Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/205—Radicals derived from carbonic acid
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
  • C07D317/66—Nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
  • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
  • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring

Definitions

• New piperazides derived from aryl piperazine methods for their preparation, their use as medicaments and pharmaceutical compositions comprising them.
• the present invention relates to new piperazides derived from aryl piperazine, 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 of the central nervous system involved in many physiological and pathological processes. Serotonin plays an important role both in the nervous system and in the cardiovascular and gastrointestinal systems. At the central level, serotonin controls functions as varied as sleep, locomotion, food intake, learning and memory, endocrine modulations, sexual behavior, thermoregulation. In the marrow, serotonin plays an important role in the control systems of the afferent peripheral nociceptives (cf. A. Moulignier, 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, migraine or various headaches (R. Glennon, Neurosci. Biobehavioral Reviews, 14, 35, 1990).
• 5HTID receptors themselves contain several receptor subtypes; thus the 5HT ⁇ rj a and 5HT ⁇ r_> b receptors were cloned and then identified in humans (cf. for example E. Hamel et al.,
• Compounds having a selective antagonist activity at the level of the central 5HT 1 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 pain, cancer, locomotion disorders, depression, anxiety, panic attacks, agoraphobia, obsessive compulsive disorders, disorders memory including dementia, amnesia, and appetite disorders, sexual dysfunctions, Alzheimer's disease, Parkinson's disease.
• 5HTID antagonists are also useful in the treatment of endocrine disorders such as hyperprolactinemia, the treatment of vasospasms, hypertension and gastrointestinal disorders in which changes in motility and secretion occur.
• the compounds according to the present invention are potent and selective antagonists of the 5HT ⁇ r_) receptors and more particularly receptors recently identified as 5HTn) ⁇ and 5HT ⁇ r_> ⁇ 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 prior art in this field is illustrated in particular by European patent applications 0533266, 0533267 and 0533268 which describe new benzanilide derivatives as 5HT antagonists) and recent publications which describe GR 127,935 as a 5HTID antagonist (cf. M. Skingle et al., J. of Psychopharm. 3 (1), 14, 1994; S. Starkey, M. Skingle, Neuropharmacol., 22,
• the derivatives of the present invention are distinguished from the prior art not only by their original chemical structure which unambiguously distinguishes them from the derivatives previously described but also by the effectiveness (overall yield, number of steps) of their preparation and their profile. original biological, in particular with regard to their selectivity for the serotonin receptor subtypes (5HTID ⁇ and
• the present invention relates to derivatives of general formula (I)
• Ari represents an aromatic residue such as phenyl, naphthyl, or pyridyl, or an aromatic residue substituted by one or more groups chosen from linear or branched alkyl residues comprising from 1 to 6 carbon atoms, trifluoromethyl, 2,2 , 2 trifluoroethyl, phenyl, benzyl, cycloalkyl, hydroxyl (OH), thiol (SH), ether (OR'2), thioether (SR'2), ester (OCOR ' 2 ), carbamate (OCONHR), carbonate (OC ⁇ 2R' 2), carbonyls (COR2, COOR ' 2 , CONHR 2 ), halogens (fluorine, chlorine, bromine or iodine), amino (NR2R3), nitro (NO2), nitrile (CN), aminocarbonyl (NHCOR'2, NHC02R'2 , NHCONR2R3), aminosulfonyles (NHSO 2 R'2,
• NHS0 2 OR ' 2 NHSO2NR2R3
• sulfonyles S0 2 R'2, SO2NR2R3
• heterocycles which can possibly be variously substituted as a 5-membered heterocycle which can contain from 1 to 4 heteroatoms such as oxygen, nitrogen or sulfur, or two substituents on neighboring carbons which can form a ring with the aromatic residue to which they are attached,
• X represents O, NH, CH2O or CH2NH
• Ar2 represents an aromatic radical such as a phenyl or a naphthyl to which X and the piperazine are attached to different carbons and which can itself be variously substituted by a branched or linear alkyl radical comprising from 1 to 6 carbon atoms, an alkoxy (OR4), or a halogen (chlorine, fluorine, iodine or bromine),
• R ⁇ , R2, R3 and R4, identical or different, represent a hydrogen, a linear or branched alkyl chain comprising from 1 to 6 carbon atoms
• R * 2 represents a linear or branched alkyl chain comprising from 1 to 6 carbon atoms
• 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.
• physiologically acceptable salts of the compounds of general formula (I) are included the salts obtained by the addition of organic or inorganic acids such as chlorohydrates, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoates, p-toluenesulfonates, methanesulfonates, sulphamates , ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates.
• organic or inorganic acids such as chlorohydrates, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoates, p-toluenesulfonates, methanesulfonates, sulphamates , ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarate
• bioprecursors as used in the present invention applies to compounds whose structure differs from that of the compounds of formula (I) but which, when administered to an animal or to a human being, are converted into the organism into a compound of formula (I).
• a particularly preferred class of compounds of formula (I) corresponds to the compounds for which Ar2 represents a phenyl which can be variously substituted, in particular the compounds of formula (la):
• Arj, X and Rj are defined as in formula (I) and R5 represents a hydrogen atom, a branched or linear alkyl radical comprising from 1 to 6 carbon atoms, an alkoxy (OR4), or a halogen ( chlorine, fluorine, iodine or bromine), R4 being defined above.
• Another particularly appreciated class of compounds of formula (I) corresponds to the compounds for which Ar2 represents a naphthyl, in particular the compounds of formula (Ib):
• Arj represents an aryl of which two substituents on neighboring carbons form a ring with the aromatic residue
• a phenyl of which two substituents on neighboring carbons form with the phenyl to which they are attached a ring with 5 or 6 elements, which can include 1 or 2 heteroatoms
• the compounds of the present invention can be prepared by various methods which will in particular depend on the nature of the substituents Aq, A 2, X and Rj. 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.
• Ar j is defined as above and Y represents a leaving group such as a halogen (chlorine, bromine or iodine) a toxylate, a mesylate or a triflate with an aryl piperazine of general formula (III):
• Y is described as above in the presence of an organic or inorganic base such as pyridine, DiPEA, DMAP, DBU, K2CO3,
• CS2CO3 or CaC ⁇ 3 in a polar aprotic anhydrous solvent such as THF, DMF, DME, DMSO or methyl ethyl ketone at a temperature between - 10 ° C and
• This reaction is preferably carried out in a polar anhydrous solvent such as DMF, acetonitrile, THF, n-butanol, t-butanol or
• DMSO dimethyl sulfoxide
• the derivatives of formula (III) in which X 'is an oxygen are preferably prepared by reaction of a lithio-piperazine of formula VIII in which R ⁇ is defined as above:
• Ar2 represents a phenyl or a naphthyl, under the conditions described previously (cf.: J. Org. Chem. ___, 5101, 1993) followed by demethylation of the aryl-methoxy group with an appropriate reagent such as BBr3 in dichloromethane.
• Xi and X2 identical or different, each represent a leaving group such as a halogen (in particular chlorine), an O-alkyl group (in particular the OCCI3 group), a succinimyl, phtalyl or imidazolyl group.
• the method of the present invention also includes the use of well known precursors or analogs of the reagents of general formula (XII). This is how, for example, the condensation of intermediates (III) and (IV) with phosgene can be advantageously carried out using diphosgene or triphosgene according to a procedure well known to those skilled in the art.
• a base such as triethylamine
• an anhydrous solvent such as dichloromethane
• Ar j , Ar2 and R1 are defined as above and X represents oxygen
• a particularly preferred method consists in first condensing an arylpiperazine of formula (IV) with triphosgene in the presence of triethylamine in an anhydrous solvent such as dichloromethane and to isolate the intermediate of general formula (XIII) thus formed:
• X ⁇ , A ⁇ 2 > R are defined as above and X represents O or NH, in the presence of an organic or inorganic base in a polar aprotic solvent at a temperature between 20 ° and 100 ° C.
• R ⁇ BOC
• Ri H after deprotection of t- butyl carbonate according to the methods and techniques well known for this type of transformation such as the use of acid (HCl, CF3CO2H, H2SO4) in an organic medium.
• the compounds of general formula (I) in which Ari represents an aromatic substituted by an NH2 group can also be transformed into numerous other derivatives of formula (I) such as derivatives in which Arj represents an aromatic substituted by NR2R3, NHCOR 2 , NHCO 2 R2, NHCOR2R3, NHS0 2 R2 , NHSO 2 OR 2 , NHSO2OR2, NHSO2NR2R3 by well known methods and techniques for transforming an aromatic resin into amide, carbonate, urea, sulfonamide, sulfonate or sulfonylurea.
• a compound according to the invention in the form of a salt, for example a salt by addition with an acid
• this can be achieved by treating the free base of general formula (I) with an appropriate acid, preferably in equivalent quantity, or with creatinine sulfate in an appropriate solvent.
• 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, acid (+) - phenylpropionic, (-) - phenylpropionic acid, followed by fractional crystallization and regeneration of the free base.
• Compound 2 is prepared according to the procedure described in Example 1 from the following reagents: triphosgene (273 mg, 0.92 mmol); 4-methoxy-3- (4-methyl piperazin-1-yl) aniline (609 mg, 2.76 mmol); triethylamine (2 x 382 ⁇ l, 5.52 mmol); 1- (o-methoxyphenyl) piperazine (530 mg, 2.76 mmol); dichloromethane (25 ml).
• Compound 2 is prepared according to the procedure described in Example 1 from the following reagents: triphosgene (240 mg, 0.81 mmol); 4-methoxy-3- (4-methyl piperazin-1-yl) aniline (490 mg, 2.22 mmol); triethylamine (2 x 340 ⁇ l, 4.86 mmol); 1- (p-methoxy phenyl) piperazine (523 mg, 2.72 mmol); dioxane (25 ml).
• Compound 4 is prepared according to the procedure described in Example 3 from the following reagents: triphosgene (262 mg, 0.88 mmol); 4-methoxy-3- (4-methyl piperazin-1-yl) aniline (531 mg, 2.40 mmol); triethylamine (4 x 365 ⁇ l, 10.55 mmol); 1- (m-methoxy phenyl) piperazine dihydrochloride (636 mg, 2.4 mmol); dioxane
• the crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
• Compound 5 is prepared according to the procedure described in Example 3 from the following reagents: triphosgene (282 mg, 0.95 mmol); 4-methoxy-3- (4-methyl piperazin-1-yl) aniline (567 mg, 2.57 mmol); triethylamine (2 x 395 ⁇ l, 5.70 mmol); 1- (2,3-dimethylphenyl) piperazine (598 mg, 3.14 mmol); dioxane (25 ml). The crude is purified by flash chromatography with a mixture (95/5/1) then
• the crude is purified by flash chromatography with a mixture (85/14/1) of dichloromethane / methanol / ammonia.
• Compound 1 is prepared according to the procedure described in Example 3 from the following reagents: triphosgene (250 mg, 0.83 mmol); 4-methoxy-3- (4-methyl piperazin-1-yl) aniline (510 mg, 2.31 mmol); triethylamine (2 x 353 ⁇ l, 5.10 mmol); 1- (3,4-methylenedioxyphenyl) piperazine (420 mg, 2.04 mmol); dioxane (25 ml). The crude product is purified by flash chromatography with a mixture (94/6/1) of dichloromethane / ammonia methanol.
• the compound _> (392 mg, 0.86 mmol), dissolved in methanol (25 ml) is stirred for 4 h at room temperature under a hydrogen atmosphere and in the presence of a catalytic amount of Pd / C.
• the reaction mixture is then filtered through celite, concentrated and purified by flash chromatography with a mixture (90/9/1) and then (85/15/1) of dichloromethane / methanol / ammonia.
• Compound H is obtained as a secondary product during the preparation of compound lfl.
• the fumarate is prepared according to the method described above (in Example 1 for example).
• the corresponding fumarate is prepared by adding 0.9 equivalents of fumaric acid to a solution of the compound in hot methanol. The methanol is evaporated and the oil obtained is crystallized from ethyl ether.
• 3-aminophenol (2 g, 18 mmol) is brought to reflux of butan-1-ol (30 ml) in the presence of 2-chloro-N- (chloroethyl) -N-methylethanamine hydrochloride (3.5 g,
• reaction mixture is concentrated and adsorbed on silica before being purified by flash chromatography with a mixture (90/10) of dichloromethane / methanol.
• the dihydrochloride is obtained by adding a solution of hydrogen chloride in ethyl ether to a solution of the compound in dichloromethane.
• the crude product obtained is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
• the extraction is done with dichloromethane instead of ethyl acetate.
• the crude product is purified by flash chromatography with a mixture (97/3/1) of dichJoromethane / methanol / ammonia.
• the crude product is purified by flash chromatography with a mixture (96/4) of petroleum ether / ethyl acetate.
• Compound 16A is prepared according to the same procedure as ______ from the following reagents: 8-aminonaphthalen-2-ol (1.6 g, 10 mmol), 2-chloro-N- (2-chloroethyl) -N-methylethananine hydrochloride (2 g, 10.4 mmol), sodium carbonate
• the crude reaction product is purified by flash chromatography with a mixture (95/4/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
• Compound J _ is prepared according to the same procedure as described above for the preparation of 12A (640 mg, 2.54 mmol), J__ ⁇ (512 mg; 2.11 mmol), potassium carbonate (35 mg, 0.21 mmol) in methyl ethyl ketone (60 ml).
• the crude reaction product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
• Compound 17A is prepared according to the same procedure as 12A from the following reagents: chloroacetyl chloride (670 ⁇ l, 8.4 mmol), l- (2-cyanophenyl . Piperazine (1.32 g, 7 mmol), calcium carbonate (2.1 g , 21 mmol), methyl ethyl ketone (30 ml).
• compound 12 is prepared according to the procedure described above for the preparation of 12 from the following intermediates: 17A (1.04 g, 3.95 mmol), 16A (1.01 g, 4.17 mmol), potassium carbonate (1.36 g, 9.88 mmol ), potassium iodide (68 mg, 0.41 mmol), in methyl ethyl ketone (50 ml).
• the crude reaction product is purified by flash chromatography with a gradient from (97/3/1) to (90/9/1) of dichloromethane / methanol / ammonia.
• the crude is purified by flash chromatography with a mixture (97.3) and then (95/5) of dichloromethane / methanol.
• reaction crude is adsorbed on silica and then purified by flash chromatography with a mixture (97/3/1) of dichloromethane / methanol / ammonia.
• the compound 2fl is prepared according to the procedure described above for the preparation of 15 from 15 ⁇ (430 mg, 1.8 mmol), _ _ ⁇ (436 mg, 1.8 mmol), sodium hydride (60%, 80 mg, 2 mmol), in tetrahydrofuran (30 ml).
• Compound 21 is prepared according to the procedure described in Example 3 from the following reagents: triphosgene (200 mg, 0.68 mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (447 mg, 2.02 mmol); triethylamine (820 ⁇ l, 5.90 mmol); 1 -phenylpiperazine (310 ml, 2.02 mmol); tetrahydrofuran (15 ml).
• the crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
• Compound 24 is prepared according to the procedure described in Example 22 from the following reagents: triphosgene (210 mg, 0.71 mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (481 mg, 2.17 mmol); triethylamine (2 x 300 ⁇ l, 4.34 mmol); 1- (pyridin-2-yl) piperazine (330 ml, 2.17 mmol); dichloromethane (40 ml).
• the crude is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
• Compound 25 is prepared according to the procedure described in Example 22 from the following reagents: triphosgene (235 mg, 0.79 mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (525 mg, 2.38 mmol); triethylamine (2 x 367 ⁇ l, 5.24 mmol); 1- (2,6-dimethylphenyl) piperazine (453 mg, 2.38 mmol); dichloromethane (40 ml). The crude is purified by flash chromatography with a mixture (95/5/1) then
• 2d_A 1 - (5,6,7,8-tetrahydronaphthalen-1-yl) piperazine
• the crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
• Compound 22 is prepared according to the procedure used for compound 22 from 4-methoxy-3- (4-methylpiperazin-1-yl) aniline and 1- (1,2,3,4,5,6 - hexamethy lphenyl) piperazine.
• Compound 2S is prepared according to the procedure described in Example 22 from the following reagents: triphosgene (226 mg, 0.76 mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (504 mg, 2.28 mmol); triethylamine (2 x 315 ⁇ l, 4.56 mmol); 1- (2,4-dimethylphenyl) piperazine (433 mg, 2.28 mmol); dichloromethane (40 ml). The crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanolic ammonia.
• aqueous phase is then basified with a 3N solution of sodium hydroxide and extracted three times with ethyl acetate. These latter organic phases are combined, washed once with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The final purification is carried out by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
• the compound ___. is prepared according to the procedure described in Example 22 from the following reagents: triphosgene (164 mg, 0.55 mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (370 mg, 1.66 mmol); triethylamine (2 x 230 ⁇ l,
• nitro derivative is extracted from the aqueous phase with ethyl acetate (4 x 80 ml), dried over magnesium sulfate and purified by flash chromatography with a gradient of eluent (2 to 5% of methanol in dichloromethane in the presence of 0.5% ammonia). Mass obtained: 5.7 g (93%) iH-NMR (200MHz, dmso-d 6 ) d: 7.90 (dd, IH, 2.8 and 9Hz); 7.62 (d, 1H,
• Amine 33A (5.7 g; 24 mmol) is dissolved in dichloromethane (48 ml) under an inert nitrogen atmosphere at room temperature in the presence of triethylamine
• the derivative 33D is prepared according to the same procedure described for 22 from the following reagents: 33C (1 g; 3.2 mmol); 1- (2,3-xylyl) piperazine (912 mg; 4.8 mmol); triethylamine (0.9 ml; 6.5 mmol); triphosgene (318 mg; 1 mmol); dichloromethane
• This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
• the derivative 25 is prepared according to the same procedure described for 24 from the following reagents: 22 (800 mg; 1.8 mmol); 1 -bromopropane (0.16 ml g; 1.8 mmol); cesium carbonate (586 mg; 1.8 mmol); DMF (13 ml). Mass obtained: 547 mg (65%)
• This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
• IBX Bj 3300, 2964, 1833, 1643, 1604, 1539, 1508, 1234.
• 3-Aminonaphthalen-2-ol (5 g, 31.4 mmol) is brought to reflux of butan-1-ol (100 ml) in the presence of 2-chloro-N- (chloroethyl) -N- methylethanamine hydrochloride (6.05 g, 31.4 mmol) and sodium carbonate (1.7 g, 16 mmol).
• the reaction mixture is concentrated and impregnated on silica before being purified by flash chromatography with a mixture (93/7/1) of dichloromethane / methanol / ammonia.
• 2-aminonaphthalen-1-ol hydrochloride (3 g, 15.3 mmol) is brought to reflux of butan-1-ol (150 ml) in the presence of 2-chloro-N- (chloroethyl) -N-methylethanamine hydrochloride (2.95 g, 15.3 mmol) and sodium carbonate (2.44 g, 23 mmol).
• reaction mixture is concentrated and impregnated on silica before being purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
• 1-aminonaphthalen-2-ol hydrochloride (5 g, 25.6 mmol) is brought to reflux of butan-1-ol (100 ml) in the presence of 2-chloro-N- (chloroethyl) -N-methylethanamine hydrochloride (4.9 g, 25.6 mmol) and sodium carbonate (5.4 g, 51 mmol). After 48 h, the reaction mixture is concentrated and impregnated on silica before being purified by flash chromatography with a mixture (93/7/1) of dichloromethane / methanol / ammonia.
• the crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
• Compound 4O is prepared according to the procedure described for compound 15 from the following reagents: compound 14B (560 mg, 2.47 mmol); compound 40A (624 mg, 2.47 mmol); sodium hydride (60%, 110 mg, 2.72 mmol); tetrahydrofuran (20 ml).
• the crude is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
• Compound 41A is prepared according to the procedure described for compound 15A from the following reagents: 1 - (2-fluorophenyl) piper ___ ine (1.54 g, 8.06 mmol); triphosgene (850 mg, 2.85 mmol); pyridine (0.69 ml, 8.6 mmol); dichloromethane (60 ml).
• the crude is purified by flash chromatography with a mixture (90/10) of petroleum ether / ethyl acetate).
• Compound 41 is prepared according to the procedure described for compound 15 from the following reagents: compound 14B (934 mg, 4.12 mmol); compound 41A (1.0 g,
• Compound 42A is prepared according to the procedure described for compound 13A from the following reagents: 2-naphthylamine (5 g, 35 mmol); bis (2-chloroethyl) amine hydrochloride (6.23 g, 35 mmol); sodium carbonate (1.85 g, 17 mmol); butan-ol (l ⁇ ml).
• the crude product obtained is purified by flash chromatography with a gradient from (95/5/1) to (85/15/1) of dichloromethane / methanol / ammonia.
• Compound 42B is prepared according to the procedure described for compound 15A from the following reagents: 1- (2-naphthyl) piperazine (600 mg, 2.82 mmol); triphosgene (298 mg, 0.94 mmol); pyridine (230 ml, 2.82 mmol); dichloromethane (20 ml).
• IRfKBr 3500, 1674, 1657, 1498.
• the derivative 45A is prepared according to the same procedure described for 43A from the following reagents: 2-amino-4-chlorophenol (3 g; 20.9 mmol); N-methylbis (2-chlorethyl) amine hydrochloride (4.2 g; 22 mmol); sodium carbonate (1.1 g; 10.5 mmol); 1 -butanol (42 ml).
• the derivative 45 is prepared according to the same procedure described for 44 from the following reagents: 45A (982 mg; 4.3 mmol); 44A (1.3 g; 4.3 mmol); cesium carbonate (1.4 g; 4.3 mmol); DMF (15 ml). Mass obtained: 1.04 g (53%)
• This compound is dissolved in methanol and treated with fumaric acid to give the corresponding fumarate.
• IRfKBr 3450, 2916, 1709, 1662, 1591, 1498, 1473, 1338, 1219.
• Compound 4S is prepared according to the procedure described for compound 12 from intermediates 36A (1.07 g, 4.0 mmol), 16A (800 mg; 3.3 mmol), potassium carbonate (1.1g, 8.3 mmol), potassium iodide (55 mg, 0.33 mmol) in methyl ethyl ketone (80 ml).
• Compound 42 is prepared according to the procedure described for compound 12 from intermediates 49A (712 mg, 2.46 mmol), l ⁇ (375 mg; 1.55 mmol), potassium carbonate (536 mg, 3.88 mmol) and iodide of potassium (25 mg, 0.15 mmol) in methyl ethyl ketone (20 ml).
• 5fl 50A 2-chloro-1- [4- (2,3-dimethoxyphenyl) piperazin-1-yl] ethanone
• Compound 50A is prepared according to the procedure described for compound 12A from the following reagents: chloroacetyl chloride (150 ml , 1.87 mmol); 1- (2,3-dimethoxyphenyl) piperazine (22 ⁇ ) (416 mg, 1.87mmol); potassium carbonate (645 mg, 4.67 mmol); methyl ethyl ketone (20 ml).
• Compound 51 ⁇ is prepared according to the procedure described for compound 12A from the following reagents: chloroacetyl chloride (127 ml, 1.6 mmol); 1- (benzodioxan-5-yl) piperazine (321 mg, 1.46 mmol); potassium carbonate (504 mg, 3.65 mmol); methyl ethyl ketone (15 ml). Mass obtained: 368 mg (yield 85%)
• Compound 51 is prepared according to the procedure described for compound 50 from intermediates 51A (368 mg, 1.24 mmol), 16A (300 mg; 1.24 mmol), cesium carbonate (978 mg, 3.0 mmol) in dimethylformamide ( 20 ml).
• the crude reaction product is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane / methanol / ammonia.
• Compound 52A is prepared according to the procedure described for compound 12A from the following reagents: chloroacetyl chloride (480 ml, 6.05 mmol); 1 - (2,4,6-trimethylphenyl) piperazine (31 A) (1,122 g, 5.5 mmol); calcium carbonate (1.65 g, 16.5 mmol); methyl ethyl ketone (25 ml) and dimethylformamide (10 ml), to dissolve 1 - (2,4,6-trimethylphenyl) piperazine).
• Compound 52 is prepared according to the procedure described for compound 50 from intermediates 52__ (559 mg, 1.99 mmol), l ⁇ (335 mg; 1.38 mmol), cesium carbonate (1.13 g, 3.46 mmol) in dimethylformamide (15 ml).
• the crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
• Compound 53A is prepared according to the same procedure as 13A from the following reagents: 8-aminonaphthalen-3-ol (10 g, 62.8 mmol), 2-chloro-N- (2-chloroethyl) -N-methylethananine hydrochloride (11.8 g, 62.8 mmol), sodium carbonate (3.32 g, 31.4 mmol), butan-1-ol (200 ml).
• the crude reaction product is purified by flash chromatography with a gradient from (98/21) to (90/9/1) of dichloromethane / methanol / ammonia.
• Compound 52 is prepared according to 1 a procedure described for the preparation of compound 12 from intermediates 53A (617 mg, 2.55 mmol), 12A (773 mg; 3.06 mmol), potassium carbonate (880 mg, 6.38 mmol ) and potassium iodide
• Compound 54 is prepared according to the procedure described in Example 22 from the following reagents: triphosgene (282 mg, 0.95 mmol); 2-methoxy-3- (4-methylpiperazin-1-yl) aniline (326 mg, 1.47 mmol); triethylamine (2 x 206 ⁇ l,
• the human receptors 5HTj ⁇ ) ⁇ and 5HT ⁇ ) ⁇ were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., __Q, 143 (1991) and Weinshenk et al., Proc. Natl. Acad. Sci. S2, 3630 (1992). Transient transfection and permanent transfection of the genes for these receptors was carried out in Cos-7 and CHO-Ki cell lines using an electroporator.
• the HeLa HA7 cell line expressing the human 5HTI receptor was obtained from Tulco (Duke Univ., Durham, N.C., USA) and cultivated according to the method of Fargin et al., J. Biol. Chem. 2__4, 14848 (1989).
• the incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand [[3H] -5CT (final concentration: 2 nM) for the 5HT o ⁇ and 5H T lD ⁇ receptors and [3H] -8OH-DPAT (final concentration: 1 nM) for the 5HTIA 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 (5HTi £) ⁇ and 5HTi j ⁇ ) or 1 ⁇ M (final concentration) of spiroxatrine (5HT IA).
• the new compounds derived from aryl piperazines forming part of the present invention are powerful and selective antagonists of the 5HT receptors ⁇ as demonstrated by the examples cited above.
• Many compounds forming part of the present invention have the advantage of being particularly selective for the 5HTI D ⁇ and ⁇ human receptors in particular compared to the 5HTIA, 5HT 1 c, 5HT 2 , ⁇ 1 , ⁇ 2 and D2 receptors.
• the derivatives of the present invention are also 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). level of serotonin release in guinea pig brain slices.
• Another particularly interesting aspect of the present invention comprises the discovery of selective antagonists for the human 5HTu) ⁇ receptor. Indeed, as indicated by the pharmacological results described above, many new compounds corresponding to the general formula (I) have a much higher affinity for the 5HT ⁇ ) ⁇ receptor vis-à-vis other receptors including the receptor 5HT ⁇ ⁇ .
• the present invention also includes a method for treating such patients, which method involves the administration of an active dose of a compound of general formula (I).
• the present invention also relates to pharmaceutical compositions containing as active ingredient a compound of general formula I or one of its acceptable salts for pharmaceutical use, mixed or associated with a suitable excipient.
• These compositions can take, for example, the form of solid, liquid compositions, emulsions, lotions or creams.
• compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
• the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon.
• inert diluents such as starch, cellulose, sucrose, lactose or silica
• These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
• compositions for oral administration use may be made of 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 may 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.
• 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.
• 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.
• active component designates one or more (generally one) of the compounds of formula (I) according to the present invention: Tablets
• They can be prepared by direct compression or by passing through wet granulation.
• the direct compression procedure is preferred, but it may not be suitable in all cases depending on the doses and the physical properties of the active component.
• the active component is passed through a sieve with a mesh opening of 250 ⁇ m on a side, it is mixed with the excipients and it is compressed using 6.0 mm punches. Tablets with other mechanical strengths can be prepared by varying the compression weight with the use of appropriate punches.
• B - 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___.
• Compressive weight 100.0 The active component is passed through a sieve with a mesh opening of
• 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
• 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 of a dilute acid or alkali or by adding buffer salts. appropriate.
• the solution is prepared, clarified and introduced into suitable size vials which are sealed by melting the glass.
• the liquid 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.
• 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 No. 3 hard gelatin capsules on an appropriate encapsulating machine.
• the contents of the cartridges are administered using a powder inhaler.
• Pressure aerosol with metering valve mg / dose for 1 can micronized active component 0.500 120 mg oleic acid Codex 0.050 12 mg trichlorofluoromethane for pharmaceutical use 22.25 5.34 g dichlorodifluoromethane for pharmaceutical use 60.90 14.62 g
• the active component is micronized in a fluid energy mill and put into the state of fine particles.
• the oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C. and the micronized drug is introduced into the solution using a mixer with a high shearing effect.
• the suspension is introduced in measured quantity into aluminum aerosol cans on which are fixed appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the boxes by injection through the valves.

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• 1994
  • 1994-07-20 FR FR9408981A patent/FR2722788B1/fr not_active Expired - Fee Related
• 1995
  • 1995-07-20 WO PCT/FR1995/000975 patent/WO1996002525A1/fr not_active Application Discontinuation
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  • 1995-07-20 JP JP8504769A patent/JPH10502920A/ja active Pending
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