7 g; 5.2 mmol) in DMF (10 ml).
Masse obtenue: 737 mg (65 %)Mass obtained: 737 mg (65%)
^-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 5H) ; 7.0-6.75 (m, 4H) ; 4.55 (brd, IH, 13Hz); 4.1-3.85 (m, 3H) ; 3.33 (brs, IH) ; 3.2-2.85 (m, 5H) ; 2.75 (brt, IH, 12.5 et 3Hz); 2.65-2.35 (m, 6H) ; 2.25 (s, 3H) ; 1.9-1.3 (m, 8H).^ -RMN (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 5H); 7.0-6.75 (m, 4H); 4.55 (brd, 1H, 13Hz); 4.1-3.85 (m, 3H); 3.33 (brs, 1H); 3.2-2.85 (m, 5H); 2.75 (brt, IH, 12.5 and 3Hz); 2.65-2.35 (m, 6H); 2.25 (s, 3H); 1.9-1.3 (m, 8H).
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. 1H-RMN (200 MHz, dmso-dό) δ : 7.4-7.1 (m, 5H) , 7.0-6.8 (m, 4H) ; 5.59 (s, fumarate); 4.65-4.45 (m, IH) ; 4.1-3.9 (m, 3H) ; 3.2-2 95 (m, 5H) ; 2.9-2.55 (m, 6H) ; 2.55-2.3 (m, 5H) ; 2.0-1.4 (m, 8H).This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. 1H-NMR (200 MHz, dmso-dό) δ: 7.4-7.1 (m, 5H), 7.0-6.8 (m, 4H); 5.59 (s, fumarate); 4.65-4.45 (m, 1H); 4.1-3.9 (m, 3H); 3.2-2 95 (m, 5H); 2.9-2.55 (m, 6H); 2.55-2.3 (m, 5H); 2.0-1.4 (m, 8H).
Analyse élémentaire: C27H37N3θ2 ; C4H4O4Elementary analysis: C 2 7H37N3θ 2 ; C4H4O4
Calculée: C = 63.55 ; H ≈ 7.30 ; N = 6.82; H2O = 2 92 Trouvée: C = 63.64 ; H = 7.16 ; N = 6.98; H2O = 2 9Calculated: C = 63.55; H ≈ 7.30; N = 6.82; H 2 O = 2 92 Found: C = 63.64; H = 7.16; N = 6.98; H 2 O = 2 9
IR fKBr): 3440, 2940, 1722, 1617, 1459, 1255IR fKBr): 3440, 2940, 1722, 1617, 1459, 1255
Rf: 0.3 (0.5-5-95 = NH4OH-MeOH-CH2Cl2) Rf: 0.3 (0.5-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
,0.0
EXEMPLE 7EXAMPLE 7
Le fumarate de la l-[4-(2,3-diméthyl-phényl)-pipérazin -l-ylJ-5-[2-4-méthyl- pipérazin-l-yl)-phénylamino]-pentan-l-one (7)1- [4- (2,3-Dimethyl-phenyl) -piperazin -l-ylJ-5- [2-4-methyl-piperazin-1-yl) -phenylamino] -pentan-1-fumarate ( 7)
Figure imgf000032_0001
Figure imgf000032_0001
7A : Le 2-(4-méthyl-pipérazin-l-yl)-nitrobenzène7A: 2- (4-methyl-piperazin-1-yl) -nitrobenzene
La l-fluoro-2-nitrobenzène (3.95 g ; 28 mmol) est chauffé à 80°C sous atmosphère d'azote dans le DMF (7 ml) en présence de N-méthyl-pipérazine (3.1 ml ; 28 mmol) et de carbonate de potassium (3.9 g ; 28 mmol) pendant un jour. Le solvant est ensuite évaporé et le résidu huileux dilué dans de l'acétate d'ethyle Cette solution est lavée deux fois avec de l'eau et une fois avec une solution saturée en chlorure d'ammonium puis séchée sur sulfate de magnésium et concentrée Le dérivé 7A est purifié par chromatographie-éclaire avec un mélange d'éluants (5-95 = MeOH-CH2Cl2).1-Fluoro-2-nitrobenzene (3.95 g; 28 mmol) is heated to 80 ° C under a nitrogen atmosphere in DMF (7 ml) in the presence of N-methyl-piperazine (3.1 ml; 28 mmol) and potassium carbonate (3.9 g; 28 mmol) for one day. The solvent is then evaporated and the oily residue diluted in ethyl acetate. This solution is washed twice with water and once with a saturated solution of ammonium chloride then dried over magnesium sulphate and concentrated. derivative 7A is purified by flash chromatography with a mixture of eluents (5-95 = MeOH-CH 2 Cl 2 ).
Masse obtenue: 5.8 g (93 %)Mass obtained: 5.8 g (93%)
}H-RMN (200 MHz, dmso-d6) δ : 7.77 (dd, IH, 8 et l .5Hz) ; 7.55 (td, IH, 8 et 1.5Hz) ; 7.28 (brd, IH, 8Hz) ; 7.10 (brt, IH, 8Hz) ; 2.96 (brs, 4H) ; 2.40 (brs, 4H) ; 2.19 (s, 3H). } H-NMR (200 MHz, dmso-d 6 ) δ: 7.77 (dd, IH, 8 and 1.5 Hz); 7.55 (td, 1H, 8 and 1.5Hz); 7.28 (brd, 1H, 8Hz); 7.10 (brt, 1H, 8Hz); 2.96 (brs, 4H); 2.40 (brs, 4H); 2.19 (s, 3H).
7B : La 2-(4-méthyl-pipérazin-l-yl)-aniline7B: 2- (4-methyl-piperazin-1-yl) -aniline
Le dérivé TA (5.77 g ; 26 mmol) est dissous dans l'ethanol (92 ml) sous atmosphère d'azote en présence d'une quantité catalytique de Nickel de Raney. L'hydrazine hydratée (7 ml) est ajoutée goutte à goutte. La réaction est exothermique. Le mélange réactionnel est agité quelques heures puis filtré. Le solvant est évaporé et le dérivé 7B est purifié par chromatographie-éclair avec un mélange d'éluants ( 1-5-95 = NH4θH-MeOH-CH2CI2). Masse obtenue: 3.99 g (79 %)The TA derivative (5.77 g; 26 mmol) is dissolved in ethanol (92 ml) under a nitrogen atmosphere in the presence of a catalytic amount of Raney Nickel. Hydrated hydrazine (7 ml) is added dropwise. The reaction is exothermic. The reaction mixture is stirred for a few hours and then filtered. The solvent is evaporated and the derivative 7B is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 CI 2 ). Mass obtained: 3.99 g (79%)
iH-RMN (200 MHz, dmso-d6) δ : 6.84 (td, IH, 7.5 et 1Hz) ; 6.75 (dd, IH, 7.5 et 1Hz) ; 6.63 (dd, IH, 7.5 et 1Hz) ; 6.50 (td, IH, 7.5 et 1Hz) ; 4.65 (brs, 2H) , 2.76 (brs, 4H) ; 2.45 (brs, 4H); 2.20 (s, 3H).iH-NMR (200 MHz, dmso-d 6 ) δ: 6.84 (td, IH, 7.5 and 1Hz); 6.75 (dd, IH, 7.5 and 1Hz); 6.63 (dd, 1H, 7.5 and 1Hz); 6.50 (td, 1H, 7.5 and 1Hz); 4.65 (brs, 2H), 2.76 (brs, 4H); 2.45 (brs, 4H); 2.20 (s, 3H).
7Ç_ : N-terf-butoxycarbonyl-2-(4-méthyl-pipérazin-l-yl)-aniline7Ç_: N-terf-butoxycarbonyl-2- (4-methyl-piperazin-1-yl) -aniline
Le dérivé 7B (2 g ; 10.5 mmol) est dissous dans le dioxane (70 ml) sous atmosphère d'azote en présence de di tert-butyldicarbonate (4.56 g , 21 mmol) et chauffé à 80°C pendant 15 heures. Le solvant est évaporé et le dérivé 7Ç_ est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4θH-MeOH-CH2CI2).The derivative 7B (2 g; 10.5 mmol) is dissolved in dioxane (70 ml) under a nitrogen atmosphere in the presence of di tert-butyldicarbonate (4.56 g, 21 mmol) and heated at 80 ° C for 15 hours. The solvent is evaporated and the derivative 7Ç_ is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 CI 2 ).
Masse obtenue: 2.42 g (79 %)Mass obtained: 2.42 g (79%)
JH-RMN (200 MHz, dmso-d6) δ : 7.85-7.70 (m, 2H) ; 7.17 (dd, IH, 1.8 et 7.2Hz) ; 7.15-6.9 (m, 2H) ; 2.77 (brs, 4H) ; 2.49 (brs, 4H) ; 2.23 (s, 3H) ; 1.46 (s, 9H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.85-7.70 (m, 2H); 7.17 (dd, IH, 1.8 and 7.2Hz); 7.15-6.9 (m, 2H); 2.77 (brs, 4H); 2.49 (brs, 4H); 2.23 (s, 3H); 1.46 (s, 9H).
7D: La N-ι,en'-butoxycarbonyl-l-[4-(2,3-diméthyl-phényl)-pipérazin-l-yl]-N-[2-(4- méthyl-p.pérazin-l-yl)-phényl]-5-amino-pentan-l-one Le dérivé 7Ç (2.4 g ; 8.2 mmol) dissous dans le DMF (20 ml) sous atmosphère d'azote est cannulé lentement sur une suspension d'hydrure de sodium (395 mg ; 9.9 mmol) dans le DMF (20 ml). Le mélange est doucement réchauffé à température ambiante puis à nouveau refroidi à 0°C. Le dérivé 2A (2.8 g ; 8 mmol) dilué dans du DMF (20 ml) est ajouté goutte à goutte au mélange réactionnel. La solution est agitée 24 heures puis neutralisée avec quelques gouttes d'eau puis le solvant est évaporé. Le résidu huileux est dilué dans de l'acétate d'ethyle et lavé deux fois à l'eau. La solution est séchée sur sulfate de magnésium et concentrée. Le dérivé 7D est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).7D: N-ι , en'-butoxycarbonyl-l- [4- (2,3-dimethyl-phenyl) -piperazin-l-yl] -N- [2- (4- methyl-p.pérazin-l- yl) -phenyl] -5-amino-pentan-l-one The derivative 7Ç (2.4 g; 8.2 mmol) dissolved in DMF (20 ml) under nitrogen atmosphere is cannulated slowly on a suspension of sodium hydride ( 395 mg; 9.9 mmol) in DMF (20 ml). The mixture is gently warmed to room temperature and then again cooled to 0 ° C. The derivative 2A (2.8 g; 8 mmol) diluted in DMF (20 ml) is added dropwise to the reaction mixture. The solution is stirred for 24 hours then neutralized with a few drops of water and then the solvent is evaporated. The oily residue is diluted in ethyl acetate and washed twice with water. The solution is dried over magnesium sulfate and concentrated. The 7D derivative is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 4.3 g (92 %)Mass obtained: 4.3 g (92%)
}H-RMN (200 MHz, dmso-d6) δ : 7.35-6.8 (m, 7H) ; 3.9-3.45 (m, 6H) ; 2.97 (brs, 2H) ; 2.71 (brs, 6H) ; 2.55-2.2 (m, 6H) ; 2.19 (s, 6H) ; 2. 16 (s, 3H) ; 1.6-1.2 (m, 13H). } H-NMR (200 MHz, dmso-d 6 ) δ: 7.35-6.8 (m, 7H); 3.9-3.45 (m, 6H); 2.97 (brs, 2H); 2.71 (brs, 6H); 2.55-2.2 (m, 6H); 2.19 (s, 6H); 2.16 (s, 3H); 1.6-1.2 (m, 13H).
Masse (DCI, NH3) : 564 (MH+) Rf: 0.6 (1-10-90 = NH4OH-MeOH-CH2Cl2)Mass (DCI, NH 3 ): 564 (MH + ) Rf: 0.6 (1-10-90 = NH 4 OH-MeOH-CH 2 Cl 2 )
7 : Le dérivé 7D (3.65 g ; 6.5 mmol) est dissous dans le dichlorométhane (179 ml) à 0°C sous atmosphère d'azote. L'acide trifluoroacétique (30 ml) est ensuite ajouté, le bain froid est retiré et le mélange réactionnel est agité jusqu'à disparition du produit de départ. La solution est neutralisée avec de la soude (1 M dans l'eau) puis ramenée à pH légèrement basique (environ 8). La phase aqueuse est extraite deux fois au dichlorométhane. Les phases organiques sont combinées, séchèes sur sulfate de magnésium et le solvant est évaporé. Le résidu huileux est purifié par chromatographie-éclair avec un mélange d'éluants (1-4-96 = NH4OH-MeOH-CH2Cl2).7: The derivative 7D (3.65 g; 6.5 mmol) is dissolved in dichloromethane (179 ml) at 0 ° C under a nitrogen atmosphere. The trifluoroacetic acid (30 ml) is then added, the cold bath is removed and the reaction mixture is stirred until the starting material disappears. The solution is neutralized with sodium hydroxide (1 M in water) and then brought back to a slightly basic pH (approximately 8). The aqueous phase is extracted twice with dichloromethane. The organic phases are combined, dried over magnesium sulfate and the solvent is evaporated. The oily residue is purified by flash chromatography with a mixture of eluents (1-4-96 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 2.6 g (86 %)Mass obtained: 2.6 g (86%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RiMN (200 MHz, dmso-d6) δ : 7.1-6.7 (m, 5H) ; 6.7-6.41 (m, 2H + fumarate) ; 5.3- 4.3 (brs, IH, NH) ; 3.57 (brs, 4H) ; 3.06 (brs, 2H) ; 2.9-2.5 (m, 12H) ; 2.5-2.25 (m, 5H) ; 2.18 (s, 3H) ; 2.15 (s, 3H) ; 1.59 (brs, 4H).JH-RiMN (200 MHz, dmso-d 6 ) δ: 7.1-6.7 (m, 5H); 6.7-6.41 (m, 2H + fumarate); 5.3-4.3 (brs, 1H, NH); 3.57 (brs, 4H); 3.06 (brs, 2H); 2.9-2.5 (m, 12H); 2.5-2.25 (m, 5H); 2.18 (s, 3H); 2.15 (s, 3H); 1.59 (brs, 4H).
Analyse élémentaire: C^H^NfO ; 1.05 C4H4O4 ; 0.2 H2O Calculée: C = 65.65 ; H = 7.80 ; N = 11.89 ; H2O = 0.61 Trouvée: C = 65.54 ; H = 7.76 ; N = 11.97 ; H2O = 0.66Elementary analysis: C ^ H ^ NfO; 1.05 C4H4O4; 0.2 H 2 O Calculated: C = 65.65; H = 7.80; N = 11.89; H 2 O = 0.61 Found: C = 65.54; H = 7.76; N = 11.97; H 2 O = 0.66
DKKBrV 3370 ; 3000-2700 ; 1709 ; 1637 ; 1599 ; 1512 ; 1458 ; 1238DKKBrV 3370; 3000-2700; 1709; 1637; 1599; 1512; 1458; 1238
Masse (DCI, NH3) : 646 (MH+)Mass (DCI, NH 3 ): 646 (MH + )
Rf: 0.6 (1-7-93 = NH4OH-MeOH-CH2CI2) EXEMPLE 8Rf: 0.6 (1-7-93 = NH 4 OH-MeOH-CH 2 CI 2 ) EXAMPLE 8
La l-[4-(2,3-diméthyl-phényl)-pipérazin-l-yll-5-[4-méthoxy-3-(4-méthyl-pipérazin- l-yl)-phénylamino]-pentan- 1-one (8)1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yll-5- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenylamino] -pentan- 1- one (8)
Figure imgf000035_0001
Figure imgf000035_0001
La 4-méthoxy-3-(4-méthyl-pipérazin-l-yl)-anιlιne est préparée selon la procédure décrite dans le brevet français n° 94089814-Methoxy-3- (4-methyl-piperazin-1-yl) -anιlιne is prepared according to the procedure described in French patent n ° 9408981
8A : La N-terι%butoxycarboπyl-4-méthoxy-3-(4-méthyl-pipérazin-I-yl)-anHine8A: N-terι% butoxycarboπyl-4-methoxy-3- (4-methyl-piperazin-I-yl) -anHine
Le dérivé 8A est préparé selon la même méthode décrite pour 7Ç_ à partir des réactifs suivants 4-méthoxy-3-(4-méthyl-pipérazin-l-yl)-anιlιne ( 1 5 g , 7 0 mmol) , di-tert- butyldicarbonateThe derivative 8A is prepared according to the same method described for 7Ç_ from the following reagents 4-methoxy-3- (4-methyl-piperazin-1-yl) -anιlιne (1 5 g, 7 0 mmol), di-tert- butyldicarbonate
(3 g , 14 mmol) dans le dioxane (50 ml)(3 g, 14 mmol) in dioxane (50 ml)
Masse obtenue 1 9 g (85 %)Mass obtained 1 9 g (85%)
iH-RMN (200 MHz, dmso-dό) δ 6 97 (m, 2H) , 6 72 (d, IH, 8 6Hz) , 6 61 (s, IH) , 3 79iH-NMR (200 MHz, dmso-dό) δ 6 97 (m, 2H), 6 72 (d, IH, 8 6Hz), 6 61 (s, IH), 3 79
(s, 3H) , 3 05 (m, 4H) , 2 59 (m, 4H) , 2 32 (s, 3H) , 1 48 (s, 9H)(s, 3H), 3 05 (m, 4H), 259 (m, 4H), 2 32 (s, 3H), 1 48 (s, 9H)
8B : La N-fcrt-butoxycarbonyl-l-[4-(2,3-diméthyl-phényl)-pipérazin-l-yl]-5-[4- méthoxy-3-(4-méthyl-pipérazin-l-yl)-phénylaminoj-pentan-l-one Le dérivé 8B est préparé selon la même méthode décrite pour 7D a partir des reactifs suivants 8A (563 mg , 1 7 mmol) , NaH (60 % , 80 mg , 2 mmol) , 2A (590 mg , 1,75 mmol) dans le DMF (20 ml) Le produit 8B a été ré-engagé dans la réaction qui suit directement après le lavage et séchage sur sulfate de magnésium.8B: N-fcrt-butoxycarbonyl-1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] -5- [4-methoxy-3- (4-methyl-piperazin-1-yl ) -phenylaminoj-pentan-l-one The derivative 8B is prepared according to the same method described for 7D from the following reagents 8A (563 mg, 1 7 mmol), NaH (60%, 80 mg, 2 mmol), 2A ( 590 mg, 1.75 mmol) in DMF (20 ml) Product 8B was re-engaged in the following reaction directly after washing and drying over magnesium sulfate.
8 : Le dérivé 8 est préparé selon la même méthode décrite pour 7 à partir des réactifs suivants: 8B brut, acide trifluoroacétique (1.8 ml) dans le dichlorométhane (10 ml).8: The derivative 8 is prepared according to the same method described for 7 from the following reagents: crude 8B, trifluoroacetic acid (1.8 ml) in dichloromethane (10 ml).
Masse obtenue: 563 mg (65 % à partir de 8A)Mass obtained: 563 mg (65% from 8A)
ÏH-RMN (200 MHz, dmso-d6) δ : 7.04 (t, IH, 7.6Hz) , 6.87 (m, 2H) ; 6.66 (d, IH, 8.5Hz) ; 6.19 (d, IH, 2.4Hz) ; 6.08 (dd, IH, 2.4 et 8.5Hz) , 5.05 (m, IH) ; 3.64 (s, 3H) ; 3.58 (m, 4H) ; 2.92 (m, 6H) ; 2.73 (m, 4H) ; 2.41 (m, 6H) , 2.21 (s, 3H) ; 2.20 (s, 3H) ; 2.18 (s, 3H) ; 1.58 (m, 4H). Ï H-NMR (200 MHz, dmso-d 6 ) δ: 7.04 (t, IH, 7.6Hz), 6.87 (m, 2H); 6.66 (d, 1H, 8.5Hz); 6.19 (d, 1H, 2.4Hz); 6.08 (dd, IH, 2.4 and 8.5Hz), 5.05 (m, IH); 3.64 (s, 3H); 3.58 (m, 4H); 2.92 (m, 6H); 2.73 (m, 4H); 2.41 (m, 6H), 2.21 (s, 3H); 2.20 (s, 3H); 2.18 (s, 3H); 1.58 (m, 4H).
Rf: 0.4 (1-9-90 = NH4OH-MeOH-CH2CI2)Rf: 0.4 (1-9-90 = NH 4 OH-MeOH-CH 2 CI 2 )
EXEMPLE 9EXAMPLE 9
Le fumarate de la 5-[4-chloro-3-(4-méthyl-pipérazin-l-yl)-phénoxy]-l-[4-(2,3- diméthyI-phényl)-pipérazin-l-yl]-pentan-l-one (9)5- [4-Chloro-3- (4-methyl-piperazin-1-yl) -phenoxy] -l- [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] fumarate - pentan-l-one (9)
Figure imgf000036_0001
Figure imgf000036_0001
Le 4-chloro-3-(4-méthyl-pipérazin-l-yl)-phénol a été préparé selon la procédure décrite dans le brevet français n °94408981.4-chloro-3- (4-methyl-piperazin-1-yl) -phenol was prepared according to the procedure described in French patent No. 94408981.
9 : Le dérivé 9 est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants: 4-chloro-3-(4-méthyl-pipérazin-l-yl)-phénol (500 mg , 2.2 mmol) ; 2A (779 mg ; 2.2 mmol) ; carbonate de césium (718 mg ; 2.2 mmol) dans le DMF (10 ml). ^9: The derivative 9 is prepared according to the same method described for 2 from the following reagents: 4-chloro-3- (4-methyl-piperazin-1-yl) -phenol (500 mg, 2.2 mmol); 2A (779 mg; 2.2 mmol); cesium carbonate (718 mg; 2.2 mmol) in DMF (10 ml). ^
Masse obtenue 576 mg (48 %)Mass obtained 576 mg (48%)
Ce composé est dissous dans le méthanol et traite avec de l'acide fumarique pour donner le fumarate correspondantThis compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate
ÏH-RMN (200 MHz, dmso-d6) δ 7 27 (d, IH, 9 2Hz) , 7 04 (t, IH, 7 6Hz) , 6 95-6 8 (m, 2H) , 6 7-6 5 (m, 2H + fumarate) , 3 97 (brs, 2H) , 3 59 (brs, 4H) , 2 98 (brs, 4H) , 2 73 (brs, 4H) , 2 65-2 35 (m, 6H) , 2 30 (s, 3H) , 2 21 (s, 3H) , 2 18 (s, 3H) , 1 71 (brs, 4H)ÏH-RMN (200 MHz, dmso-d 6 ) δ 7 27 (d, IH, 9 2Hz), 7 04 (t, IH, 7 6Hz), 6 95-6 8 (m, 2H), 6 7-6 5 (m, 2H + fumarate), 3 97 (brs, 2H), 3 59 (brs, 4H), 2 98 (brs, 4H), 2 73 (brs, 4H), 2 65-2 35 (m, 6H ), 2 30 (s, 3H), 2 21 (s, 3H), 2 18 (s, 3H), 1 71 (brs, 4H)
Analyse élémentaire C2gH39N4θ2 , C4H4O4 Calculée C = 62 48 , H = 7 05 , N = 9 1 1 Trouvée C = 62 50 , H = 7 16 , N = 8 70Elementary analysis C 2 gH39N4θ 2 , C4H4O4 Calculated C = 62 48, H = 7 05, N = 9 1 1 Found C = 62 50, H = 7 16, N = 8 70
Rf 0 25 (0 5-5-95 = NH4OH-MeOH-CH2Cl2)Rf 0 25 (0 5-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
IR OCBr) 3447 , 3940 , 1637 , 1597 , 1479IR OCBr) 3447, 3940, 1637, 1597, 1479
EXEMPLE 10EXAMPLE 10
Le fumarate de la [4-(2,3-diméthyl-phényI)-pipérazin-l-yI)-{2-[2-(4-méthyI- pipérazin-l-yl)-phénoxyméthyl]-phényl}-méthanone (10)[4- (2,3-Dimethyl-phenyl) -piperazin-1-yI) - {2- [2- (4-methyl-piperazin-1-yl) -phenoxymethyl] -phenyl} -methanone fumarate ( 10)
Figure imgf000037_0001
Figure imgf000037_0001
10A : La [4-(2,3-diméthyl-phényl)-pipérazin-l-yl]-[2-benzoyloxyméthyl-phényl)- méthanone Le composé B (2 1 g , 9 1 mmol) est dissous dans le dichlorométhane (18 ml) en présence de pyridine (1 76 ml , 22 mmol) sous atmosphère d'azote La solution est refroidie à 0°C et le chlorure de 2-benzoyloxyméthyl-benzoyle (3 g , 1 1 mmol) est ajouté goutte à goutte Le bain froid est retiré Lorsque le produit de départ a été totalement consommé, la solution est diluée dans de l'acétate d'ethyle et lavée avec de l'eau, séchée sur sulfate de magnésium et concentrée La pyridine résiduelle est co-évaporée au toluène Le dérivé 10A est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4θH-MeOH-CH2Cl2)10A: [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - [2-benzoyloxymethyl-phenyl) - methanone Compound B (2 1 g, 9 1 mmol) is dissolved in dichloromethane (18 ml) in the presence of pyridine (176 ml, 22 mmol) under a nitrogen atmosphere The solution is cooled to 0 ° C and the chloride of 2-benzoyloxymethyl-benzoyl (3 g, 11 mmol) is added dropwise The cold bath is removed When the starting material has been completely consumed, the solution is diluted in ethyl acetate and washed with l water, dried over magnesium sulphate and concentrated The residual pyridine is co-evaporated with toluene The derivative 10A is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 )
Masse obtenue 3 61 g (93 %)Mass obtained 361 g (93%)
^-RMN (200 MHz, dmso-d6) δ 7 97 (d, 2H, 7 3 Hz) , 7 75-7 30 (m, 7H) , 6 95 (t, IH, 7 6Hz) , 6 84 (d, IH, 7 2Hz) , 6 60 (d, IH, 7 9Hz) , 5 6-5 2 (m, 2H) , 3 70 (brs, 2H) , 3 30 (brs, 2H) , 2 62 (brs, 4H) , 2 16 (s, 3H) , 2 09 (s, 3H)^ -RMN (200 MHz, dmso-d 6 ) δ 7 97 (d, 2H, 7 3 Hz), 7 75-7 30 (m, 7H), 6 95 (t, IH, 7 6Hz), 6 84 ( d, IH, 7 2Hz), 6 60 (d, IH, 7 9Hz), 5 6-5 2 (m, 2H), 3 70 (brs, 2H), 3 30 (brs, 2H), 2 62 (brs , 4H), 2 16 (s, 3H), 2 09 (s, 3H)
10B : La [4-(2,3-diméthyl-phényl)-p.pérazin-l-yl]-(2-hydroxyméthyl-phényl)- méthanone10B: [4- (2,3-dimethyl-phenyl) -p.perazin-1-yl] - (2-hydroxymethyl-phenyl) - methanone
Le dérivé 1QA (3 61 g , 8 5 mmol) est dissous dans 17 ml d'une solution de méthanol contenant 1% (massique) d'hydroxyde de sodium L'huile résiduelle est diluée dans du dichlorométhane et neutralisée avec de l'acide chlorhydrique (pH environ 7-8) La phase aqueuse est extraite trois fois au dichlorométhane Les phases organiques sont combinées, séchèes sur sulfate de magnésium et concentrées Le dérivé 10B est purifié par chromatographie-éclair avec un mélange d'éluants (1-4-95 = NH^OH-MeOH- CH2C12)The 1QA derivative (361 g, 85 mmol) is dissolved in 17 ml of a methanol solution containing 1% (by mass) of sodium hydroxide The residual oil is diluted in dichloromethane and neutralized with acid hydrochloric (pH about 7-8) The aqueous phase is extracted three times with dichloromethane The organic phases are combined, dried over magnesium sulfate and concentrated The derivative 10B is purified by flash chromatography with a mixture of eluents (1-4- 95 = NH ^ OH-MeOH- CH 2 C1 2 )
Masse obtenue 762 mg (27 %)Mass obtained 762 mg (27%)
iH-RMN (200 MHz, dmso-d6) δ 7 53 (d, IH, 7 2Hz) , 7 40 (td, IH, 1 5 et 7 2Hz) , 7 32 (td, IH, 1 5 et 7 2Hz) , 7 22 (dd, IH, 1 5 et 7 4Hz) , 7 04 (t, IH, 7 6Hz) , 6 88 (d, 2H, 7 6Hz) , 5 23 (t, IH, OH, 5 4Hz) , 4 49 (d, 2H, 5 4Hz) , 3 80 (brs, 2H) , 3 29 (brs, 2H) , 2 84 (brs, 2H) , 2 72 (brs, 2H) , 2 21 (s, 3H) , 2 17 (s, 3H)iH-RMN (200 MHz, dmso-d 6 ) δ 7 53 (d, IH, 7 2Hz), 7 40 (td, IH, 1 5 and 7 2Hz), 7 32 (td, IH, 1 5 and 7 2Hz ), 7 22 (dd, IH, 1 5 and 7 4Hz), 7 04 (t, IH, 7 6Hz), 6 88 (d, 2H, 7 6Hz), 5 23 (t, IH, OH, 5 4Hz) , 4 49 (d, 2H, 5 4Hz), 3 80 (brs, 2H), 3 29 (brs, 2H), 2 84 (brs, 2H), 2 72 (brs, 2H), 2 21 (s, 3H ), 2 17 (s, 3H)
10C : La [4-(2,3-diméthyl-phényl)-pipérazin-l-yll-(2-chlorométhyl-phényI)- méthanone Le dérivé 10B (755 mg ; 2.3 mmol) est mélangé sous atmosphère d'azote à la 2,6- lutidine (540μl ; 4.6 mmol) dans le DMF (10 ml) et canule sur une suspension de chlorure de lithium dans le DMF (3 ml) à 0°C. Le mélange réactinnel est agité 20 min puis le chlorurr de méthane sulfonyle (157 mg ; 3.7 mmol) est ajouté. Après 20 heures d'agitation à température ambiante du chlorure de lithium (98 mg ; 2,3 mmol) et du chlorure de méthane sulfonyle (179μl ; 2,3 mmol) sont ajoutés. Lorsque le produit de départ est consommé le solvant est évaporé et le dérivé 10C est purifié par chromatographie-éclair.10C: [4- (2,3-Dimethyl-phenyl) -piperazin-1-yll- (2-chloromethyl-phenyl) - methanone The derivative 10B (755 mg; 2.3 mmol) is mixed under a nitrogen atmosphere with 2,6-lutidine (540 μl; 4.6 mmol) in DMF (10 ml) and cannulated on a suspension of lithium chloride in DMF ( 3 ml) at 0 ° C. The reaction mixture is stirred 20 min then the methane sulfonyl chlorurr (157 mg; 3.7 mmol) is added. After 20 hours of stirring at room temperature, lithium chloride (98 mg; 2.3 mmol) and methane sulfonyl chloride (179 μl; 2.3 mmol) are added. When the starting product is consumed the solvent is evaporated and the derivative 10C is purified by flash chromatography.
Masse obtenue: 637 mg (80 %)Mass obtained: 637 mg (80%)
]H-RMN (200 MHz, dmso-d6) δ : 7.65-7.3 (m, 4H) ; 7.04 (t, IH, 7-6Hz) ; 6.88 (brd, 2H, 7.6Hz) ; 5.0-5.6 (m, 2H) ; 3.81 (brs, 2H) ; 3.33 (brs, 2H) ; 2.86 (brs, 2H) , 2.76 (brs, 2H) ; 2.20 (s, 3H) ; 2.17 (s, 3H). ] H-NMR (200 MHz, dmso-d 6 ) δ: 7.65-7.3 (m, 4H); 7.04 (t, 1H, 7-6 Hz); 6.88 (brd, 2H, 7.6Hz); 5.0-5.6 (m, 2H); 3.81 (brs, 2H); 3.33 (brs, 2H); 2.86 (brs, 2H), 2.76 (brs, 2H); 2.20 (s, 3H); 2.17 (s, 3H).
10 : Le dérivé 1J) est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants : A (347 mg ; 1.8 mmol) ; 10C (619 mg ; 1.8 mmol) ; carbonate de césium (1,2 g ; 3.6 mmol) ; dans le DMF (16 ml).10: The derivative 1J) is prepared according to the same method described for 2 from the following reagents: A (347 mg; 1.8 mmol); 10C (619 mg; 1.8 mmol); cesium carbonate (1.2 g; 3.6 mmol); in DMF (16 ml).
Masse obtenue: 361 mg (40 %)Mass obtained: 361 mg (40%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
]H-RMN (200 MHz, dmso-d6) δ : 7.66 (d, IH, 8.9Hz); 7.55-7.3 (m, 3H); 7.1-6.8 (m, 6H); 6.70 (d, IH, 7.7Hz); 6.58 (s, fumarate); 5.06 (s, 2H); 3.77 (brs, 2H), 3.32 (brs, 2H); 3.01 (brs, 4H); 2.9-2.6 (m, 4H), 2.55 (brs, 4H); 2.29 (s, 3H); 2.18 (s, 3H); 2.14 (s, 3H). ] H-NMR (200 MHz, dmso-d 6 ) δ: 7.66 (d, IH, 8.9Hz); 7.55-7.3 (m, 3H); 7.1-6.8 (m, 6H); 6.70 (d, 1 H, 7.7 Hz); 6.58 (s, fumarate); 5.06 (s, 2H); 3.77 (brs, 2H), 3.32 (brs, 2H); 3.01 (brs, 4H); 2.9-2.6 (m, 4H), 2.55 (brs, 4H); 2.29 (s, 3H); 2.18 (s, 3H); 2.14 (s, 3H).
Analyse élémentaire: C3 iH3gN4θ2 ; 1.1 C4H4O4 ; 1.2 H20 Calculée: C = 65.62 ; H = 6.97 ; N = 8.65 ; H20 = 3.34 Trouvée: C = 65.64 ; H = 6.75 ; N = 8.70 ; H2O = 3.73Elementary analysis: C3 iH3gN4θ 2 ; 1.1 C4H4O4; 1.2 H 2 0 Calculated: C = 65.62; H = 6.97; N = 8.65; H 2 0 = 3.34 Found: C = 65.64; H = 6.75; N = 8.70; H 2 O = 3.73
IR rKBrV 3400 ; 1720 ; 1630 ; 1499 ; 1239 V*IR rKBrV 3400; 1720; 1630; 1499; 1239 V *
Masse (DCI, NH3) : 499 (MH+) ; 193 (base)Mass (DCI, NH 3 ): 499 (MH + ); 193 (base)
Rf: 0.55 (1-12-90 = NH4OH-MeOH-CH2Cl2)Rf: 0.55 (1-12-90 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 11EXAMPLE 11
Le fumarate de la [4-(2,3-diméthyl-phényl)-pipérazin-l-yIj-{3-[2-(4-méthyl- pipérazin-l-yl)-phénoxyméthyl|-phényI}-ιnéthanone (11)[4- (2,3-Dimethyl-phenyl) -piperazin-1-yIj- {3- [2- (4-methyl-piperazin-1-yl) -phenoxymethyl | -phenyI} -ιethanone fumarate (11 )
Figure imgf000040_0001
Figure imgf000040_0001
11A : La [4-(2,3-diméthyl-phényl)-pipérazin-l-yl|-(3-chlorométhyl-phényI)- méthanone Le dérivé 11A est préparé selon la même méthode décrite pour LA à partir des réactifs suivants: B (3 g ; 13,2 mmol) ; chlorure de 3-chiorométhyl-benzoyle (2,3 ml ; 16, 3 mmol); pyridine (2,6 ml ; 32.7 mmol) dans le dichlorométhane (30 ml).11A: [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl | - (3-chloromethyl-phenyl) - methanone The derivative 11A is prepared according to the same method described for LA from the following reagents: B (3 g; 13.2 mmol); 3-chioromethyl-benzoyl chloride (2.3 ml; 16.3 mmol); pyridine (2.6 ml; 32.7 mmol) in dichloromethane (30 ml).
Masse obtenue: 4.67 g (91%)Mass obtained: 4.67 g (91%)
1H-RMN (200 MHz, dmso-d6) δ : 7.6-7.85 (m, 3H) , 7 3-7.0 (m, 2H) ; 7.0-6.85 (m, 2H) ; 4.84 (s, 2H) ; 3.79 (brs, 2H) ; 3.50 (brs , 2H) ; 2 82 (brs, 4H) ; 2.22 (s, 3H) ; 2.20 (s, 3H).1H-NMR (200 MHz, dmso-d 6 ) δ: 7.6-7.85 (m, 3H), 7 3-7.0 (m, 2H); 7.0-6.85 (m, 2H); 4.84 (s, 2H); 3.79 (brs, 2H); 3.50 (brs, 2H); 282 (brs, 4H); 2.22 (s, 3H); 2.20 (s, 3H).
11 : Le dérivé Ll est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants : A (1 g; 5.2 mmol) ; 11A (1.78 g ; 5.2 mmol) , carbonate de césium (1.69 g ; 5.2 mmol) dans le DMF (30 ml).11: The derivative L1 is prepared according to the same method described for 2 from the following reagents: A (1 g; 5.2 mmol); 11A (1.78 g; 5.2 mmol), cesium carbonate (1.69 g; 5.2 mmol) in DMF (30 ml).
Masse obtenue: 710 mg (48 %) iSMass obtained: 710 mg (48%) iS
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
1H-RMN (200 MHz, dmso-d6) δ : 7.1-7.3 (m, 4H) ; 7.15-6.2 (m, 7H) ; 6.57 (s, s fumarate) ; 7.15 (s, 2H) ; 3.95-3.65 (m, 2H) ; 3.65-3.3 (m, 2H) ; 3.05 (brs, 4H) ; 2.95- 2.55 (m, 8H) ; 2.31 (s, 3H) ; 2.20 (s, 3H) ; 2.17 (s, 3H).1H-NMR (200 MHz, dmso-d 6 ) δ: 7.1-7.3 (m, 4H); 7.15-6.2 (m, 7H); 6.57 (s, s fumarate); 7.15 (s, 2H); 3.95-3.65 (m, 2H); 3.65-3.3 (m, 2H); 3.05 (brs, 4H); 2.95-2.55 (m, 8H); 2.31 (s, 3H); 2.20 (s, 3H); 2.17 (s, 3H).
Analyse élémentaire: C3 iH3gN4θ2 ; 1.15 C4H4O4 ; 0.35 H20 Calculée: C = 66.97 ; H = 6.84 ; N = 8.78 ; H2O = 0.99 0 Trouvée: C = 66.89 ; H = 6.97 ; N = 8.93 ; H20 = 0.92Elementary analysis: C3 iH3gN4θ 2 ; 1.15 C4H4O4; 0.35 H 2 0 Calculated: C = 66.97; H = 6.84; N = 8.78; H 2 O = 0.99 0 Found: C = 66.89; H = 6.97; N = 8.93; H 2 0 = 0.92
IR (KBr): 3100-2700 ; 1707 ; 1630 ; 1583 ; 1500 ; 1458 ; 1383IR (KBr): 3100-2700; 1707; 1630; 1583; 1500; 1458; 1383
Masse (DCI, NH3) : 499 (MH+)Mass (DCI, NH 3 ): 499 (MH + )
Rf: 0.5 (1-10-90 = NH4OH-MeOH-CH2Cl2) Rf: 0.5 (1-10-90 = NH 4 OH-MeOH-CH 2 Cl 2 )
HrûHru
EXEMPLE 12EXAMPLE 12
Le fumarate de la [4-(2,3-diméthyJ-phényl)-pipérazin-l-yl)-{4-(2-(4-méthyl- pipérazin-l-yl)-phénoxyméthylJ-phényl}-méthanone (12)[4- (2,3-DimethylJ-phenyl) -piperazin-1-yl) - {4- (2- (4-methyl-piperazin-1-yl) -phenoxymethylJ-phenyl} -methanone fumarate (12 )
Figure imgf000042_0001
Figure imgf000042_0001
12A : La (4-chlorométhyl-phényl)-[4-(2,3-diméthy-phényl-pipérazin-l-yll- méthanone12A: (4-Chloromethyl-phenyl) - [4- (2,3-dimethyl-phenyl-piperazin-1-yll-methanone
Le dérivé 12A est préparé selon la même méthode décrite pour LA à partir des réactifs suivants: B (3 g ; 13 mmol) ; chlorure de 4-chlorométhylbenzoyle (3.1 g ; 16 mmol) ; pyridine (2.6 ml ; 33 mmol) dans le dichlorométhane (30 ml).The derivative 12A is prepared according to the same method described for LA from the following reagents: B (3 g; 13 mmol); 4-chloromethylbenzoyl chloride (3.1 g; 16 mmol); pyridine (2.6 ml; 33 mmol) in dichloromethane (30 ml).
Masse obtenue: 4.3 g (96 %)Mass obtained: 4.3 g (96%)
!H-RMN (200 MHz, dmso-d6) δ : 7.6-7.35 (m, 4H) ; 7.02 (t, IH, 7.5Hz) ; 6.86 (d, 2H, 7.5Hz); 4.79 (s, 2H) ; 3.73 (brs, 2H) ; 3.45 (brs, 2H) ; 2.77 (brs, 4H) ; 2.18 (s, 3H) ; 2.15 (s, 3H)! H-NMR (200 MHz, dmso-d 6 ) δ: 7.6-7.35 (m, 4H); 7.02 (t, 1H, 7.5Hz); 6.86 (d, 2H, 7.5Hz); 4.79 (s, 2H); 3.73 (brs, 2H); 3.45 (brs, 2H); 2.77 (brs, 4H); 2.18 (s, 3H); 2.15 (s, 3H)
12 : Le dérivé L2 est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants : A (800 mg ; 4.2 mmol) ; 12A (1.4 g ; 4.2 mmol) ; carbonate de césium (2.7 g ; 8.3 mmol) dans le DMF (20 ml).12: The L2 derivative is prepared according to the same method described for 2 from the following reagents: A (800 mg; 4.2 mmol); 12A (1.4 g; 4.2 mmol); cesium carbonate (2.7 g; 8.3 mmol) in DMF (20 ml).
Masse obtenue: 1.0 g (50 %)Mass obtained: 1.0 g (50%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. MThis compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. M
ÏH-RMN (200 MHz, dmso-d6) δ 7 56 (d, 2H, 8 2Hz) , 7 48 (d, 2H, 8 2Hz) , 7 15-6 8 (m, 7H) , 6 59 (s, fumarate) , 5 17 (s, 2H) , 4 0-3 3 (m, 4H) , 3 08 (brs, 4H) , 2 95-2 6 (m, 8H) , 2 36 (s, 3H) , 2 21 (s, 3H) , 2 19 (s, 3H) Ï H-NMR (200 MHz, dmso-d 6 ) δ 7 56 (d, 2H, 8 2Hz), 7 48 (d, 2H, 8 2Hz), 7 15-6 8 (m, 7H), 6 59 ( s, fumarate), 5 17 (s, 2H), 4 0-3 3 (m, 4H), 3 08 (brs, 4H), 2 95-2 6 (m, 8H), 2 36 (s, 3H) , 2 21 (s, 3H), 2 19 (s, 3H)
IR (KBr) 3450 , 3100-2700 , 1709 , 1631 , 1500 , 1458 , 1282 , 1239IR (KBr) 3450, 3100-2700, 1709, 1631, 1500, 1458, 1282, 1239
Analyse élémentaire C3 ]H3gN4θ2 , 1 15 C4H4O4 , 0 25 H20 Calculée C = 67 16 , H = 6 82 , N = 8 80 , H2O = 0 71 Trouvée C = 67 02 , H = 6 79 , N = 8 84 , H2O = 0 65Elementary analysis C3] H3gN4θ 2 , 1 15 C4H4O4, 0 25 H 2 0 Calculated C = 67 16, H = 6 82, N = 8 80, H 2 O = 0 71 Found C = 67 02, H = 6 79, N = 8 84, H 2 O = 0 65
Masse (DCI. NH3) 499 (MH+)Mass (DCI. NH3) 499 (MH + )
Rf 0 5 (0 9-9-91 = NH4OH-MeOH-CH2Cl2)Rf 0 5 (0 9-9-91 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 13EXAMPLE 13
Le fumarate de la {3-[4-chIoro-2-(4-méthyI-pipérazin-l-yl)-phénoxyméthylJ- phényl}-[4-(2,3-diméthyl-phényl)-pipérazin-l-yl]-méthanone (13){3- [4-chIoro-2- (4-methyl-piperazin-1-yl) -phenoxymethylJ-phenyl} - [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] fumarate -methanone (13)
Figure imgf000043_0001
Figure imgf000043_0001
13 Le déπvé L3 est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants C (870 mg , 3 8 mmol) , 11A (1 3 g , 3 8 mmol) , carbonate de césium (1 2 g , 3 8 mmol) dans le DMF (20 ml)13 Deπvé L3 is prepared according to the same method described for 2 from the following reagents C (870 mg, 3 8 mmol), 11A (1 3 g, 3 8 mmol), cesium carbonate (1 2 g, 3 8 mmol ) in DMF (20 ml)
Masse obtenue 1 2 g (59 %)Mass obtained 1 2 g (59%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant Va-This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate Go-
1H-RMN (200 MHz, dmso-dό) δ : 7.6-7.3 (m, 4H) ; 7.15-6.8 (m, 6H) ; 6.58 (s, fumarate) ; 5.17 (s, 2H) ; 3.9-3.3 (m, 4H) ; 3.05 (brs, 4H) , 2.80 (brs, 4H) ; 2.57 (brs, 4H) ; 2.29 (s, 3H) ; 2.20 (s, 3H) ; 2.17 (s, 3H).1H-NMR (200 MHz, dmso-dό) δ: 7.6-7.3 (m, 4H); 7.15-6.8 (m, 6H); 6.58 (s, fumarate); 5.17 (s, 2H); 3.9-3.3 (m, 4H); 3.05 (brs, 4H), 2.80 (brs, 4H); 2.57 (brs, 4H); 2.29 (s, 3H); 2.20 (s, 3H); 2.17 (s, 3H).
Analyse élémentaire: C3 iH37ClN/|O2 : 1.1
Figure imgf000044_0001
: 0 2 H2Q Calculée: C = 64.00 ; H = 6.34 ; N = 8.43 ; H2O = 0.54 Trouvée. C = 64.00 ; H = 6.46 ; N = 8.43 ; H20 = 0.60Elementary analysis: C3 iH37ClN / | O 2 : 1.1
Figure imgf000044_0001
: 0 2 H 2 Q Calculated: C = 64.00; H = 6.34; N = 8.43; H 2 O = 0.54 Found. C = 64.00; H = 6.46; N = 8.43; H 2 0 = 0.60
IR(KBr): 3431, 2914, 1709, 1631, 1496, 1458IR (KBr): 3431, 2914, 1709, 1631, 1496, 1458
Masse(DCI, NH3) : 533 (MH+)Mass (DCI, NH 3 ): 533 (MH + )
Rf: 0.75 (1-10-90 = NH4OH-MeOH-CH2CI2)Rf: 0.75 (1-10-90 = NH 4 OH-MeOH-CH 2 CI 2 )
EXEMPLE 14EXAMPLE 14
Le fumarate de la {3-[2-[4-méthyI-pipérazin-l-yl)-phénoxyméthyl]-phényl}-(4- phènéthyl-pipérazin-l-yI)-méthanone (14){3- [2- [4-methyl-piperazin-1-yl) -phenoxymethyl] -phenyl} - (4-phenethyl-piperazin-1-yI) -methanone fumarate (14)
Figure imgf000044_0002
Figure imgf000044_0002
14A : (3-chlorométhyl-phényl)-(4-phénéthyl-pipérazin- 1 -yl)-méthanone14A: (3-chloromethyl-phenyl) - (4-phenethyl-piperazin-1 -yl) -methanone
Le dérivé 14A est préparé selon la même méthode décrite pour LA à partir des réactifs suivants: N-phénéthyl-pipérazine (2 g ; 10.5 mmol) , chlorure de 3-chlorométhyl- benzoyle (1.8 ml ; 12.6 mmol) ; triéthylamine (2 2 ml ; 15.8 mmol) dans le dichlorométhane (21 ml).The derivative 14A is prepared according to the same method described for LA from the following reagents: N-phenethyl-piperazine (2 g; 10.5 mmol), 3-chloromethylbenzoyl chloride (1.8 ml; 12.6 mmol); triethylamine (22 ml; 15.8 mmol) in dichloromethane (21 ml).
Masse obtenue: 3.6 g (100%) iH-RMN (200 MHz, CDCI3) δ : 7.55-7.10 (m, 9H) ; 4.60 (s, 2H) ; 3.82 (brs, 2H) ; 3.47 (brs, 2H) ; 2.9-2.3 (m, 8H).Mass obtained: 3.6 g (100%) 1 H-NMR (200 MHz, CDCI3) δ: 7.55-7.10 (m, 9H); 4.60 (s, 2H); 3.82 (brs, 2H); 3.47 (brs, 2H); 2.9-2.3 (m, 8H).
14 : Le dérivé L4 est préparé selon la même méthode décrite pour 7_D à partir des réactifs suivants : A (372 mg ; 1.9 mmol) ; 14A (1 g ; 2.9 mmol) ; NaH (139 mg ; 2.9 mmol) dans le DMF (12 ml).14: The L4 derivative is prepared according to the same method described for 7_D from the following reagents: A (372 mg; 1.9 mmol); 14A (1 g; 2.9 mmol); NaH (139 mg; 2.9 mmol) in DMF (12 ml).
Masse obtenue: 525 mg (54 %)Mass obtained: 525 mg (54%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
!H-RMN (200 MHz, dmso-d6) δ : 7.6-6.8 (m, 13H) ; 6.58 (s, fumarate) ; 5.15 (s, 2H) ; 3.56 (brs, 2H) ; 3.30 (brs, 2H) ; 3.03 (brs, 4H) ; 2.8-2.2 (m, 15H).! H-NMR (200 MHz, dmso-d 6 ) δ: 7.6-6.8 (m, 13H); 6.58 (s, fumarate); 5.15 (s, 2H); 3.56 (brs, 2H); 3.30 (brs, 2H); 3.03 (brs, 4H); 2.8-2.2 (m, 15H).
Analyse élémentaire: C3 ]H3gN4θ2 ; C4H4O4 ; 0.5 H2O Calculée: C = 67.40 ; H = 7.68 ; N = 8.98 ; H2O = 1.44 Trouvée: C = 67.41 ; H = 6.76 ; N = 8.68 ; H2O = 1.4Elemental analysis: C3] H3gN4θ 2 ; C4H4O4; 0.5 H 2 O Calculated: C = 67.40; H = 7.68; N = 8.98; H 2 O = 1.44 Found: C = 67.41; H = 6.76; N = 8.68; H 2 O = 1.4
IR (KBr): 3434, 1624, 1499, 1459, 1249.IR (KBr): 3434, 1624, 1499, 1459, 1249.
Rf: 0.2 (1-5-95 = NH4θH-MeOH-CH2Cl2) Rf: 0.2 (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 )
rt*rt *
EXEMPLE 15EXAMPLE 15
Le fumarate du N-{3-[2-(4-méthyl-pipérazin-l-yl)-phénoxyméthylj-phényI}-4-(2,3- diméthyl-phényl)-pipérazine-l-carboxamine (15)N- {3- [2- (4-methyl-piperazin-1-yl) -phenoxymethylj-phenylI} -4- (2,3-dimethyl-phenyl) -piperazine-1-carboxamine fumarate (15)
Figure imgf000046_0001
Figure imgf000046_0001
15A : Le 3-[2-(4-méthyl-pipérazin-l-yl)-phénoxyméthylJ-l-nitrobenzène15A: 3- [2- (4-methyl-piperazin-1-yl) -phenoxymethylJ-1-nitrobenzene
Le dérivé 15A est préparé selon la même méthode décrite pour 7D à partir des réactifs suivants: A (1.5 g ; 7.8 mmol) ; 3-chlorométhyI-l-nitrobenzène (2 g ; 1 1.7 mmol) ; NaH (561 mg ; 11.7 mmol) dans le DMF (16 ml).The derivative 15A is prepared according to the same method described for 7D from the following reagents: A (1.5 g; 7.8 mmol); 3-chloromethyl-1-nitrobenzene (2 g; 1 1.7 mmol); NaH (561 mg; 11.7 mmol) in DMF (16 ml).
Masse obtenue: 1.19 g (46 %)Mass obtained: 1.19 g (46%)
iH-RMN (200 MHz, dmso-d6) δ : 8.41 (brs, IH) ; 8.19 (brd, IH, 8Hz) ; 7.89 (brd, IH, 8Hz); 7.01 (t, IH, 8Hz) ; 7.15-6.85 (m, 4H) ; 5.26 (s, 2H) ; 3.00 (brs, 4H) ; 2.49 (brs, 4H); 2.21 (s, 3H). iH-NMR (200 MHz, dmso-d 6 ) δ: 8.41 (brs, 1H); 8.19 (brd, 1H, 8Hz); 7.89 (brd, 1H, 8Hz); 7.01 (t, 1H, 8Hz); 7.15-6.85 (m, 4H); 5.26 (s, 2H); 3.00 (brs, 4H); 2.49 (brs, 4H); 2.21 (s, 3H).
15B : La 3-[2-(4-méthyl-pipérazin-l-yL)-phénoxyméthyl]-aniIine15B: 3- [2- (4-methyl-piperazin-1-yL) -phenoxymethyl] -aniIine
Le dérivé 15B est préparé selon la même méthode décrite pour 7B à partir des réactifs suivants 15A (1 19 g , 3 6 mmol) , hydrazine hydratée (907μl) , Nickel de Raney (cat) dans l'ethanol (12 ml)The derivative 15B is prepared according to the same method described for 7B from the following reagents 15A (1 19 g, 36 mmol), hydrated hydrazine (907 μl), Raney nickel (cat) in ethanol (12 ml)
Masse obtenue 1 05 g (98 %)Mass obtained 1 05 g (98%)
!H-RMN (200 MHz, dmso-dô) δ 7 15-7 85 (m, 5H) , 6 7-6 45 (m, 3 H) , 5 10 (brs, 2H) , 4 96 (s, 2H) , 3 02 (brs, 4H) , 2 46 (brs, 4H) , 2 22 (s, 2H)! H-NMR (200 MHz, dmso-dô) δ 7 15-7 85 (m, 5H), 6 7-6 45 (m, 3H), 5 10 (brs, 2H), 4 96 (s, 2H ), 3 02 (brs, 4H), 2 46 (brs, 4H), 2 22 (s, 2H)
15 Le déπvé 15B (979 mg , 3 3 mmol) dilué dans le dichlorométhane (7 ml) est ajoute sous atmosphère d'azote à une solution de triphosgéne (390 mg , 1 3 mmol) dans le dichlorométhane (7 ml) à 0°C La pyridine (266μl , 3 3 mmol) est ajoutée La réaction est agitée 10 minutes à 0°C puis le bain froid est retiré Lorsque la solution est revenue à température ambiante la N-xylylpipérazine désalifiee (1 05 g , 5 2 mmol) et diluée dans le dichlorométhane (7 ml) est ajoutée goutte à goutte La pyridine (266μl , 3 3 mmol) est ajoutée Lorsque le produit de départ a totalement réagi, la solution est diluée dans du dichlorométhane, lavée avec une solution saturée en chlorure de sodium et séchée sur sulfate de magnésium Le solvant est évaporé Le dérivé L5 est isolé sous forme de base libre après purification par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2)15 Deπvé 15B (979 mg, 3 3 mmol) diluted in dichloromethane (7 ml) is added under a nitrogen atmosphere to a solution of triphosgéne (390 mg, 1 3 mmol) in dichloromethane (7 ml) at 0 ° C The pyridine (266 μl, 3 3 mmol) is added The reaction is stirred for 10 minutes at 0 ° C. then the cold bath is removed When the solution has returned to ambient temperature the desalified N-xylylpiperazine (105 g, 5 2 mmol) and diluted in dichloromethane (7 ml) is added dropwise The pyridine (266μl, 3 3 mmol) is added When the starting product has completely reacted, the solution is diluted in dichloromethane, washed with a saturated solution of chloride chloride sodium and dried over magnesium sulfate The solvent is evaporated The L5 derivative is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse obtenue 1 28 g (75 %)Mass obtained 1 28 g (75%)
Ce composé est dissous dans le méthanol et traite avec de l'acide fumarique pour donner le fumarate correspondantThis compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate
]H-RMN (200 MHz, dmso-d6) δ 8 65 (brs, IH, NH) , 7 66 (brs, 1 H) , 7 5-7 2 (m, 2H) , 7 2-6 8 (m, 8H) , 6 56 (s, fumarate) , 5 04 (brs, 2H) , 3 61 (brs, 4H) , 3 04 (brs, 4H) , 2 81 (brs, 4H) , 2 55 (brs, 4H) , 2 26 (s, 3H) , 2 20 (s, 6H) ] H-NMR (200 MHz, dmso-d 6 ) δ 8 65 (brs, IH, NH), 7 66 (brs, 1 H), 7 5-7 2 (m, 2H), 7 2-6 8 ( m, 8H), 6 56 (s, fumarate), 5 04 (brs, 2H), 361 (brs, 4H), 3 04 (brs, 4H), 281 (brs, 4H), 2 55 (brs, 4H), 2 26 (s, 3H), 2 20 (s, 6H)
Analyse élémentaire C3 jH39N5θ2 , 0 6 C4H4O4 , 0 25 H20 Çjkujée C = 68 25 , H = 7 18 , N = 11 91 , H20 = 0 77 Trouvée: C = 68.50 ; H = 7.22 ; N = 1 1.87 ; H20 = 0.80Elementary analysis C3 jH39N5θ 2 , 0 6 C4H4O4, 0 25 H 2 0 Çjkujée C = 68 25, H = 7 18, N = 11 91, H 2 0 = 0 77 Found: C = 68.50; H = 7.22; N = 1.187; H 2 0 = 0.80
IR (KBr): 1671, 1597, 1557, 1359, 1234IR (KBr): 1671, 1597, 1557, 1359, 1234
Rf: 0.40 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.40 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 16EXAMPLE 16
Le fumarate de la 1-{(1S) 2-[4-(2,3-DiméthylphényI)pipérazin-l-ylJ-l-méthyl-2- oxoéthyl}-3-[2-(4-méthylpipérazin-l-yl)phényl)uréylène (16)1 - {(1S) 2- [4- (2,3-Dimethylphenyl) piperazin-1-ylJ-1-methyl-2-oxoethyl} -3- [2- (4-methylpiperazin-1-yl) fumarate ) phenyl) ureylene (16)
V
Figure imgf000048_0001
 V
Figure imgf000048_0001
16A : La (2S) 2-ι'ert-butoxycarbonylamino-l-[4-(2,3-diméthyl-phényI)-pipérazin-l- ylj-propan-l-one16A: La (2S) 2-ι'ert-butoxycarbonylamino-l- [4- (2,3-dimethyl-phenyl) -piperazin-l-ylj-propan-l-one
La (L) BOC-alanine (2 g ; 10.5 mmol) est dissoute sous atmosphère d'azote dans l'acétate d'ethyle (105 ml) et le chloroforme (105 ml) en présence de 3 -hydroxy- 1,2,3 - benzotriazin-4(3H)-one (1.9 g ; 1 1.6 mmol) et de le chlorhydrate de la l-(3- dimethylaminopropyl)-3-éthylcarbodiimide (2 g ; 10.5 mmol) à température ambiante. La solution est agitée 30 minutes puis la diisopropyléthylamine (2 ml ; 1 1.6 mmol) et le dérivé B (2.6g ; 11.6 mmol) sont ajoutés. Après quelques heures, la réaction est complète. Elle est lavée avec une solution aqueuse de bicarbonate de sodium saturée puis une solution aqueuse saturée en chlorure d'ammonium. La phase organique est séchée sur sulfate de magnésium, filtrée et le solvant est évaporé. Le dérivé 16A est purifié par chromatographie-éclair avec un mélange d'éluants (20 % EtOH dans EDP).(L) BOC-alanine (2 g; 10.5 mmol) is dissolved under nitrogen atmosphere in ethyl acetate (105 ml) and chloroform (105 ml) in the presence of 3-hydroxy-1,2, 3 - benzotriazin-4 (3H) -one (1.9 g; 1 1.6 mmol) and 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2 g; 10.5 mmol) at room temperature. The solution is stirred for 30 minutes then the diisopropylethylamine (2 ml; 1 1.6 mmol) and the derivative B (2.6 g; 11.6 mmol) are added. After a few hours, the reaction is complete. It is washed with a saturated aqueous sodium bicarbonate solution and then a saturated aqueous ammonium chloride solution. The organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated. The derivative 16A is purified by flash chromatography with a mixture of eluents (20% EtOH in EDP).
Masse obtenue. 3.28 g (86 %) JH-RMN (200 MHz, dmso-d6) δ : 7.15-6.8 (m, 4H) ; 4.75 (p, IH, 7.3 Hz); 3.62 (brs, 4H); 2.75 (brs, 4H); 2.21 (s, 3H); 2.17 (s, 3H); 1.37 (s, 9H), 1.15 (d, 3H, 7.3 Hz).Mass obtained. 3.28 g (86%) JH-NMR (200 MHz, dmso-d 6 ) δ: 7.15-6.8 (m, 4H); 4.75 (p, 1 H, 7.3 Hz); 3.62 (brs, 4H); 2.75 (brs, 4H); 2.21 (s, 3H); 2.17 (s, 3H); 1.37 (s, 9H), 1.15 (d, 3H, 7.3 Hz).
16B: La (2S) 2-amino-l-[4-(2,3-diméthyl-phényl)-pipérazin-l-yl]-propan-l-one Le dérivé 16B est préparé selon la méthode utilisée pour 7 à partir des réactifs suivants. 16A (3.28 g ; 9.07 mmol) ; acide trifluoroacétique (42 ml) dans le dichlorométhane (250 ml).16B: (2S) 2-amino-1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] -propan-1-derivative 16B is prepared according to the method used for 7 from of the following reagents. 16A (3.28 g; 9.07 mmol); trifluoroacetic acid (42 ml) in dichloromethane (250 ml).
Masse obtenue: 2.27 g (95 %)Mass obtained: 2.27 g (95%)
^-RMN (200 MHz, dmso-dό) δ : 7.04 (t, IH, 7.6Hz) , 6 95-6.80 (m, 2H) , 3.77 (q, IH, 6.6Hz) ; 3.62 (brs, 4H) ; 2.76 (brs, 4H) ; 2.21 (s, 3H) , 2 19 (s, 3H) ; 1.68 (brs, 2H, NH2) ; 1.10 (d, 3H, 6.6 Hz).^ -RMN (200 MHz, dmso-dό) δ: 7.04 (t, 1H, 7.6Hz), 6 95-6.80 (m, 2H), 3.77 (q, 1H, 6.6Hz); 3.62 (brs, 4H); 2.76 (brs, 4H); 2.21 (s, 3H), 219 (s, 3H); 1.68 (brs, 2H, NH 2 ); 1.10 (d, 3H, 6.6 Hz).
16 : Le dérivé 7B (500 mg; 2.6 mmol) dissous dans le dichlorométhane (6 ml) en présence de pyridine (210ml; 2.6 mmol) est canule sur une solution refroidie à 0°C de triphosgéne (309 mg; 1 mmol) dans le dichlorométhane (6 ml). Le mélange réactionnel est agité 20 minutes puis le dérivé 16B (1.02 g; 3.9 mmol) dilué dans le dichlorométhane (6 ml) en présence de pyridine (210ml; 2.6 mmol) est ajouté goutte à goutte. La réaction n'évolue plus après quelques heures d'agitation à 0°C. Elle est ensuite diluée dans le dichlorométhane, lavée avec une solution aqueuse saturée en bicarbonate de sodium, séchée sur sulfate de magnésium et filtrée. Le solvant est évaporé et le dérivé 16 est isolé par chromatographie-éclair.16: The derivative 7B (500 mg; 2.6 mmol) dissolved in dichloromethane (6 ml) in the presence of pyridine (210 ml; 2.6 mmol) is cannulated on a solution cooled to 0 ° C of triphosgene (309 mg; 1 mmol) in dichloromethane (6 ml). The reaction mixture is stirred for 20 minutes then the derivative 16B (1.02 g; 3.9 mmol) diluted in dichloromethane (6 ml) in the presence of pyridine (210 ml; 2.6 mmol) is added dropwise. The reaction no longer progresses after a few hours of stirring at 0 ° C. It is then diluted in dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and filtered. The solvent is evaporated and the derivative 16 is isolated by flash chromatography.
Masse obtenue: 784 mg (62 %)Mass obtained: 784 mg (62%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
1H-RMN (200 MHz, dmso-d6) δ : 8.03 (dd, IH); 7 92 (s, IH), 7 66 (d, IH); 7.2-6.8 (m, 6H); 6.60 (s, fumarate); 4 78 (p, IH); 3.69 (brs, 4H), 2 9-2 6 (m, 12H), 2.36 (s, 3H); 2.23 (s, 3H); 2.20 (s, 3H); 1.26 (d, 3H).1H-NMR (200 MHz, dmso-d 6 ) δ: 8.03 (dd, 1H); 792 (s, 1H), 766 (d, 1H); 7.2-6.8 (m, 6H); 6.60 (s, fumarate); 478 (p, 1H); 3.69 (brs, 4H), 2 9-2 6 (m, 12H), 2.36 (s, 3H); 2.23 (s, 3H); 2.20 (s, 3H); 1.26 (d, 3H).
Analyse élémentaire: C27H38N6O2 ; 1.05 C4H4O4 , 0.9 H20, 0 2 Et20 Calculée: C = 60.86 : H = 7.34 ; N = 13.31 tfElementary analysis: C 2 7H 38 N 6 O 2 ; 1.05 C4H4O4, 0.9 H 2 0, 0 2 And 2 0 Calculated: C = 60.86: H = 7.34; N = 13.31 tf
Trouvée: C = 60.94 ; H = 7.65 ; N = 13.00 IR ftCBr): 3319, 1656, 1530, 1452, 1242. Rf: 0.2 (1-3-97 = NH4OH-MeOH-CH2Cl2) Masse (DCI, NH3) : 479 (MH+) aD24°= +29.5 (c = 0.3485, méthanol).Found: C = 60.94; H = 7.65; N = 13.00 IR ftCBr): 3319, 1656, 1530, 1452, 1242. Rf: 0.2 (1-3-97 = NH 4 OH-MeOH-CH 2 Cl 2 ) Mass (DCI, NH 3 ): 479 (MH + ) a D 24 ° = +29.5 ( c = 0.3485, methanol).
EXEMPLE 17EXAMPLE 17
La l-[4-(2,3-diméthyl-phényl)-pipérazin-l-ylJ-5-| l-(4-méthyl-pipérazin-l-yI)- naphtalèn-2-yloxy]-pentatι-l-one (17)1- [4- (2,3-dimethyl-phenyl) -piperazin-1-ylJ-5- | l- (4-methyl-piperazin-l-yI) - naphthalen-2-yloxy] -pentatι-l-one (17)
Figure imgf000050_0001
Figure imgf000050_0001
Le 2-hydroxy-l-(4-méthyl-pipérazin-l-yl)-naphtalène est préparé selon la procédure décrite dans le brevet français n°9408981.2-hydroxy-1- (4-methyl-piperazin-1-yl) -naphthalene is prepared according to the procedure described in French patent No. 9408981.
17 : Le dérivé 17 est préparé selon la même méthode décrite pour 2 à partir des réactifs suivants : 2A (780 mg ; 2.3 mmol) ; 2-hydroxy-l-(4-méthyl-pipérazin-l-yl)-naphtalène (468 mg ; 1.9 mmol) ; carbonate de césium (1.26 g , 3.9 mmol) dans le DMF (30 ml).17: The derivative 17 is prepared according to the same method described for 2 from the following reagents: 2A (780 mg; 2.3 mmol); 2-hydroxy-1- (4-methyl-piperazin-1-yl) -naphthalene (468 mg; 1.9 mmol); cesium carbonate (1.26 g, 3.9 mmol) in DMF (30 ml).
Masse obtenue: 452mg (46%)Mass obtained: 452 mg (46%)
^-RMN (200 MHz, CDC13) δ : 8.38 (d, IH, 8.5Hz) , 7 72 (d, IH, 7.9Hz) ; 7.62 (d, IH, 9Hz); 7.26-7.48 (m, 2H) ; 7.23 (d, IH, 9Hz) ; 7.05 (t, IH, 7.6Hz) ; 6.90 (d, IH, 7.1Hz) ; 6.83 (d, IH, 7.9Hz) ; 4.1 1 (t, 2H, 5.9Hz) , 3.62-3 75 (m, 4H) ; 2.82 (m, 8H) ; 2.46 (m, 4H) ; 2.37 (s, 3H) ; 2.26 (s, 3H) ; 2.22 (s, 3H) , 1 92 (m, 6H).^ -RMN (200 MHz, CDC1 3 ) δ: 8.38 (d, IH, 8.5Hz), 7 72 (d, IH, 7.9Hz); 7.62 (d, 1H, 9Hz); 7.26-7.48 (m, 2H); 7.23 (d, 1H, 9Hz); 7.05 (t, 1H, 7.6Hz); 6.90 (d, 1H, 7.1Hz); 6.83 (d, 1H, 7.9 Hz); 4.1 1 (t, 2H, 5.9Hz), 3.62-3 75 (m, 4H); 2.82 (m, 8H); 2.46 (m, 4H); 2.37 (s, 3H); 2.26 (s, 3H); 2.22 (s, 3H), 1,92 (m, 6H).
Rf: 0.3 (1-3-30-70 = NH4OH-MeOH-acétone-CH2Cl2) EXEMPLE 18Rf: 0.3 (1-3-30-70 = NH 4 OH-MeOH-acetone-CH 2 Cl 2 ) EXAMPLE 18
Le fumarate du 5-[3-chloro-2-(4-méthylpipérazin-l-yl)phénylamino]-l-[4-(2,3- diméthylphényl)pipérazin-l-yI]pentan-l-one (18)5- [3-Chloro-2- (4-methylpiperazin-1-yl) phenylamino] -l- [4- (2,3-dimethylphenyl) piperazin-1-yI] pentan-1-one fumarate (18)
Figure imgf000051_0001
Figure imgf000051_0001
18A: la N-tert-butoxycarbonyl-3-chloro-2-(4-méthylpipérazin-l-yl)-anHine18A: N-tert-butoxycarbonyl-3-chloro-2- (4-methylpiperazin-1-yl) -anHine
Le dérivé 26B est dissous dans du toluène (39 ml) en présence de ài-terl- butyldicarbonate (2 05 g; 9 4 mmol) sous atmosphère d'azote La solution est chauffée à 70°C pendant 24 heures Le solvant est évaporé et le dérivé 18A est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4θH-MeOH-CH2CI2)The derivative 26B is dissolved in toluene (39 ml) in the presence of α-tert-butyldicarbonate (2 05 g; 94 mmol) under a nitrogen atmosphere The solution is heated at 70 ° C for 24 hours The solvent is evaporated and derivative 18A is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 CI 2 )
Masse obtenue . 1.53 g (56 %)Mass obtained. 1.53 g (56%)
1H-RMN (200 MHz, dmso-d6) δ - 8.39 (s, IH), 7 81 (dd, IH, 1 4 et 8 Hz), 7 16 (t, IH, 8 Hz), 7 03 (dd, IH, 1 4 et 8 Hz), 3 45 (brs, 2H), 2 72 (brd, 4H), 2 23 (s, 3H), 2 12 (brs, 2H), 1 48 (s, 9H)1H-NMR (200 MHz, dmso-d 6 ) δ - 8.39 (s, IH), 7 81 (dd, IH, 1 4 and 8 Hz), 7 16 (t, IH, 8 Hz), 7 03 (dd , IH, 1 4 and 8 Hz), 3 45 (brs, 2H), 2 72 (brd, 4H), 2 23 (s, 3H), 2 12 (brs, 2H), 1 48 (s, 9H)
18B le 5-[N-fcrt-butoxycarbonyI-3-chloro-2-(4-méthylpipérazin-l- yl)phénylamino]-l-[4-(2,3-diméthylphényl)pipérazin-l-yl]pentan-l-one18B 5- [N-fcrt-butoxycarbonyI-3-chloro-2- (4-methylpiperazin-1-yl) phenylamino] -l- [4- (2,3-dimethylphenyl) piperazin-1-yl] pentan-1 -one
Le dérivé 18A (1.4 g, 4.3 mmol) est dissous dans du DMF (20 ml) à 0°C en présence d'hydrure de sodium (60% dans l'huile, 414 mg, 10 3 mmol) sous atmosphère d'azote Une solution de 2A (1.82 g, 5 2 mmol) dans le DMF (13 ml) est ajoutée goutte à goutte Le mélange réactionnel est agité 4 heures à température ambiante puis neutralisé avec quelques gouttes d'eau Le solvant est évaporé Le résidu huileux est repris dans de l'acétate d'ethyle et lavé deux fois avec de l'eau La solution est séchée sur sulfate de magnésium, filtrée puis concentrée Le dérivé 18B est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2CI2)The derivative 18A (1.4 g, 4.3 mmol) is dissolved in DMF (20 ml) at 0 ° C in the presence of sodium hydride (60% in oil, 414 mg, 10 3 mmol) under a nitrogen atmosphere A solution of 2A (1.82 g, 5 2 mmol) in DMF (13 ml) is added dropwise The reaction mixture is stirred for 4 hours at room temperature then neutralized with a few drops of water The solvent is evaporated The oily residue is taken up in ethyl acetate and washed twice with water The solution is dried over magnesium sulphate, filtered then concentrated The derivative 18B is purified by flash chromatography with a mixture of eluents (1-5- 95 = NH 4 OH-MeOH-CH 2 CI 2 )
Masse obtenue . 2 13 g (82 %) O 97/14689 PC17FR96/01626Mass obtained. 2 13 g (82%) O 97/14689 PC17FR96 / 01626
]H-RMN (200 MHz, dmso-d6) δ : 7.4-6.8 (m, 6H); 3.87 (brs, 2H); 3.55 (brs, 4H); 3.6- 2.6 (m, 10H); 2.35 (brs, 4H); 2.20 (s, 6H); 2.17 (s, 3H), 1.7-1.2 (m, 13H). ] H-NMR (200 MHz, dmso-d 6 ) δ: 7.4-6.8 (m, 6H); 3.87 (brs, 2H); 3.55 (brs, 4H); 3.6-2.6 (m, 10H); 2.35 (brs, 4H); 2.20 (s, 6H); 2.17 (s, 3H), 1.7-1.2 (m, 13H).
18: Le dérivé 18B est dissous dans du dichlorométhane (98 ml) sous atmosphère d'azote et l'acide trifluoroacétique (17 ml) est ajouté. La solution est agitée 3 heures à température ambiante, puis le solvant et l'acide sont évaporés. Le résidu huileux est repris dans du dichlorométhane et lavé à l'eau. La phase aqueuse est extraite 3 fois avec du dichlorométhane. Les phases organiques sont combinées, séchèes sur MgSθ4 et concentrées. Le dérivé 18 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = l - 10-90).18: The derivative 18B is dissolved in dichloromethane (98 ml) under a nitrogen atmosphere and trifluoroacetic acid (17 ml) is added. The solution is stirred for 3 hours at room temperature, then the solvent and the acid are evaporated. The oily residue is taken up in dichloromethane and washed with water. The aqueous phase is extracted 3 times with dichloromethane. The organic phases are combined, dried over MgSθ4 and concentrated. Derivative 18 is purified in the form of the free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-10-90).
Masse obtenue : 1.6 g (91 %)Mass obtained: 1.6 g (91%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RMN (200 MHz, dmso-d6) δ : 7.1-6.85 (m, 4H); 6.57 (s, fumarate); 6.49 (t, 2H, J=7.5Hz); 5.61 (brs, IH, NH); 3.55 (brs, 6H); 3.09 (brs, 2H); 2.91 (brd, 2H, J=10Hz); 2.8-2.3 (m, 13H); 2.20 (s, 3H); 2.17 (s, 3H); 1.59 (brs, 4H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.1-6.85 (m, 4H); 6.57 (s, fumarate); 6.49 (t, 2H, J = 7.5Hz); 5.61 (brs, 1H, NH); 3.55 (brs, 6H); 3.09 (brs, 2H); 2.91 (brd, 2H, J = 10Hz); 2.8-2.3 (m, 13H); 2.20 (s, 3H); 2.17 (s, 3H); 1.59 (brs, 4H).
Analyse élémentaire: C2gH4()ClN5θ , C4H4O4 ; 0. 1 H2O Calculée: C = 62.58 ; H = 7.22 ; N = 1 1.40 Trouvée: C = 62.60 : H = 7.31 ; N = 1 1.32Elemental analysis: C 2 gH4 () ClN5θ, C4H4O4; 0.1 H 2 O Calculated: C = 62.58; H = 7.22; N = 1 1.40 Found: C = 62.60: H = 7.31; N = 1 1.32
IR OCBr): 3600-2300, 1722, 1620, 1590, 1550.IR OCBr): 3600-2300, 1722, 1620, 1590, 1550.
Masse (DCI, NH3) : 498 (MH+)Mass (DCI, NH3): 498 (MH +)
Rf: 0.7 (1-10-90 = NH4OH-MeOH-CH2CI2) EXEMPLE 19Rf: 0.7 (1-10-90 = NH 4 OH-MeOH-CH 2 CI 2 ) EXAMPLE 19
Le fumarate de la 1-{(1R) 2-[4-(2,3-Diméthylphényl)pipérazin-l-y!|-l-méthyI-2- oxoéthyl}-3-[2-(4-méthylpipérazin-l-yl)phényl]uréylène (19)1 - {(1R) 2- [4- (2,3-Dimethylphenyl) piperazin-ly! | -L-methyl-2-oxoethyl} -3- [2- (4-methylpiperazin-1-yl) fumarate ) phenyl] ureylene (19)
Figure imgf000053_0001
Figure imgf000053_0001
19A : La (2R) 2-«'en'-butoxycarbonylamino-l-[4-(2,3-diméthyl-phényl)-pipérazin-l- ylj-propan-l-one19A: La (2R) 2 - "'en'-butoxycarbonylamino-l- [4- (2,3-dimethyl-phenyl) -piperazin-l- ylj-propan-l-one
La (D) BOC-alanine (2 g ; 10.5 mmol) est dissoute sous atmosphère d'azote dans l'acétate d'ethyle (105 ml) et le chloroforme (105 ml) en présence de le chlorhydrate de la l-(3-dimethylaminopropyl)-3-éthylcarbodiimide (2.22 g ; 1 1 6 mmol) à température ambiante. La solution est agitée 30 minutes puis la diisopropyléthylamine (2 ml ; 1 1.6 mmol) et le dérivé B (2.63g ; 11.6 mmol) sont ajoutés Après quelques heures, la réaction est complète. Elle est lavée avec une solution aqueuse saturée en bicarbonate de sodium puis une solution aqueuse saturée en chlorure d'ammonium. La phase organique est séchée sur sulfate de magnésium, filtrée et concentrée Le dérivé 19A est purifié par chromatographie-éclair avec un mélange d'éluants (20 % EtOH dans EDP).(D) BOC-alanine (2 g; 10.5 mmol) is dissolved under nitrogen atmosphere in ethyl acetate (105 ml) and chloroform (105 ml) in the presence of l- (3 hydrochloride -dimethylaminopropyl) -3-ethylcarbodiimide (2.22 g; 1 1 6 mmol) at room temperature. The solution is stirred for 30 minutes then the diisopropylethylamine (2 ml; 11.6 mmol) and the derivative B (2.63 g; 11.6 mmol) are added After a few hours, the reaction is complete. It is washed with a saturated aqueous solution of sodium bicarbonate and then a saturated aqueous solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated. The derivative 19A is purified by flash chromatography with a mixture of eluents (20% EtOH in EDP).
Masse obtenue: 1.86 g (48 %)Mass obtained: 1.86 g (48%)
19B: La (2R) 2-amino-l-[4-(2,3-diméthyl-phényl)-pipérazin-l-yl]-propan-l-one19B: La (2R) 2-amino-1- [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] -propan-1-one
Le dérivé 19B est préparé selon la méthode utilisée pour 7 à partir des réactifs suivants: 19A (1.86 g ; 5.1 mmol) ; acide trifluoroacétique (24 ml) dans le dichlorométhane (140 ml).The derivative 19B is prepared according to the method used for 7 from the following reagents: 19A (1.86 g; 5.1 mmol); trifluoroacetic acid (24 ml) in dichloromethane (140 ml).
Masse obtenue: 1.24 g (92 %) JH-RMN (200 MHz, dmso-d6) δ : 7.04 (t, IH, 7.6Hz) ; 6 95-6.80 (m, 2H) ; 3.77 (q, IH, 6.6Hz) ; 3.62 (brs, 4H) ; 2.76 (brs, 4H) ; 2.21 (s, 3H) ; 2.19 (s, 3H) ; 1.68 (brs, 2H, NH2) ; 1.10 (d, 3H, 6.6 Hz).Mass obtained: 1.24 g (92%) JH-NMR (200 MHz, dmso-d 6 ) δ: 7.04 (t, IH, 7.6Hz); 6 95-6.80 (m, 2H); 3.77 (q, 1H, 6.6Hz); 3.62 (brs, 4H); 2.76 (brs, 4H); 2.21 (s, 3H); 2.19 (s, 3H); 1.68 (brs, 2H, NH 2 ); 1.10 (d, 3H, 6.6 Hz).
s 19 : Sous atmosphère d'azote, le dérivé 7B (1.17 g; 6. 1 mmol) dissous dans le dichlorométhane (12 ml) en présence de pyridine (380ml; 4 7 mmol) est canule sur une solution refroidie à 0°C de triphosgéne (560 mg; 1.88 mmol) dans le dichlorométhane (12 ml). Le mélange réactionnel est agité 40 minutes puis le dérivé 19B (1.23 g; 4.7 mmol) dilué dans le dichlorométhane (12 ml) en présence de pyridine (380ml; 4.7 mmol) 0 est ajouté gpoutte à goutte. La réaction n'évolue plus après quelques heures d'agitation à 0°C. Elle est ensuite diluée dans le dichlorométhane, lavée avec une solution aqueuse saturée en bicarbonate de sodium, séchée sur sulfate de magnésium et filtrée. Le solvant est évaporé et le dérivé 19 est isolé par chromatographie-éclairs 19: Under a nitrogen atmosphere, the derivative 7B (1.17 g; 6.1 mmol) dissolved in dichloromethane (12 ml) in the presence of pyridine (380 ml; 47 mmol) is cannulated on a solution cooled to 0 ° C. of triphosgene (560 mg; 1.88 mmol) in dichloromethane (12 ml). The reaction mixture is stirred for 40 minutes then the derivative 19B (1.23 g; 4.7 mmol) diluted in dichloromethane (12 ml) in the presence of pyridine (380 ml; 4.7 mmol) 0 is added dropwise. The reaction no longer progresses after a few hours of stirring at 0 ° C. It is then diluted in dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and filtered. The solvent is evaporated and derivative 19 is isolated by flash chromatography
5 Masse obtenue: 1,08 g (48 %)5 Mass obtained: 1.08 g (48%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
0 1H-RMN (200 MHz, dmso-d6) δ : 8.03 (dd, IH); 7.92 (s, IH), 7.66 (d, IH); 7.2-6.8 (m, 6H); 6.60 (s, fumarate); 4.78 (p, IH); 3.69 (brs, 4H), 2.9-2 6 (m, 12H); 2.36 (s, 3H); 2.23 (s, 3H); 2.20 (s, 3H); 1.26 (d, 3H).0 1H-NMR (200 MHz, dmso-d 6 ) δ: 8.03 (dd, 1H); 7.92 (s, 1H), 7.66 (d, 1H); 7.2-6.8 (m, 6H); 6.60 (s, fumarate); 4.78 (p, 1H); 3.69 (brs, 4H), 2.9-2 6 (m, 12H); 2.36 (s, 3H); 2.23 (s, 3H); 2.20 (s, 3H); 1.26 (d, 3H).
Analyse élémentaire: C27H38N6θ2 ; 0.9 C4H4O4 ; 0.55 H20, 0.2 Et2O 5 Calculée: C = 60.86 : H = 7.34 : N = 13.31 : H2O = 2.57 Trouvée: C = 60.94 ; H = 7.65 ; N = 13.00 ; H2O = 2.6Elementary analysis: C 2 7H 38 N6θ 2 ; 0.9 C4H4O4; 0.55 H 2 0, 0.2 And 2 O 5 Calculated: C = 60.86: H = 7.34: N = 13.31: H 2 O = 2.57 Found: C = 60.94; H = 7.65; N = 13.00; H 2 O = 2.6
IR(KBr): 3319, 1656, 1530, 1452, 1242.IR (KBr): 3319, 1656, 1530, 1452, 1242.
0 Rf: 0.2 (1-3-97 = NH4OH-MeOH-CH2Cl2)0 Rf: 0.2 (1-3-97 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 479 (MH+)Mass (DCI, NH3): 479 (MH + )
aD24°= "31.7 (c = 0.4035, méthanol). Si a D 24 ° = " 3 1.7 (c = 0.4035, methanol). Yes
EXEMPLE 20EXAMPLE 20
Le fumarate du N-{2-[2-(4-méthylpipérazin-l-yl)phènoxyméthyl) phényl} 4-(2,3- diméthylphényl)pipérazine-l-carboxamide (20)N- {2- [2- (4-methylpiperazin-1-yl) phenoxymethyl) phenyl} 4- (2,3-dimethylphenyl) piperazine-1-carboxamide fumarate (20)
Figure imgf000055_0001
Figure imgf000055_0001
20A : Le 2-[2-(4-méthylpipérazin-l-yI)phénoxyméthylJ-l-nitrobenzène20A: 2- [2- (4-methylpiperazin-1-yI) phenoxymethylJ-1-nitrobenzene
Le dérivé 20A est préparé selon la même méthode décrite pour 7D à partir des réactifs suivants: A (1.5 g ; 7.8 mmol) ; 2-chlorométhyl-l-nitrobenzène (2 g ; 1 1.7 mmol) ; NaH (561 mg ; 1 1.7 mmol) dans le DMF (16 ml).The derivative 20A is prepared according to the same method described for 7D from the following reagents: A (1.5 g; 7.8 mmol); 2-chloromethyl-1-nitrobenzene (2 g; 1 1.7 mmol); NaH (561 mg; 11.7 mmol) in DMF (16 ml).
Masse obtenue: 1.44 g (56 %)Mass obtained: 1.44 g (56%)
1H-RMN (200 MHz, dmso-d6) δ : 8.2-7.5 (m, 4H); 7. 1-6.9 (m, 4H); 5.43 (s, 2H) ; 2.94 (brs, 4H) ; 2.40 (brs, 4H); 2.18 (s, 3H).1H-NMR (200 MHz, dmso-d 6 ) δ: 8.2-7.5 (m, 4H); 7. 1-6.9 (m, 4H); 5.43 (s, 2H); 2.94 (brs, 4H); 2.40 (brs, 4H); 2.18 (s, 3H).
20B : La 2-[2-(4-méthyl-pipérazin-l-yl)-phénoxyméthyIJ-aniIine20B: 2- [2- (4-methyl-piperazin-1-yl) -phenoxymethyIJ-aniIine
Le dérivé 20B est préparé selon la même méthode décrite pour 7B à partir des réactifs suivants: 20A (1.41 g ; 4.33 mmol) ; hydrazine hydratée (1.08 ml) ; Nickel de Raney (cat) dans l'ethanol (15 ml).The derivative 20B is prepared according to the same method described for 7B from the following reagents: 20A (1.41 g; 4.33 mmol); hydrazine hydrate (1.08 ml); Raney nickel (cat) in ethanol (15 ml).
Masse obtenue: 366 mg (28 %)Mass obtained: 366 mg (28%)
ÏH-RMN (200 MHz, dmso-d6) δ : 7.3-6.5 (m, 8H) ; 5. 18 (brs, 2H) ; 4.97 (s, 2H) ; 2.98 (brs, 4H) ; 2.51 (brs, 4H) ; 2.22 (s, 3H). Ï H-NMR (200 MHz, dmso-d 6 ) δ: 7.3-6.5 (m, 8H); 5.18 (brs, 2H); 4.97 (s, 2H); 2.98 (brs, 4H); 2.51 (brs, 4H); 2.22 (s, 3H).
20 : Le dérivé 20B (356 mg ; 1.19 mmol) dilué dans le dichlorométhane (3 ml) est ajouté sous atmosphère d'azote à une solution de triphosgéne (141 mg ; 0.47 mmol) dans le dichlorométhane (3 ml) à 0°C. De la pyridine (48μl ; 0.6 mmol) est ajoutée. La réaction «S *20: The derivative 20B (356 mg; 1.19 mmol) diluted in dichloromethane (3 ml) is added under a nitrogen atmosphere to a solution of triphosgene (141 mg; 0.47 mmol) in dichloromethane (3 ml) at 0 ° C . Pyridine (48μl; 0.6 mmol) is added. The reaction "S *
est agitée 10 minutes à 0°C puis le bain froid est retiré. Lorsque la solution est revenue à température ambiante la N-xylylpipérazine désalifiée (383 mg ; 2 mmol) et diluée dans le dichlorométhane (3 ml) est ajoutée goutte à goutte. De la pyridine (48μl ; 0.6 mmol) est ajoutée. Lorsque le produit de départ a totalement réagi, la solution est diluée dans du dichlorométhane, lavée avec une solution saturée en chlorure de sodium et séchée sur sulfate de magnésium. Le solvant est évaporé. Le dérivé 20 est isolé sous forme de base libre après purification par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).is stirred for 10 minutes at 0 ° C. then the cold bath is removed. When the solution has returned to room temperature, the desalified N-xylylpiperazine (383 mg; 2 mmol) and diluted in dichloromethane (3 ml) is added dropwise. Pyridine (48μl; 0.6 mmol) is added. When the starting material has completely reacted, the solution is diluted in dichloromethane, washed with a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated. The derivative 20 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue : 426 mg (69 %)Mass obtained: 426 mg (69%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
^-RMN (200 MHz, dmso-d6) δ : 8.33 (s, IH); 7.52 (d, IH); 7.45-6.8 (m, 10H); 6.58 (s, fumarate); 5.07 (s, 2H); 3.57 (brs, 4H); 3.04 (brs, 4H); 2.74 (brs, 4H); 2.61 (brs, 4H); 2.33 (s, 3H); 2.21 (s, 3H); 2.17 (s, 3H).^ -RMN (200 MHz, dmso-d 6 ) δ: 8.33 (s, 1H); 7.52 (d, 1H); 7.45-6.8 (m, 10H); 6.58 (s, fumarate); 5.07 (s, 2H); 3.57 (brs, 4H); 3.04 (brs, 4H); 2.74 (brs, 4H); 2.61 (brs, 4H); 2.33 (s, 3H); 2.21 (s, 3H); 2.17 (s, 3H).
Analyse élémentaire: C3 iH39N5Û2 ; 1.1 C4H4O4 ; 0.35 H20 ; 0.2 Et2O Calculée: C = 65.63 ; H = 7.01 ; N = 10.97 ; H2O = 0.95 Trouvée: C = 65.63 ; H = 7.05 ; N = 10.58 ; H2O = 1.0Elementary analysis: C3 iH39N5Û 2 ; 1.1 C4H4O4; 0.35 H 2 0; 0.2 And 2 O Calculated: C = 65.63; H = 7.01; N = 10.97; H 2 O = 0.95 Found: C = 65.63; H = 7.05; N = 10.58; H 2 O = 1.0
IR (KBr): 1709, 1650, 1600, 1499, 1453, 1242.IR (KBr): 1709, 1650, 1600, 1499, 1453, 1242.
Rf: 0.5 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.5 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 514 (MH+) EXEMPLE 21Mass (DCI, NH3): 514 (MH +) EXAMPLE 21
Le fumarate du N-{4-[2-(4-méthyIpipérazin-l-yl)phènoxyméthylJphényI} 4-(2,3- diméthyIphényl)pipérazine-l-carboxamide (21)N- {4- [2- (4-methylPiperazin-1-yl) phenoxymethylJphenyI} 4- (2,3-dimethyphenyl) piperazine-1-carboxamide fumarate (21)
OO
Figure imgf000057_0001
Figure imgf000057_0001
21A : Le 4-[2-(4-méthylpipérazin-l-yI)phénoxyméthyl]-l-nitrobenzène21A: 4- [2- (4-methylpiperazin-1-yI) phenoxymethyl] -l-nitrobenzene
Le dérivé 21A est préparé selon la même méthode décrite pour 7D à partir des réactifs suivants A (1 8 g , 9 4 mmol) , 4-chlorométhyl- 1 -nitrobenzene (2 42 g , 14 1 mmol) , NaH (677 mg , 14 1 mmol) dans le DMF (20 ml)The derivative 21A is prepared according to the same method described for 7D from the following reagents A (1 8 g, 9 4 mmol), 4-chloromethyl-1-nitrobenzene (2 42 g, 14 1 mmol), NaH (677 mg, 14 1 mmol) in DMF (20 ml)
Masse obtenue 851 mg (27 %)Mass obtained 851 mg (27%)
*H-RMN (200 MHz, dmso-d6) δ 8.28 (d, 8 7 Hz, 2H), 7 75 (d, 8 7 Hz, 2H), 7 1-6 9 (m, 4H), 5 28 (s, 2H) , 3 01 (brs, 4H) , 2.50 (brs, 4H), 2 23 (s, 3H)* H-NMR (200 MHz, dmso-d 6 ) δ 8.28 (d, 8 7 Hz, 2H), 7 75 (d, 8 7 Hz, 2H), 7 1-6 9 (m, 4H), 5 28 (s, 2H), 3 01 (brs, 4H), 2.50 (brs, 4H), 2 23 (s, 3H)
21B : La 4-[2-(4-méthyl-pipérazin-l-yI)-phénoxyméthyl]-aniline21B: 4- [2- (4-methyl-piperazin-1-yI) -phenoxymethyl] -aniline
Le dérivé 21B est préparé selon la même méthode décrite pour 7B à partir des réactifs suivants 21A (1 56 g , 4 8 mmol) , hydrazine hydratée (1 2 ml) , Nickel de Raney (cat) dans l'ethanol (16 ml)The derivative 21B is prepared according to the same method described for 7B from the following reagents 21A (1 56 g, 4 8 mmol), hydrazine hydrate (1 2 ml), Raney nickel (cat) in ethanol (16 ml)
Masse obtenue 788 mg (55 %)Mass obtained 788 mg (55%)
*H-RMN (200 MHz, dmso-d6) δ 7 9 (d, 8 7 Hz, 2H), 7 1-6 8 (m, 4H) , 6 54 (d, 8 7 Hz, 2H), 5 08 (brs, 2H), 4 84 (s, 2H) , 2 96 (brs, 4H) , 2 39 (brs, 4H) , 2 17(s, 3H)* H-NMR (200 MHz, dmso-d 6 ) δ 7 9 (d, 8 7 Hz, 2H), 7 1-6 8 (m, 4H), 6 54 (d, 8 7 Hz, 2H), 5 08 (brs, 2H), 4 84 (s, 2H), 2 96 (brs, 4H), 2 39 (brs, 4H), 2 17 (s, 3H)
21 Le déπvé 21B (780 mg , 2 62 mmol) dilue dans le dichlorométhane (6 ml) est ajouté sous atmosphère d'azote à une solution de triphosgéne (310 mg , 1 04 mmol) dans le dichlorométhane (6 ml) à 0°C De la pyπdme (105 μl , 0 6 mmol) est ajoutée La réaction est agitée 10 minutes à 0°C puis le bain froid est retiré. Lorsque la solution est revenue à température ambiante la N-xylylpipérazine désalifiée (832 mg ; 4.38 mmol) et diluée dans le dichlorométhane (6 ml) est ajoutée goutte à goutte. De la pyridine (105 μl; 0.6 mmol) est ajoutée. Lorsque le produit de départ a totalement réagi, la solution est diluée dans du dichlorométhane, lavée avec une solution saturée en chlorure de sodium et séchée sur sulfate de magnésium. Le solvant est évaporé. Le dérivé 2_! est isolé sous forme de base libre après purification par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).21 The deπvé 21B (780 mg, 262 mmol) diluted in dichloromethane (6 ml) is added under a nitrogen atmosphere to a solution of triphosgéne (310 mg, 104 mmol) in dichloromethane (6 ml) at 0 ° C Pyπdme (105 μl, 0 6 mmol) is added La the reaction is stirred for 10 minutes at 0 ° C. then the cold bath is removed. When the solution has returned to ambient temperature the desalified N-xylylpiperazine (832 mg; 4.38 mmol) and diluted in dichloromethane (6 ml) is added dropwise. Pyridine (105 μl; 0.6 mmol) is added. When the starting material has completely reacted, the solution is diluted in dichloromethane, washed with a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated. The derivative 2_! is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue : 1.15 g (85 %)Mass obtained: 1.15 g (85%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
1H-RMN (200 MHz, dmso-d6) δ : 8.63 (s, IH), 7.50 (d, 2H); 7.32 (d, 2H), 7.15-6.8 (m, 7H); 6.56 (s, fumarate); 4.99 (s, 2H); 3.60 (brs, 4H), 3 01 (brs, 4H); 2.79 (brs, 4H); 2.52 (brs, 4H); 2.26 (s, 3H); 2.21 (s, 3H); 2.19 (s, 3H).1H-NMR (200 MHz, dmso-d 6 ) δ: 8.63 (s, 1H), 7.50 (d, 2H); 7.32 (d, 2H), 7.15-6.8 (m, 7H); 6.56 (s, fumarate); 4.99 (s, 2H); 3.60 (brs, 4H), 3 01 (brs, 4H); 2.79 (brs, 4H); 2.52 (brs, 4H); 2.26 (s, 3H); 2.21 (s, 3H); 2.19 (s, 3H).
Analyse élémentaire: C31H39N5O;? ; 0.55 C4H4O4 , 0 3 H20 Calculée: C = 68.41 ; H = 7.23 ; N = 12.01 ; H2O = 0.9 Trouvée: C = 68.34 ; H = 7.14 ; N = 11.87 ; H2O = 0.9Elementary analysis: C31H39N5O ;? ; 0.55 C4H4O4, 0 3 H 2 0 Calculated: C = 68.41; H = 7.23; N = 12.01; H 2 O = 0.9 Found: C = 68.34; H = 7.14; N = 11.87; H 2 O = 0.9
IR (KBr): 3325, 2938, 1795, 1640IR (KBr): 3325, 2938, 1795, 1640
Rf: 0.3 (1-5-95 = NH4θH-MeOH-CH2Cl2)Rf: 0.3 (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 514 (MH+) EXEMPLE 22Mass (DCI, NH 3 ): 514 (MH + ) EXAMPLE 22
Le fumarate de la 4-[2-(4-Méthylpipérazin-l-yl)phènoxy|-l-(4-phènétlιyIpipérazin- i-yi) butan-1-one (22)4- [2- (4-Methylpiperazin-1-yl) phenoxy | -l- (4-phenetlιyIpiperazin-i-yi) butan-1-one fumarate (22)
Figure imgf000059_0001
Figure imgf000059_0001
22A : La 4-chloro-l-[4-phènéthyIpipérazin-l-yIJbutan-l-one22A: 4-Chloro-l- [4-PhenethyIpiperazin-l-yIJbutan-l-one
Le dérivé 22A est préparé selon la même procédure décrite pour LA à partir des réactifs suivants: 1 -phènéthylpipérazine (700 mg ; 3.7 mmol) ; chlorure de 4-chlorobutanoyle (493 ml ; 4.4 mmol) ; triéthylamine (767 ml ; 5.5 mmol) dans le dichlorométhane (7.3 ml).The derivative 22A is prepared according to the same procedure described for LA from the following reagents: 1 -phenethylpiperazine (700 mg; 3.7 mmol); 4-chlorobutanoyl chloride (493 ml; 4.4 mmol); triethylamine (767 ml; 5.5 mmol) in dichloromethane (7.3 ml).
Masse obtenue: 1.0 g (65 %)Mass obtained: 1.0 g (65%)
'H-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 5H) ; 3.64 (t, 2H) ; 3.4 (m, 4H) ; 2.7 (m, 2H) ; 2.6-2.2 (m, 8H); 1.91 (p, 2H).'H-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 5H); 3.64 (t, 2H); 3.4 (m, 4H); 2.7 (m, 2H); 2.6-2.2 (m, 8H); 1.91 (p, 2H).
2 : Le dérivé A (313 mg ; 1.6 mmol) est dissous dans le DMF (8 ml) en présence de 22A (980 mg ; 2.4 mmol) et d'hydrure de sodium (1 16 mg ; 2.4 mmol) sous atmosphère d'azote à 0°C. Le mélange est agité 24 heures à température ambiante, puis dilué dans de l'acétate d'ethyle, lavé deux fois avec de l'eau, séché sur sulfate de magnésium et concentré. Le dérivé 22 est isolé sous forme de base libre après purification par chromatographie-éclair avec un mélange d'éluants (1-7-93 = NH4θH-MeOH-CH2CI2).2: The derivative A (313 mg; 1.6 mmol) is dissolved in DMF (8 ml) in the presence of 22A (980 mg; 2.4 mmol) and sodium hydride (1 16 mg; 2.4 mmol) under an atmosphere of nitrogen at 0 ° C. The mixture is stirred for 24 hours at room temperature, then diluted in ethyl acetate, washed twice with water, dried over magnesium sulfate and concentrated. Derivative 22 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-7-93 = NH4θH-MeOH-CH 2 CI 2 ).
Masse obtenue: 249 mg (34%)Mass obtained: 249 mg (34%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. ]H-RMN (200 MHz, dmso-dg) δ : 7.4-7.1 (m, 6H); 6.88 (brd, 3H); 6.57 (s, fumarate); 3.96 (t, 2H, 6Hz); 3.44 (brs, 4H); 3.00 (brs, 4H); 2.8-2.2 (m, 17H); 1.94 (p, 2H, 6Hz).This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. ] H-NMR (200 MHz, dmso-dg) δ: 7.4-7.1 (m, 6H); 6.88 (brd, 3H); 6.57 (s, fumarate); 3.96 (t, 2H, 6Hz); 3.44 (brs, 4H); 3.00 (brs, 4H); 2.8-2.2 (m, 17H); 1.94 (p, 2H, 6Hz).
Analyse élémentaire: C27H3gN4θ2 ; 1.2 C4H4O4 ; 0.17 H2O Calculée: C = 65.14 ; H = 7.64 ; N = 9.44 Trouvée: C = 64.99 ; H = 7.53 ; N = 9.35Elemental analysis: C 2 7H3gN4θ 2 ; 1.2 C4H4O4; 0.17 H 2 O Calculated: C = 65.14; H = 7.64; N = 9.44 Found: C = 64.99; H = 7.53; N = 9.35
DKKBr): 3422, 2945, 1716, 1642DKKBr): 3422, 2945, 1716, 1642
Masse (DCI, NH3) : 451 (MH+)Mass (DCI, NH 3 ): 451 (MH + )
Rf: 0.3 (1-7-93 = NH4OH-MeOH-CH2Cl2)Rf: 0.3 (1-7-93 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 23EXAMPLE 23
Le fumarate de la N-{2-[2-(4-méthylpipérazin-l-yl)phènoxy] éthyl} 4-(2,3- Diméthy]phény.)pipérazine-l-carboxamide (23)N- {2- [2- (4-methylpiperazin-1-yl) phenoxy] ethyl} 4- (2,3-Dimethyl] pheny.) Fumerate piperazine-1-carboxamide (23)
Figure imgf000060_0001
Figure imgf000060_0001
23 A: le [2-(4-méthylpipérazin-l-yl)phènoxy]acétonitrile23 A: [2- (4-methylpiperazin-1-yl) phenoxy] acetonitrile
Le dérivé A (554 mg; 2.9 mmol) est dissous dans du diméthylformamide (20 ml) en présence de bromoacétonitrile (220 ml ; 3.2 mmol) et de carbonate de potassium (1.2 g ; 8.4 mmol) sous atmosphère d'azote. La suspension est agitée 4 jours à température ambiante puis chauffée 1 jour à 60°C. La réaction n'évolue plus. Le solvant est évaporé, le résidu huileux est dissous dans de l'acétate d'ethyle, lavé deux fois avec de l'eau et séché sur sulfate de magnésium. Le dérivé 23A est purifié sous forme de base libre par chromatographie-éclair avec un gradient de NH4θH-MeOH-CH2Cl2 (0.5-2 à 5- 98 à 95). Masse obtenue : 179 mg (27 %)Derivative A (554 mg; 2.9 mmol) is dissolved in dimethylformamide (20 ml) in the presence of bromoacetonitrile (220 ml; 3.2 mmol) and potassium carbonate (1.2 g; 8.4 mmol) under a nitrogen atmosphere. The suspension is stirred for 4 days at room temperature and then heated for 1 day at 60 ° C. The reaction no longer evolves. The solvent is evaporated, the oily residue is dissolved in ethyl acetate, washed twice with water and dried over magnesium sulfate. The derivative 23A is purified in the form of the free base by flash chromatography with a gradient of NH4θH-MeOH-CH 2 Cl 2 (0.5-2 to 5-98 to 95). Mass obtained: 179 mg (27%)
]H-RMN (200 MHz, dmso-d6) δ : 7.00 (brs, 4H); 5 13 (s, 2H), 2 94 (brs, 4H), 2.47 (brs, 4H); 2.20 (s, 3H). ] H-NMR (200 MHz, dmso-d 6 ) δ: 7.00 (brs, 4H); 5 13 (s, 2H), 294 (brs, 4H), 2.47 (brs, 4H); 2.20 (s, 3H).
23B: le l-amino-2-[2-(4-méthylpipérazin-l-yl)phènoxy]éthane23B: 1-amino-2- [2- (4-methylpiperazin-1-yl) phenoxy] ethane
Le dérivé 23A (560 mg; 2.4 mmol) est dissous dans du THF (17 ml) sous atmosphère d'azote et l'hydrure de lithium et d'aluminium (IM dans le THF, 7.5 ml, 7.5 mmol) est ajouté goutte à goutte à 0°C. Le mélange réactionnel est agité 1 heure à température ambiante, puis neutralisé par ajout successif de 190 ml d'eau, 190 ml de NaOH 10% dans l'eau et 570 ml d'eau. Le précipité est retiré par filtration et le filtrat est concentré. Le dérivé 23B est purifié par chromatographie-éclair avec un mélange d'éluants (1- 10-90 = NH4OH-MeOH-CH2Cl2).The derivative 23A (560 mg; 2.4 mmol) is dissolved in THF (17 ml) under a nitrogen atmosphere and the lithium aluminum hydride (IM in THF, 7.5 ml, 7.5 mmol) is added dropwise. drop at 0 ° C. The reaction mixture is stirred for 1 hour at room temperature, then neutralized by successive addition of 190 ml of water, 190 ml of 10% NaOH in water and 570 ml of water. The precipitate is removed by filtration and the filtrate is concentrated. The derivative 23B is purified by flash chromatography with a mixture of eluents (1- 10-90 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 258 mg (45%)Mass obtained: 258 mg (45%)
^-RMN (200 MHz, dmso-d6) δ : 6.89 (brs, 4H), 3.92 (t, 2H, 5.6Hz); 2.98 (brs, 4H); 2.88 (brs, 2H); 2.46 (brs, 4H); 2.23 (s, 3H).^ -RMN (200 MHz, dmso-d 6 ) δ: 6.89 (brs, 4H), 3.92 (t, 2H, 5.6Hz); 2.98 (brs, 4H); 2.88 (brs, 2H); 2.46 (brs, 4H); 2.23 (s, 3H).
Le chlorure de 4-(2,3-diméthylphényl)pipérazin-l-ylcarbonyle est préparé selon la procédure décrite dans le brevet français n°94089814- (2,3-dimethylphenyl) piperazin-1-ylcarbonyl chloride is prepared according to the procedure described in French patent n ° 9408981
23: Le chlorure de 4-(2,3-diméthylphényl)pipérazin-l-yIcarbonyle (405 mg; 1.6 mmol) est dissous dans du THF (6 ml) en présence de 23B (253 mg; 1.07 mmol) et de carbonate de césium (348 mg ; 1.07 mmol) sous atmosphère d'azote. La suspension est agitée 1 jour à température ambiante. La réaction n'évolue plus. Le solvant est évaporé, le résidu huileux est dissous dans de l'acétate d'ethyle, lavé deux fois avec de l'eau, une fois avec de la soude IM et séché sur sulfate de magnésium Le dérivé 23 est purifié sous forme de base libre par chromatographie-éclair avec un gradient de NH4θH-MeOH- CH2Cl2 (0.5-2 à 5- 98 à 95).23: 4- (2,3-Dimethylphenyl) piperazin-1-yIcarbonyl chloride (405 mg; 1.6 mmol) is dissolved in THF (6 ml) in the presence of 23B (253 mg; 1.07 mmol) and carbonate cesium (348 mg; 1.07 mmol) under a nitrogen atmosphere. The suspension is stirred for 1 day at room temperature. The reaction no longer evolves. The solvent is evaporated off, the oily residue is dissolved in ethyl acetate, washed twice with water, once with IM soda and dried over magnesium sulfate Derivative 23 is purified in the form of the base free by flash chromatography with a gradient of NH4θH-MeOH-CH 2 Cl 2 (0.5-2 to 5-98 to 95).
Masse obtenue : 275 mg (56 %)Mass obtained: 275 mg (56%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. boThis compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. bo
1H-RMN (200 MHz, dmso-d6) δ : 7.1-6.8 (m, 7H); 6.75 (brt, IH); 6.59 (fumarate); 4.01 (t, 2H, 5.6Hz); 3.47 (brs, 6H); 3.06 (brs, 4H), 2.74 (brs, 8H); 2.37 (s, 3H); 2.22 (s, 3H); 2.18 (s, 3H).1H-NMR (200 MHz, dmso-d 6 ) δ: 7.1-6.8 (m, 7H); 6.75 (brt, 1H); 6.59 (fumarate); 4.01 (t, 2H, 5.6Hz); 3.47 (brs, 6H); 3.06 (brs, 4H), 2.74 (brs, 8H); 2.37 (s, 3H); 2.22 (s, 3H); 2.18 (s, 3H).
Analyse élémentaire: C26H37NsO2 ; 0.95 C4H4O4 , 0.38 H?0 Calculée: C = 63.47 ; H = 7.28 ; N = 12.34 Trouvée: C = 63.90 : H ≈ 7.31 ; N = 12.36Elemental analysis: C 2 6H37NsO 2 ; 0.95 C4H4O4, 0.38 H ? 0 Calculated: C = 63.47; H = 7.28; N = 12.34 Found: C = 63.90: H ≈ 7.31; N = 12.36
IR (KBr): 3348, 3100-2700, 1702, 1642.IR (KBr): 3348, 3100-2700, 1702, 1642.
Masse (DCI, NH3) : 452 (MH+)Mass (DCI, NH3): 452 (MH + )
Rf: 0.26 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.26 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 24EXAMPLE 24
Le fumarate de la 4-[4-(2,3-Diméthylphényl)pipérazin-l-yl]-Λ'-[2-(4- méthylpipérazin-l-yl)phényl]-4-oxobutanamide (24)4- [4- (2,3-Dimethylphenyl) piperazin-1-yl] -Λ '- [2- (4-methylpiperazin-1-yl) phenyl] -4-oxobutanamide fumarate (24)
Figure imgf000062_0001
°
Figure imgf000062_0001
°
24: L'aniline 7B (1.91 g; 10 mmol) est dissoute dans le toluène (24 ml) à -78°C sous atmosphère d'azote. L'anhydride succinique (1 g; 10 mmol) dissoute dans du toluène (15 ml) est ajoutée goutte à goutte. Le bain froid est retiré. Le mélange réactionnel est agité 1 heure à température ambiante puis chauffé 48 heures à 80°C. De la triéthylamine (10 mmol) est ajouté et la réaction est à nouveau chauffée 24 heures. Le solvant est évaporé. Le résidu est dissous dans du dichlorométhane (33 ml) sous atmosphère d'azote en présence de B (2.71 g, 12 mmol), de triéthylamine (2.53 ml; 1 1 mmol), de chlorhydrate de la l-(3-dimethylaminopropyl)-3-éthylcarbodiimide (2.1 g ; 1 1 mmol) et de 4-N,N- diméthylaminopyridine (40 mg). Le mélange réactionnel est agité 24 heures à température ambiante, puis dilué dans du dichlorométhane, lavé une fois avec de l'eau et une fois avec une solution aqueuse saturée en bicarbonate de sodium, séché sur sulfate de magnésium et concentré. Le dérivé 24 est isolé sous forme de base libre après purification par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH- MeOH-CH2Cl2).24: Aniline 7B (1.91 g; 10 mmol) is dissolved in toluene (24 ml) at -78 ° C under a nitrogen atmosphere. The succinic anhydride (1 g; 10 mmol) dissolved in toluene (15 ml) is added dropwise. The cold bath is removed. The reaction mixture is stirred for 1 hour at room temperature and then heated for 48 hours at 80 ° C. Triethylamine (10 mmol) is added and the reaction is again heated for 24 hours. The solvent is evaporated. The residue is dissolved in dichloromethane (33 ml) under a nitrogen atmosphere in the presence of B (2.71 g, 12 mmol), triethylamine (2.53 ml; 11 mmol), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (2.1 g; 11 mmol) and 4-N, N-dimethylaminopyridine (40 mg). The reaction mixture is stirred for 24 hours at room temperature, then diluted in dichloromethane, washed once with water and once with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated. Derivative 24 is isolated in the form of a free base after purification by flash chromatography with a mixture of eluents (1-5-95 = NH4OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 2.22 g (48%)Mass obtained: 2.22 g (48%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
ÏH-RMN (200 MHz, dmso-d6) δ : 7.2-6.75 (m, 6H); 6.56 (s, fumarate); 3.59 (brs, 4H); 3.0-2.5 (m, 16H); 2.38 (s, 3H); 2.19 (s, 3H); 2.16 (s, 3H). Ï H-NMR (200 MHz, dmso-d 6 ) δ: 7.2-6.75 (m, 6H); 6.56 (s, fumarate); 3.59 (brs, 4H); 3.0-2.5 (m, 16H); 2.38 (s, 3H); 2.19 (s, 3H); 2.16 (s, 3H).
Analyse élémentaire: C27H37N5Û2 ; C4H4O4 ; 0.26 H2O Calculée: C = 64.23 ; H = 7.13 ; N = 12.08 Trouvée: C = 64.13 : H ≈ 7.18 : N ≈ 12.11 IR (KBr): 2918, 281, 1642, 1514, .Elementary analysis: C 2 7H37N5Û 2 ; C4H4O4; 0.26 H 2 O Calculated: C = 64.23; H = 7.13; N = 12.08 Found: C = 64.13: H ≈ 7.18: N ≈ 12.11 IR (KBr): 2918, 281, 1642, 1514,.
Masse (DCI, NH3) : 464 (MH+)Mass (DCI, NH 3 ): 464 (MH + )
Rf: 0.25 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.25 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 25EXAMPLE 25
Le fumarate de la 5-[4-(2,3-Diméthylphényl)pipérazin-l-yl]-N-[2-(4- méthylpipérazin-l-yl)phényI]-5-oxopentanamide (25)5- [4- (2,3-Dimethylphenyl) piperazin-1-yl] -N- [2- (4-methylpiperazin-1-yl) phenyl] -5-oxopentanamide fumarate (25)
Figure imgf000063_0001
bis
Figure imgf000063_0001
bis
25: L'aniline 7B (1.62 g; 8.5 mmol) est dissoute dans le toluène (22 ml) à -78°C sous atmosphère d'azote. L'anhydride glutarique (1 g; 8.5 mmol) dissoute dans du toluène (20 ml) est ajoutée goutte à goutte. Le bain froid est retiré. Le mélange réactionnel est agité 1 heure à température ambiante puis chauffé 24 heures à 80°C. Le solvant est évaporé. Le résidu est dissous dans du dichlorométhane (29 ml) sous atmosphère d'azote en présence de B (2.29 g, 10.1 mmol), de triéthylamine (1.29.ml; 9.3 mmol), de chlorhydrate de la l-(3-dimethylaminopropyl)-3-éthylcarbodiimide (1.77 g ; 9.3 mmol) et de 4-N,N-diméthylaminopyridine (30 mg). Le mélange réactionnel est agité 24 heures à température ambiante, puis dilué dans du dichlorométhane, lavé une fois avec de l'eau et une fois avec une solution aqueuse saturée en bicarbonate de sodium, séché sur sulfate de magnésium et concentré. Le dérivé 25 est isolé sous forme de base libre après purification par chromatographie-éclair avec un mélange d'éluants (1 -5-95 = NH4OH- MeOH-CH2Cl2).25: Aniline 7B (1.62 g; 8.5 mmol) is dissolved in toluene (22 ml) at -78 ° C under a nitrogen atmosphere. Glutaric anhydride (1 g; 8.5 mmol) dissolved in toluene (20 ml) is added dropwise. The cold bath is removed. The reaction mixture is stirred for 1 hour at room temperature and then heated for 24 hours at 80 ° C. The solvent is evaporated. The residue is dissolved in dichloromethane (29 ml) under a nitrogen atmosphere in the presence of B (2.29 g, 10.1 mmol), triethylamine (1.29.ml; 9.3 mmol), l- (3-dimethylaminopropyl) hydrochloride -3-ethylcarbodiimide (1.77 g; 9.3 mmol) and 4-N, N-dimethylaminopyridine (30 mg). The reaction mixture is stirred for 24 hours at room temperature, then diluted in dichloromethane, washed once with water and once with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated. The derivative 25 is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1 -5-95 = NH4OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 658 mg (16%)Mass obtained: 658 mg (16%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RMN (200 MHz, dmso-d6) δ : 8.79 (s, IH); 7.94 (brs, IH); 7.2-6.95 (m, 4H); 6.87 (brt, 2H); 6.59 (s, fumarate); 3.59 (brs, 4H); 3.42 (q, EtOH), 2.9-2.55 (m, 12H); 2.55- 2.3 (m, 4H); 2.33 (s, 3H); 2.20 (s, 3H); 2.19 (s, 3H), 1.85 (p, 2H, J=7Hz); 1.05 (t, EtOH).JH-NMR (200 MHz, dmso-d 6 ) δ: 8.79 (s, 1H); 7.94 (brs, 1H); 7.2-6.95 (m, 4H); 6.87 (brt, 2H); 6.59 (s, fumarate); 3.59 (brs, 4H); 3.42 (q, EtOH), 2.9-2.55 (m, 12H); 2.55-2.3 (m, 4H); 2.33 (s, 3H); 2.20 (s, 3H); 2.19 (s, 3H), 1.85 (p, 2H, J = 7Hz); 1.05 (t, EtOH).
Analyse élémentaire: C28H39N5θ2 ; 1.25 C4H4O4 ; 0.18 H2O; 0.5 EtOH Calculée: C = 62.92 ; H = 7.36 ; N = 10.79 Trouvée: C = 62.92 ; H = 7.63 ; N = 10.99Elementary analysis: C 2 8H 39 N5θ 2 ; 1.25 C4H4O4; 0.18 H 2 O; 0.5 Calculated EtOH: C = 62.92; H = 7.36; N = 10.79 Found: C = 62.92; H = 7.63; N = 10.99
IR rKBr): 3470, 3362, 3100-2800, 1680, 1635. Masse (DCI, NH3) : 478 (MH+)IR rKBr): 3470, 3362, 3100-2800, 1680, 1635. Mass (DCI, NH 3 ): 478 (MH + )
Rf: 0.3 (0.5-5-95 = NH4OH-MeOH-CH2CI2) EXEMPLE 26Rf: 0.3 (0.5-5-95 = NH 4 OH-MeOH-CH 2 CI 2 ) EXAMPLE 26
Le fumarate de la 3-[3-Chloro-2-(4-méthylpipérazin-l-yl)phényJamino)-l-[4-(2,3- diméthyIphényl)pipérazin-l-yl]propan-l-one (26)3- [3-Chloro-2- (4-methylpiperazin-1-yl) phenyJamino) -l- [4- (2,3-dimethylphenyl) piperazin-1-yl] propan-1-one fumarate (26 )
Figure imgf000065_0001
Figure imgf000065_0001
26A: le 3-chloro-2-(4-méthylpipérazin-l-yl)-l-nitrobenzène Le 2,3-dichloro-l -nitrobenzene (10 g; 52 mmol) est chauffé à 100°C sous atmosphère d'azote, pendant 24 heures dans le DMF (15 ml) en présence de N-méthylpipérazine (6.9 ml; 62 mmol) et de carbonate de potassium (8.62 g; 62 mmol). La suspension est filtée. Le filtrat est dilué dans l'acétate d'ethyle et lavé deux fois avec de l'eau. La solution est séchée sur sulfate de magnésium et filtrée. Le solvant est évaporé. Le dérivé 26A est purifié par chromatographie-éclair avec un mélange d'éluants (0.5-3-97 = NH4OH- MeOH-CH2Cl2).26A: 3-chloro-2- (4-methylpiperazin-1-yl) -l-nitrobenzene 2,3-dichloro-1-nitrobenzene (10 g; 52 mmol) is heated to 100 ° C. under a nitrogen atmosphere , for 24 hours in DMF (15 ml) in the presence of N-methylpiperazine (6.9 ml; 62 mmol) and potassium carbonate (8.62 g; 62 mmol). The suspension is filtered. The filtrate is diluted in ethyl acetate and washed twice with water. The solution is dried over magnesium sulfate and filtered. The solvent is evaporated. The 26A derivative is purified by flash chromatography with a mixture of eluents (0.5-3-97 = NH4OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 1 1.1 g (84%)Mass obtained: 1 1.1 g (84%)
tH-RMN (200 MHz, dmso-dό) δ : 7.8-7.65 (m, 2H); 7.18 (t, IH, 8Hz); 2.98 (brs, 4H); 2.40 (brs, 4H); 2.19 (s, 3H).tH-NMR (200 MHz, dmso-dό) δ: 7.8-7.65 (m, 2H); 7.18 (t, 1H, 8Hz); 2.98 (brs, 4H) ; 2.40 (brs, 4H); 2.19 (s, 3H).
26B: le 3-chloro-2-(4-méthylpipérazin-l-yl)-aniline26B: 3-chloro-2- (4-methylpiperazin-1-yl) -aniline
Le dérivé 26A (10.95 g ; 42.8 mmol) est dissous dans l'ethanol (143 ml) sous atmosphère d'azote en présence d'une quantité catalytique de Nickel de Raney. L'hydrazine hydratée (10.7 ml) est ajoutée goutte à goutte. La réaction est exothermique. Le mélange réactionnel est agité quelques heures puis filtré. Le solvant est évaporé et le dérivé 26B est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH- MeOH-CH2Cl2).The derivative 26A (10.95 g; 42.8 mmol) is dissolved in ethanol (143 ml) under a nitrogen atmosphere in the presence of a catalytic amount of Raney Nickel. Hydrated hydrazine (10.7 ml) is added dropwise. The reaction is exothermic. The reaction mixture is stirred for a few hours and then filtered. The solvent is evaporated and the derivative 26B is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 8.7 g (90 %) JH-RMN (200 MHz, dmso-d6) δ : 6.82 (t, IH, 7.9Hz); 6.60 (dd, IH, 7.9 et 1.4Hz); 6.43 (dd, IH, 7.9 et 1.4Hz); 5.25 (brs, 2H); 3.42 (dt, 2H, 10.9 et 2.1 Hz); 2.66 (brd, 2H); 2.57 (brd, 2H); 2.19 (s, 3H); 2.13 (dt, 2H, 10.8 et 2.7 Hz)Mass obtained: 8.7 g (90%) JH-NMR (200 MHz, dmso-d 6 ) δ: 6.82 (t, 1H, 7.9Hz); 6.60 (dd, IH, 7.9 and 1.4Hz); 6.43 (dd, IH, 7.9 and 1.4Hz); 5.25 (brs, 2H); 3.42 (dt, 2H, 10.9 and 2.1 Hz); 2.66 (brd, 2H); 2.57 (brd, 2H); 2.19 (s, 3H); 2.13 (dt, 2H, 10.8 and 2.7 Hz)
Analyse élémentaire: C] iHig^ClElementary analysis: C ] iHig ^ Cl
Calculée: C = 58.53 ; H = 7.14 ; N = 18.62 Trouvée: C = 58.38 ; H = 7.25 ; N = 18.43Calculated: C = 58.53; H = 7.14; N = 18.62 Found: C = 58.38; H = 7.25; N = 18.43
26C: le 3-tertbutoxycarbonylamino-l-[4-(2,3-diméthylphényl)pipérazin-l- yl]propan-l-one26C: 3-tertbutoxycarbonylamino-1- [4- (2,3-dimethylphenyl) piperazin-1-yl] propan-1-one
La N-/e/7-butoxycarbonylhomogIycine (2 g; 10.5 mmol) est dissoute dans du dichlorométhane (35 ml) sous atmosphère d'azote en présence de B (2.87 g; 12.7 mmol), de triéthylamine (1.62 ml; 11.6 mmol), de chlorhydrate de la l -(3-dimethylaminopropyl)- 3-éthylcarbodiimide (2.22 g ; 11.6 mmol) et de 4-N,N-diméthylaminopyridine (30 mg). Le mélange réactionnel est agité 24 heures à température ambiante, puis dilué dans du dichlorométhane, lavé une fois avec de l'eau et une fois avec une solution aqueuse saturée en bicarbonate de sodium, séché sur sulfate de magnésium et concentré. Le dérivé 26C est isolé sous forme de base libre après purification par chromatographie- éclair avec un mélange d'éluants (1-5-95 = NH4θH-MeOH-CH2Cl2).The N- / e / 7-butoxycarbonylhomogIycin (2 g; 10.5 mmol) is dissolved in dichloromethane (35 ml) under a nitrogen atmosphere in the presence of B (2.87 g; 12.7 mmol), of triethylamine (1.62 ml; 11.6 mmol ), 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride (2.22 g; 11.6 mmol) and 4-N, N-dimethylaminopyridine (30 mg). The reaction mixture is stirred for 24 hours at room temperature, then diluted in dichloromethane, washed once with water and once with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated. The 26C derivative is isolated in the form of the free base after purification by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 3.58 g (93%)Mass obtained: 3.58 g (93%)
iH-RMN (200 MHz, dmso-d6) δ : 7.03 (t, IH, 7.6Hz), 6.95-6.6 (m, 3H); 3.56 (brs, 4H); 3.15 (q, 2H, 6.9Hz); 2.85-2.65 (m, 4H); 2.6-2 4 (m, 2H); 2.21 (s, 3H), 2.18 (s, 3H); 1.37 (s, 9H).iH-NMR (200 MHz, dmso-d 6 ) δ: 7.03 (t, IH, 7.6Hz), 6.95-6.6 (m, 3H); 3.56 (brs, 4H); 3.15 (q, 2H, 6.9Hz); 2.85-2.65 (m, 4H); 2.6-2 4 (m, 2H); 2.21 (s, 3H), 2.18 (s, 3H); 1.37 (s, 9H).
26: Le dérivé 26B est dissous dans du THF (12 ml) sous atmosphère d'azote et refroidi à 0°C. Le Λ-buthyllitium (1.6M dans le THF; 1.5 ml, 2.4 mmol) est ajouté goutte à goutte suivi par le dérivé 26C (798 mg; 2.2 mmol). Le bain froid est retiré et la solution est chauffée 24 heures à 65°C. La réaction est neutralisée avec quelques gouttes d'eau et le solvant est évaporé. Le produit 26 est isolé sous forme de base libre après purification par chromatographie-éclair avec un gradient d'éluants (1 -2-98 à 1-6-94 = NH4OH- MeOH-CH2Cl2).26: The derivative 26B is dissolved in THF (12 ml) under a nitrogen atmosphere and cooled to 0 ° C. Λ-Buthyllitium (1.6M in THF; 1.5 ml, 2.4 mmol) is added dropwise followed by the derivative 26C (798 mg; 2.2 mmol). The cold bath is removed and the solution is heated for 24 hours at 65 ° C. The reaction is neutralized with a few drops of water and the solvent is evaporated. Product 26 is isolated in the form of the free base after purification by flash chromatography with a gradient of eluents (1 -2-98 to 1-6-94 = NH4OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 148 mg (14%) Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondantMass obtained: 148 mg (14%) This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate
1H-RMN (200 MHz, dmso-d6) δ 7 1-6 7 (m, 4H), 6 59 (s, fumarate), 6 65-6 45 (m, 2H), 5 88 (brs, IH), 3 7-3 2 (m, 8H), 2 9-2 25 (m, 12H), 2 35 (s, 3H), 2 21 (s, 3H), 2 18 (s, 3H)1H-NMR (200 MHz, dmso-d 6 ) δ 7 1-6 7 (m, 4H), 6 59 (s, fumarate), 6 65-6 45 (m, 2H), 5 88 (brs, IH) , 3 7-3 2 (m, 8H), 2 9-2 25 (m, 12H), 2 35 (s, 3H), 2 21 (s, 3H), 2 18 (s, 3H)
Analyse élémentaire C26H36CIN5θ , 1 1 C4H4O4 , 0 17 H20, 0 5 EtOH Calculée C = 61 09, H = 6 81, N = 11 72 Trouvée C = 61 06, H = 6 80, N = 11 60Elementary analysis C 26 H 3 6CIN5θ, 1 1 C4H4O4, 0 17 H 2 0, 0 5 EtOH Calculated C = 61 09, H = 6 81, N = 11 72 Found C = 61 06, H = 6 80, N = 11 60
IR (KBr) 3600-2300, 1716, 1650, 1647, 1600IR (KBr) 3600-2300, 1716, 1650, 1647, 1600
Masse (DCI. NH3) 470 (MH+)Mass (DCI. NH3) 470 (MH + )
Rf 0 55 (0 5-5-95 = NH4OH-MeOH-CH2Cl2)Rf 0 55 (0 5-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 27EXAMPLE 27
Le fumarate de la l-[2-(4-méthylpipérazin-l-yl)phényI]-3-[2-oxo-2-(4- phènéthylpipérazin-l-yl)éthyl]uréylène (27)1- [2- (4-methylpiperazin-1-yl) phenyl] -3- [2-oxo-2- (4-phenethylpiperazin-1-yl) ethyl] ureylene fumarate (27)
Figure imgf000067_0001
Figure imgf000067_0001
27A: le 2-i*ertbutoxycarbonylamino-l-[4-phènéthylpipérazin-l-yl]éthan-l-one27A: 2-i * ertbutoxycarbonylamino-1- [4-phenethylpiperazin-1-yl] ethan-1-one
Le déπvé 27A est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants jV-te/7-butoxycarbonylglycine (3 g, 17 1 mmol), 1 -phenéthylpipéridine (3 9 g, 20 5 mmol), triéthylamine (2 62 ml, 18 8 mmol), le chlorhydrate de l-(3- dimethylaminopropyl)-3-éthylcarbodiimide (3 6 g , 18 8 mmol), 4-N,N- diméthylaminopyridine (30 mg) dans le dichlorométhane (60 ml) Le dérivé 27A est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).Deπvé 27A is prepared according to the same method described for 26C from the following reagents jV-te / 7-butoxycarbonylglycine (3 g, 17 1 mmol), 1 -phenethylpiperidine (3 9 g, 20 5 mmol), triethylamine (2 62 ml, 18 8 mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (366, 18 8 mmol), 4-N, N- dimethylaminopyridine (30 mg) in dichloromethane (60 ml) The derivative 27A is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 4.76 g (80%)Mass obtained: 4.76 g (80%)
JH-RMN (200 MHz, dmso-dό) δ : 7.35-7.1 (m, 5H); 6.71 (brt, IH); 3.74 (d, 2H, 5.9Hz); 3.85 (brs, 4H); 2.8-2.3 (m, 8H); 1.36 (s, 9H).JH-NMR (200 MHz, dmso-dό) δ: 7.35-7.1 (m, 5H); 6.71 (brt, 1H); 3.74 (d, 2H, 5.9Hz); 3.85 (brs, 4H); 2.8-2.3 (m, 8H); 1.36 (s, 9H).
Analyse élémentaire: C19H29N3O3 Calculée: C ≈ 65.68: H = 8.41: N = 12.09 Trouvée: C = 65.46: H = 8.38: N = 12.15Elementary analysis: C19H29N3O3 Calculated: C ≈ 65.68: H = 8.41: N = 12.09 Found: C = 65.46: H = 8.38: N = 12.15
27B: le 2-amino-l-[4-phènéthyIpipérazin-l-yl]éthan-l-one27B: 2-amino-l- [4-phenethylIpiperazin-l-yl] ethan-l-one
Le dérivé 27A est dissous dans du dichlorométhane (377 ml) sous atmosphère d'azote et l'acide trifluoroacétique ( 65 ml) est ajouté. La solution est agitée 3 heures à température ambiante, puis le solvant et l'acide sont évaporés. Le résidu huileux est repris dans du dichlorométhane et lavé à l'eau. La phase aqueuse est extraite 3 fois avec du dichlorométhane. Les phases organiques sont combinées, séchèes sur MgSθ4 et concentrées. Le dérivé 27B est utilisé sans autre purification.The derivative 27A is dissolved in dichloromethane (377 ml) under a nitrogen atmosphere and trifluoroacetic acid (65 ml) is added. The solution is stirred for 3 hours at room temperature, then the solvent and the acid are evaporated. The oily residue is taken up in dichloromethane and washed with water. The aqueous phase is extracted 3 times with dichloromethane. The organic phases are combined, dried over MgSθ4 and concentrated. Derivative 27B is used without further purification.
Masse obtenue: 2.67 g (79 %)Mass obtained: 2.67 g (79%)
1H-RMN (200 MHz, dmso-d6) δ : 7.22 (brs, 5H); 3.7-2.7 (brs, 2H, NH2); 3.5-3.2 (m, 4H); 2.8-2.25 (m, 8H).1H-NMR (200 MHz, dmso-d 6 ) δ: 7.22 (brs, 5H); 3.7-2.7 (brs, 2H, NH2); 3.5-3.2 (m, 4H); 2.8-2.25 (m, 8H).
Analyse élémentaire: C14H21N3O; 1.6 H2O Calculée: C = 60.89; H = 8.83; N = 15.22 Trouvée: C = 60.81; H = 8.64; N = 14.99Elemental analysis: C14H21N3O; 1.6 H 2 O Calculated: C = 60.89; H = 8.83; N = 15.22 Found: C = 60.81; H = 8.64; N = 14.99
27: Le dérivé 27 est préparé selon la même méthode décrite pour j_6 à partir des réactifs suivants: 7B (500 mg; 2.6 mmol); triphosgéne (309 mg, 1 mmol), pyridine (422ml; 5.22 mmol); 27B (774 mg; 3.1 mmol) dans le dichlorométhane (18 ml).27: The derivative 27 is prepared according to the same method described for day 6 from the following reagents: 7B (500 mg; 2.6 mmol); triphosgene (309 mg, 1 mmol), pyridine (422ml; 5.22 mmol); 27B (774 mg; 3.1 mmol) in dichloromethane (18 ml).
Le dérivé 27 est purifié par chromatographie-éclair avec un mélange d'éluants (1 -5-95 = NH4OH-MeOH-CH2Cl2). b ?Derivative 27 is purified by flash chromatography with a mixture of eluents (1 -5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ). b?
Masse obtenue: 952 mg (78 %)Mass obtained: 952 mg (78%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
1H-RMN (200 MHz, dmso-d6) δ : 8.05-7.9 (m, 2H), 7 42 (brt, IH); 7.3-6.8 (m, 8H); 6.54 (s, fumarate), 3.96 (d, 2H, 5Hz); 3.43 (brs, 4H), 2 9-2.6 (m, 10H); 2.6-2.2 (m, 9H).1H-NMR (200 MHz, dmso-d 6 ) δ: 8.05-7.9 (m, 2H), 7 42 (brt, 1H); 7.3-6.8 (m, 8H); 6.54 (s, fumarate), 3.96 (d, 2H, 5Hz); 3.43 (brs, 4H), 2 9-2.6 (m, 10H); 2.6-2.2 (m, 9H).
Analyse élémentaire: C26H36NgO2 ; 1.15 C4H4O4 ; 0 43 H20 Calculée: C = 61.26 : H ≈ 6.81 : N = 13.92 Trouvée: C = 61.04 : H = 6.98 : N ≈ 13.99Elemental analysis: C 2 6H36NgO 2 ; 1.15 C4H4O4; 0 43 H 2 0 Calculated: C = 61.26: H ≈ 6.81: N = 13.92 Found: C = 61.04: H = 6.98: N ≈ 13.99
IRflCBr): 3297, 1655, 1514, 1441IRflCBr): 3297, 1655, 1514, 1441
Rf: 0.2 (1-4-96 = NH4OH-MeOH-CH2Cl2)Rf: 0.2 (1-4-96 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 465 (MH+)Mass (DCI, NH 3 ): 465 (MH +)
EXEMPLE 28EXAMPLE 28
Le fumarate de la l-[2-(4-méthylpipérazin-l-yI)phényl]-3-{2-oxo-2-[4-(2,3- diméthylphényl)pipérazin-l-yljéthyl}uréylène (28)1- [2- (4-methylpiperazin-1-yI) phenyl] -3- {2-oxo-2- [4- (2,3-dimethylphenyl) piperazin-1-yljethyl} ureylene fumarate (28)
Figure imgf000069_0001
Figure imgf000069_0001
28A: le 2-i'erι'butoxycarbonylamino-l-{4-(2,3-diméthylphényl)pipérazin-l-yIJéthan- 1-one28A: 2-i'erι'butoxycarbonylamino-l- {4- (2,3-dimethylphenyl) piperazin-l-yIJéthan- 1-one
Le dérivé 28A est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: N-teri'-butoxycarbonylgiycine (1.69 g; 9.7 mmol); le chlorhydrate de la l-(2,3- diméthylphényl)pipéridine (2 g; 8.8 mmol); triéthylamine (2.58 ml; 18.5 mmol); le chlorhydrate de l-(3-dimethylaminopropyl)-3-éthylcarbodiimide (1.85 g ; 9.7 mmol); 4- N.N-diméthylaminopyridine (30 mg) dans le dichlorométhane (30 ml).The derivative 28A is prepared according to the same method described for 26C from the following reagents: N-teri'-butoxycarbonylgiycin (1.69 g; 9.7 mmol); 1- (2,3-dimethylphenyl) piperidine hydrochloride (2 g; 8.8 mmol); triethylamine (2.58 ml; 18.5 mmol); the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.85 g; 9.7 mmol); 4- NN-dimethylaminopyridine (30 mg) in dichloromethane (30 ml).
Le dérivé 28A est purifié par chromatographie-éclair avec un mélange d'éluants (1-3-97 = NH4OH-MeOH-CH2Cl2).The derivative 28A is purified by flash chromatography with a mixture of eluents (1-3-97 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 1.79 g (58%)Mass obtained: 1.79 g (58%)
*H-RMN (200 MHz, dmso-d6) δ : 7.06 (t, IH, 7.6Hz), 7 0-6.7 (m, 3H); 4.04 (d, 2H, 5.8Hz); 3.57 (brs, 4H); 2.78 (brs, 4H); 2.23 (s, 3H), 2.20 (s, 3H), 1.40 (s, 9H).* H-NMR (200 MHz, dmso-d 6 ) δ: 7.06 (t, IH, 7.6Hz), 7 0-6.7 (m, 3H); 4.04 (d, 2H, 5.8Hz); 3.57 (brs, 4H); 2.78 (brs, 4H); 2.23 (s, 3H), 2.20 (s, 3H), 1.40 (s, 9H).
28B: le 2-amino-l-[4-(2,3-diméthylphényl)pipérazin-l-yl|éthan-l-one28B: 2-amino-1- [4- (2,3-dimethylphenyl) piperazin-1-yl | ethan-1-one
Le dérivé 28B est préparé selon la même méthode décrite pour 27B à partir des réactifs suivants: 28A (1.79 g; 5.14 mmol); dichlorométhane (142 ml); trifluoroacétique ( 24 ml). Le résidu huileux est repris dans du dichlorométhane et lavé à la soude IM. La phase aqueuse est extraite 3 fois avec du dichlorométhane. Les phases organiques sont combinées, séchèes sur MgSθ4 et concentrées. Le dérivé 28B est purifié par chromatographie-éclair avec un mélange d'éluants (1-10-90 = NH4θH-MeOH-CH2Cl2).The derivative 28B is prepared according to the same method described for 27B from the following reagents: 28A (1.79 g; 5.14 mmol); dichloromethane (142 ml); trifluoroacetic (24 ml). The oily residue is taken up in dichloromethane and washed with IM soda. The aqueous phase is extracted 3 times with dichloromethane. The organic phases are combined, dried over MgSθ4 and concentrated. The derivative 28B is purified by flash chromatography with a mixture of eluents (1-10-90 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 1.05 g (82 %)Mass obtained: 1.05 g (82%)
JH-RMN (200 MHz, dmso-d6) δ : 7.02 (t, IH, 7.6Hz); 6.9-6.8 (m, 2H); 3.8-3.1 (m, 8H); 2.71 (brs, 4H); 2.19 (s, 3H); 2.16 (s, 3H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.02 (t, IH, 7.6Hz); 6.9-6.8 (m, 2H); 3.8-3.1 (m, 8H); 2.71 (brs, 4H); 2.19 (s, 3H); 2.16 (s, 3H).
28: Le dérivé 28 est préparé selon la même méthode décrite pour 16 à partir des réactifs suivants: 7B (500 mg; 2.6 mmol); triphosgéne (309 mg; 1 mmol); pyridine (422ml; 5.22 mmol); 28B (968 mg; 3.91 mmol) dans le dichlorométhane (18 ml). Le dérivé 28 est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).28: The derivative 28 is prepared according to the same method described for 16 from the following reagents: 7B (500 mg; 2.6 mmol); triphosgene (309 mg; 1 mmol); pyridine (422ml; 5.22 mmol); 28B (968 mg; 3.91 mmol) in dichloromethane (18 ml). Derivative 28 is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 875 mg (72 %)Mass obtained: 875 mg (72%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. 1H-RMN (200 MHz, dmso-d6) δ : 8.05-7.9 (m, 2H); 7.42 (brt, IH); 7.3-6.8 (m, 8H); 6.54 (s, fumarate); 3.96 (d, 2H, 5Hz); 3.43 (brs, 4H); 2.9-2.6 (m, 10H); 2.6-2.2 (m, 9H).This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. 1H-NMR (200 MHz, dmso-d 6 ) δ: 8.05-7.9 (m, 2H); 7.42 (brt, 1H); 7.3-6.8 (m, 8H); 6.54 (s, fumarate); 3.96 (d, 2H, 5Hz); 3.43 (brs, 4H); 2.9-2.6 (m, 10H); 2.6-2.2 (m, 9H).
Analyse élémentaire: C26H36NgO2 ; 1.25 C4H4O4 ; 0.5 H2O Calculée: C = 60.18 ; H = 6.84 ; N = 13.58; H2O = 1.46 Trouvée: C = 60.06 ; H = 6.90 ; N = 13.73; H2O = 1.5Elemental analysis: C 2 6H36NgO 2 ; 1.25 C4H4O4; 0.5 H 2 O Calculated: C = 60.18; H = 6.84; N = 13.58; H 2 O = 1.46 Found: C = 60.06; H = 6.90; N = 13.73; H 2 O = 1.5
IR (KBr): 3322, 1657, 1525, 1249.IR (KBr): 3322, 1657, 1525, 1249.
Rf: 0.35 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.35 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 465 (MH+)Mass (DCI, NH3): 465 (MH +)
EXEMPLE 29EXAMPLE 29
Le fumarate de la l-[3-chloro-2-(4-méthylpipérazin-l-yl)phényI]-3-{2-oxo-2-[4- (2,3-diméthylphényl)pipérazin-l-yl|éthyl}uréylène (29)1- [3-Chloro-2- (4-methylpiperazin-1-yl) phenyl] -3- {2-oxo-2- [4- (2,3-dimethylphenyl) piperazin-1-yl fumarate | ethyl} ureylene (29)
Figure imgf000071_0001
Figure imgf000071_0001
29: Le dérivé 29 est préparé selon la même méthode décrite pour 16 à partir des réactifs suivants: 7B (500 mg; 2.21 mmol); triphosgéne (262 mg; 0.88 mmol); pyridine (357 ml; 2.4 mmol); 28B (819 mg; 3.3 mmol) dans le dichlorométhane (15 ml). Le dérivé 29 est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4θH-MeOH-CH2Cl2).29: The derivative 29 is prepared according to the same method described for 16 from the following reagents: 7B (500 mg; 2.21 mmol); triphosgene (262 mg; 0.88 mmol); pyridine (357 ml; 2.4 mmol); 28B (819 mg; 3.3 mmol) in dichloromethane (15 ml). Derivative 29 is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 308 mg (28 %)Mass obtained: 308 mg (28%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. ^-RiMN (200 MHz, dmso-d6) δ : 8.35 (s, IH); 8.06 (dd, IH, 1.4 et 8.3Hz); 7.67 (m, IH); 7.2-6.8 (m, 5H); 6.59 (s, fumarate); 4.05 (d, 2H, 5.2Hz); 3.62 (brs, 6H); 3.9-2.6 (m, 10H); 2.40 (s, 3H); 2.22 (s, 3H); 2.20 (s, 3H).This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. ^ -RiMN (200 MHz, dmso-d 6 ) δ: 8.35 (s, 1H); 8.06 (dd, IH, 1.4 and 8.3Hz); 7.67 (m, 1H); 7.2-6.8 (m, 5H); 6.59 (s, fumarate); 4.05 (d, 2H, 5.2Hz); 3.62 (brs, 6H); 3.9-2.6 (m, 10H); 2.40 (s, 3H); 2.22 (s, 3H); 2.20 (s, 3H).
s Analyse élémentaire: C26H35ClNgO2 ; 1 C4H4O4 ; 0.52 H2O Calculée: C = 58.58 ; H = 6.39 ; N = 13.66 Trouvée. C = 58.59 ; H = 6.43 ; N = 13.67s Elemental analysis: C 2 6H35ClNgO 2 ; 1 C4H4O4; 0.52 H 2 O Calculated: C = 58.58; H = 6.39; N = 13.66 Found. C = 58.59; H = 6.43; N = 13.67
IR (KBr): 3331, 1700, 1560 0IR (KBr): 3331, 1700, 1560 0
Rf: 0.3 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.3 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 499 (MH+)Mass (DCI, NH 3 ): 499 (MH + )
5 EXEMPLE 305 EXAMPLE 30
Le fumarate de la l-[3-chloro-2-(4-méthylpipérazin-l-yl)phényl]-3-[2-oxo-2-(4- phènéthylpipérazin-l-yl)éthyl|uréylène (30)1- [3-Chloro-2- (4-methylpiperazin-1-yl) phenyl] -3- [2-oxo-2- (4-phenphenipiperazin-1-yl) ethyl | ureylene fumarate (30)
Figure imgf000072_0001
Figure imgf000072_0001
30: Le dérivé 30 est préparé selon la même méthode décrite pour 16 à partir des réactifs suivants: 26B (500 mg; 2.21 mmol); triphosgéne (216 mg; 0.72 mmol); pyridine (356 ml; 4.4 mmol); 27B (819 mg; 3.3 mmol) dans le dichlorométhane (15 ml). 530: The derivative 30 is prepared according to the same method described for 16 from the following reagents: 26B (500 mg; 2.21 mmol); triphosgene (216 mg; 0.72 mmol); pyridine (356 ml; 4.4 mmol); 27B (819 mg; 3.3 mmol) in dichloromethane (15 ml). 5
Le dérivé 30 est purifié par chromatographie-éclair avec un mélange d'éluants (1-10-90 = NH4θH-MeOH-CH2Cl2).The derivative 30 is purified by flash chromatography with a mixture of eluents (1-10-90 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 1.09 g (99 %) 0 Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.Mass obtained: 1.09 g (99%) 0 This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RMN (200 MHz, dmso-d6) δ : 8.33 (s, IH); 8.06 (dd, IH, 1.3 et 8Hz); 7.63 (brt, IH); 7.6-7.1 (m, 5H); 7.10 (t, IH, 8Hz); 6.91 (dd, IH, 1.3 et 8Hz); 6.60 (s, fumarate); 3.99 (brd, 2H); 3.7-3.3 (m, 6H); 3.0-2.2 (m, 14H), 2.42 (s, 3H).JH-NMR (200 MHz, dmso-d 6 ) δ: 8.33 (s, 1 H); 8.06 (dd, IH, 1.3 and 8Hz); 7.63 (brt, 1H); 7.6-7.1 (m, 5H); 7.10 (t, 1H, 8Hz); 6.91 (dd, IH, 1.3 and 8Hz); 6.60 (s, fumarate); 3.99 (brd, 2H); 3.7-3.3 (m, 6H); 3.0-2.2 (m, 14H), 2.42 (s, 3H).
Analyse élémentaire: C26H35ClN6θ2 ; 1.4 C4H4O4 ; 0.42 H20 Calculée: C = 57.16 : H = 6.50 : N = 12.42 Trouvée: C = 57.39 : H = 6.45 : N = 12.14Elemental analysis: C 2 6H35ClN6θ 2 ; 1.4 C4H4O4; 0.42 H 2 0 Calculated: C = 57.16: H = 6.50: N = 12.42 Found: C = 57.39: H = 6.45: N = 12.14
IR flCBr): 3600-2300, 1650, 1580, 1500, 1450.IR flCBr): 3600-2300, 1650, 1580, 1500, 1450.
Rf: 0.6 (1-8-92 = NH4OH-MeOH-CH2Cl2)Rf: 0.6 (1-8-92 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 499 (MH+)Mass (DCI, NH3): 499 (MH + )
EXEMPLE 31EXAMPLE 31
Le fumarate de la l-[3-chIoro-2-(4-méthylpipérazin-l-yl)phényl]-3-{2-oxo-2-[4-(4- fluorobenzoyl)pipéridin-l-yl]éthyl}uréylène (31)1- [3-Choro-2- (4-methylpiperazin-1-yl) phenyl] -3- {2-oxo-2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} fumarate ureylene (31)
Figure imgf000073_0001
Figure imgf000073_0001
31A: le 2-tert-butoxycarbonylamino-l-[4-(4-fluorobenzoyl)pipéridin-l-yl]éthan-l- one31A: 2-tert-butoxycarbonylamino-l- [4- (4-fluorobenzoyl) piperidin-l-yl] ethan-l-one
Le dérivé 31A est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: N-/er/-butoxycarbonylgιycine (891 mg; 5.1 mmol); le tosylate de la 4-(4- fluorobenzoyl)pipéridine (2.32 g; 6.1 mmol); triéthylamine (780 ml; 5.6 mmol); le -i 9The derivative 31A is prepared according to the same method described for 26C from the following reagents: N- / er / -butoxycarbonylgιycine (891 mg; 5.1 mmol); 4- (4-fluorobenzoyl) piperidine tosylate (2.32 g; 6.1 mmol); triethylamine (780 ml; 5.6 mmol); the -i 9
chlorhydrate de l-(3-dιmethylamιnopropyl)-3-éthylcarbodnmιde (1 07 g , 5 6 mmol), 4- NN-diméthylaminopyridine (20 mg) dans le dichlorométhane (17 ml)1- (3-dimethylamιnopropyl) -3-ethylcarbodnmid hydrochloride (1 07 g, 5 6 mmol), 4- NN-dimethylaminopyridine (20 mg) in dichloromethane (17 ml)
Le dérivé 31A est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2)Derivative 31A is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse obtenue 1 72 g (92%)Mass obtained 1 72 g (92%)
JH-RMN (200 MHz, dmso-d6) δ 8 2-8 05 (m, 2H), 7 39 (t, 2H, 8 8Hz), 6 76 (brs, IH), 4 35 (brd, IH), 4 0-3 6 (m, 4H), 3 17 (brt, I H), 2 79 (brt, IH), 1 9-1 2 (m, 4H), 1 39 (s, 9H)JH-RMN (200 MHz, dmso-d 6 ) δ 8 2-8 05 (m, 2H), 7 39 (t, 2H, 8 8Hz), 6 76 (brs, IH), 4 35 (brd, IH) , 4 0-3 6 (m, 4H), 3 17 (brt, IH), 279 (brt, IH), 1 9-1 2 (m, 4H), 1 39 (s, 9H)
Analyse élémentaire C]9H25N2O2F , 0 2 H2O Calculée C = 62 01 , H = 6 96 , N = 7 61 Trouvée C = 62 02 , H = 6 90 , N = 7 59Elementary analysis C] 9H 2 5N 2 O 2 F, 0 2 H 2 O Calculated C = 62 01, H = 6 96, N = 7 61 Found C = 62 02, H = 6 90, N = 7 59
31B: le 2-amino-l-[4-(4-fluorobenzoyl)pipéridin-l-yl|éthan-l-one31B: 2-amino-1- [4- (4-fluorobenzoyl) piperidin-1-yl | ethan-1-one
Le déπvé 31B est préparé selon la même méthode décπte pour 27B à partir des réactifs suivants 31A (1 7 g; 4 7 mmol), dichlorométhane (129 ml), tπfluoroacétique ( 22 ml) Le déπvé 31B est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2CI2)The product 31B is prepared according to the same method for 27B using the following reagents 31A (1 7 g; 4 7 mmol), dichloromethane (129 ml), torofluoroacetic (22 ml) The product 31B is purified by flash chromatography with a eluent mixture (1-5-95 = NH 4 OH-MeOH-CH 2 CI 2 )
Masse obtenue 800 mg (65 %)Mass obtained 800 mg (65%)
ÏH-RMN (200 MHz, dmso-d6) δ 8 15-8 0 (m, 2H), 7 31 (t, 2H, 8 8Hz), 4 36 (brd, 1 H), 4 1-3 5 (m, 2H), 3 32 (brs, 2H), 3 1 (brt, IH), 2 76 (brt, 1 H), 1 9-1 2 (m, 4H) Ï H-NMR (200 MHz, dmso-d 6 ) δ 8 15-8 0 (m, 2H), 7 31 (t, 2H, 8 8Hz), 4 36 (brd, 1 H), 4 1-3 5 (m, 2H), 3 32 (brs, 2H), 3 1 (brt, IH), 2 76 (brt, 1 H), 1 9-1 2 (m, 4H)
31 Le dénvé 3J. est préparé selon la même méthode décrite pour .16 à partir des reactifs suivants 26B (400 mg, 1 77 mmol), triphosgéne (1 73 mg, 0 58 mmol), pyridine (286 ml, 3 5 mmol), 31B (701 mg, 2 65 mmol) dans le dichlorométhane (12 ml)31 The day 3J. is prepared according to the same method described for .16 from the following reagents 26B (400 mg, 1,77 mmol), triphosgene (1,73 mg, 0 58 mmol), pyridine (286 ml, 3,5 mmol), 31B (701 mg , 265 mmol) in dichloromethane (12 ml)
Le dérivé 3_! est purifié par chromatographie-éclair avec un mélange d'éluants (1 -7-93 = NH4OH-MeOH-CH2Cl2)The derivative 3_! is purified by flash chromatography with a mixture of eluents (1 -7-93 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse obtenue 749 mg (81 %) A hMass obtained 749 mg (81%) At h
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondantThis compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate
^-RMN (200 MHz, dmso-d6) δ • 8.31 (s, IH), 8 15-8 0 (m, 3H), 7 62 (brt, IH), 7 36 (t, 2H, 8.8Hz), 7.07 (t, IH, 8.1Hz), 6.88 (dd, IH, 1 5 et 8 1Hz), 6 56 (s, fumarate), 4 37 (brd, IH), 3 98 (d, 2H, 5 2Hz), 3.88 (brd, IH), 3 72 (brtt, IH), 3 55 (brt, IH), 3 35 (q, Et2O), 3.20 (brt, IH), 2.9-2.6 (m, 8H), 2.39 (s, 3H), 1 95- 1 7 (m, 2H), 1 7-1 2 (m, 2H), 1 07 (t, Et20)^ -RMN (200 MHz, dmso-d 6 ) δ • 8.31 (s, IH), 8 15-8 0 (m, 3H), 7 62 (brt, IH), 7 36 (t, 2H, 8.8Hz) , 7.07 (t, IH, 8.1Hz), 6.88 (dd, IH, 1 5 and 8 1Hz), 6 56 (s, fumarate), 4 37 (brd, IH), 3 98 (d, 2H, 5 2Hz) , 3.88 (brd, IH), 3 72 (brtt, IH), 3 55 (brt, IH), 3 35 (q, Et2O), 3.20 (brt, IH), 2.9-2.6 (m, 8H), 2.39 ( s, 3H), 1 95- 1 7 (m, 2H), 1 7-1 2 (m, 2H), 1 07 (t, Et20)
Analyse élémentaire C26H31CIFN5O3 , 1 C4H4O4 , 0 14 H20, 0 15 Et2O Calculée C = 57.14 , H = 5.72 , N = 10 89 Trouvée C = 57.26 , H = 5 60 ; N = 10.96Elementary analysis C26H31CIFN5O3, 1 C4H4O4, 0 14 H 2 0, 0 15 And 2 O Calculated C = 57.14, H = 5.72, N = 10 89 Found C = 57.26, H = 5 60; N = 10.96
DKKBr) 3500-2300, 1700-1 100DKKBr) 3500-2300, 1700-1 100
Rf 0 2 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf 0 2 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 516 (MH+)Mass (DCI, NH 3 ): 516 (MH +)
EXEMPLE 32EXAMPLE 32
Le fumarate de la l-[3-chloro-2-(4-méthyIpipérazin-l-yl)phényl]-3-{2-oxo-2-[4-(2- méthoxyphéπy_)pipérazin-l-yl]éthyl}uréyIène (32)1- [3-chloro-2- (4-methylpiperazin-1-yl) phenyl] -3- {2-oxo-2- [4- (2-methoxyphéπy_) piperazin-1-yl] ethyl fumarate} uréyIène (32)
0 Λ v ^
Figure imgf000075_0001
 0 Λ v ^
Figure imgf000075_0001
32 A: le 2-tert-butoxycarbony.amino-l-[4-(2-méthoxyphényl)pipérazin-l-yl]éthan- 1-one32 A: 2-tert-butoxycarbony.amino-1- [4- (2-methoxyphenyl) piperazin-1-yl] ethan-1-one
Le dérivé 32A est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants N-fert-butoxycarbonylglycine (2 g, 11 4 mmol), l-(2-méthoxyphényl)pipérazme -4 HrThe derivative 32A is prepared according to the same method described for 26C from the following reagents N-fert-butoxycarbonylglycine (2 g, 11 4 mmol), l- (2-methoxyphenyl) pipérazme -4 Hr
(2.63 g; 13.7 mmol); triéthylamine (1.74 ml; 12.5 mmol); le chlorhydrate de l-(3- dimethylaminopropyl)-3-éthylcarbodiimide (2.4 g ; 12.5 mmol); 4-N,N- diméthylaminopyridine (40 mg) dans le dichlorométhane (38 ml).(2.63 g; 13.7 mmol); triethylamine (1.74 ml; 12.5 mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.4 g; 12.5 mmol); 4-N, N- dimethylaminopyridine (40 mg) in dichloromethane (38 ml).
Le dérivé 32A est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4θH-MeOH-CH2Cl2).The 32A derivative is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 2.7 g (68%)Mass obtained: 2.7 g (68%)
JH-RiMN (200 MHz, dmso-d6) δ : 7.0-6.65 (m, 5H), 3.90-3.70 (m, 5H); 3.52 (brs, 4H); 2.89 (brs, 4H); 1.35 (s, 9H).JH-RiMN (200 MHz, dmso-d 6 ) δ: 7.0-6.65 (m, 5H), 3.90-3.70 (m, 5H); 3.52 (brs, 4H); 2.89 (brs, 4H); 1.35 (s, 9H).
Analyse élémentaire: CjgH27N3θ4 ; 0.2 H2O Çajçulée: C = 61.24 ; H = 7.82 ; N = 1 1.90 Trouvée: C = 61.29 ; H = 7.67 ; N = 1 1.85Elemental analysis: CjgH 2 7N3θ4; 0.2 H 2 O Çajçulée: C = 61.24; H = 7.82; N = 1 1.90 Found: C = 61.29; H = 7.67; N = 1 1.85
32B: le 2-amino-l-[4-(2-méthoxyphényl)pipérazin-l-yl]éthan-l-one32B: 2-amino-1- [4- (2-methoxyphenyl) piperazin-1-yl] ethan-1-one
Le dérivé 32B est préparé selon la même méthode décrite pour 27B à partir des réactifs suivants: 32A (2.7 g; 7.7 mmol); dichlorométhane (214 ml); trifluoroacétique ( 36 ml). Le dérivé 32B est purifié par chromatographie-éclair avec un mélange d'éluants (1-7-93 = NH4θH-MeOH-CH2Cl2).The derivative 32B is prepared according to the same method described for 27B from the following reagents: 32A (2.7 g; 7.7 mmol); dichloromethane (214 ml); trifluoroacetic (36 ml). The 32B derivative is purified by flash chromatography with a mixture of eluents (1-7-93 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 1.8 g (93 %)Mass obtained: 1.8 g (93%)
^-RMN (200 MHz, dmso-d6) δ : 7.1-6.8 (m, 4H); 3.78 (s, 3H); 3.59 (brs, 2H); 3.47 (brs, 2H); 3.36 (brs, 2H); 2.90 (brs, 4H).^ -RMN (200 MHz, dmso-d 6 ) δ: 7.1-6.8 (m, 4H); 3.78 (s, 3H); 3.59 (brs, 2H); 3.47 (brs, 2H); 3.36 (brs, 2H); 2.90 (brs, 4H).
32: Le dérivé 32 est préparé selon la même méthode décrite pour .16 à partir des réactifs suivants: 26B (500 mg; 2.21 mmol); triphosgéne (216 mg; 0.72 mmol); pyridine (356 ml; 4.4 mmol); 32B (826 mg; 3.3 mmol) dans le dichlorométhane (15 ml).32: Derivative 32 is prepared according to the same method described for .16 from the following reagents: 26B (500 mg; 2.21 mmol); triphosgene (216 mg; 0.72 mmol); pyridine (356 ml; 4.4 mmol); 32B (826 mg; 3.3 mmol) in dichloromethane (15 ml).
Le dérivé 32 est purifié par chromatographie-éclair avec un mélange d'éluants ( 1 -5-95 = NH4OH-MeOH-CH2Cl2).Derivative 32 is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 946 mg (86 %) -4 sMass obtained: 946 mg (86%) -4s
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
1H-RMN (200 MHz, dmso-d6) δ : 8.32 (s, IH), 8.03 (dd, IH, 1.4 et 8.3Hz); 7.64 (brt, IH); 7.07 (t, IH, 8.2Hz); 7.0-6.8 (m, 5H); 6.56 (s, fumarate); 4.01 (d, 2H, 5.2Hz); 3.76 (s, 3H); 3.57 (brs, 6H); 3.1-2.55 (m, 10H); 2.39 (s, 3H).1H-NMR (200 MHz, dmso-d 6 ) δ: 8.32 (s, IH), 8.03 (dd, IH, 1.4 and 8.3Hz); 7.64 (brt, 1H); 7.07 (t, 1 H, 8.2 Hz); 7.0-6.8 (m, 5H); 6.56 (s, fumarate); 4.01 (d, 2H, 5.2Hz); 3.76 (s, 3H); 3.57 (brs, 6H); 3.1-2.55 (m, 10H); 2.39 (s, 3H).
Analyse élémentaire: C25H33C1N603 ; 1.1 C4H4O4 ; 0.14 H20 Calculée: C = 56.17 ; H = 6.00 ; N = 13.37 Trouvée: C = 56.12 : H = 6.03 : N = 13.34Elementary analysis: C 2 5H33C1N 6 03; 1.1 C4H4O4; 0.14 H 2 0 Calculated: C = 56.17; H = 6.00; N = 13.37 Found: C = 56.12: H = 6.03: N = 13.34
DUKBr): 3500-2300, 1649, 1575, 1501, 1450, 1239DUKBr): 3500-2300, 1649, 1575, 1501, 1450, 1239
Rf: 0.45 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.45 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse (DCI, NH3) : 501 (MH+)Mass (DCI, NH 3 ): 501 (MH +)
EXEMPLE 33EXAMPLE 33
Le fumarate de la l-[3-chIoro-2-(4-méthylpipérazin-l-yl)phényl]-3-{2-oxo-2-(4- phénylpipéridin-l-yl)éthyl}uréylène (33)1- [3-Choro-2- (4-methylpiperazin-1-yl) phenyl] -3- {2-oxo-2- (4-phenylpiperidin-1-yl) ethyl} ureylene fumarate (33)
à
Figure imgf000077_0001
 at
Figure imgf000077_0001
33 A: le 2-tert-butoxycarbonylam-no-l-(4-phénylpipéridin-l-yI)éthan-l-one33 A: 2-tert-butoxycarbonylam-no-1- (4-phenylpiperidin-1-yI) ethan-1-one
Le dérivé 33A est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: N-/er/-butoxycarbonylglycine (1.8 g; 10.3 mmol), 4-phénylpipéridine (1.98 g; 12.3 mmol); triéthylamine (1.57 ml; 1 1.3 mmol); le chlorhydrate de l-(3- dimethylaminopropyl)-3-éthylcarbodiimide (2.16 g ; 1 1.3 mmol); 4-N,N- diméthylaminopyridine (40 mg) dans le dichlorométhane (35 ml). 1^The derivative 33A is prepared according to the same method described for 26C from the following reagents: N- / er / -butoxycarbonylglycine (1.8 g; 10.3 mmol), 4-phenylpiperidine (1.98 g; 12.3 mmol); triethylamine (1.57 ml; 1 1.3 mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.16 g; 1 1.3 mmol); 4-N, N- dimethylaminopyridine (40 mg) in dichloromethane (35 ml). 1 ^
Le dérivé 33A est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).The derivative 33A is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 2.76 g (84%)Mass obtained: 2.76 g (84%)
^-RMN (200 MHz, dmso-d6) δ : 7.24 (brs, 5H); 6.74 (brt, IH); 4.47 (brd, IH); 3.88 (brd, IH); 3.80 (d, 2H, 5.7Hz); 3.07 (brt, IH); 2.76 (brtt, IH); 2.63 (brt, IH); 1.8-1.3 (m, 4H); 1.39 (s, 9H).^ -RMN (200 MHz, dmso-d 6 ) δ: 7.24 (brs, 5H); 6.74 (brt, 1H); 4.47 (brd, 1H); 3.88 (brd, 1H); 3.80 (d, 2H, 5.7Hz); 3.07 (brt, 1H); 2.76 (brtt, 1H); 2.63 (brt, 1H); 1.8-1.3 (m, 4H); 1.39 (s, 9H).
33B: le 2-amino-l-(4-phénylpipéridin-l-yl)éthan-l-one33B: 2-amino-1- (4-phenylpiperidin-1-yl) ethan-1-one
Le dérivé 33B est préparé selon la même méthode décrite pour 27B à partir des réactifs suivants: 33A (2.76 g; 8.7 mmol); dichlorométhane (240 ml); trifluoroacétique ( 40 ml). Le dérivé 33B est purifié par chromatographie-éclair avec un mélange d'éluants ( l -7-93 ≈ NH4θH-MeOH-CH2Cl2).The derivative 33B is prepared according to the same method described for 27B from the following reagents: 33A (2.76 g; 8.7 mmol); dichloromethane (240 ml); trifluoroacetic (40 ml). The derivative 33B is purified by flash chromatography with a mixture of eluents (1-7-93 ≈ NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 1.65 g (87 %)Mass obtained: 1.65 g (87%)
iH-RMN (200 MHz, dmso-d6) δ : 7.24 (brs, 5H); 4.52 (brd, IH), 3.84 (brd, IH); 3.34 (s, 2H); 3.02 (brt, IH); 2.77 (brtt, IH); 2.63 (brt, IH); 1.85-1.3 (m, 4H).iH-NMR (200 MHz, dmso-d 6 ) δ: 7.24 (brs, 5H); 4.52 (brd, 1H), 3.84 (brd, 1H); 3.34 (s, 2H); 3.02 (brt, 1H); 2.77 (brtt, 1H); 2.63 (brt, 1H); 1.85-1.3 (m, 4H).
33: Le dérivé 33 est préparé selon la même méthode décrite pour .16 à partir des réactifs suivants: 26B (500 mg; 2.21 mmol); triphosgéne (216 mg; 0.72 mmol); pyridine (356 ml; 4.4 mmol); 33B (723 mg; 3.3 mmol) dans le dichlorométhane (15 ml). Le dérivé 33 est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4θH-MeOH-CH2Cl2).33: The derivative 33 is prepared according to the same method described for .16 from the following reagents: 26B (500 mg; 2.21 mmol); triphosgene (216 mg; 0.72 mmol); pyridine (356 ml; 4.4 mmol); 33B (723 mg; 3.3 mmol) in dichloromethane (15 ml). Derivative 33 is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 691 mg (67 %)Mass obtained: 691 mg (67%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
^-RMN (200 MHz, dmso-d6) δ : 8.33 (s, IH); 8.04 (dd, IH, 1.4 et 8Hz); 7.64 (brs, IH); 7.4-7.0 (m, 6H); 6.89 (dd, IH, 1.4 et 8Hz); 6.57 (s, fumarate), 4.52 (brd, IH); 4.1- 3.8 (m, 3H); 3.55 (brt, 2H); 3.12 (brt, IH), 2.9-2.5 (m, 8H); 2.38 (s, 3H); 2.0-1.3 (m, 4H). Analyse élémentaire: C25H32ClN5θ2 ; 1.1 C4H4O4 ; 0.14 H2O; 0.4 Et2O Calculée: C = 59.35 ; H = 6.49 ; N = 11.16 Trouvée: C = 59.13 ; H = 6.33 ; N = 1 1.45^ -RMN (200 MHz, dmso-d 6 ) δ: 8.33 (s, 1H); 8.04 (dd, IH, 1.4 and 8Hz); 7.64 (brs, 1H); 7.4-7.0 (m, 6H); 6.89 (dd, IH, 1.4 and 8Hz); 6.57 (s, fumarate), 4.52 (brd, 1H); 4.1-3.8 (m, 3H); 3.55 (brt, 2H); 3.12 (brt, 1H), 2.9-2.5 (m, 8H); 2.38 (s, 3H); 2.0-1.3 (m, 4H). Elemental analysis: C 2 5H3 2 ClN5θ 2 ; 1.1 C4H4O4; 0.14 H 2 O; 0.4 And 2 O Calculated: C = 59.35; H = 6.49; N = 11.16 Found: C = 59.13; H = 6.33; N = 1 1.45
IR (KBr): 3600-2500, 1700, 1635, 1580, 1500, 1450IR (KBr): 3600-2500, 1700, 1635, 1580, 1500, 1450
Rf: 0.2 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.2 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 34EXAMPLE 34
Le fumarate du 5-[3-chloro-2-(4-méthylpipérazin-l-yI)phénylamino]-l-(4- phénylpipéridin-l-yl)pentan-l-one (34)5- [3-Chloro-2- (4-methylpiperazin-1-yI) phenylamino] -l- (4-phenylpiperidin-1-yl) pentan-1-one fumarate (34)
Figure imgf000079_0001
Figure imgf000079_0001
34A: le 5-[N-tert-butoxycarbony.-3-chloro-2-(4-méthylpipérazin-l- yl)phénylamino]-l-(4-phényIpipéridin-l-yl)pentan-l-one34A: 5- [N-tert-butoxycarbony.-3-chloro-2- (4-methylpiperazin-1-yl) phenylamino] -l- (4-phenyIpiperidin-1-yl) pentan-1-one
Le dérivé 34A est préparé selon la même méthode décrite pour 18B à partir des réactifs suivants: J18A (900 mg; 2.76 mmol); NaH (60% dans l'huile; 264 mg; 6.6 mmol); 6A (1.07 g; 3.3 mmol); DMF (25 ml).The derivative 34A is prepared according to the same method described for 18B from the following reagents: D18A (900 mg; 2.76 mmol); NaH (60% in oil; 264 mg; 6.6 mmol); 6A (1.07 g; 3.3 mmol); DMF (25 ml).
Le dérivé 34A est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4θH-MeOH-CH2Cl2).Derivative 34A is purified by flash chromatography with a mixture of eluents (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue : 1.25 g (79 %)Mass obtained: 1.25 g (79%)
JH-RMN (200 MHz, dmso-d6) δ : 7.45-7.0 (m, 8H), 4 54 (brd, IH); 4.1-3.7 (m, 2H); 3.5-2.2 (m, 14H); 2.21 (s, 3H); 2.0-1.15 (m, 17H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.45-7.0 (m, 8H), 454 (brd, 1H); 4.1-3.7 (m, 2H); 3.5-2.2 (m, 14H); 2.21 (s, 3H); 2.0-1.15 (m, 17H).
Analyse élémentaire: C31H45CIN4O3 Calculée: C = 66.83 ; H = 8.14 ; N = 10.06 Trouvée: C = 66.86 ; H = 8.09 ; N = 9.72 34: Le dérivé 34 est préparé selon la même méthode décrite pour 18 à partir des réactifs suivants: 34A (1.23 g; 2.16 mmol); TFA (10.2 ml); dichlorométhane (60 ml).Elementary analysis: C31H45CIN4O3 Calculated: C = 66.83; H = 8.14; N = 10.06 Found: C = 66.86; H = 8.09; N = 9.72 34: The derivative 34 is prepared according to the same method described for 18 from the following reagents: 34A (1.23 g; 2.16 mmol); TFA (10.2 ml); dichloromethane (60 ml).
Le dérivé 34 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1-5-95).Derivative 34 is purified in the form of the free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-5-95).
Masse obtenue : 933 mg (94 %)Mass obtained: 933 mg (94%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
1H-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 6H), 6 97 (t, IH, 7.9 Hz); 6.58 (s, fumarate); 6.50 (t, 2H, 7Hz); 5.62 (brs, IH); 4.55 (brd, IH), 3.98 (brd, IH); 3.54 (brt, 2H); 3.2-3.0 (m, 3H); 3.0-2.55 (m, 5H); 2.55-2.2 (m, 7H), 1.9-1.3 (m, 8H).1H-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 6H), 6 97 (t, 1H, 7.9 Hz); 6.58 (s, fumarate); 6.50 (t, 2H, 7Hz); 5.62 (brs, 1H); 4.55 (brd, 1H), 3.98 (brd, 1H); 3.54 (brt, 2H); 3.2-3.0 (m, 3H); 3.0-2.55 (m, 5H); 2.55-2.2 (m, 7H), 1.9-1.3 (m, 8H).
Analyse élémentaire: C27H37C1N4Û ; C4H4O4 ; 0.83 H20 Calculée: C = 63.63 ; H = 7.06 ; N = 9.57 Trouvée: C = 63.61 ; H = 7.06 ; N = 9.46Elementary analysis: C 2 7H37C1N4Û; C4H4O4; 0.83 H 2 0 Calculated: C = 63.63; H = 7.06; N = 9.57 Found: C = 63.61; H = 7.06; N = 9.46
IR (KBr): 3700-2300, 1723, 1635IR (KBr): 3700-2300, 1723, 1635
Masse (DCI, NH3) : 469 (MH+)Mass (DCI, NH 3 ): 469 (MH + )
Rf: 0.45 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.45 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 35EXAMPLE 35
Le fumarate du 5-[3-chloro-2-(4-méthylpipérazin-l-yI)phénylamino]-l-[4-(2- méthoxyphényl)pipérazin-l-yl]pentan-l-one (35)5- [3-Chloro-2- (4-methylpiperazin-1-yI) phenylamino] -l- [4- (2-methoxyphenyl) piperazin-1-yl] pentan-1-one fumarate (35)
Figure imgf000080_0001
35 A: Le 5-bromo-l-[4-(2-méthoxyphényl)pipérazin-l-ylJpentan-l-one
Figure imgf000080_0001
35 A: 5-bromo-1- [4- (2-methoxyphenyl) piperazin-1-ylJpentan-1-one
Le dérivé 35A est préparé selon la même méthode décrite pour 1_A à partir des réactifs suivants: l-(2-méthoxyphényl)pipérazine (3.45 g ; 18 mmol) ; chlorure de 5-bromo- pentanoyle (2.88 ml ; 21.5 mmol) ; triéthylamine (3 75 ml ; 27 mmol) dans le dichlorométhane (35 ml).The derivative 35A is prepared according to the same method described for 1_A from the following reagents: 1- (2-methoxyphenyl) piperazine (3.45 g; 18 mmol); 5-bromopentanoyl chloride (2.88 ml; 21.5 mmol); triethylamine (375 ml; 27 mmol) in dichloromethane (35 ml).
Masse obtenue: 6.2 g (97 %)Mass obtained: 6.2 g (97%)
*H-RMN (200 MHz, dmso-dό) δ : 7.1-6.75 (m, 4H), 3 76 (s, 3H), 3.53 (brs, 6H), 2.88 (brs, 4H); 2.35 (t, 2H, 7.2 Hz); 1.60 (p, 2H, 7.4 Hz), 1 79 (p, 2H, 7 4 Hz).* H-NMR (200 MHz, dmso-dό) δ: 7.1-6.75 (m, 4H), 376 (s, 3H), 3.53 (brs, 6H), 2.88 (brs, 4H); 2.35 (t, 2H, 7.2 Hz); 1.60 (p, 2H, 7.4 Hz), 1,79 (p, 2H, 7 4 Hz).
35B: le 5-[N-terf-butoxycarbonyI-3-chIoro-2-(4-méthylpipérazin-I- yl)phénylamino]-l-[4-(2-méthoxyphényl)pipérazin-l-yIJpentan-l-one Le dérivé 35B est préparé selon la même méthode décrite pour 18B à partir des réactifs suivants: !8A (900 mg; 2.76 mmol); NaH (60% dans l'huile, 264 mg; 6.6 mmol); 35A (1.17 g; 3.3 mmol); DMF (25 ml).35B: 5- [N-terf-butoxycarbonyI-3-chIoro-2- (4-methylpiperazin-I-yl) phenylamino] -l- [4- (2-methoxyphenyl) piperazin-1-yIJpentan-1-Le derivative 35B is prepared according to the same method described for 18B from the following reagents:! 8A (900 mg; 2.76 mmol); NaH (60% in oil, 264 mg; 6.6 mmol); 35A (1.17 g; 3.3 mmol); DMF (25 ml).
Le dérivé 35B est purifié par chromatographie-éclair avec un mélange d'éluants (1-8-92 = NH4OH-MeOH-CH2Cl2).The 35B derivative is purified by flash chromatography with a mixture of eluents (1-8-92 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue : 1.45 g (88 %)Mass obtained: 1.45 g (88%)
^-RMN (200 MHz, dmso-d6) δ : 7.4-6.8 (m, 7H); 4.0-2.7 (m, 10H); 3.79 (s, 3H); 3.56 (brs, 4H); 2.35 (brs, 6H); 2.20 (s, 3H); 1.7-1.15 (m, 13H)^ -RMN (200 MHz, dmso-d 6 ) δ: 7.4-6.8 (m, 7H); 4.0-2.7 (m, 10H); 3.79 (s, 3H); 3.56 (brs, 4H); 2.35 (brs, 6H); 2.20 (s, 3H); 1.7-1.15 (m, 13H)
35: Le dérivé 35 est préparé selon la même méthode décrite pour .18 à partir des réactifs suivants: 35B (1.454 g; 2.4 mmol); TFA (1 1.4 ml); dichlorométhane (67 ml). Le dérivé 35 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1-6-94). Masse obtenue : 898 mg (74 %)35: The derivative 35 is prepared according to the same method described for .18 from the following reagents: 35B (1.454 g; 2.4 mmol); TFA (1 1.4 ml); dichloromethane (67 ml). The derivative 35 is purified in the form of the free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-6-94). Mass obtained: 898 mg (74%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. *H-RMN (200 MHz, dmso-d6) δ : 7.1-6.8 (m, 5H); 6.58 (s, fumarate); 6.49 (t, 2H, 7.5Hz); 5.62 (brs, IH); 3.78 (s, 3H); 3.55 (brs, 6H); 3. 10 (brs, 2H); 2.89 (brs, 6H); 2.7- 2.3 (m, 9H); 1.59 (brs, 4H).This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. * H-NMR (200 MHz, dmso-d 6 ) δ: 7.1-6.8 (m, 5H); 6.58 (s, fumarate); 6.49 (t, 2H, 7.5Hz); 5.62 (brs, 1H); 3.78 (s, 3H); 3.55 (brs, 6H); 3.10 (brs, 2H); 2.89 (brs, 6H); 2.7-2.3 (m, 9H); 1.59 (brs, 4H).
Analyse élémentaire: C27H3gClN5θ2 ; C4H4O4; 0.07 H2O Calculée: C = 60.43 ; H = 6.87 ; N = 11.37 Trouvée: C = 60.35 ; H = 6.89 ; N = 1 1.13Elemental analysis: C 2 7H3gClN5θ 2 ; C4H4O4; 0.07 H 2 O Calculated: C = 60.43; H = 6.87; N = 11.37 Found: C = 60.35; H = 6.89; N = 1 1.13
IR (KBr): 3700-2400, 1700, 1640, 1588, 1500.IR (KBr): 3700-2400, 1700, 1640, 1588, 1500.
Masse (DCI, NH3) : 500 (MH+)Mass (DCI, NH 3 ): 500 (MH + )
Rf: 0.4 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf: 0.4 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 36EXAMPLE 36
Le fumarate de la l-[4-(2,3-diméthylphényl)pipérazin-l-yl]-5-[3-méthyl-2-(4- méthyIpipérazin-l-yl)phénoxy]pentan-l-one (36)1- [4- (2,3-dimethylphenyl) piperazin-1-yl] -5- [3-methyl-2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-fumarate (36 )
Figure imgf000082_0001
Figure imgf000082_0001
36 A: le 3-méthyl-2-(4-méthylpipérazin-l-yI)phéπol36 A: 3-methyl-2- (4-methylpiperazin-1-yI) pheπol
Le 2-amino meta crésol (7 g; 56.8 mmol) est dissous dans le 1-butanol (1 13 ml) en présence de de chlorhydrate de méchloéthamine (1 1.5 g, 59.7 mmol) et de carbonate de sodium (3 g; 28.4 mmol) sous atmosphère d'azote. La réaction est chauffée à 123°C pendant 3 jours. Le solvant est évaporé. Le dérivé 36A est purifié par chromatographie- éclair avec un premier mélange (0.5-20-80 = NH4θH-acétone-CH2Cl2) puis un deuxième mélange (1-5-95 = NH4OH-MeOH-CH2Cl2).The 2-amino meta cresol (7 g; 56.8 mmol) is dissolved in 1-butanol (1 13 ml) in the presence of mechloethamine hydrochloride (1 1.5 g, 59.7 mmol) and sodium carbonate (3 g; 28.4 mmol) under a nitrogen atmosphere. The reaction is heated to 123 ° C for 3 days. The solvent is evaporated. The derivative 36A is purified by flash chromatography with a first mixture (0.5-20-80 = NH4θH-acetone-CH 2 Cl 2 ) then a second mixture (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 8.44 g (72 %) iH-RMN (200 MHz, dmso-d6) δ : 9.04 (brs, IH); 6.81 (t, IH, 7.8 Hz); 6.65-6.45 (m, 2H); 4.0-2.0 (m, 4H); 2.36 (s, 3H); 2.20 (s, 3H).Mass obtained: 8.44 g (72%) iH-NMR (200 MHz, dmso-d 6 ) δ: 9.04 (brs, IH); 6.81 (t, 1 H, 7.8 Hz); 6.65-6.45 (m, 2H); 4.0-2.0 (m, 4H); 2.36 (s, 3H); 2.20 (s, 3H).
36: Le dérivé 36A (500 mg; 2.4 mmol) est dissous dans du DMF (15 ml) à 0°C en s présence d'hydrure de sodium (60% dans l'huile; 146 mg; 3.6 mmol) sous atmosphère d'azote. Une solution de 2A (1.28 g; 3.6 mmol) dans le DMF (5 ml) est ajoutée goutte à goutte. Le mélange réactionnel est agité 4 heures à température ambiante puis neutralisé avec quelques gouttes d'eau. Le solvant est évaporé. Le résidu huileux est repris dans de l'acétate d'ethyle et lavé deux fois avec de l'eau. La solution est séchée sur sulfate de 0 magnésium, filtrée puis concentrée. Le dérivé 36 est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).36: The derivative 36A (500 mg; 2.4 mmol) is dissolved in DMF (15 ml) at 0 ° C in the presence of sodium hydride (60% in oil; 146 mg; 3.6 mmol) under an atmosphere of 'nitrogen. A solution of 2A (1.28 g; 3.6 mmol) in DMF (5 ml) is added dropwise. The reaction mixture is stirred for 4 hours at room temperature and then neutralized with a few drops of water. The solvent is evaporated. The oily residue is taken up in ethyl acetate and washed twice with water. The solution is dried over 0 magnesium sulfate, filtered and then concentrated. Derivative 36 is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue : 743 mg (64 %)Mass obtained: 743 mg (64%)
5 Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RMN (200 MHz, dmso-d6) δ : 7.10-6.7 (m, 7H); 6.55 (s, fumarate); 3.92 (brt, 2H); 3.7-3.2 (m, 6H); 2.9-2.5 (m, 8H); 2.5-2.25 (m, 4H); 2.33 (s, 3H); 2.21 (s, 3H); 2. 19 (s, 3H); 2.16 (s, 3H); 1.74 (brs, 4H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.10-6.7 (m, 7H); 6.55 (s, fumarate); 3.92 (brt, 2H); 3.7-3.2 (m, 6H); 2.9-2.5 (m, 8H); 2.5-2.25 (m, 4H); 2.33 (s, 3H); 2.21 (s, 3H); 2.19 (s, 3H); 2.16 (s, 3H); 1.74 (brs, 4H).
Analyse élémentaire: C29H42N4θ2 ; C4H4O4; 0.1 H20 Calculée: C = 66.64 ; H = 7.80 ; N = 9.42 Trouvée: C = 66.73 ; H = 7.73 ; N = 9.36Elementary analysis: C 2 9H4 2 N4θ 2 ; C4H4O4; 0.1 H 2 0 Calculated: C = 66.64; H = 7.80; N = 9.42 Found: C = 66.73; H = 7.73; N = 9.36
IR flCBr): 3100-2700, 1716, 1649, 1582, 1454.IR flCBr): 3100-2700, 1716, 1649, 1582, 1454.
Masse (DCI, NH3) : 479 (MH+)Mass (DCI, NH 3 ): 479 (MH +)
Rf: 0.15 (1-5-95 = NH4θH-MeOH-CH2Cl2) EXEMPLE 37Rf: 0.15 (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 ) EXAMPLE 37
Le fumarate de la 5-[3-méthyl-2-(4-méthylpipérazin-l-yl)phénoxyJ-l-(4- phènéthylpipérazin-l-yl)pentan-l-one (37)5- [3-methyl-2- (4-methylpiperazin-1-yl) phenoxyJ-1- (4-phenphenipiperazin-1-yl) pentan-1-one fumarate (37)
Figure imgf000084_0001
Figure imgf000084_0001
37: Le dérivé 37 est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants. 36A (500 mg; 2.4 mmol); NaH (60% dans l'huile; 145 mg; 3.6 mmol); 4A (1.28 g, 3.6 mmol); DMF (15 ml).37: The derivative 37 is prepared according to the same method described for 36 from the following reagents. 36A (500 mg; 2.4 mmol); NaH (60% in oil; 145 mg; 3.6 mmol); 4A (1.28 g, 3.6 mmol); DMF (15 ml).
Le dérivé 37 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1-6-94)Derivative 37 is purified in the form of the free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-6-94)
Masse obtenue : 475 mg (41 %)Mass obtained: 475 mg (41%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate coπespondant.This compound is dissolved in methanol and treated with fumaric acid to give the coπespondant fumarate.
1H-RMN (200 MHz, dmso-d6) δ : 7.35-7.1 (m, 5H); 6.97 (t, IH, J=7.8Hz);6.76 (t, 2H, J=7.6Hz); 6.57 (s, fumarate); 3.92 (brt, 2H); 3.43 (brs, 6H), 3.0-2.2 (m, 19H); 2.24 (s, 3H); 1.9-1.6 (m, 4H).1H-NMR (200 MHz, dmso-d 6 ) δ: 7.35-7.1 (m, 5H); 6.97 (t, 1H, J = 7.8Hz); 6.76 (t, 2H, J = 7.6Hz); 6.57 (s, fumarate); 3.92 (brt, 2H); 3.43 (brs, 6H), 3.0-2.2 (m, 19H); 2.24 (s, 3H); 1.9-1.6 (m, 4H).
Analyse élémentaire: C29H42N4Û2 ; 1.2 C4H4O4; 0.3 1 H2O Calculée: C = 66.64 ; H = 7.80 ; N = 9.42 Trouvée: C = 66.62 : H = 7.81 : N = 9.15Elementary analysis: C 2 9H4 2 N4Û 2 ; 1.2 C4H4O4; 0.3 1 H 2 O Calculated: C = 66.64; H = 7.80; N = 9.42 Found: C = 66.62: H = 7.81: N = 9.15
IR (KBr): 3600-3200, 3000, 2932, 2864, 1642, 1600, 1461IR (KBr): 3600-3200, 3000, 2932, 2864, 1642, 1600, 1461
Masse (DCI, NH3) : 479 (MH+)Mass (DCI, NH3): 479 (MH +)
Rf: 0.2 (1-5-95 = NH4OH-MeOH-CH2Cl2) EXEMPLE 38Rf: 0.2 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ) EXAMPLE 38
Le fumarate de la 5-[3-méthyl-2-(4-méthylpipérazin-l-yl)phénoxy|-l-(4- phénylpipéridin-l-yl)pentan-l-one (38)5- [3-methyl-2- (4-methylpiperazin-1-yl) phenoxy | -l- (4-phenylpiperidin-1-yl) pentan-1-one fumarate (38)
Figure imgf000085_0001
Figure imgf000085_0001
38: Le dérivé 38 est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants: 36A (500 mg; 2.4 mmol); NaH (60% dans l'huile; 145 mg; 3.6 mmol); 6A (1. 17 g, 3.6 mmol); DMF (20 ml).38: The derivative 38 is prepared according to the same method described for 36 from the following reagents: 36A (500 mg; 2.4 mmol); NaH (60% in oil; 145 mg; 3.6 mmol); 6A (1.17 g, 3.6 mmol); DMF (20 ml).
Le dérivé 38 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1-5-95).Derivative 38 is purified in the form of a free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-5-95).
Masse obtenue : 716 mg (66 %)Mass obtained: 716 mg (66%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
1H-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 5H); 6.99 (t, IH, 8Hz); 6.79 (brt, 2H, 9Hz); 6.58 (s, fumarate); 4.56 (brd, IH); 4.1-3.8 (m, 3H); 3.44 (m, IH); 3.1 (brt, IH); 2.9-2.2 (m, 12H); 2.39 (t, 2H, 6Hz); 2.25 (s, 3H); 2.0-1.2 (m, 8H).1H-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 5H); 6.99 (t, 1H, 8Hz); 6.79 (brt, 2H, 9Hz); 6.58 (s, fumarate); 4.56 (brd, 1H); 4.1-3.8 (m, 3H); 3.44 (m, 1H); 3.1 (brt, 1H); 2.9-2.2 (m, 12H); 2.39 (t, 2H, 6Hz); 2.25 (s, 3H); 2.0-1.2 (m, 8H).
Analyse élémentaire: C2gH39N3θ2 ; 1.1 C4H4O4; 0.06 H2O Calculée: C = 67.41 ; H = 7.58 ; N = 7.28 Trouvée: C = 67.58 : H ≈ 7.61 : N = 7.24Elemental analysis: C 2 gH39N3θ 2 ; 1.1 C4H4O4; 0.06 H 2 O Calculated: C = 67.41; H = 7.58; N = 7.28 Found: C = 67.58: H ≈ 7.61: N = 7.24
DKKBr): 3600-3200, 3000, 2932, 2864, 1642, 1600, 1461DKKBr): 3600-3200, 3000, 2932, 2864, 1642, 1600, 1461
Masse (DCI, NH3) : 450 (MH+)Mass (DCI, NH3): 450 (MH + )
Rf: 0.3 (1-5-95 = NH4OH-MeOH-CH2Cl2) EXEMPLE 39Rf: 0.3 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ) EXAMPLE 39
Le fumarate de la l-[4-(2-méthoxyphényl)pipérazin-l-yl]-5-[3-méthyl-2-(4- méthylpipérazin-l-yI)phénoxy]pentan-l-one (39)1- [4- (2-methoxyphenyl) piperazin-1-yl] -5- [3-methyl-2- (4-methylpiperazin-1-yI) phenoxy] pentan-1-fumarate (39)
Figure imgf000086_0001
Figure imgf000086_0001
39: Le dérivé 39 est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants: 36A (500 mg; 2.4 mmol); NaH (60% dans l'huile; 145 mg; 3.6 mmol); 35A (1.28 g, 3.6 mmol); DMF (20 ml). Le dérivé 39 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4θH-MeOH-CH2Cl2 = 1-7-93).39: The derivative 39 is prepared according to the same method described for 36 from the following reagents: 36A (500 mg; 2.4 mmol); NaH (60% in oil; 145 mg; 3.6 mmol); 35A (1.28 g, 3.6 mmol); DMF (20 ml). Derivative 39 is purified in the form of the free base by flash chromatography with a mixture of eluents (NH4θH-MeOH-CH 2 Cl 2 = 1-7-93).
Masse obtenue : 735 mg (63 %)Mass obtained: 735 mg (63%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
iH-RMN (200 MHz, dmso-d6) δ : 7.0-6.7 (m, 7H); 6.56 (s, fumarate); 3.91 (t, 2H, 6Hz); 3.77 (s, 3H); 3.65-3.2 (m, 6H); 3.1-2.6 (m, 6H); 2.6-2.3 (m, 9H); 2.22 (s, 3H); 1.75 (brs, 4H).iH-NMR (200 MHz, dmso-d 6 ) δ: 7.0-6.7 (m, 7H); 6.56 (s, fumarate); 3.91 (t, 2H, 6Hz); 3.77 (s, 3H); 3.65-3.2 (m, 6H); 3.1-2.6 (m, 6H); 2.6-2.3 (m, 9H); 2.22 (s, 3H); 1.75 (brs, 4H).
Analyse élémentaire: Q28H40N4O3 ; 1.15 C4H4O4; 0.05 H2O Calculée: C = 63.57 ; H = 7.33 ; N = 9.10 Trouvée: C = 63.81 ; H = 7.35 ; N = 9.12Elemental analysis: Q28H40N4O3; 1.15 C4H4O4; 0.05 H 2 O Calculated: C = 63.57; H = 7.33; N = 9.10 Found: C = 63.81; H = 7.35; N = 9.12
IR ftCBr): 3700-2400, 1716, 1700, 1642, 1610.IR ftCBr): 3700-2400, 1716, 1700, 1642, 1610.
Masse (DCI, NH3) : 481 (MH+)Mass (DCI, NH3): 481 (MH +)
Rf: 0.16 ( 1 -5-95 ≈ NH4OH-MeOH-CH2Cl2) -S SRf: 0.16 (1 -5-95 ≈ NH 4 OH-MeOH-CH 2 Cl 2 ) -SS
EXEMPLE 40EXAMPLE 40
Le fumarate de la l-[4-(2,4-diméthylphényI)pipérazin-l-yl]-5-[3-méthyl-2-(4- méthylpipérazin-l-yI)phénoxy]pentan-l-one (40)1- [4- (2,4-dimethylphenyl) piperazin-1-yl] -5- [3-methyl-2- (4-methylpiperazin-1-yI) phenoxy] pentan-1-fumarate (40 )
Figure imgf000087_0001
Figure imgf000087_0001
40 A: Le 5-bromo-l-[4-(2,4-diméthylphényl)pipérazin-l-yl]pentan-l-one40 A: 5-bromo-1- [4- (2,4-dimethylphenyl) piperazin-1-yl] pentan-1-one
Le dérivé 40A est préparé selon la même méthode décrite pour 1_A à partir des réactifs suivants: l-(2,4-diméthylphényl)pipérazine (2.73 g ; 14.3 mmol) ; chlorure de 5-bromo- pentanoyle (2.3 ml ; 17.2 mmol) ; triéthylamine (3 ml ; 21.5 mmol) dans le dichlorométhane (28 ml).The derivative 40A is prepared according to the same method described for 1_A from the following reagents: 1- (2,4-dimethylphenyl) piperazine (2.73 g; 14.3 mmol); 5-bromopentanoyl chloride (2.3 ml; 17.2 mmol); triethylamine (3 ml; 21.5 mmol) in dichloromethane (28 ml).
Masse obtenue: 5 g (98 %)Mass obtained: 5 g (98%)
^-RMN (200 MHz, dmso-d6) δ : 7.1-6.8 (m, 3H); 3.53 (brs, 6H); 2.74 (brs, 4H); 2.40 (t, 2H, 7.2 Hz); 2.20 (s, 3H); 2.18 (s, 3H); 1.83 (p, 2H, 7.4 Hz); 1.68 (p, 2H, 7.4 Hz).^ -RMN (200 MHz, dmso-d 6 ) δ: 7.1-6.8 (m, 3H); 3.53 (brs, 6H); 2.74 (brs, 4H); 2.40 (t, 2H, 7.2 Hz); 2.20 (s, 3H); 2.18 (s, 3H); 1.83 (p, 2H, 7.4 Hz); 1.68 (p, 2H, 7.4 Hz).
40: Le dérivé 40 est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants: 36A (500 mg; 2.4 mmol); NaH (60% dans l'huile; 145 mg; 3.6 mmol); 40A (1.28 g, 3.6 mmol); DMF (20 ml).40: The derivative 40 is prepared according to the same method described for 36 from the following reagents: 36A (500 mg; 2.4 mmol); NaH (60% in oil; 145 mg; 3.6 mmol); 40A (1.28 g, 3.6 mmol); DMF (20 ml).
Le dérivé 40 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4θH-MeOH-CH2Cl2 = 1-5-95)Derivative 40 is purified in the form of the free base by flash chromatography with a mixture of eluents (NH4θH-MeOH-CH 2 Cl 2 = 1-5-95)
Masse obtenue : 510 mg (44 %)Mass obtained: 510 mg (44%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. ]H-RMN (200 MHz, dmso-d6) δ : 7.1-6 7 (m, 6H), 6 58 (s, fumarate); 3 94 (t, 2H, 5.9Hz); 3.7-3.2 (m, 6H), 3.1-2 0 (m, 12H), 2.39 (s, 3H), 2 25 (s, 3H), 2.24 (s, 3H); 2.22 (s, 3H); 1.78 (m, 4H).This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. ] H-NMR (200 MHz, dmso-d 6 ) δ: 7.1-6 7 (m, 6H), 6 58 (s, fumarate); 394 (t, 2H, 5.9 Hz); 3.7-3.2 (m, 6H), 3.1-2 0 (m, 12H), 2.39 (s, 3H), 2 25 (s, 3H), 2.24 (s, 3H); 2.22 (s, 3H); 1.78 (m, 4H).
s IR (KBr): 3000-2200, 1709, 1655.s IR (KBr): 3000-2200, 1709, 1655.
Analyse élémentaire: C29H42N4θ2 ; 1 C4H4O4; 0 13 H20 Calculée: C = 66.64 ; H = 7.80 ; N = 9.42 Trouvée: C ≈ 66.66 ; H = 7.87 ; N = 9.34Elementary analysis: C 2 9H4 2 N4θ 2 ; 1 C4H4O4; 0 13 H 2 0 Calculated: C = 66.64; H = 7.80; N = 9.42 Found: C ≈ 66.66; H = 7.87; N = 9.34
0 Masse (DCI, NH3) : 479 (MH+)0 Mass (DCI, NH3): 479 (MH +)
Rf 0.5 (1-5-95 = NH4OH-MeOH-CH2Cl2)Rf 0.5 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 41 5EXAMPLE 41 5
Le fumarate de la l-[4-(4-fluorobenzoyI)pipéridin-l-yI]-5-[2-(4-méthylpipérazin-l- yI)phénoxyJpentan-l-one (41)1- [4- (4-fluorobenzoyI) piperidin-l-yI] -5- [2- (4-methylpiperazin-l- yI) phenoxyJpentan-l-one fumarate (41)
Figure imgf000088_0001
Figure imgf000088_0001
41A: Le 5-bromo-l-[4-(4-fluorobenzoyl)pipéridin-l-yl]pentan-l-one41A: 5-bromo-l- [4- (4-fluorobenzoyl) piperidin-l-yl] pentan-l-one
Le dérivé 41A est préparé selon la même méthode décrite pour IA à partir des réactifs suivants: 1 -(4-fluorobenzoyl)pipéridine (2.36 g , 1 1 5 mmol) , chlorure de 5-bromo- 5 pentanoyle (1.84 ml ; 13.7 mmol) ; triéthylamine (2 39 ml , 17.2 mmol) dans le dichlorométhane (25 ml)The 41A derivative is prepared according to the same method described for IA from the following reagents: 1 - (4-fluorobenzoyl) piperidine (2.36 g, 1 15 mmol), 5-bromopentanoyl chloride (1.84 ml; 13.7 mmol ); triethylamine (239 ml, 17.2 mmol) in dichloromethane (25 ml)
Masse obtenue: 4.24 g (100 %) iH-RMN (200 MHz, dmso-d6) δ : 8.2-8.05 (m, 2H); 7.5-7.25 (m, 2H); 4.40 (brd, IH); 3.92 (brd, IH); 3.69 (tt, IH, 3.5 et 11.2 Hz); 3.56 (t, 2H, 6.5 Hz); 3.12 (brt, I H); 2.74 (brt, IH); 2.40 (t, 2H, 6.5 Hz); 2.0-1.1 (m, 8H).Mass obtained: 4.24 g (100%) iH-NMR (200 MHz, dmso-d 6 ) δ: 8.2-8.05 (m, 2H); 7.5-7.25 (m, 2H); 4.40 (brd, 1H); 3.92 (brd, 1H); 3.69 (tt, IH, 3.5 and 11.2 Hz); 3.56 (t, 2H, 6.5 Hz); 3.12 (brt, 1H); 2.74 (brt, 1H); 2.40 (t, 2H, 6.5 Hz); 2.0-1.1 (m, 8H).
Analyse élémentaire: Ci7H2ιBrFN02 ;0.8 H2O Calculée: C = 53.08 ; H = 5.92 ; N = 3.64 Trouvée: C = 52.95 ; H = 5.81 ; N ≈ 3.71Elementary analysis: Ci7H 2 ιBrFN0 2 ; 0.8 H 2 O Calculated: C = 53.08; H = 5.92; N = 3.64 Found: C = 52.95; H = 5.81; N ≈ 3.71
41: Le dérivé 4J. est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants: A (500 mg; 2.6 mmol); NaH (50% dans l'huile; 187 mg; 3.9 mmol); 41A (1.44 g, 3.9 mmol); DMF (20 ml).41: The derivative 4J. is prepared according to the same method described for 36 from the following reagents: A (500 mg; 2.6 mmol); NaH (50% in oil; 187 mg; 3.9 mmol); 41A (1.44 g, 3.9 mmol); DMF (20 ml).
Le dérivé 4_1 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1-5-95)The derivative 4_1 is purified in the form of the free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-5-95)
Masse obtenue : 933 mg (74 %)Mass obtained: 933 mg (74%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
^-RMN (200 MHz, dmso-d6) δ : 8.2-8.0 (m, 2H); 7.37 (t, 2H); 7.0-6.8 (m, 4H); 6.59 (s, fumarate); 4.42 (brd, IH); 4.05-3.9 (m, 3H); 3.72 (tt, IH); 3.20 (brt, IH); 3.03 (brs, 4H); 2.75 (brt, IH); 2.65 (brs, 4H); 2.42 (brt, 2H); 2.35 (s, 3H); 2.0-1.2 (m, 8H).^ -RMN (200 MHz, dmso-d 6 ) δ: 8.2-8.0 (m, 2H); 7.37 (t, 2H); 7.0-6.8 (m, 4H); 6.59 (s, fumarate); 4.42 (brd, 1H); 4.05-3.9 (m, 3H); 3.72 (tt, 1H); 3.20 (brt, 1H); 3.03 (brs, 4H); 2.75 (brt, 1H); 2.65 (brs, 4H); 2.42 (brt, 2H); 2.35 (s, 3H); 2.0-1.2 (m, 8H).
IR (KBr): 3429, 2958, 1689, 1595IR (KBr): 3429, 2958, 1689, 1595
Analyse élémentaire: C28H36FN3O3 ; 0.95 C4H4O4; 0.3 H2O Calculée: C ≈ 63.95; H = 6.82 ; N = 7.04 Trouvée: C = 64.04 ; H = 6.89 ; N = 6.74Elemental analysis: C28H36FN3O3; 0.95 C4H4O4; 0.3 H 2 O Calculated: C ≈ 63.95; H = 6.82; N = 7.04 Found: C = 64.04; H = 6.89; N = 6.74
Masse (DCI, NH3) : 482 (MH+)Mass (DCI, NH 3 ): 482 (MH +)
Rf: 0.5 (1-5-95 = NH4θH-MeOH-CH2Cl2) EXEMPLE 42Rf: 0.5 (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 ) EXAMPLE 42
Le fumarate de la l-[4-(4-fluorobenzoyl)pipérazin-l-yl)-5-[2-(4-méthylpipérazin-l- yl)phénoxyjpentan-l-one (42)1- [4- (4-fluorobenzoyl) piperazin-1-yl) -5- [2- (4-methylpiperazin-1-yl) phenoxyjpentan-1-one fumarate (42)
Figure imgf000090_0001
Figure imgf000090_0001
42 A: le 5-[2-(4-méthylpipérazin-l-yl)phénoxy]pentanoate d'ethyle42 A: 5- [2- (4-methylpiperazin-1-yl) phenoxy] ethyl pentanoate
Le dérivé A (5.25 g, 27.1 mmol) est dissous dans du DMF (100 ml) à 0°C sous atmosphère d'azote en présence d'hydrure de sodium (50% dans l'huile; 1.960g; 41 mmol). Le 5-bromo-pentanoate d'ethyle dilué dans du DMF (70 ml) est ajouté goutte à goutte à 0°C. Le bain froid est retiré et la réaction est agitée 15 heures à température ambiante. La suspension est neutralisée avec quelques gouttes d'eau, puis diluée dans de l'acétate d'ethyle, lavée deux fois avec de l'eau, séchée sur sulfate de magnésium, filtrée et concentrée. Le dérivé 42A est purifié par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1-5-95).The derivative A (5.25 g, 27.1 mmol) is dissolved in DMF (100 ml) at 0 ° C under a nitrogen atmosphere in the presence of sodium hydride (50% in oil; 1.960g; 41 mmol). The ethyl 5-bromo-pentanoate diluted in DMF (70 ml) is added dropwise at 0 ° C. The cold bath is removed and the reaction is stirred for 15 hours at room temperature. The suspension is neutralized with a few drops of water, then diluted in ethyl acetate, washed twice with water, dried over magnesium sulfate, filtered and concentrated. The 42A derivative is purified by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-5-95).
Masse obtenue: 5.08 g (58 %)Mass obtained: 5.08 g (58%)
]H-RMN (200 MHz, dmso-d6) δ : 6.95-6.75 (m, 4H); 4.03 (q, 2H, 7.1 Hz); 3.92 (brt, 2H); 2.93 (brs, 4H); 2.47 (brs, 6H); 2.18 (s, 3H); 1.70 (brs, 4H); 1.16 (t, 3H, 7.2 Hz). ] H-NMR (200 MHz, dmso-d 6 ) δ: 6.95-6.75 (m, 4H); 4.03 (q, 2H, 7.1 Hz); 3.92 (brt, 2H); 2.93 (brs, 4H); 2.47 (brs, 6H); 2.18 (s, 3H); 1.70 (brs, 4H); 1.16 (t, 3H, 7.2 Hz).
42B: l'acide 5-[2-(4-méthylpipérazin-l-yl)phénoxy]pentanoique.42B: 5- [2- (4-methylpiperazin-1-yl) phenoxy] pentanoic acid.
Le dérivé 42A (5.08 g, 15.8 mmol) est dissous dans du THF (18 ml). Une solution de soude (IM dans l'eau, 17.43 ml, 17.43 mmol) est ajoutée et la solution est chauffée à 50°C pendant 6 heures. La réaction est refroidie à température ambiante puis neutralisée par ajout d'acide chlorhydrique (IN dans l'eau, 17.43 ml, 17.43 mmol). Les solvants sont évaporés. Le résidu semi-solide est trituré dans un peu d'éthanol et filtré. Le filtrat est concentré pour donner une mousse. Le dérivé 42B est utilisé sans autre purification pour la suite des synthèses. Masse obtenue : 5 gThe 42A derivative (5.08 g, 15.8 mmol) is dissolved in THF (18 ml). A sodium hydroxide solution (IM in water, 17.43 ml, 17.43 mmol) is added and the solution is heated at 50 ° C for 6 hours. The reaction is cooled to room temperature and then neutralized by adding hydrochloric acid (IN in water, 17.43 ml, 17.43 mmol). The solvents are evaporated. The semi-solid residue is triturated in a little ethanol and filtered. The filtrate is concentrated to give a foam. The 42B derivative is used without further purification for the rest of the syntheses. Mass obtained: 5 g
42C: la N-tert-butoxycarbonyI-l-(4-fluorobenzoyl)pipérazine42C: N-tert-butoxycarbonyI-1- (4-fluorobenzoyl) piperazine
Sous atmosphère d'azote, à -8°C , l'acide 4-fluorobenzoique (3 g, 21 mmol) est dissous dans du dichlorométhane (42 ml) en présence de N-méthylmorpholine-N-oxide (2.6 ml,Under a nitrogen atmosphere, at -8 ° C, 4-fluorobenzoic acid (3 g, 21 mmol) is dissolved in dichloromethane (42 ml) in the presence of N-methylmorpholine-N-oxide (2.6 ml,
24 mmol). Le chloroformiate d'ethyle (2.25 ml, 24 mmol) est ajouté goutte à goutte. La solution est agitée 15 minutes à -8°C puis la N-Boc pipérazine (4 g, 21 mmol) est ajoutée. Le bain froid est retiré et la réaction est agitée 2 heures à température ambiante.24 mmol). Ethyl chloroformate (2.25 ml, 24 mmol) is added dropwise. The solution is stirred for 15 minutes at -8 ° C. and then the N-Boc piperazine (4 g, 21 mmol) is added. The cold bath is removed and the reaction is stirred for 2 hours at room temperature.
Le mélange réactionnel est dilué dans du dichlorométhane, lavé une fois avec de la soude IM et une fois avec de l'HCl IN, puis séché sur sulfate de magnésium, filtré et concentré.The reaction mixture is diluted in dichloromethane, washed once with IM soda and once with IN HCl, then dried over magnesium sulfate, filtered and concentrated.
Le dérivé 42C est purifié par chromatographie-éclair avec un mélange d'éluants (50-50 =The 42C derivative is purified by flash chromatography with a mixture of eluents (50-50 =
EtOAc-EDP).EtOAc-EDP).
Masse obtenue: 2.71 g (41%)Mass obtained: 2.71 g (41%)
JH-RMN (200 MHz, dmso-d6) δ : 7.55-7.45 (m, 2H); 7.35-7.2 (m, 2H); 3.6-3.2 (m, 8H); 1.40 (s, 9H). J H-NMR (200 MHz, dmso-d 6 ) δ: 7.55-7.45 (m, 2H); 7.35-7.2 (m, 2H); 3.6-3.2 (m, 8H); 1.40 (s, 9H).
42D: le chlorhydrate de la l-(4-fluorobenzoyl)pipérazine Le dérivé 42C (2.71 g, 8.8 mmol) dissous dans du méthanol (20 ml) est traité avec de l'éther-HCl (1.3 M, 100 ml) sous atmosphère d'azote à température ambiante. Un précipité blanc apparaît. La suspension est agitée 5 heures, puis filtrée. Le solide est rincé abondamment à l'éther et séché.42D: 1- (4-fluorobenzoyl) piperazine hydrochloride The derivative 42C (2.71 g, 8.8 mmol) dissolved in methanol (20 ml) is treated with ether-HCl (1.3 M, 100 ml) under atmosphere nitrogen at room temperature. A white precipitate appears. The suspension is stirred for 5 hours, then filtered. The solid is rinsed thoroughly with ether and dried.
Masse obtenue: 1.88 g f87%)Mass obtained: 1.88 g f87%)
1H-RMN (200 MHz, dmso-d6) δ : 9.37 (brs, 2H); 7.65-7.4 (m, 2H); 7.35-7.15 (m, 2H); 3.66 (brs, 4H); 3.10 (brs, 4H).1H-NMR (200 MHz, dmso-d 6 ) δ: 9.37 (brs, 2H); 7.65-7.4 (m, 2H); 7.35-7.15 (m, 2H); 3.66 (brs, 4H); 3.10 (brs, 4H).
Analyse élémentaire: C\ ]Hi3FN2Oι .HClElementary analysis: C \] Hi3FN 2 Oι .HCl
Calculée: C = 53.99 ; H = 5.77 ; N = 1 1.45 ; Cl = 14.49 Trouvée: C = 53.76 ; H = 5.78 ; N = 1 1.42 ; Cl = 14.47Calculated: C = 53.99; H = 5.77; N = 1 1.45; Cl = 14.49 Found: C = 53.76; H = 5.78; N = 1 1.42; Cl = 14.47
42: Le dérivé 42 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: 42D (389 mg; 1.5 mmol); 42B (400 mg, 1.25 mmol); triéthylamine go42: The derivative 42 is prepared according to the same method described for 26C from the following reagents: 42D (389 mg; 1.5 mmol); 42B (400 mg, 1.25 mmol); triethylamine go
(191 ml; 1.37 mmol); le chlorhydrate de l-(3-dimethylaminopropyl)-3-éthylcarbodiimide (263 mg ; 1.37 mmol); 4-N,N-diméthylaminopyridine (8 mg) dans le dichlorométhane (20 ml).(191 ml; 1.37 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (263 mg; 1.37 mmol); 4-N, N-dimethylaminopyridine (8 mg) in dichloromethane (20 ml).
Le dérivé 42 est purifié par chromatographie-éclair avec un mélange d'éluants (1 -7-93 = s NH4OH-MeOH-CH2Cl2).Derivative 42 is purified by flash chromatography with a mixture of eluents (1-7-93 = s NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 442 mg (73%)Mass obtained: 442 mg (73%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner 0 le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give 0 the corresponding fumarate.
iH-RMN (200 MHz, dmso-d6) δ : 7.6-7.4 (m, 2H); 7.4-7.2 (m, 2H); 6.95-6.8 (m, 4H); 6.56 (s, fumarate); 3.94 (brt, 2H); 3.49 (brs, 8H), 3.00 (brs, 4H); 2.63 (brs, 4H), 2.40 (brt, 2H); 2.33 (s, 3H); 1.72 (brs, 4H). 5iH-NMR (200 MHz, dmso-d 6 ) δ: 7.6-7.4 (m, 2H); 7.4-7.2 (m, 2H); 6.95-6.8 (m, 4H); 6.56 (s, fumarate); 3.94 (brt, 2H); 3.49 (brs, 8H), 3.00 (brs, 4H); 2.63 (brs, 4H), 2.40 (brt, 2H); 2.33 (s, 3H); 1.72 (brs, 4H). 5
DKKBr): 3441, 2934, 1610, 1480.DKKBr): 3441, 2934, 1610, 1480.
Analyse élémentaire: C27H36FN4O3 ; 1.2 C4H4O4; 1.2 H2O Calculée: C = 59.35; H = 6.61 ; N = 8.71 0 Trouvée: C = 59.36 ; H = 6.53 ; N = 8.82Elemental analysis: C27H36FN4O3; 1.2 C4H4O4; 1.2 H 2 O Calculated: C = 59.35; H = 6.61; N = 8.71 0 Found: C = 59.36; H = 6.53; N = 8.82
Rf: 0.35 (1-6-94 = NH4θH-MeOH-CH2Cl2)Rf: 0.35 (1-6-94 = NH4θH-MeOH-CH 2 Cl 2 )
EXEMPLE 43 5EXAMPLE 43 5
Le fumarate de la l-(4-benzoylp.péridin-l-yl)-5-(2-(4-méthylpipérazin-l- yl)phénoxy)pentan-l-one (43)1- (4-Benzoylp.peridin-1-yl) -5- (2- (4-methylpiperazin-1-yl) phenoxy) pentan-1-fumarate (43)
Figure imgf000092_0001
0 43: Le dérivé 43 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: 4-benzoylpipéridine (371 mg; 1.96 mmol); 42B (403 mg; 1.29 mmol); triéthylamine (210 ml; 1.5 mmol); le chlorhydrate de l-(3-dimethylaminopropyl)-3- éthylcarbodiimide (288 mg ; 1.5 mmol); 4-NJV-diméthylaminopyridine (8 mg) dans le dichlorométhane (17 ml).
Figure imgf000092_0001
0 43: The derivative 43 is prepared according to the same method described for 26C from the following reagents: 4-benzoylpiperidine (371 mg; 1.96 mmol); 42B (403 mg; 1.29 mmol); triethylamine (210 ml; 1.5 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288 mg; 1.5 mmol); 4-NJV-dimethylaminopyridine (8 mg) in dichloromethane (17 ml).
Le dérivé 43 est purifié par chromatographie-éclair avec un mélange d'éluants (1-7-93 =Derivative 43 is purified by flash chromatography with a mixture of eluents (1-7-93 =
NH4OH-MeOH-CH2Cl2).NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 462 mg (77%)Mass obtained: 462 mg (77%)
JH-RMN (200 MHz, dmso-d6) δ : 8.01 (d, 2H, 7.1 Hz), 7.8-7.5 (m, 3H); 7.0-6.8 (m, 4H); 4.42 (brd, IH); 3.97 (brs, 3H); 3.72 (brtt, IH); 3.20 (brt, IH); 2.97 (brs, 4H); 2.76 (brt, IH); 2.6-2.4 (m, 6H); 2.21 (s, 3H); 2.0-1.3 (m, 8H).JH-NMR (200 MHz, dmso-d 6 ) δ: 8.01 (d, 2H, 7.1 Hz), 7.8-7.5 (m, 3H); 7.0-6.8 (m, 4H); 4.42 (brd, 1H); 3.97 (brs, 3H); 3.72 (brtt, 1H); 3.20 (brt, 1H); 2.97 (brs, 4H); 2.76 (brt, 1H); 2.6-2.4 (m, 6H); 2.21 (s, 3H); 2.0-1.3 (m, 8H).
Analyse élémentaire: C28H37N3O3 ; 0.15 CH2CI2 Calculée: C = 70.98; H = 7.89 ; N = 8.82 Trouvée: C = 70.91 ; H = 8.04 ; N = 8.71Elemental analysis: C28H37N3O3; 0.15 CH 2 CI 2 Calculated: C = 70.98; H = 7.89; N = 8.82 Found: C = 70.91; H = 8.04; N = 8.71
EXEMPLE 44EXAMPLE 44
Le fumarate de la l-[4-(hydroxydiphényIméthy.)pipéridin-l-yl]-5-[2-(4- méthylpipérazin-l-yl)phénoxy]pentan-l-one (44)1- [4- (hydroxydiphenyimethy.) Piperidin-l-yl] -5- [2- (4-methylpiperazin-l-yl) phenoxy] pentan-l-one fumarate (44)
Figure imgf000093_0001
Figure imgf000093_0001
44: Le dérivé 44 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: chlorhydrate de 4-hydroxydiphénylméthyl)pipéridine (499 mg; 1.64 mmol); 42B (403 mg; 1.29 mmol); triéthylamine (210 ml; 1.5 mmol); le chlorhydrate de l-(3-dimethylaminopropyl)-3-éthylcarbodiimide (288 mg ; 1.5 mmol); 4-N.N- diméthylaminopyridine (8 mg) dans le dichlorométhane (20 ml). IL44: The derivative 44 is prepared according to the same method described for 26C from the following reagents: 4-hydroxydiphenylmethyl hydrochloride) piperidine (499 mg; 1.64 mmol); 42B (403 mg; 1.29 mmol); triethylamine (210 ml; 1.5 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288 mg; 1.5 mmol); 4-NN- dimethylaminopyridine (8 mg) in dichloromethane (20 ml). HE
Le dérivé 44 est purifié par chromatographie-éclair avec un mélange d'éluants (1-7-93 = NH4OH-MeOH-CH2Cl2).Derivative 44 is purified by flash chromatography with a mixture of eluents (1-7-93 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 358 mg (44%)Mass obtained: 358 mg (44%)
JH-RMN (200 MHz, dmso-d6) δ : 7.54 (brd, 4H); 7.27 (brt,4H); 7.14 (brt, 2H); 7.0- 6.85 (m, 4H); 5.32 (s, IH); 4.43 (brd, IH); 4.1-3.8 (m, 3H); 3.6-2.2 (m, 13H); 2.31 (s, 3H); 1.71 (brs, 4H); 1.07 (brs, 4H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.54 (brd, 4H); 7.27 (brt, 4H); 7.14 (brt, 2H); 7.0- 6.85 (m, 4H); 5.32 (s, 1H); 4.43 (brd, 1H); 4.1-3.8 (m, 3H); 3.6-2.2 (m, 13H); 2.31 (s, 3H); 1.71 (brs, 4H); 1.07 (brs, 4H).
Analyse élémentaire: C34H43N3O3 ; 1.2 H2O Calculée: C = 72.49; H = 8.12 ; N = 7.46 Trouvée: C = 72.51 ; H = 7.93 ; N = 7.43Elemental analysis: C34H43N3O3; 1.2 H 2 O Calculated: C = 72.49; H = 8.12; N = 7.46 Found: C = 72.51; H = 7.93; N = 7.43
EXEMPLE 45EXAMPLE 45
Le fumarate de la l-[4-(2-méthoxyphényl)p_pérazin-l-yl]-5-[2-(4-méthγlpipérazin- l-yl)phénoxyJpentan-l-one (45)1- [4- (2-methoxyphenyl) p_perazin-l-yl] -5- [2- (4-methγlpiperazin- l-yl) phenoxyJpentan-l-one fumarate (45)
Figure imgf000094_0001
Figure imgf000094_0001
45: Le dérivé 45 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: l-(2-méthoxyphényl)pipérazine (708 mg; 3.7 mmol); 42B (900 mg; 2.9 mmol); triéthylamine (470 ml; 3.4 mmol); le chlorhydrate de l-(3-dimethylaminopropyl)- 3-éthylcarbodiimide (647 mg ; 3.4 mmol); 4-N,Λr-diméthylaminopyridine (15 mg) dans le dichlorométhane (25 ml).45: The derivative 45 is prepared according to the same method described for 26C from the following reagents: 1- (2-methoxyphenyl) piperazine (708 mg; 3.7 mmol); 42B (900 mg; 2.9 mmol); triethylamine (470 ml; 3.4 mmol); 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride (647 mg; 3.4 mmol); 4-N, Λ r -dimethylaminopyridine (15 mg) in dichloromethane (25 ml).
Le dérivé 45 est purifié par chromatographie-éclair avec un mélange d'éluants (1-7-93 = NH4OH-MeOH-CH2Cl2).Derivative 45 is purified by flash chromatography with a mixture of eluents (1-7-93 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 903 mg (67%) Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.Mass obtained: 903 mg (67%) This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
^-RMN (200 MHz, dmso-dό) δ : 7.1-6.8 (m, 8H), 6 59 (s, fumarate), 3.97 (brt, 2H); 3.79 (s, 3H); 3.60 (brs, 4H); 3.02 (brs, 4H), 2.91 (brs, 4H); 2.64 (brs, 4H); 2.43 (brt, 2H); 2.34 (s, 3H); 1.75 (brs, 4H).^ -RMN (200 MHz, dmso-dό) δ: 7.1-6.8 (m, 8H), 659 (s, fumarate), 3.97 (brt, 2H); 3.79 (s, 3H); 3.60 (brs, 4H); 3.02 (brs, 4H), 2.91 (brs, 4H); 2.64 (brs, 4H); 2.43 (brt, 2H); 2.34 (s, 3H); 1.75 (brs, 4H).
Analyse élémentaire: C27H3gN4θ3 ; 1.1 C4H4O4; 1 H20 Calculée: C = 61.59: H = 7.31 ; N = 9.15 Trouvée: C = 61.40 : H = 7.18 : N = 8.91Elemental analysis: C 2 7H3gN4θ3; 1.1 C4H4O4; 1 H 2 0 Calculated: C = 61.59: H = 7.31; N = 9.15 Found: C = 61.40: H = 7.18: N = 8.91
Rf: 0.4 (1-7-93 = NH4OH-MeOH-CH2Cl2)Rf: 0.4 (1-7-93 = NH 4 OH-MeOH-CH 2 Cl 2 )
EXEMPLE 46EXAMPLE 46
Le fumarate de la l-(4-benzhydryloxypipéridin-l-yl)-5-[2-(4-méthylpipérazin-l- yl)phénoxy]pentan-l-one (46)1- (4-Benzhydryloxypiperidin-1-yl) -5- [2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-one fumarate (46)
Figure imgf000095_0001
Figure imgf000095_0001
46: Le dérivé 46 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: 1-benzhydryloxypipéridine (446 mg; 1 47 mmol); 42B (394 mg; 1.23 mmol); triéthylamine (188 ml, 1.35 mmol); le chlorhydrate de l-(3- dimethylaminopropyl)-3-éthylcarbodiimide (259 mg , 1.35 mmol); 4-N.N- diméthylaminopyridine (8 mg) dans le dichlorométhane (17 ml).46: The derivative 46 is prepared according to the same method described for 26C from the following reagents: 1-benzhydryloxypiperidine (446 mg; 147 mmol); 42B (394 mg; 1.23 mmol); triethylamine (188 ml, 1.35 mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (259 mg, 1.35 mmol); 4-N.N- dimethylaminopyridine (8 mg) in dichloromethane (17 ml).
Le dérivé 46 est purifié par chromatographie-éclair avec un mélange d'éluants (1-7-93 = NH4OH-MeOH-CH2Cl2).Derivative 46 is purified by flash chromatography with a mixture of eluents (1-7-93 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 495 mg (74%) S UMass obtained: 495 mg (74%) SU
ÏH-RMN (200 MHz, dmso-d6) δ : 7.4-7.15 (m, 10H); 6.95-6.75 (m, 4H); 5.74 (s, CH2C12); 5.64 (s, IH); 3.92 (brt, 2H); 4.0-3.4 (m, 3H); 3.3-3.0 (m, 2H); 2.92 (brs, 4H); 2.39 (brs, 6H); 2.16 (s, 3H); 2.0-1.3 (m, 8H).HI-NMR (200 MHz, dmso-d 6 ) 7.4: 7.4-7.15 (m, 10H); 6.95-6.75 (m, 4H); 5.74 (s, CH 2 C1 2 ); 5.64 (s, 1H); 3.92 (brt, 2H); 4.0-3.4 (m, 3H); 3.3-3.0 (m, 2H); 2.92 (brs, 4H); 2.39 (brs, 6H); 2.16 (s, 3H); 2.0-1.3 (m, 8H).
Analyse élémentaire: C34H43N3O3 ; 0.35 CH2C12 Calculée: C = 72.20; H = 7.71 ; N = 7.35 Trouvée: C = 72.18 : H = 7.63 ; N = 7.40Elemental analysis: C34H43N3O3; 0.35 CH 2 C1 2 Calculated: C = 72.20; H = 7.71; N = 7.35 Found: C = 72.18: H = 7.63; N = 7.40
EXEMPLE 47EXAMPLE 47
Le fumarate de la 5-[2-(4-méthylpipérazin-l-yl)phènoxy]-l-[4-phènoxypipéridin-l- yl]pentan-l-one (47)5- [2- (4-methylpiperazin-1-yl) phenoxy] -l- [4-phenoxypiperidin-1-yl] pentan-1-one fumarate (47)
Figure imgf000096_0001
Figure imgf000096_0001
47: Le dérivé 47 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: chlorhydrate de la 1-phènoxypipéridine (329 mg; 1.54 mmol); 42B (41 1 mg; 1.29 mmol); triéthylamine (197 ml; 1.41 mmol); le chlorhydrate de l-(3- dimethylaminopropyl)-3-éthylcarbodiimide (272 mg ; 1.41 mmol); 4-N,N- diméthylaminopyridine (8 mg) dans le dichlorométhane ( 18 ml).47: The derivative 47 is prepared according to the same method described for 26C from the following reagents: 1-phenoxypiperidine hydrochloride (329 mg; 1.54 mmol); 42B (41 1 mg; 1.29 mmol); triethylamine (197 ml; 1.41 mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (272 mg; 1.41 mmol); 4-N, N- dimethylaminopyridine (8 mg) in dichloromethane (18 ml).
Le dérivé 47 est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).Derivative 47 is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 418 mg (71%)Mass obtained: 418 mg (71%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
!H-RMN (200 MHz, dmso-d6) δ : 7.29 (brt, 2H); 7.0-6.8 (m, 7H); 4.7-4.5 (m, IH); 3.98 (brt, 2H); 4.0-3.6 (m, 2H); 3.5-3.1 (m, 2H); 3.03 (brs, 4H); 2.65 (brs, 4H); 2.42 (brt, 2H); 2.35 (s, 3H); 2.1-1.4 (m, 8H). Analyse élémentaire: C27H37N3θ3 ; C4H4O4; 1.25 H20 Calculée: C = 63.09: H = 7.43 ; N = 7.12 Trouvée: C = 63.04 ; H = 7.45 ; N = 7.08! H-NMR (200 MHz, dmso-d 6 ) δ: 7.29 (brt, 2H); 7.0-6.8 (m, 7H); 4.7-4.5 (m, 1H); 3.98 (brt, 2H); 4.0-3.6 (m, 2H); 3.5-3.1 (m, 2H); 3.03 (brs, 4H); 2.65 (brs, 4H); 2.42 (brt, 2H); 2.35 (s, 3H); 2.1-1.4 (m, 8H). Elemental analysis: C 2 7H37N3θ3; C4H4O4; 1.25 H 2 0 Calculated: C = 63.09: H = 7.43; N = 7.12 Found: C = 63.04; H = 7.45; N = 7.08
Rf: 0.4 ( 1 -6-94 = NH4OH-MeOH-CH2Cl2)Rf: 0.4 (1 -6-94 = NH 4 OH-MeOH-CH 2 Cl 2 )
IR (KBr): 3436, 2950, 1630, 1500IR (KBr): 3436, 2950, 1630, 1500
EXEMPLE 48EXAMPLE 48
Le fumarate de la l-(4-benzylpipéridin-l-yl)-5-[2-(4-méthyIpipérazin-l- yl)phénoxy]pentan-l-one (48)1- (4-Benzylpiperidin-1-yl) -5- [2- (4-methylpiperazin-1-yl) phenoxy] pentan-1-one fumarate (48)
Figure imgf000097_0001
Figure imgf000097_0001
48: Le dérivé 48 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: 1-benzylpiperidine (280 ml; 1.59 mmol); 42 B (423 mg; 1.33 mmol); triéthylamine (203 ml; 1.46 mmol); le chlorhydrate de l-(3-dimethylaminopropyl)-3- éthylcarbodiimide (280 mg ; 1.46 mmol); 4-N,N-diméthylaminopyridine (10 mg) dans le dichlorométhane (22 ml).48: The derivative 48 is prepared according to the same method described for 26C from the following reagents: 1-benzylpiperidine (280 ml; 1.59 mmol); 42 B (423 mg; 1.33 mmol); triethylamine (203 ml; 1.46 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (280 mg; 1.46 mmol); 4-N, N-dimethylaminopyridine (10 mg) in dichloromethane (22 ml).
Le dérivé 48 est purifié par chromatographie-éclair avec un mélange d'éluants (1-6-94 = NH4OH-MeOH-CH2Cl2).Derivative 48 is purified by flash chromatography with a mixture of eluents (1-6-94 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 375 mg (62%)Mass obtained: 375 mg (62%)
1H-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 5H); 7.0-6.7 (m, 4H); 4.33 (brd, IH); 3.93 (bit, 2H); 3.82 (brd, IH); 2.95 (brs, 5H); 2.6-2.25 (m, 9H); 2.18 (s, 3H); 1.9-1.4 (m, 7H); 1.25-0.8 (m, 2H). EXEMPLE 491H-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 5H); 7.0-6.7 (m, 4H); 4.33 (brd, 1H); 3.93 (bit, 2H); 3.82 (brd, 1H); 2.95 (brs, 5H); 2.6-2.25 (m, 9H); 2.18 (s, 3H); 1.9-1.4 (m, 7H); 1.25-0.8 (m, 2H). EXAMPLE 49
Le fumarate de la l-[4-(3-phénylpropyl)pipéridin-l-yl)-5-[2-(4-méthylpipérazin-l- yI)phénoxy]pentan-l-one (49)1- [4- (3-phenylpropyl) piperidin-1-yl) -5- [2- (4-methylpiperazin-1-yI) phenoxy] pentan-1-one fumarate (49)
Figure imgf000098_0001
Figure imgf000098_0001
49: Le dérivé 49 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: l-(3-phénylpropyl)pipéridine (724 mg; 3.56 mmol); 42B (871 mg; 2.80 mmol); triéthylamine (455 ml; 3.26 mmol); le chlorhydrate de l-(3- dimethylaminopropyl)-3-éthylcarbodiimide (626 mg ; 3.26 mmol); 4-N,N- diméthylaminopyridine (15 mg) dans le dichlorométhane (15 ml). Le dérivé 49 est purifié par chromatographie-éclair avec un mélange d'éluants (1-7-93 = NH4OH-MeOH-CH2Cl2).49: Derivative 49 is prepared according to the same method described for 26C from the following reagents: 1- (3-phenylpropyl) piperidine (724 mg; 3.56 mmol); 42B (871 mg; 2.80 mmol); triethylamine (455 ml; 3.26 mmol); 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (626 mg; 3.26 mmol); 4-N, N- dimethylaminopyridine (15 mg) in dichloromethane (15 ml). Derivative 49 is purified by flash chromatography with a mixture of eluents (1-7-93 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 936 mg (70%)Mass obtained: 936 mg (70%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
]H-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 5H); 7.05-6.8 (m, 4H); 6.59 (s, fumarate); 4.36 (brd, IH); 3.96 (brt, 2H); 3.83 (brd, IH); 3.04 (brs, 4H); 2.94 (brt, IH); 2.70 (brs, 4H); 2.7-2.4 (m, 3H); 2.39 (brs, 5H); 1.9-1.35 (m, 9H); 1.3-1.1 (m, 2H); 1.1- 0.7 (m, 2H). ] H-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 5H); 7.05-6.8 (m, 4H); 6.59 (s, fumarate); 4.36 (brd, 1H); 3.96 (brt, 2H); 3.83 (brd, 1H); 3.04 (brs, 4H); 2.94 (brt, 1H); 2.70 (brs, 4H); 2.7-2.4 (m, 3H); 2.39 (brs, 5H); 1.9-1.35 (m, 9H); 1.3-1.1 (m, 2H); 1.1- 0.7 (m, 2H).
Analyse élémentaire: C3QH43N3O2 ; C4H4O4; 0.1 H20 Calculée: C = 68.57; H = 7.99 ; N = 7.09 Trouvée: C = 68.57 ; H = 8.11 ; N = 6.93Elementary analysis: C3QH43N3O 2 ; C4H4O4; 0.1 H 2 0 Calculated: C = 68.57; H = 7.99; N = 7.09 Found: C = 68.57; H = 8.11; N = 6.93
Rf: 0.45 (1-7-93 = NH4θH-MeOH-CH2Cl2) IR (KBr): 3446, 2929, 1620, 1500, 1450. EXEMPLE 50Rf: 0.45 (1-7-93 = NH4θH-MeOH-CH 2 Cl 2 ) IR (KBr): 3446, 2929, 1620, 1500, 1450. EXAMPLE 50
Le fumarate de la 6-[2-(4-méthylpipérazin-l-yl)phénoxy]-l-(4-phénylpipéridin-l- y.)hexan-l-one (50)6- [2- (4-methylpiperazin-1-yl) phenoxy] -l- (4-phenylpiperidin-1-y.) Hexan-1-one fumarate (50)
Figure imgf000099_0001
Figure imgf000099_0001
50A: Le 6-bromo-l-(4-phénylpipéridin-l-yl)hexan-l-one50A: 6-bromo-1- (4-phenylpiperidin-1-yl) hexan-1-one
Le dérivé 50A est préparé selon la même méthode décrite pour .LA à partir des réactifs suivants: 4-phénylpipéridine (1.1 g ; 6.8 mmol) ; chlorure de 6-bromo-hexanoyle (1.02 ml ; 6.7 mmol) ; triéthylamine (1.16 ml ; 8.38 mmol) dans le dichlorométhane (1 1 ml).The derivative 50A is prepared according to the same method described for .LA from the following reagents: 4-phenylpiperidine (1.1 g; 6.8 mmol); 6-bromo-hexanoyl chloride (1.02 ml; 6.7 mmol); triethylamine (1.16 ml; 8.38 mmol) in dichloromethane (11 ml).
Masse obtenue: 1.7 g (75 %)Mass obtained: 1.7 g (75%)
JH-RMN (200 MHz, dmso-d6) δ : 7.4-7.1 (m, 5H); 4.52 (brd, IH); 3.96 (brd, 1 H); 3.55 (t, 2H, 6.7 Hz); 3.05 (brt, IH); 2.73 (brtt, IH); 2.54 (brt, IH); 2.32 (t, 2H, 6.7 Hz); 2.0- 1.2 (m, 10H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.1 (m, 5H); 4.52 (brd, 1H); 3.96 (brd, 1 H); 3.55 (t, 2H, 6.7 Hz); 3.05 (brt, 1H); 2.73 (brtt, 1H); 2.54 (brt, 1H); 2.32 (t, 2H, 6.7 Hz); 2.0-1.2 (m, 10H).
Analyse élémentaire: Ci 7H24BrNO Ç^çuiée: C = 60.36 ; H = 7.15 ; N = 4.14Elementary analysis: Ci 7H 2 4BrNO Ç ^ çuiée: C = 60.36; H = 7.15; N = 4.14
Trouvée: C = 60.55 ; H ≈ 7.25 ; N = 4.16Found: C = 60.55; H ≈ 7.25; N = 4.16
50: Le dérivé 50 est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants: A (576 mg; 2.99 mmol); NaH (50% dans l'huile; 215 mg; 4.5 mmol); 50A (1.67 g, 4.9 mmol); DMF (20 ml).50: The derivative 50 is prepared according to the same method described for 36 from the following reagents: A (576 mg; 2.99 mmol); NaH (50% in oil; 215 mg; 4.5 mmol); 50A (1.67 g, 4.9 mmol); DMF (20 ml).
Le dérivé 50 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4θH-MeOH-CH2Cl2 = 1-5-95).The derivative 50 is purified in the form of the free base by flash chromatography with a mixture of eluents (NH4θH-MeOH-CH 2 Cl 2 = 1-5-95).
Masse obtenue : 933 mg (74 %) Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.Mass obtained: 933 mg (74%) This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RMN (200 MHz, dmso-d6) δ : 7.35-7.1 (m, 5H); 7 0-6.75 (m, 4H); 6.57 (s, fumarate); 4.54 (brd, IH); 4.1-3.85 (m, 3H); 3.2-2.9 (m, 6H), 2.9-2.45 (m, 5H); 2.35 (brs, 5H); 1.9-2.3 (m, 10H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.35-7.1 (m, 5H); 7 0-6.75 (m, 4H); 6.57 (s, fumarate); 4.54 (brd, 1H); 4.1-3.85 (m, 3H); 3.2-2.9 (m, 6H), 2.9-2.45 (m, 5H); 2.35 (brs, 5H); 1.9-2.3 (m, 10H).
IR (KBr): 3700-2400, 1710, 1629, 1615, 1520, 1460.IR (KBr): 3700-2400, 1710, 1629, 1615, 1520, 1460.
Analyse élémentaire: C2gH39N3θ2 ; 1.2 C4H4O4 Calculée: C = 66.90; H = 7.50 ; N = 7.14 Trouvée: C = 66.98 ; H = 7.58 ; N = 7.43Elemental analysis: C 2 gH39N3θ 2 ; 1.2 C4H4O4 Calculated: C = 66.90; H = 7.50; N = 7.14 Found: C = 66.98; H = 7.58; N = 7.43
Masse (DCI, NH3) : 450 (MH+)Mass (DCI, NH 3 ): 450 (MH + )
Rf: 0.2 (1-5-95 = NH4θH-MeOH-CH2Cl2)Rf: 0.2 (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 )
EXEMPLE 51EXAMPLE 51
Le fumarate de la l-[4-(2-méthoxyphényl)pipérazin-l-yl]-6-[2-(4-méthylpipérazin- l-yI)phénoxy]hexan-l-one (51)1- [4- (2-methoxyphenyl) piperazin-1-yl] -6- [2- (4-methylpiperazin-1-yI) phenoxy] hexan-1-one fumarate (51)
Figure imgf000100_0001
Figure imgf000100_0001
51A: Le 6-bromo-l-[4-(2-méthoxyphényl)pipérazin-l-yl]hexan-l-one51A: 6-bromo-1- [4- (2-methoxyphenyl) piperazin-1-yl] hexan-1-one
Le dérivé 51A est préparé selon la même méthode décrite pour .LA à partir des réactifs suivants: 1 -(2-méthoxyphényl)pipérazine (1.2 g ; 6.24 mmol) , chlorure de 6-bromo- hexanoyle (1.14 ml ; 7.48 mmol) ; triéthylamine (1.3 ml ; 9.36 mmol) dans le dichlorométhane (15 ml). Masse obtenue: 2.3 g (100 %)The derivative 51A is prepared according to the same method described for .LA from the following reagents: 1 - (2-methoxyphenyl) piperazine (1.2 g; 6.24 mmol), 6-bromo-hexanoyl chloride (1.14 ml; 7.48 mmol); triethylamine (1.3 ml; 9.36 mmol) in dichloromethane (15 ml). Mass obtained: 2.3 g (100%)
1H-RMN (200 MHz, dmso-dό) δ : 7.1-6.8 (m, 4H); 3.78 (s, 3H); 3.65-3.4 (m, 6H); 2.9 (m, 4H); 2.34 (t, 2H, 6.8 Hz); 1.81 (p, 2H, 6.8 Hz); 1.65-1.3 (m, 4H).1H-NMR (200 MHz, dmso-dό) δ: 7.1-6.8 (m, 4H); 3.78 (s, 3H); 3.65-3.4 (m, 6H); 2.9 (m, 4H); 2.34 (t, 2H, 6.8 Hz); 1.81 (p, 2H, 6.8 Hz); 1.65-1.3 (m, 4H).
51: Le dérivé 5_1 est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants: A (845 mg; 4.4 mmol); NaH (50% dans l'huile, 316 mg; 6.6 mmol); 5LA (2.3 g, 6.2 mmol); DMF (28 ml).51: The derivative 5_1 is prepared according to the same method described for 36 from the following reagents: A (845 mg; 4.4 mmol); NaH (50% in oil, 316 mg; 6.6 mmol); 5LA (2.3 g, 6.2 mmol); DMF (28 ml).
Le dérivé 5_! est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1 -5-95)The 5_ derivative! is purified in the form of the free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1 -5-95)
Masse obtenue : 938 mg (44 %)Mass obtained: 938 mg (44%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RMN (200 MHz, dmso-d6) δ : 7.1-6.8 (m, 8H); 6.61 (s, fumarate); 3.97 (t, 2H, 6Hz); 3.79 (s, 3H); 3.59 (brs, 4H); 3.12 (brs, 4H); 2.92 (brs, 8H); 2.54 (s, 3H); 2.39 (t, 2H, 7Hz); 1.9-1.3 (m, 6H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.1-6.8 (m, 8H); 6.61 (s, fumarate); 3.97 (t, 2H, 6Hz); 3.79 (s, 3H); 3.59 (brs, 4H); 3.12 (brs, 4H); 2.92 (brs, 8H); 2.54 (s, 3H); 2.39 (t, 2H, 7Hz); 1.9-1.3 (m, 6H).
IR fKBr): 3700-2300, 1709, 1635, 1600, 1495, 1470, 1240 Analyse élémentaire. C2gH4QN4θ3 ; 1 C4H4O4; 1.8 H2O Calculée: C = 61.09: H = 7.63 ; N = 8.91 Trouvée: C = 60.89 ; H = 7.41 ; N = 8.71IR fKBr): 3700-2300, 1709, 1635, 1600, 1495, 1470, 1240 Elementary analysis. C 2 gH4QN4θ3; 1 C4H4O4; 1.8 H 2 O Calculated: C = 61.09: H = 7.63; N = 8.91 Found: C = 60.89; H = 7.41; N = 8.71
Masse (DCI, NH3) : 481 (MH+)Mass (DCI, NH 3 ): 481 (MH +)
Rf: 0.4 (1-5-95 = NH4OH-MeOH-CH2Cl2) EXEMPLE 52Rf: 0.4 (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ) EXAMPLE 52
Le fumarate de la l-[4-(2,3-diméthylphényl)pipérazin-l-yIJ-7-[2-(4- méthyIpipérazin-l-yl)phénoxy]heptan-l-one (52)1- [4- (2,3-dimethylphenyl) piperazin-1-yIJ-7- [2- (4-methylpiperazin-1-yl) phenoxy] heptan-1-one fumarate (52)
Figure imgf000102_0001
Figure imgf000102_0001
52A: le 7-[2-(4-méthylpipérazin-l-yl)phénoxy]heptanoate d'ethyle52A: 7- [2- (4-methylpiperazin-1-yl) phenoxy] ethyl heptanoate
Le dérivé 52A est préparé selon la même méthode décrite pour 42A à partir des réactifs suivants: A (5.07 g; 26.4 mmol); NaH (50% dans l'huile; 1.89 g; 39.6 mmol); 7- bromoheptanoate d'ethyle (8.2 g, 34.3 mmol); DMF (164 ml).The derivative 52A is prepared according to the same method described for 42A from the following reagents: A (5.07 g; 26.4 mmol); NaH (50% in oil; 1.89 g; 39.6 mmol); 7- ethyl bromoheptanoate (8.2 g, 34.3 mmol); DMF (164 ml).
Le dérivé 52A est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4θH-MeOH-CH2Cl2 = 1-3-97).The derivative 52A is purified in the form of the free base by flash chromatography with a mixture of eluents (NH4θH-MeOH-CH 2 Cl 2 = 1-3-97).
Masse obtenue: 4.97 g (54 %)Mass obtained: 4.97 g (54%)
}H-RMN (200 MHz, dmso-d6) δ : 6.95-6.75 (m, 4H); 4.02 (q, 2H, 7.1 Hz); 3.90 (t, 2H, 7.1 Hz); 2.94 (brs, 4H); 2.42 (brs, 4H); 2.27 (t, 2H, 7.1 Hz); 2.19 (s, 3H); 1.9-1.2 (m, 8H); 1.15 (t, 3H, 7.1 Hz). } H-NMR (200 MHz, dmso-d 6 ) δ: 6.95-6.75 (m, 4H); 4.02 (q, 2H, 7.1 Hz); 3.90 (t, 2H, 7.1 Hz); 2.94 (brs, 4H); 2.42 (brs, 4H); 2.27 (t, 2H, 7.1 Hz); 2.19 (s, 3H); 1.9-1.2 (m, 8H); 1.15 (t, 3H, 7.1 Hz).
Analyse élémentaire: C2gH4oN4θ3 ; 0.1 CH2C12 Calculée: C = 67.63; H = 9.09 ; N = 7.85 Trouvée: C = 67.87 ; H = 9.16 ; N = 7.93Elemental analysis: C 2 gH4oN4θ3; 0.1 CH 2 C1 2 Calculated: C = 67.63; H = 9.09; N = 7.85 Found: C = 67.87; H = 9.16; N = 7.93
52B. l'acide 7-[2-(4-méthylpipérazin-l-yl)phénoxy]heptanoique.52B. 7- [2- (4-methylpiperazin-1-yl) phenoxy] heptanoic acid.
Le dérivé 52A (4.87 g, 14 mmol) est dissous dans du THF (15 ml). Une solution de soude (IM dans l'eau, 15.4 ml, 15.4 mmol) est ajoutée et la solution est chauffée à 50°C pendant 6 heures. La réaction est refroidie à température ambiante puis neutralisée par ajout d'acide chlorhydrique (IN dans l'eau, 15.4 ml, 15.4 mmol). Les solvants sont évaporés. Le résidu semi-solide est trituré dans un peu d'éthanol et filtré. Le filtrat est O 97/14689 PC17FR96/01626The derivative 52A (4.87 g, 14 mmol) is dissolved in THF (15 ml). A sodium hydroxide solution (IM in water, 15.4 ml, 15.4 mmol) is added and the solution is heated at 50 ° C for 6 hours. The reaction is cooled to room temperature and then neutralized by adding hydrochloric acid (IN in water, 15.4 ml, 15.4 mmol). The solvents are evaporated. The semi-solid residue is triturated in a little ethanol and filtered. The filtrate is O 97/14689 PC17FR96 / 01626
JβΛJβΛ
concentré pour donner une mousse Le dérivé 52B est utilisé sans autre purification pour la suite des synthèsesconcentrate to give a foam The derivative 52B is used without further purification for the continuation of the syntheses
Masse obtenue 4 77 gMass obtained 4 77 g
52: Le dérivé 52 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants chlorhydrate de la l-(2,3-diméthylphenyl)pιperazιne (1 18 g, 5 2 mmol), 52B (1 5 g, 4 3 mmol), triéthylamine (668 ml, 4 8 mmol), le chlorhydrate de l -(3- dimethylamιnopropyl)-3-éthylcarbodιimide (919 mg , 4 8 mmol), 4-N.N- diméthylaminopyridine (10 mg) dans le dichlorométhane ( 15 ml)52: The derivative 52 is prepared according to the same method described for 26C from the following reagents l- (2,3-dimethylphenyl) pιperazιne hydrochloride (1 18 g, 5 2 mmol), 52B (1 5 g, 4 3 mmol), triethylamine (668 ml, 4 8 mmol), l - (3- dimethylamιnopropyl) -3-ethylcarbodιimide hydrochloride (919 mg, 4 8 mmol), 4-NN- dimethylaminopyridine (10 mg) in dichloromethane (15 ml)
Le dérivé 52 est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2)Derivative 52 is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 )
Masse obtenue 1 66 g (77%)Mass obtained 1 66 g (77%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondantThis compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate
!H-RMN (200 MHz, dmso-d6) δ : 7.1-6 7 (m, 7H), 6 58 (s, fumarate), 3 94 (brt, 2H), 3.58 (brs, 4H), 3 30 (brs, 4H), 2 70 (brs, 8H), 2 37 (brs, 5H), 2 21 (s, 3H), 2 17 (s, 3H), 1 9-1 3 (m, 8H)! H-NMR (200 MHz, dmso-d 6 ) δ: 7.1-6 7 (m, 7H), 6 58 (s, fumarate), 3 94 (brt, 2H), 3.58 (brs, 4H), 3 30 (brs, 4H), 2 70 (brs, 8H), 2 37 (brs, 5H), 2 21 (s, 3H), 2 17 (s, 3H), 1 9-1 3 (m, 8H)
Analyse élémentaire C3oH44N4θ2 , C4H4O4, 0 5 H20 Calculée C = 66 10, H = 7 99 , N = 9 07 Trouvée. C = 66.25 ; H = 7 84 , N = 8.99Elementary analysis C3oH44N4θ 2 , C4H4O4, 0 5 H 2 0 Calculated C = 66 10, H = 7 99, N = 9 07 Found. C = 66.25; H = 7 84, N = 8.99
Rf 0 15 (1-5-95 = NH4θH-MeOH-CH2Cl2)Rf 0 15 (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 )
DUKBr) 3700-2400, 1700, 1631, 1510, 1490DUKBr) 3700-2400, 1700, 1631, 1510, 1490
Masse (DCI. NH3) 493 (MH+) Λ 0 ?SMass (DCI. NH 3 ) 493 (MH + ) Λ 0? S
EXEMPLE 53EXAMPLE 53
Le fumarate de la l-[4-(2-méthoxyphényl)pipérazin-l-yl]-7-[2-(4-méthylpipérazin- l-yl)phénoxy]heptan-l-one (53)1- [4- (2-methoxyphenyl) piperazin-1-yl] -7- [2- (4-methylpiperazin-1-yl) phenoxy] heptan-1-one fumarate (53)
Figure imgf000104_0001
Figure imgf000104_0001
53: Le dérivé 53 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: l-(2-méthoxyphényl)pipérazine ( 1. 12 g, 4 88 mmol); 52B (1.68 g; 4.88 mmol); triéthylamine (748 ml; 5.36 mmol), le chlorhydrate de l-(3- dimethylaminopropyl)-3-éthylcarbodiimide (1.02 g , 5.36 mmol); 4-N.N- diméthylaminopyridine (10 mg) dans le dichlorométhane (20 ml).53: The derivative 53 is prepared according to the same method described for 26C from the following reagents: 1- (2-methoxyphenyl) piperazine (1.12 g, 4 88 mmol); 52B (1.68 g; 4.88 mmol); triethylamine (748 ml; 5.36 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.02 g, 5.36 mmol); 4-N.N- dimethylaminopyridine (10 mg) in dichloromethane (20 ml).
Le dérivé 53 est purifié par chromatographie-éclair avec un mélange d'éluants (1-5-95 = NH4OH-MeOH-CH2Cl2).Derivative 53 is purified by flash chromatography with a mixture of eluents (1-5-95 = NH 4 OH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 2.01g (83%)Mass obtained: 2.01g (83%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
*H-RMN (200 MHz, dmso-d6) δ : 7.1-6.75 (8H); 6.60 (s, fumarate); 3.96 (t, 2H, 6.1 Hz); 3.80 (s, 3H); 3.59 (brs, 4H); 3.04 (brs, 4H); 2.91 (brs, 4H), 2.66 (brs, 4H); 2.36 (brs, 5H); 1.9-1.2 (m, 8H).* H-NMR (200 MHz, dmso-d 6 ) δ: 7.1-6.75 (8H); 6.60 (s, fumarate); 3.96 (t, 2H, 6.1 Hz); 3.80 (s, 3H); 3.59 (brs, 4H); 3.04 (brs, 4H); 2.91 (brs, 4H), 2.66 (brs, 4H); 2.36 (brs, 5H); 1.9-1.2 (m, 8H).
Analyse élémentaire: C3oH44N4θ2 ; C4H4O4; 0.7 H20 Calculée: C = 63.58; H ≈ 7.66 ; N = 8.99 Trouvée: C = 63.84 ; H = 7.50 ; N = 8.69Elementary analysis: C3oH44N4θ 2 ; C4H4O4; 0.7 H 2 0 Calculated: C = 63.58; H ≈ 7.66; N = 8.99 Found: C = 63.84; H = 7.50; N = 8.69
Rf: 0.2 (1-5-95 = NH4θH-MeOH-CH2Cl2) IR OCBr): 3700-2400, 1700, 1630, 1510, 1500. Masse (DCI, NH3) : 495 (MH+) / OS EXEMPLE 54Rf: 0.2 (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 ) IR OCBr): 3700-2400, 1700, 1630, 1510, 1500. Mass (DCI, NH3): 495 (MH + ) / OS EXAMPLE 54
Le fumarate de la 7-[2-(4-méthyIpipérazin-l-yl)phénoxy]-l-(4-phénylpipéridin-l- yl)heptan-l-one (54)7- [2- (4-methylPiperazin-1-yl) phenoxy] -l- (4-phenylpiperidin-1-yl) fumarate heptan-1-one (54)
Figure imgf000105_0001
Figure imgf000105_0001
54: Le dérivé 54 est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: 4-phénylpipéridine (1.02 g; 6.3 mmol); 52 B (1.5 g; 4.36 mmol); triéthylamine (667 ml; 4.79 mmol); le chlorhydrate de l-(3-dimethylaminopropyl)-3- éthylcarbodiimide (919 mg ; 4.79 mmol); 4-N,N-diméthylaminopyridine (10 mg) dans le dichlorométhane (15 ml).54: The derivative 54 is prepared according to the same method described for 26C from the following reagents: 4-phenylpiperidine (1.02 g; 6.3 mmol); 52 B (1.5 g; 4.36 mmol); triethylamine (667 ml; 4.79 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (919 mg; 4.79 mmol); 4-N, N-dimethylaminopyridine (10 mg) in dichloromethane (15 ml).
Le dérivé 54 est purifié par chromatographie-éclair avec un mélange d'éluants (1-6-94 = NH4θH-MeOH-CH2Cl2).Derivative 54 is purified by flash chromatography with a mixture of eluents (1-6-94 = NH4θH-MeOH-CH 2 Cl 2 ).
Masse obtenue: 1.74 g (86%)Mass obtained: 1.74 g (86%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
!H-RMN (200 MHz, dmso-d6) δ : 7.4-7.15 (m, 5H); 7.05-6.8 (m, 4H); 6.60 (s, fumarate); 4.55 (brd, IH); 4.1-3.85 (m, 3H); 3.2-2.95 (m, 5H); 2.9-2.5 (m, 6H); 2.5-2.3 (m, 5H); 1.9-1.2 (m, 12H).! H-NMR (200 MHz, dmso-d 6 ) δ: 7.4-7.15 (m, 5H); 7.05-6.8 (m, 4H); 6.60 (s, fumarate); 4.55 (brd, 1H); 4.1-3.85 (m, 3H); 3.2-2.95 (m, 5H); 2.9-2.5 (m, 6H); 2.5-2.3 (m, 5H); 1.9-1.2 (m, 12H).
Analyse élémentaire: C29H4jN3θ2 ; C4H4O4; 0.9 H2O Calculée: C = 66.51; H = 7.92 ; N = 7.05 Trouvée: C = 66.50 ; H ≈ 7.89 ; N = 6.93Elementary analysis: C 2 9H4jN3θ 2 ; C4H4O4; 0.9 H 2 O Calculated: C = 66.51; H = 7.92; N = 7.05 Found: C = 66.50; H ≈ 7.89; N = 6.93
Rf: 0.16 (1-5-95 = NH4OH-MeOH-CH2CI2) IR (KBr): 3700-2400, 1700, 1630, 1500. Masse (DCI, NH3) : 464 (MH+) EXEMPLE 55Rf: 0.16 (1-5-95 = NH 4 OH-MeOH-CH 2 CI 2 ) IR (KBr): 3700-2400, 1700, 1630, 1500. Mass (DCI, NH 3 ): 464 (MH +) EXAMPLE 55
Le fumarate de ia l-[4-(2,3-diméthylphényl)pipérazin-l-yl]-8-[2-(4 méthylpipérazin-l-yl)phénoxy]octan-l-one (55)1- [4- (2,3-dimethylphenyl) piperazin-1-yl] -8- [2- (4 methylpiperazin-1-yl) phenoxy] octan-1-one fumarate (55)
Figure imgf000106_0001
Figure imgf000106_0001
55 A: Le dérivé 55A est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: chlorhydrate de l-(2,3-diméthylphényl)pipérazine (1.82 g; 8 mmol); l'acide 8-bromooctanoique (1.5 g; 6.72 mmol); triéthylamine (1.03 ml; 7.4 mmol); le chlorhydrate de l-(3-dimethylaminopropyl)-3-éthylcarbodiimide (1.41 g ; 7.4 mmol); 4- N,N-diméthylaminopyridine (15 mg) dans le dichlorométhane (22 ml).55 A: The derivative 55A is prepared according to the same method described for 26C from the following reagents: 1- (2,3-dimethylphenyl) piperazine hydrochloride (1.82 g; 8 mmol); 8-bromooctanoic acid (1.5 g; 6.72 mmol); triethylamine (1.03 ml; 7.4 mmol); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.41 g; 7.4 mmol); 4- N, N-dimethylaminopyridine (15 mg) in dichloromethane (22 ml).
Masse obtenue: 2.05 g (77%)Mass obtained: 2.05 g (77%)
^-RMN (200 MHz, dmso-d6) δ : 7.06 (t, IH, 7.6 Hz); 7.0-6.8 (m, 2H); 3.8-3.4 (m, 6H); 2.75 (brs, 4H); 2.35 (t, 2H, 7.6 Hz); 2.23 (s, 3H); 2.20 (s, 3H); 1.81 (p, 2H, 7.6 Hz); 1.65-1.2 (m, 8H).^ -RMN (200 MHz, dmso-d 6 ) δ: 7.06 (t, IH, 7.6 Hz); 7.0-6.8 (m, 2H); 3.8-3.4 (m, 6H); 2.75 (brs, 4H); 2.35 (t, 2H, 7.6 Hz); 2.23 (s, 3H); 2.20 (s, 3H); 1.81 (p, 2H, 7.6 Hz); 1.65-1.2 (m, 8H).
Analyse élémentaire: C2oH3]BrN2O Calculée: C = 60.76; H = 7.90 ; N = 7.09 Trouvée: C = 60.95 ; H = 8.16 ; N = 6.99Elementary analysis: C 2 oH3] BrN 2 O Calculated: C = 60.76; H = 7.90; N = 7.09 Found: C = 60.95; H = 8.16; N = 6.99
55: Le dérivé 55 est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants: A (766 mg; 4 mmol); NaH (50% dans l'huile; 286 mg; 6 mmol); 55A (2.05 g, 5.2 mmol); DMF (25 ml).55: The derivative 55 is prepared according to the same method described for 36 from the following reagents: A (766 mg; 4 mmol); NaH (50% in oil; 286 mg; 6 mmol); 55A (2.05 g, 5.2 mmol); DMF (25 ml).
Le dérivé 55 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1-5-95).Derivative 55 is purified in the form of a free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-5-95).
Masse obtenue : 1.21 g (60 %) ΛO ≤Mass obtained: 1.21 g (60%) ΛO ≤
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant. iH-RMN (200 MHz, dmso-d6) δ : 7.15-6.75 (m, 7H), 6.59 (s, fumarate); 3.94 (t, 2H, 6.1Hz); 3.57 (brs, 4H); 3.04 (brs, 4H); 2.75 (brs, 8H), 2.39 (s, 3H); 2.35 (t, 2H, 7 5Hz); 2.20(s, 3H); 2.17 (s, 3H); 1.9-1.3 (m, 10H).This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate. iH-NMR (200 MHz, dmso-d 6 ) δ: 7.15-6.75 (m, 7H), 6.59 (s, fumarate); 3.94 (t, 2H, 6.1Hz); 3.57 (brs, 4H); 3.04 (brs, 4H); 2.75 (brs, 8H), 2.39 (s, 3H); 2.35 (t, 2H, 75Hz); 2.20 (s, 3H); 2.17 (s, 3H); 1.9-1.3 (m, 10H).
IR (KBr): 3700-2300, 1702, 1635, 1520, 1500IR (KBr): 3700-2300, 1702, 1635, 1520, 1500
Analyse élémentaire. C3 ]H46N4θ2 ; 1.1 C4H4O4, 1 2 H20 Calculée: C = 64.81: H = 8.1 1 : N = 8.54 Trouvée: C = 64.74 ; H = 7.96 ; N = 8.55Elementary analysis. C3] H46N4θ 2 ; 1.1 C4H4O4, 1 2 H 2 0 Calculated: C = 64.81: H = 8.1 1: N = 8.54 Found: C = 64.74; H = 7.96; N = 8.55
Masse (DCI, NH3) : 507 (MH+)Mass (DCI, NH3): 507 (MH + )
Rf: 0.2 (1-5-95 = NH4θH-MeOH-CH2Cl2)Rf: 0.2 (1-5-95 = NH4θH-MeOH-CH 2 Cl 2 )
EXEMPLE 56EXAMPLE 56
Le fumarate de la l-[4-(2-méthoxyphényl)pipérazin-l-yIJ-8-[2-(4-méthylpipérazin- l-yl)phénoxy]octan-l-one (56)1- [4- (2-methoxyphenyl) piperazin-1-yIJ-8- [2- (4-methylpiperazin-1-yl) phenoxy] octan-1-one fumarate (56)
Figure imgf000107_0001
Figure imgf000107_0001
56A: Le dérivé 56A est préparé selon la même méthode décrite pour 26C à partir des réactifs suivants: l-(2-méthoxyphényl)pipérazine (1 55 g, 8 mmol); l'acide 8- bromooctanoique (1.5 g; 6.72 mmol); triéthylamine (1 03 ml, 7 4 mmol), le chlorhydrate de l-(3-dimethylaminopropyl)-3-éthylcarbodiimide (1 41 g , 7.4 mmol); 4-N,N- diméthylaminopyridine (15 mg) dans le dichlorométhane (22 ml)56A: The derivative 56A is prepared according to the same method described for 26C from the following reagents: 1- (2-methoxyphenyl) piperazine (1 55 g, 8 mmol); 8-bromooctanoic acid (1.5 g; 6.72 mmol); triethylamine (103 ml, 744 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1441 g, 7.4 mmol); 4-N, N- dimethylaminopyridine (15 mg) in dichloromethane (22 ml)
Masse obtenue: 818 mg (30%) λ0loMass obtained: 818 mg (30%) λ 0lo
]H-RMN (200 MHz, dmso-d6) δ : 7.1-6.8 (m, 4H), 3.78 (s, 3H); 3.7-3.4 (m, 6H); 2.90 (brs, 4H); 2.32 (t, 2H, 7.5 Hz); 1.9-1.2 (m, 10H). ] H-NMR (200 MHz, dmso-d 6 ) δ: 7.1-6.8 (m, 4H), 3.78 (s, 3H); 3.7-3.4 (m, 6H); 2.90 (brs, 4H); 2.32 (t, 2H, 7.5 Hz); 1.9-1.2 (m, 10H).
56: Le dérivé 56 est préparé selon la même méthode décrite pour 36 à partir des réactifs suivants: A (297 mg; 1.54 mmol); NaH (50% dans l'huile, 1 10 mg; 2.31 mmol); 56A (799 mg, 2 mmol); DMF (10 ml).56: The derivative 56 is prepared according to the same method described for 36 from the following reagents: A (297 mg; 1.54 mmol); NaH (50% in oil, 1 10 mg; 2.31 mmol); 56A (799 mg, 2 mmol); DMF (10 ml).
Le dérivé 56 est purifié sous forme de base libre par chromatographie-éclair avec un mélange d'éluants (NH4OH-MeOH-CH2Cl2 = 1-5-95)Derivative 56 is purified in the form of a free base by flash chromatography with a mixture of eluents (NH 4 OH-MeOH-CH 2 Cl 2 = 1-5-95)
Masse obtenue : 447 mg (62 %)Mass obtained: 447 mg (62%)
Ce composé est dissous dans le méthanol et traité avec de l'acide fumarique pour donner le fumarate correspondant.This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
JH-RMN (200 MHz, dmso-d6) δ : 7.05-6.7 (m, 8H); 6.57 (s, fumarate); 3.92 (t, 2H; 6.1Hz); 3.75 (s, 3H); 3.54 (brs, 4H); 3.07 (brs, 4H), 2.87 (brs, 8H); 2.49 (s, 3H); 2.32 (t, 2H, 7.2Hz); 1.8-1.15 (m, 10H).JH-NMR (200 MHz, dmso-d 6 ) δ: 7.05-6.7 (m, 8H); 6.57 (s, fumarate); 3.92 (t, 2H; 6.1Hz); 3.75 (s, 3H); 3.54 (brs, 4H); 3.07 (brs, 4H), 2.87 (brs, 8H); 2.49 (s, 3H); 2.32 (t, 2H, 7.2Hz); 1.8-1.15 (m, 10H).
DKKBr): 3700-2300, 1629, 1501, 1246DKKBr): 3700-2300, 1629, 1501, 1246
Analyse élémentaire: C30H44N4O3 ; 1.1 C4H4O4; 2 H20 Calculée: C = 61.45; H = 7.85 ; N ≈ 8.33 Trouvée: C = 61.34 ; H = 7.67 ; N = 8.34Elemental analysis: C30H44N4O3; 1.1 C4H4O4; 2 H 2 0 Calculated: C = 61.45; H = 7.85; N ≈ 8.33 Found: C = 61.34; H = 7.67; N = 8.34
Masse (DCI, NH3) : 509 (MH+)Mass (DCI, NH 3 ): 509 (MH + )
Rf: 0.2 (0.5-5-95 = NH4θH-MeOH-CH2Cl2) 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 5HTj£> tel que la sérotonine, le sumatriptan ou la 5-CT, études qui ont été réalisées au niveau des récepteurs humains clones 5HTiQα et 5HTi£)β.Rf: 0.2 (0.5-5-95 = NH4θH-MeOH-CH 2 Cl 2 ) The derivatives of the present invention are potent antagonists of 5HT receptors £) as evidenced by binding studies and antagonism of study of the inhibition of adenylate cyclase (forskolin-stimulated) by a 5HT agonist j £> such as serotonin, sumatriptan or 5-CT, studies which have been carried out at the level of human receptors cloned 5HTiQ α and 5HTi £) β.
Les récepteurs humains 5HTj£)a et SHTjDtj ont été clones selon les séquences publiées par M. Hamblin et M. Metcalf, Mol. Pharmacol., 40, 143 (1991) et Weinshenk et coll., Proc. NatI. Acad. Sci. 89,3630 (1992).The human receptors 5HTj £) a and SHTjDt j were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40, 143 (1991) and Weinshenk et al., Proc. NatI. 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-K] en utilisant un électroporateur. 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).Transient transfection and permanent transfection of the genes for these receptors was carried out in Cos-7 and CHO-K ] cell lines using an electroporator. The HeLa HA7 cell line expressing the human 5HTj ^ receptor was obtained from Tulco (Duke Univ., Durham, NC, 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 5HTjj)a, 5HT]£)b et 5HTj A 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 the 5HT jj) a , 5HT] £) b and 5HTj A human 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 [[3HJ-5CT (concentration finale : 2nM) pour les récepteurs 5HT]Da et 5HTIDD et [3HJ-8OH-DPAT (concentration finale : 1 nM) pour le récepteur 5HT] ^J 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]rja et 5HTi£)v,Λ ou 1 μM (concentration finale) de spiroxatrine (5HT IA).The incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand [[3HJ-5CT (final concentration: 2nM) for the 5HT] D a and 5HTID D and [3HJ -8OH-DPAT (final concentration: 1 nM) for the 5HT] ^ J receptor and 0.05 ml of the test molecule (final concentrations of 0.1 nM to 1000 nM) or 10 μM (final concentration) of seretonin (5HT] rj a and 5HTi £) v, Λ or 1 μM (final concentration) of spiroxatrine (5HT IA).
L'étude de l'inhibition de la formation d'AMP cyclique (stimulée par la forskoline) médiée par le récepteur 5HTij)b humain a été réalisée dans les cellules CHO-K1 transfectées par le récepteur selon la technique décrite préalablement pour le récepteur 5HTJB (P. Pauwels et C. Palmier, Neuropharmacology, 33,67, 1994). Les nouveaux composés dérivés d'aryl pipérazines faisant partie de la présente invention sont des antagonistes puissants et sélectifs des récepteurs 5HT]£) et présentent l'avantage d'être particulièrement sélectifs pour les récepteurs 5HTu)α et β humains en particulier par rapport aux récepteurs 5HTj j^, 5HTιc 5HT2, cq, α2 et D2. A oiThe study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by the human 5HTij) b receptor was carried out in CHO-K1 cells transfected by the receptor according to the technique described previously for the 5HTJB receptor (P. Pauwels and C. Palmier, Neuropharmacology, 33.67, 1994). The new compounds derived from aryl piperazines forming part of the present invention are potent and selective antagonists of the 5HT] () receptors) and have the advantage of being particularly selective for the human 5HTu) α and β receptors in particular with respect to 5HTj j ^, 5HTιc 5HT 2 , cq, α 2 and D 2 receptors. Where
Les dérivés de la présente invention sont, en outre, capables d'inhiber la contraction induite par la 5-hydroxy-tryptamine dans les anneaux de veine saphène de lapin et d'antagoniser l'inhibition induite par la 5-carboxamido-tryptamine (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 caracterisation fonctionnelle des récepteurs 5HTJD 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, in addition, capable of inhibiting the contraction induced by 5-hydroxy-tryptamine in the rabbit saphenous vein rings and of antagonizing the inhibition induced by 5-carboxamido-tryptamine (5CT ) at the level of serotonin release in guinea pig brain slices. These two pharmacological models are generally recognized as particularly relevant in the functional characterization of the 5HTJD receptors and, in the case of the products of the present invention, 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) démontre de façon inattendue la supériorité des produits de la présente invention, comme l'illustre l'étude comparative suivante (table 1).The 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 demonstrates the superiority of the products of the present invention, as illustrated by the following comparative study (table 1).
Figure imgf000110_0001
Figure imgf000110_0001
Λ<&Λ <&
Table 1Table 1
Figure imgf000111_0001
Figure imgf000111_0001
""Composé revendiqué dans la demande de brevet FR 9408981 """Composés revendiqués dans la présente invention: exemples (I), (2) et (3)"" Compound claimed in patent application FR 9408981 "" "Compounds claimed in the present invention: examples (I), (2) and (3)
Les quelques exemples illustratifs repris dans la table 1 démontrent que les produits de la présente invention présentent l'avantage d'avoir une meilleure affinité (Ki) et une meilleure activité antagoniste (Kg) au niveau des récepteurs 5HT]r> Ces propriétés inattendues des antagonistes 5HTi£) 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).The few illustrative examples given in Table 1 demonstrate that the products of the present invention have the advantage of having better affinity (Ki) and better antagonistic activity (Kg) at the level of the 5HT receptors] r> These unexpected properties of 5HTi £ antagonists claimed in the present invention make them particularly interesting and useful for the treatment of patients suffering from disorders of the central nervous system. As a result, the present invention also comprises a method for treating such patients, a method which involves the administration of an active dose of a compound corresponding to the general formula (I).
Par ailleurs, les dérivés de la présente invention sont également capables de contrôler la croissance et la prolifération de cellules gliales de type Cg transfectées par le gène du récepteur 5HTj£)β, 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 CI50 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 des cancers et autres désordres liés à la prolifération cellulaire. M°Furthermore, the derivatives of the present invention are also capable of controlling the growth and proliferation of glial cells of the Cg type transfected by the gene for the receptor 5HT j £) β, 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 IC50 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. M °
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 vernisAs 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 colorant, a coating (dragees) or a varnish
Comme compositions liquides pour administration orale, on peut utiliser des solutions, des suspensions, des émulsions, des sirops et des élixirs pharmaceutiquement acceptables contenant des diluants inertes tels que l'eau, l'ethanol, 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 parentérale, peuvent être de préférence des solutions aqueuses ou non aqueuses, des suspensions ou des émulsions. Comme solvant ou véhicule, on peut employer l'eau, le propylèneglycol, un polyéthylèneglycol, des huiles végétales, en particulier l'huile d'olive, des esters organiques injectables, par exemple l'oléate d'ethyle 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. Λλ ΛThe sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a 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 can 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. Λλ Λ
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 glycerides 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 allant de 0, 1 mg à 500 mg de substance active, de préférence de 1 mg à 50 mg.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.
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]: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 directe mg pour 1 comprimé composant actif 10,0 cellulose microcristalline B.P.C. 89,5 stéarate de magnésium 0.5A - By direct compression mg for 1 tablet active component 10.0 microcrystalline cellulose B.P.C. 89.5 magnesium stearate 0.5
100,0100.0
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 AΛhThe 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. We AΛh
peut préparer des comprimés présentant d'autres résistances mécaniques en modifiant le poids de compression avec utilisation de poinçons appropriés.can prepare tablets with other mechanical strengths by modifying the compression weight with the use of appropriate punches.
B - Granulation au mouillé mg pour un comprimé composant actif 10,0 lactose Codex 74,5 amidon Codex 10,0 amidon de maïs prégélatinisé Codex 5,0 stéarate de magnésium 0.5B - Wet granulation mg for one tablet active component 10.0 lactose Codex 74.5 starch Codex 10.0 corn starch pregelatinized 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, ramidon 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 l'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 the lactose, ramidon 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 hydroxy-propyl-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 100,0Filling weight 100.0
*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 maille 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 sieve with a mesh opening of 250 μm and mixed with the other substances. The mixture is introduced into hard gelatin capsules No. 2 on an appropriate filling machine. We can prepare other units by changing the filling weight and, when necessary, by changing the size of the capsule.
Sirop mg par dose de 5 ml composant actif 10,0 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 10.0 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 mgActive ingredient 10.0 mg
*Witepsol H15 complément à 1,0 g* Witepsol H15 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 H15 et on l'introduit dans une machine appropriée avec moules à suppositoires de 1 g.A suspension of the active component in Witepsol H15 is prepared and introduced into a suitable machine with 1 g suppository molds.
Liquide pour administration par injection intraveineuse g/l composant actif 2,0 eau pour injection Codex complément à 1000,0Liquid for administration by intravenous injection g / l active component 2.0 water for injection Codex supplement 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 Λ Λ UfSodium 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 Λ Λ Uf
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 injection 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.diluted acid or alkali or by adding appropriate buffer salts. The solution is prepared, clarified and introduced into suitable size vials which are sealed by melting the glass. The liquid for injection can also be sterilized 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 inhalation g/cartouche composant actif micronise 1,0 lactose Codex 39,0Cartridges for inhalation g / cartridge active ingredient micronized 1.0 lactose Codex 39.0
Le composant actif est micronise 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.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.
Aérosol sous pression à valve doseuse mg/dose pour 1 boîte composant actif micronise 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 gPressure aerosol with metering valve mg / dose for 1 can micronized active ingredient 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 micronise 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 10-15°C et on introduit dans la solution à l'aide d'un mélangeur à haut effet de cisaillement le médicament micronise. 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 boîtes par injection au travers des valves The active component is micronized in a fluid energy mill and put into the state of fine particles. Oleic acid is mixed with 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 imgf000117_0001
Figure imgf000117_0001
dans laquelle,in which,
Rj = H, Cj -Ce alkyle;Rj = H, Cj -Ce alkyl;
R2 représente un résidu alkyle, linéaire ou ramifié comprenant de 1 à 8 atomes de carbone, un cycloalkyle (comprenant de 3 à 8 atomes de carbone), un aryle, un arylalkyle, un aryl carbonyl ou encore un aryl éther lorsque X est différent d'un azote dans lesquels le cycle aromatique peut-être un phényle, un naphtyle, un tétrahydronaphtyle, un benzothiényle, un benzofuryle, un indole, un benzodioxanne ou une benzodioxine pouvant être diversement substitués par un ou plusieurs groupes choisis parmi Rβ, OH, ORό, SRό, NO2, CN, COR^, CO2Rό, CONHR6, NH2, NHRs, NHCOR6, NHCO2R6, NHCONHRό, OCONHR6, SO2R6, SO2NHR6, CF3, CH=CH2, c≡c-H ou un halogène (F, Cl, Br ou I) dans lesquels Rβ représente un reste alkyle comprenant de 1 à 5 atomes de carbone ou un phényl ;R 2 represents an alkyl residue, linear or branched comprising from 1 to 8 carbon atoms, a cycloalkyl (comprising from 3 to 8 carbon atoms), an aryl, an arylalkyl, an aryl carbonyl or even an aryl ether when X is different of a nitrogen in which the aromatic ring may be a phenyl, a naphthyl, a tetrahydronaphthyl, a benzothienyl, a benzofuryl, an indole, a benzodioxane or a benzodioxin which can be variously substituted by one or more groups chosen from Rβ, OH, ORό, SRό, NO 2 , CN, COR ^, CO 2 Rό, CONHR 6 , NH 2 , NHRs, NHCOR6, NHCO 2 R6, NHCONHRό, OCONHR 6 , SO 2 R 6 , SO 2 NHR 6 , CF 3 , CH = CH 2 , c≡cH or a halogen (F, Cl, Br or I) in which Rβ represents an alkyl residue comprising from 1 to 5 carbon atoms or a phenyl;
R3 et R4 identiques ou différents représentent un hydrogène ou un groupe choisi parmi un alkyle linéaire ou ramifié (R7), un alcoxy (OR7), thioéther (SR7), nitrile, trifluorométhyle ou halogène (Cl, F, BR ou I) dans lesquels R7 représente un reste alkyle comprenant de 1 à 5 atomes de carbone, ou, R3 et R4 lorsqu'ils sont adjacents, pris ensemble, forment un cycle à 5 ou 6 chainons avec le résidu aromatique auxquels ils sont attachés de façon à constituer, par exemple, un naphtyl ou un tétrahydronaphtyle, étant entendu que les substituants -Z, R3 et R4 peuvent être situés en diverses positions relatives sur le cycle aromatique auquel ils sont attachés; X-Y représente CH, CH-CH2, C=CH, NCH2 ou NCH2CH2; Z = Zl-(CH2)m-Z2, Z,-Ar-(CH2)n-Z2, Z^CH^-CONH-, Z j - Ar-(CH2)n. j - CONH-, -CH(R5)-NHCO-Z2 dans lequels Z\ et Z2, identiques ou différents peuvent être omis ou représenter O ou NH, m représente un nombre entier compris entre 2 et 8, n représente un nombre entier compris entre 1 et 6, R5 représente un hydrogène, un alkyle linéaire ou ramifié comprenant de 1 à 5 atomes de carbone, un aryle (tel qu'un phényle) ou un arylalkyle (tel qu'un benzyle) pouvant être diversement substitué par un hydroxyle, une amine, un thiol ou un thiométhyle Ar représente un reste aromatique (tel qu'un phényle) auquel les substituants sont attachés sur des carbones différents et peuvent être en diverses positions relatives, et leurs sels, hydrates, solvates et bioprécurseurs physiologiquement acceptables pour leur usage thérapeutique.R3 and R4, identical or different, represent a hydrogen or a group chosen from a linear or branched alkyl (R7), an alkoxy (OR7), thioether (SR7), nitrile, trifluoromethyl or halogen (Cl, F, BR or I) in which R7 represents an alkyl residue comprising from 1 to 5 carbon atoms, or, R3 and R4 when they are adjacent, taken together, form a 5 or 6-membered ring with the aromatic residue to which they are attached so as to constitute, by example, a naphthyl or a tetrahydronaphthyl, it being understood that the substituents -Z, R3 and R4 can be located in various relative positions on the aromatic ring to which they are attached; XY represents CH, CH-CH 2 , C = CH, NCH 2 or NCH 2 CH 2 ; Z = Z l - (CH 2 ) m -Z 2 , Z, -Ar- (CH 2 ) n -Z 2 , Z ^ CH ^ -CONH-, Z j - Ar- (CH 2 ) n . j - CONH-, -CH (R 5 ) -NHCO-Z 2 in which Z \ and Z 2 , identical or different may be omitted or represent O or NH, m represents an integer between 2 and 8, n represents an integer between 1 and 6, R5 represents hydrogen, linear alkyl or branched comprising from 1 to 5 carbon atoms, an aryl (such as a phenyl) or an arylalkyl (such as a benzyl) which can be variously substituted by a hydroxyl, an amine, a thiol or a thiomethyl Ar represents a residue aromatic (such as phenyl) to which the substituents are attached to different carbons and may be in various relative positions, and their physiologically acceptable salts, hydrates, solvates and bioprecursors for their therapeutic use.
Les isomères géométriques et optiques des composés de formule générale (I) font également partie de la présente invention ainsi que leurs mélanges en toutes proportions et 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 mixtures in all proportions and in racemic form.
2. Composés selon la revendication 1 caractérisés en ce que X-Y représente N-CH2 ou CH-CH2.2. Compounds according to Claim 1, characterized in that XY represents N-CH 2 or CH-CH 2 .
3. Composés selon la revendication 1 caractérisés en ce que Ri représente un méthyle.3. Compounds according to Claim 1, characterized in that Ri represents a methyl.
4. Composés selon la revendication 1 caractérisés en ce que R3 représente un hydrogène et R4 un atome de chlore ou OCH3.4. Compounds according to claim 1 characterized in that R3 represents a hydrogen and R4 a chlorine atom or OCH3.
5. Composés selon la revendication 1 caractérisés en ce que R3 et R4 sont adjacents et, pris ensemble, forment un cycle à 6 chaînons avec le résidu aromatique auquel ils sont attachés.5. Compounds according to claim 1 characterized in that R3 and R4 are adjacent and, taken together, form a 6-membered ring with the aromatic residue to which they are attached.
6. Composés selon la revendication 1 caractérisés en ce que Z représente -Zι-(CH2)m- Z2 ou Z 1 - Ar(CH2)n-Z2.6. Compounds according to claim 1 characterized in that Z represents -Zι- (CH 2 ) m - Z 2 or Z 1 - Ar (CH 2 ) n -Z 2 .
7. Composés selon la revendication 1 caractérisés en ce que Z représente Zι-(CH2)m. 1-CONH ou Zi-ArtCH^n^-CONH-. 7. Compounds according to claim 1 characterized in that Z represents Zι- (CH 2 ) m . 1-CONH or Zi-ArtCH ^ n ^ -CONH-.
8. Composés selon la revendication 1 caractérisés en ce que Z représente CH(R5)- NHCO-Z2.8. Compounds according to Claim 1, characterized in that Z represents CH (R5) - NHCO-Z 2 .
9. Composé selon l'une des revendications 1 à 8 à l'état de sel acceptable pour l'usage thérapeutique caractérisés en ce que ces sels sont des chlorhydrates, bromhydrates, sulfates, méthanesulfonates, fumarates, maléates ou succinates.9. Compound according to one of claims 1 to 8 in the form of a salt acceptable for therapeutic use, characterized in that these salts are hydrochlorides, hydrobromides, sulfates, methanesulfonates, fumarates, maleates or succinates.
10. Procédé de préparation des composés de formule (I) selon la revendication 1 caractérisés en ce que l'on condense un dérivé de formule générale (III) :10. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that a derivative of general formula (III) is condensed:
Figure imgf000119_0001
Figure imgf000119_0001
dans laquelle R\ , R4, R5 et Z sont définis comme dans la formule (I) et X représente un groupe partant (par exemple Cl), OH ou encore le groupe COX représente une forme activée d'un carbonyle propice à la formation d'amide, carbamate ou urée (par condensation avec une amine) avec une amine cyclique de formule générale (II)in which R \, R4, R5 and Z are defined as in formula (I) and X represents a leaving group (for example Cl), OH or the COX group represents an activated form of a carbonyl suitable for the formation of d amide, carbamate or urea (by condensation with an amine) with a cyclic amine of general formula (II)
/ \/ \
•x NH • x NH
( I I )(I I)
par des méthodes et techniques et dans des conditions qui dépendront de la nature deby methods and techniques and under conditions which will depend on the nature of
Z.Z.
1 1 . Compositions pharmaceutiques contenant, à titre d'ingrédients actifs, un composé selon l'une des revendications 1 à 9, en combinaison avec un véhicule pharmaceutique acceptable comme médicaments.1 1. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 9, in combination with a pharmaceutical vehicle acceptable as medicaments.
12. Compositions pharmaceutiques contenant, à titre d'ingrédients actifs, un composé selon l'une des revendications 1 à 9, en combinaison avec un véhicule pharmaceutique acceptable, pour le traitement tant curatif que préventif de la dépression et des désordres compulsifs obsessionnels.
Figure imgf000120_0001
12. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 9, in combination with an acceptable pharmaceutical vehicle, for the curative and preventive treatment of depression and obsessive compulsive disorders.
Figure imgf000120_0001
13. Compositions pharmaceutiques contenant, à titre d'ingrédients actifs, un composé selon l'une des revendications 1 à 9, en combinaison avec un véhicule pharmaceutique acceptable, pour le traitement tant curatif que préventif de l'anxiété, des attaques de panique, de la schizophrénie, de l'agressivité, de l'alcoolisme, de la boulimie, de s l'anorexie, de le migraine, des dysfonctionnements sexuels, de la douleur et des maladies neurodegeneratives telles que par exemple la maladie de Parkinson ou d'Alzheimer.13. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 9, in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of anxiety, panic attacks, schizophrenia, aggression, alcoholism, bulimia, anorexia, migraine, sexual dysfunctions, pain and neurodegenerative diseases such as for example Parkinson's disease or Alzheimer's.
14. Compositions pharmaceutiques contenant, à titre d'ingrédients actifs, un composé 0 selon l'une des revendications 1 à 9, en combinaison avec un véhicule pharmaceutique acceptable, pour le traitement des tumeurs cancéreuses 14. Pharmaceutical compositions containing, as active ingredients, a compound 0 according to one of claims 1 to 9, in combination with an acceptable pharmaceutical vehicle, for the treatment of cancerous tumors
PCT/FR1996/001626 1995-10-18 1996-10-17 Aryl-piperazine cyclic amine derivatives, preparation thereof and pharmaceutical compositions containing same WO1997014689A1 (en)

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