WO1997028140A1 - Nouvelles piperidines derivees de la 1-/(piperazin-1-yl-)aryl(oxy/amino)carbonyl/-4-aryl-piperidine comme antagonistes selectifs des recepteurs 5-ht-1d.beta - Google Patents
Nouvelles piperidines derivees de la 1-/(piperazin-1-yl-)aryl(oxy/amino)carbonyl/-4-aryl-piperidine comme antagonistes selectifs des recepteurs 5-ht-1d.beta Download PDFInfo
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- WO1997028140A1 WO1997028140A1 PCT/FR1997/000195 FR9700195W WO9728140A1 WO 1997028140 A1 WO1997028140 A1 WO 1997028140A1 FR 9700195 W FR9700195 W FR 9700195W WO 9728140 A1 WO9728140 A1 WO 9728140A1
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- 0 C=[Al]*(BC1)CCN1C(Cl)=O Chemical compound C=[Al]*(BC1)CCN1C(Cl)=O 0.000 description 2
- KBGPGAYUXPUNPL-UHFFFAOYSA-N CC1=C(C)C(C(CC2)CCN2C(NC(CC=C2OC)C=C2N2CCN(C)CC2)=O)=CCC1 Chemical compound CC1=C(C)C(C(CC2)CCN2C(NC(CC=C2OC)C=C2N2CCN(C)CC2)=O)=CCC1 KBGPGAYUXPUNPL-UHFFFAOYSA-N 0.000 description 1
- IREUWBVSRVGLNT-UHFFFAOYSA-N CN(CC1)CCN1c(c1c2)cccc1ccc2OC(N(CC1)CC=C1c1cc(cccc2)c2cc1)=O Chemical compound CN(CC1)CCN1c(c1c2)cccc1ccc2OC(N(CC1)CC=C1c1cc(cccc2)c2cc1)=O IREUWBVSRVGLNT-UHFFFAOYSA-N 0.000 description 1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
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- 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 piperidines 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 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), 1 50, 3 - 1 5, 1 994).
- Serotonin can play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggression, panic attacks, obsessive compulsive disorders, schizophrenia, tendency to suicide), certain neurodegenerative disorders (dementia of the ⁇ lzheimer type , Parkinsonism, Huntington's chorea), anorex, bulimia, alcohol-related disorders, cerebrovascular accidents, pain, migraine or various headaches (R. G lennon, Neurosci. Biobehavioral Reviews 14.35, 1 990). Numerous recent pharmacological studies have demonstrated the diversity of serotonin receptors as well as their respective involvement in its various modes of action (cf. E. Zifa, G.
- the receptors 5HTjr_ themselves contain many ur receptor subtypes; thus the receptors 5HT ⁇ r ja and 5HTi £) b were cloned and then identified in humans (cf. for example E. Hamel et al., Mol. Pharmacol., 4_4, 242, 1993; GW Rebeck et al. ., Proc. Natl. Acad. Sci. USA, 9_L, 3666.1994). Furthermore, it has recently been demonstrated that the 5HTj ⁇ auto-receptors in rodents and 5HTj £) in other species are capable of controlling the release of serotonin in nerve endings (cf. M. Briley, C. Moret, Cl.
- Compounds having a selective antagonist activity at the level of central SHTJD receptors can therefore exert a beneficial effect on subjects suffering from disorders of the central nervous system.
- such compounds find their use in the treatment of locomotion disorders, depression, anxiety, panic attacks, agoraphobia, obsessive compulsive disorders, memory disorders including dementia, amnesia , and appetite disorders, sexual dysfunctions, Alzheimer's disease, Parkinson's disease.
- the 5HTID antagonists also find their utility 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 powerful and selective antagonists of 5HT ⁇ j3 receptors and more particularly receptors recently identified as 5HT ⁇ rj a and 5HT ⁇ r3b in humans and, therefore, find their utility, alone or in combination with other molecules. , as drugs and more particularly as therapeutic means for both curative and preventive treatment of disorders related to serotonin.
- the derivatives of the present invention are distinguished from the prior art not only by their original chemical structure which distinguishes them without ambiguity of the previously described derivatives may also be due to their original biological profile, in particular with regard to their selectivity for the serotonin receptor subtypes and with regard to their antagonistic activity in particular at the receptors known as name 5-HT j rj ⁇ .
- the present invention relates to derivatives of general formula (I)
- Ar j represents an aromatic residue such as phenyl, naphthyl. a pyridyl which can be variously substituted by one or more groups chosen from a linear or branched alkyl residue comprising from 1 to 6 carbon atoms. trifluoromethyl, trifluoromethoxy, 2,2.2- trifluoroethyl, phenyl, benzyl. cycloalkyl. hydroxyl (OH), thiol (SH). ether (OR'2), thioether (SR ' 2 ), ester (OCOR' 2 ). carbamate (OCONHR2), carbonate (OC ⁇ 2R'2), carbonyl (COR 2. COOR'2. CONHR2).
- halogen fluorine, chlorine, bromine or iodine
- amine N2R3. nitro (NO2).
- CN nitrile
- aminocarbonyl NHC ⁇ 2R'2 - NHCONR2R3, aminosul fonyl (NHS0 2 R'2> N (S02R'2) 2> NHS0 2 OR ' 2.
- NHSO2NR2R3 sulfonyl (S0 2 R' 2, SO2NR2R3) or a heterocycle which may optionally be variously substituted such as a 5-membered heterocycle which may contain from 1 to 4 heteroatoms such as oxygen, nitrogen or sulfur or two substituents on neighboring carbons which may form a cycle with the aromatic residue to which they are attached.
- X represents O, NH, CH2O or CH2-NH.
- Ar ? 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 i. RT, R3 and R4, identical or different, represent 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
- geometric and optical isomers of the compounds of general formula e (I) also form part of the present invention as well as their mixture in racemic form.
- physiologically acceptable salts of the compounds of general formula (I) are included the salts obtained by adding organic or inorganic acids such as chlorohydrates, hydrobromides, sulfates, phosphates, benzoates, acetates, naphthoates, p-toluenesulfonates, methanesulfonates, sulphamates , ascorbates, tartrates, citrates, oxa lates, maleates, sal icylates. 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, oxa lates, maleates, sal icylates. fum
- bioprecursors as used in the present invention applies to compounds whose structure differs from that of compounds of formula (I) but which, when administered to an animal or to a human being are converted in the organism into a compound of formula (I).
- a particularly appreciated class of compounds of formula (I) corresponds to the compounds of formula (la):
- Ar i, A-B, X and R ⁇ are defined as in formula I and R ⁇ represents a hydrogen, a CH3, OCH3 radical or a chlorine.
- Y represents a leaving group such as a halogen (chlorine, bromine or iodine), a tosylate, a mesylate or a triflate with an aryl piperazine of general formula (III): / ⁇
- X ' represents O or NH
- An represents an aromatic ring such as a phenyl or a naphthyl to which X' and the piperazine ring are attached in different positions and R ] is described as above.
- the condensation of the arylpiperazines of formula (III) with the electrophiles of formula (II) is carried out in the presence of an organic or inorganic base such as NaH, KH, DiPEA, DBU, pyridine, DMAP, K2CO3, CaC ⁇ 3, CS2CO3, in possible presence of iodide such as Nal, Kl, BU4NI, in a polar anhydrous solvent such as THF, DME, n-butanol, t-butanol, DMF, DMSO, methyl ethyl ketone, at a temperature between - 10 ° and 80 ° C.
- the intermediates of general formula (II) are easily prepared by condensation of an aryl piperidine (satur
- Y is described as above in the presence of an organic or inorganic base such as pyridine, Di PEA, DMAP, ie DBU, K2CO3, CS2CO3 or CaCO ⁇ , in an aprotic anhydrous solvent polar such as THF, DMF, DME, DMS O or methyl ethyl ketone at a temperature between ⁇ 10 ° C. and 30 ° C.
- an organic or inorganic base such as pyridine, Di PEA, DMAP, ie DBU, K2CO3, CS2CO3 or CaCO ⁇
- an aprotic anhydrous solvent polar such as THF, DMF, DME, DMS O or methyl ethyl ketone
- R 'i. is equivalent to R ⁇ as defined above or R '] represents a protective group such as t-butoxycarbonyl or tosyle which will be transformed into R j later and Y represents a chlorine, a bromine, an iodine, a tosylate or a mesylate.
- This reaction is preferably carried out in a polar anhydrous solvent such as DMF, acetonitrile, THF, n-butanol, t-butanol or DMSO, generally at reflux temperature of the soil before use, in the presence of a organic or inorganic base generally used for this type of reaction, such as potassium, sodium or calcium carbonate.
- the derivatives of formula (III) in which X ′ is oxygen are preferably prepared by reaction of a lithio-piperazine of formula VIII in which R] is defined as above: Rr-N N - Li (VIII) V_7
- Ar 2 represents a phenyl or a naphthyl
- X represents a function which can subsequently be transformed into an amine (such as for example a nitro group) either with a bis (haloethyl) amine derivative of formula (VII) under the conditions described above for this type of reaction, either with an amino acid of general formula (XI)
- the X j and X 2 each represent a leaving group such as a halogen (in particular chlorine), an O-alkylated group (in particular the group OCCI3), a succinimyl group, phtal y le or imidazolyle.
- the method of the present invention also includes the use of well known precursors or analogs of the reagents of general formula (XII). It is thus and by way of example that the condensation of intermediates (III) and (IV) with phosgene can be advantageously carried out using diphosgene or triphosgene according to a procedure well known to those skilled in the art.
- a particularly appreciated method consists in first condensing a arylpiperidine of formula (IV) with triphosgene in the presence of triethylamine in an anhydrous solvent such as dichloromethane and isolate the intermediate of general formula (XIII) thus formed '
- BOC t-butoxycarbonyl
- the unsaturated piperidines or piperidines of general formula (IV) are prepared by various techniques and methods described for example in patents DE 2801195, EP 7067 (800123), EP 12643 (800625), FR 2459795 (810116), EP 372776 (900613) , FR 2678270 (921231), FR 2675801 (921231), FR 2675801 (921030), EP 580398 (940126), WO 9401403 (940120) as well as the recent publication by Shanklin JR et al. (J. Med. Chem. 34, 3011 , 1991).
- a particularly preferred method for the preparation of unsaturated aryl piperidines consists in coupling the vinyl triflate of formula XV
- organometallic of formula XVI or XVII
- M represents ZnBr, SnBu3, SnMe3 or B (OR) 2 where R represents alkyl or hydrogen and M 'represents Zn in the presence a palladium derivative such as for example Pd (Ph3) 4 in a polar aprotic solvent such as THF, DME or DMF at a temperature between 20 ° C and 80 ° C followed by deprotection of nitrogen cyclic by methods well known to those skilled in the art for hydrolyzing a t-butoxycarbonyl such as for example the use of trifluoroacetic acid in dichloromethane.
- a palladium derivative such as for example Pd (Ph3) 4
- a polar aprotic solvent such as THF, DME or DMF
- the unsaturated triflate of formula XV is prepared from N-BOC-4-piperidone by reaction successively with lithium diisopropylamide in a polar anhydrous solvent such as THF at -78 ° C and with (CF 3 S0 2 ) 2 NC 6 H5 (cf. Synthesis, 993, 1 991).
- Organometallic derivatives XVI and XVII are prepared from aryl halides, more particularly from the corresponding aryl bromides by methods well known to those skilled in the art as described for example in “Organometal Lics in Synthesis, M. Schlosser Ed.; John Wiley & Sons, 1,994 ".
- NR ' 2 R3, NHCOR'2, NHC0 2 R' 2 , NHCOR2R3, NHS0 2 R'2, NHS0 2 OR ' 2 , NHSO2NR2R3 by well known methods and techniques for transforming an aniline into a secondary or tertiary aromatic amine, amide, carbonate, urea, sulfonamide or sulfonylurea.
- This transformation can be carried out using the methods well known to those skilled in the art for reducing a double carbon-carbon link such as, for example, catalytic hydrogenation using atmospheric hydrogen in the presence of a catalyst such as palladium on carbon, platinum in a solvent such as methanol or ethanol
- 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 creatimne sulfate in a suitable 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 at least one asymmetric center can for example be separated into their enantiomers by the usual techniques such as the formation of diastereomeric pairs by formation of a salt with an optically active acid such as acid (-) - d ⁇ -p-toluoyl- l-tart ⁇ que, (+) - d ⁇ -p-toluoyl-l-tart ⁇ que, (+) - camphorsulfonic acid, (-) - camphorsulfonic acid, (+) - phenylpropionic acid, (-) - phenylpropionic acid, followed by fractional crystalization and regeneration of the free base, the compounds of formula (I) in which R]
- the proton NMR spectra were recorded on a Brucker AC 200 device. The chemical shifts are expressed in ppm and the following abbreviations have been used "s” for singlet, “se” for widened singlet, “d” for doublet, “dd” for doublet of doublet, “t” for t ⁇ plet, “q” for quadruplet, “sx” for sextuplet, "m” for multiplet, "M” for solid
- the infrared spectra were recorded on a Nicolet 51 OP device. The absorption bands are given in cm ⁇ l- Elemental analyzes were carried out on a Fisons EA 1108 device.
- Compound 2 is prepared according to the procedure described in Example 1 from the following reagents: triphosgene (365mg, 1.23mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (815mg, 3.69mmol); triethylamine (510 ⁇ lx2, 3.69mmolx2); 4- phenylpiperidine (723mg, 4.49mmol); dichloromethane (80ml). The crude is purified by flash chromatography with a mixture (93/7/1) of dichloromethane / methanol / ammonia.
- Fe / 7-butyHithium (10.8 ml of a 1.7 M solution in pentane, 18.4 mmol) is added dropwise to a solution of o-bromoxylene (1.24 ml, 9.18 mmol) in tetrahydrofuran (70 ml) to - 78 ° C and under an argon atmosphere.
- the reaction mixture is stirred for 20 min at -78 ° C. then the zinc bromide (9.2 ml of a 1 M solution in tetrahydrofuran, 9.18 mmol) is added.
- the mixture is then brought slowly to room temperature and left for one hour.
- Trifluoroacetic acid (6 ml) is added slowly to a solution of compound 3a (1.87 g; 6.5 1 mmo) in dichloromethane (30 ml) kept at 0 ° C.
- the reaction mixture is then brought to ambient temperature and the reaction is followed by thin layer chromatography. After 1 h, the reaction is completed.
- the trifluoroacetic acid is neutralized with a saturated solution of sodium hydrogencarbonate.
- the phases are separated and the organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated.
- the crude reaction product is purified by flash chromatography with an 85/1 5/1 mixture of dichloromethane / methanol / ammonia.
- the crude is purified by flash chromatography with a mixture (93/7/1) of dichloromethane / methanol / ammonia.
- Compound 4a is prepared according to the procedure described for compound 3a from the following reagents: 2,3,4,5,6-pentamethylbromobenzene (593 mg, 2.61 mmol); / er / -butylithium (3.22 ml of a 1.7 M solution in pentane; 5.48 mmol); zinc bromide (1.44 ml of an IM solution in tetrahydrofuran; 1.4 mmol); tetrakis (triphenylphosphine) palladium (a tip of a spatula); 1- (Cer / -butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethyl) sulfonyl oxyjpyridine (864mg, 2.61mmol); tetrahydrofuran (30 ml).
- the crude reaction product is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl
- Compound 4b is prepared according to the procedure described for compound 3b from the following reagents: compound 4a (514 mg; 1.56 mmol), trifluoroacetic acid (1.6 ml); dichloromethane (20 ml).
- the crude reaction product is purified by flash chromatography with a 90/9/1 mixture of dichloromethane / methanol / ammonia.
- Compound 4 is prepared according to the procedure described in Example 1 from the following reagents: triphosgene (130mg, 0.44mmol); 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (290mg, 1.31mmol); pyridine (106 ⁇ lx2, 1.31mmolx2); 4- (2,3,4,5,6-pentamethylphenyl) -1,2,3,6-tetrahydropyridine (4b) (299mg, 1.31mmol); dichloromethane (50ml). The crude is purified by flash chromatography with a mixture (90/9/1) of dichloromethane / methanol / ammonia.
- Chloroacetyl chloride (1ml, 13.0mmol) is added dropwise to a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (2.06g, 13.0mmol) and calcium carbonate (3g, 30mmol) in methyl ethyl ketone (50ml) cooled to 0 ° C.
- the reaction mixture is stirred at this temperature for 1 h 30 then it is filtered through Celite. Celite is rinsed several times with ethyl acetate and a 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulfate, filtered and concentrated to give the expected product in the form of an orange solid.
- the 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (2.4g, 12mmol) is desalted and then dissolved in dichloromethane (40ml) in the presence of pyridine (0.97ml, 12mmol). This is then added slowly to a solution of triphosgene (1.19g, 4mmol) in dichloromethane (60ml) at 0 ° C and under a nitrogen atmosphere. The reaction mixture is brought to ambient temperature. After 30 minutes, it is diluted with water. The phases are separated and the organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude reaction product is purified by filtration on silica with dichloromethane.
- Compound 9a is prepared according to the procedure described for compound 3a from the following reagents: 2-cyanobromobenzene (790 mg, 4.32 mmol); / e / 7-butylithium (5.35 ml of a 1.7 M solution in pentane; 9.07 mmol); zinc bromide (2.40 ml of an IM solution in tetrahydrofuran; 2.38 mmol); tetrakis (triphenylphosphine) palladium (a tip of a spatula); 1- (/ er / -butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethyl) sulfonyloxyjpyridine (1.43g, 4.32mmol); tetrahydro furan (30 ml). The reaction crude is used directly in the next step.
- Compound 9b is prepared according to the procedure described for compound 3b from the following reagents: compound 9a (1.23g; 4.32 mmol), trifluoroacetic acid (4.3 ml); dichloromethane (40 ml). The crude reaction product is purified by flash chromatography with a 90/9/1 mixture of dichloromethane / methanol / ammonia.
- Chloroacetyl chloride (110ml, 1.37mmol) is added dropwise to a solution of 4- (2-cyanophenyl) -1,2,3,6- tetrahydropyridine 9b (250mg, 1.37mmol) and calcium carbonate (400mg, 4mmol) in methyl ethyl ketone (10ml) cooled to 0 ° C.
- the reaction mixture is stirred at this temperature for 1 h 30 then it is filtered through Celite. Celite is rinsed several times with ethyl acetate and a 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulfate, filtered and concentrated.
- the reaction crude is directly engaged in the next step.
- Compound 10a is prepared according to the procedure described for compound 3a from the following reagents: 2-methoxybromobenzene (1.51 ml, 12. lmmol); tert-butylithium (15 ml of a 1.7 M solution in pentane; 25.4 mmol); zinc bromide (12.1 ml of a 1 M solution in tetrahydrofuran; 12. lmmol); tetrakis (triphenylphosphine) palladium (a tip of a spatula);
- Compound 10b is prepared according to the procedure described for compound 3b from the following reagents compound 10a (1.31g; 4.73mmoI), trifluoroacetic acid (4.7ml); dichloromethane (50 ml).
- reaction crude is purified by flash chromatography with an 85/15/1 mixture of dichloromethane / methanol / ammonia.
- Compound 10c is prepared according to the procedure described for compound 5a from the following reagents: compound 10b (537mg, 2.84mmol), chloroacetyl chloride (226ml, 2.84mmol); calcium carbonate (570mg, 5.68mmol); methyl ethyl ketone (20ml).
- the crude reaction product is purified by flash chromatography with a mixture (95/5) of dichloromethane / methanol.
- Compound 10 is prepared according to the procedure described for compound 5 from the following reagents: compound 10c (470mg, 1.77mmol); 4- chloro-3- (4-methylpiperazin-1-yl) phenol prepared according to the method described in French Patent No. 9408981 (400mg, 1.77mmol); cesium carbonate (1.7g, 5.3mmol); dimethylformamide (20ml). The crude reaction product is purified by flash chromatography with a mixture (94/6/1) then (90/9 / l) of dichloromethane / methanol / ammonia.
- Compound 11 is prepared according to the procedure described for compound 6 from the following reagents: compound 10 (273 mg, O. ⁇ mmol); palladium on charcoal (a spatula); ethanol (10ml). The crude reaction product is purified by flash chromatography with a mixture (94/6/1) and then (95/5/1) of dichloromethane / methanol / ammonia.
- Compound 12b is prepared according to the procedure described for compound 7 from the following reagents: 2-hydroxy-8- (4-methylpiperazin-1-yl) naphthalene (128mg, 0.53mmol); sodium hydride (60%. 25mg, 0.64mmol); compound 12a (130mg, 0.53mmol); tetrahydrofuran (30ml).
- the crude reaction product is purified by flash chromatography with a mixture (96/4/1) of dichloromethane / methanol / ammonia.
- Compound 12 is prepared according to the procedure described for compound 6 from the following reagents: compound 12b (75mg, O. l ⁇ mmol); palladium on carbon (90mg); methanol (20ml). The crude reaction product is purified by flash chromatography with a mixture (97/3/1) of dichloromethane / methanol / ammonia.
- Compound 13a is prepared according to the procedure described for compound 3a from the following reagents: 3-bromoanisole (2g, 10.69mmol); tert-butylithium (13.80 ml of a 1.7M solution in pentane, 23.52mmol); zinc bromide (10.7 ml of an IM solution in tetrahydrofuran, 10.69 mmol); tetrakis (triphenylphosphine) palladium (a tip of a spatula); 1- (tert-butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethyl) sulfonyl oxyjpyridine (4.15g, 10.69mmol); tetrahydrofuran (70ml).
- the crude reaction product is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
- Compound 13b is prepared according to the procedure described for compound 3b from the following reagents: compound 13a (1.42g, 4.9 lmmol), trifluoroacetic acid (5ml); dichloromethane (20ml).
- reaction crude is purified by flash chromatography with a mixture
- Compound 13c is prepared according to the procedure described for compound 12a from the following reagents: compound 13b (0.78g, 4.13mmol); triphosgene (0.41g, 1.38mmol); triethylamine (0.62ml, 4.54mmol); dichloromethane (55ml).
- the crude reaction product is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.
- Compound 13 is prepared according to the procedure described for compound 7 from the following reagents: 2-hydroxy-8- (4-methylpiperazin-1-yl) naphthalene (0.51g, 2.10mmol); sodium hydride (60%, 100 mg, 2.52 mmol); compound 13c (0.53g, 2.10mmol); tetrahydrofuran (70ml). The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
- Compound 14 is prepared according to the procedure described for compound 6 from the following reagents: compound 13 (480mg, 1.05mmol); palladium on charcoal (450mg); methanol (30ml). The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
- Compound 15a is prepared according to the procedure described for compound 3a from the following reagents: 4-bromoanisole (2g, 10.69mmol); tert-buty lithium (13.80 ml of a 1.7M solution in pentane, 23.52mmol); zinc bromide (10.7 ml of an IM solution in tetrahydrofuran, 10.69 mmol); tetrakis (triphenylphosphine) palladium (a tip of a spatula); 1 - (tert-butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethyl) sulfonyl oxyjpyridine (4.15g, 10.69mmol): tetrahydrofuran (70ml).
- the crude reaction product is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.
- Compound 15b is prepared according to the procedure described for compound 3b from the following reagents: compound 15a (1.71g, 5.91mmol), trifluoroacetic acid (6ml); dichloromethane (30ml).
- Compound 15c is prepared according to the procedure described for compound 12a from the following reagents: compound 15b (0.89g, 4.70mmoi); triphosgene (0.47g, 1.57mmol); triethylamine (0.71ml, 5.18mmol); dichloromethane (65ml).
- the crude reaction product is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.
- Compound 15 is prepared according to the procedure described for compound 7 from the following reagents: 2-hydroxy-8- (4-methylpiperazin-1-yl) naphthalene (0.38g, 1.59mmol); sodium hydride (60%, 80mg, 1.9 lmmol); compound 15c (0.40g. 1.59mmol); tetrahydrofuran (70ml).
- the crude reaction product is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
- Compound 16 is prepared according to the procedure described for compound 6 from the following reagents: compound 15 (380mg, 0.83mmol); palladium on charcoal (450mg); methanol (30ml). The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
- Compound 17a is prepared according to the procedure described for compound 3a from the following reagents: 2-bromonapthalene (2g, 9.66mmol); tert-butylithium (12.50 ml of a 1.7M solution in pentane, 21.26mmol); zinc bromide (9.7 ml of an IM solution in tetrahydrofuran, 9.66mmol); tetrakis (triphenylphosphine) palladium (a tip of a spatula); 1 - (tert-butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethy) sulfonyl oxyjpyridine (3.75 g, 9.66 mmol); tetrahydrofuran (70ml).
- the crude reaction product is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate. Mass obtained: 2.25g (YId:
- Compound 17b is prepared according to the procedure described for compound 3b from the following reagents: compound 17a (2.20g, 7.1 l mmol), trifluoroacetic acid (7ml); dichloromethane (20ml).
- the crude reaction product is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
- Compound 17c is prepared according to the procedure described for compound 12a from the following reagents: compound 17b (1.03g, 4.93mmol); triphosgene (0.49g, 1.64mmol); triethylamine (0.75ml, 5.42mmol); dichloromethane (65ml).
- the crude reaction product is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.
- Compound 17 is prepared according to the procedure described for compound 7 from the following reagents: 2-hydroxy-8- (4-methylpiperazin-1-yl) naphthalene (0.68g, 2.80mmol); sodium hydride (60%, 160mg, 3.36mmol); compound 17c (0.76g, 2.80mmol); tetrahydrofuran (70ml). The crude reaction product is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
- Compound 18 is prepared according to the procedure described for compound 6 from the following reagents: compound 17 (830mg, 1.74mmol); palladium on charcoal (450mg); methanol (50ml). The crude reaction product is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / arnmonia.
- Compound 19a is prepared according to the procedure described for compound 3a from the following reagents: 1 -bromonapthalene (2g, 9.66mmol); tert-butylithium (12.50 ml of a 1.7M solution in pentane, 21.26mmol); zinc bromide (9.7 ml of an IM solution in tetrahydrofuran, 9.66mmol); tetrakis (triphenylphosphine) palladium (a tip of a spatula); 1- (tert-butyloxycarbonyl) -1,2,3,6-tetrahydro-4 - [(trifluoromethyl) sulfonyl oxyjpyridine (3.75g, 9.66mmol); tetrahydrofuran (70ml).
- the crude reaction product is purified by chromatography-light with a mixture (95/5) of petroleum ether / ethyl acetate. Mass obtained: 1.54g (Yield: 52%)
- Compound 19b is prepared according to the procedure described for compound 3b from the following reagents: compound 19a (1.53g, 4.95mmol), trifluoroacetic acid (5ml); dichloromethane (20ml).
- the crude reaction product is purified by flash chromatography with a mixture (92/8/1) of dichloromethane / methanol / ammonia.
- Compound 19c is prepared according to the procedure described for compound 12a from the following reagents: compound 19b (0.94g, 4.50mmol); triphosgene (0.45g, 1.50mmol); triethylamine (0.68ml, 4.95mmol); dichloromethane (65ml).
- the crude reaction product is purified by flash chromatography with a mixture (95/5) of petroleum ether / ethyl acetate.
- Compound 19 is prepared according to the procedure described for compound 7 from the following reagents: 2-hydroxy-8- (4-methylpiperazin-1-yl) naphthalene (0.45g, 1.88mmol); sodium hydride (60%, 90mg, 2.25mmol); compound 19c (0.51g, 1.88mmol); tetrahydrofuran (70ml). The crude reaction product is purified by flash chromatography with a mixture (95/5/1) of dichloromethane / methanol / ammonia.
- Compound 20 is prepared according to the procedure described for compound 6 from the following reagents: compound 19 (450mg, 0.94mmol); palladium on carbon (440mg); methanol (50ml). The crude reaction product is purified by flash chromatography with a mixture (92/8/1) dichloromethane / methanol / ammonia.
- the derivatives of the present invention are potent 5HTj £ receptor antagonists as shown by the linkage studies and the antagonism studies of the inhibition of adenylate cyclase (stimulated by forskolin) by a 5HT ⁇ rj agonist such as serotonin, sumatriptan or 5-CT, studies which have been carried out at the level of human receptors clones SHTiD ⁇ .
- the HeLa HA7 cell line expressing the human 5HT] A receptor was obtained from Tulco (Duke Univ., Durham, N.C., USA) and cultivated according to the method of Fargin et al., J. Biol. Chem. 264.14848 (1989).
- the incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand [[3H] -5CT (final concentration: 2nM) for the receptors 5HTi £ ) a and 5HT ⁇ r) b and [3HJ-80H-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 £) t-,) or 1 ⁇ M (final concentration) of spiroxatrine (5HTJA).
- a tritiated ligand [[3H] -5CT (final concentration: 2nM) for the receptors 5HTi £ ) a and 5HT ⁇ r) b and [3HJ-80H-DPAT (final concentration: 1 nM) for the 5HT ⁇ /
- the new compounds derived from aryl piperazines forming part of the present invention are powerful and selective antagonists of the 5HTj receptors () and have the advantage of being particularly selective for the human SHTJQR receptors in particular with respect to the receptors 5HTjç, 5HT2, cq, c ⁇ 2 and D2-
- 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.
- 5-carboxamido-tryptamine 5CT
- level of serotonin release in guinea pig brain slices are generally recognized as particularly relevant in the functional characterization of the SHTJD and receptors. 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 includes a method for treating such patients, which method involves the administration of an active dose of a compound of general formula (I).
- the derivatives of the present invention are also capable of controlling the growth and proliferation of glial cells of the C ⁇ type transfected by the 5HT] D ⁇ receptor gene, 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 by 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.
- compositions containing, as active ingredients, a compound of general formula (I) or a physiologically acceptable salt of a compound of formula (I) associated with one or more agents therapeutic agents, such as, for example antidepressant agents such as tricyclic antidepressants (eg amitryptyline, clomipramine, desipramine, imipramine), monoamine oxidase inhibitors (eg isocarboxazide, moclobemide, phenelzine or tranylcyclopramine), inhibitors of re- serotonin uptake (e.g.
- antidepressant agents such as tricyclic antidepressants (eg amitryptyline, clomipramine, desipramine, imipramine), monoamine oxidase inhibitors (eg isocarboxazide, moclobemide, phenelzine or tranylcyclopramine), inhibitors of re- serotonin uptake (e.g.
- the derivatives of the present invention or their physiologically acceptable salts can also be administered in form of pharmaceutical compositions, in combination with an antagonist of the 5 -HT JA (te l 1 ue> F or example pindolol, WAY 1 00 1 35 , UH-301 or WAY 1 00635). This association is also part of the present invention.
- the present invention also relates to pharmaceutical compositions containing as active ingredient a compound of general formula I or one of its acceptable salts for pharmaceutical use, mixed or associated with a suitable excipient.
- These compositions can take, for example, the form of solid, liquid compositions, emulsions, lotions or creams.
- compositions for oral administration tablets, capsules, 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.
- These compositions can also comprise substances other than thinners, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.
- liquid 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 the like. paraffin oil .
- inert diluents such as water, ethanol, glycerol, vegetable oils or the like. paraffin oil .
- 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, can be used.
- These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. 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 substance active, preferably from 1 mg to
- compositions according to the invention 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 May opening 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 changing the compression weight using appropriate punches.
- the active component is passed through a sieve with a mesh opening of 250 ⁇ m and mixed with lactose, starch and pregelatinized starch.
- the mixed powders are moistened with purified water, they are granulated, dried, sieved and mixed with magnesium stearate.
- the lubricated granules are put into tablets as for the formulas by direct compression.
- a coating film can be applied to the tablets using suitable film-forming materials, for example methyl cellulose or hydroxypropyl-methyl cellulose, according to conventional techniques. Sugar tablets can also be coated.
- 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.
- Active ingredient 1 0.0 mg
- a suspension of the active component in Witepsol H 1 5 is prepared and it is introduced into an appropriate machine with suppository molds of 1 g.
- Sodium chloride may be added to adjust the tone of the solution and to adjust the pH to maximum stability and / or to facilitate dissolution of the active component by means of a dilute 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.
- 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 pul pulverulent mixture is introduced into hard gelatin capsules No. 3 on a encapsulate appropriate.
- the contents of the cartridges are administered using a powder inhaler.
- mg / dose for 1 can micronized active component 0.500 120 mg oleic acid Codex 0.050 1 2 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.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU16070/97A AU1607097A (en) | 1996-02-02 | 1997-01-31 | Novel piperidines derived from 1-/(piperazin-1-yl)aryl(oxy/amino)carbonyl/-4-aryl-piperidin e as selective 5-ht1db receptor antagonists |
BR9707261A BR9707261A (pt) | 1996-02-02 | 1997-01-31 | Compostos processos de preparação dos mesmos e de produtos e composições farmacéuticas |
NZ331221A NZ331221A (en) | 1996-02-02 | 1997-01-31 | Novel piperidines derived from 1-/(piperazin-1-yl)aryl-(oxo/amino)carbonyl/-4-aryl-piperidine as selective 5-ht 1dbeta receptor antagonists |
EP97902419A EP0886636A1 (fr) | 1996-02-02 | 1997-01-31 | Nouvelles piperidines derivees de la 1-/(piperazin-1-yl-)aryl(oxy/amino)carbonyl/-4-aryl-piperidine comme antagonistes selectifs des recepteurs 5-ht-1d.beta |
JP9527373A JP2000504004A (ja) | 1996-02-02 | 1997-01-31 | 選択的な5―HT▲1Dβ▼レセプター拮抗薬としての1―/(ピペラジン―1―イル)アリール―(オキシ/アミノ)カルボニル/―4―アリール―ピペリジンから誘導される新規ピペリジン |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9601275A FR2744448B1 (fr) | 1996-02-02 | 1996-02-02 | Nouvelles piperidines derivees d'aryl piperazine, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments |
FR96/01275 | 1996-02-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997028140A1 true WO1997028140A1 (fr) | 1997-08-07 |
Family
ID=9488770
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1997/000195 WO1997028140A1 (fr) | 1996-02-02 | 1997-01-31 | Nouvelles piperidines derivees de la 1-/(piperazin-1-yl-)aryl(oxy/amino)carbonyl/-4-aryl-piperidine comme antagonistes selectifs des recepteurs 5-ht-1d.beta |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0886636A1 (fr) |
JP (1) | JP2000504004A (fr) |
CN (1) | CN1212690A (fr) |
AU (1) | AU1607097A (fr) |
BR (1) | BR9707261A (fr) |
CA (1) | CA2244940A1 (fr) |
FR (1) | FR2744448B1 (fr) |
MX (1) | MX9806246A (fr) |
NZ (1) | NZ331221A (fr) |
WO (1) | WO1997028140A1 (fr) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2758327A1 (fr) * | 1997-01-15 | 1998-07-17 | Pf Medicament | Nouvelles arylpiperazines derivees de piperidine |
WO2003053927A1 (fr) * | 2001-12-21 | 2003-07-03 | Taisho Pharmaceutical Co.,Ltd. | Dérivé de piperazine |
WO2005009988A1 (fr) * | 2003-07-24 | 2005-02-03 | Euro-Celtique S.A. | Composes de 4-heteroaryle-tetrahydropiperidyle utiles pour le traitement ou la prevention de la douleur |
WO2005009987A1 (fr) * | 2003-07-24 | 2005-02-03 | Euro-Celtique S.A. | Composes de piperidine et compositions pharmaceutiques les contenant |
EP1867644A1 (fr) | 2003-07-24 | 2007-12-19 | Euro-Celtique S.A. | Composés de hétéroaryl-tétrahydropipéridyle utiles pour traiter ou prévenir la douleur |
US7473698B2 (en) | 2002-07-03 | 2009-01-06 | H. Lunbeck A/S | Secondary amino anilinic piperidines as MCH1 antagonists and uses thereof |
WO2009150387A1 (fr) * | 2008-06-13 | 2009-12-17 | Sanofi-Aventis | Derives de 2-oxo-alkyl-1-piperazin-2-one, leur preparation et leur application en therapeutique |
FR2932482A1 (fr) * | 2008-06-13 | 2009-12-18 | Sanofi Aventis | Nouveaux derives de (phenyl-3,6-dihydro-2h-pyridinyl)- (piperazinyl ponte)-1-alcanone et leur utilisation comme inhibiteurs de p75 |
EP2479173A1 (fr) | 2007-04-27 | 2012-07-25 | Purdue Pharma LP | Agents thérapeutiques utiles pour traiter la douleur |
WO2012176061A1 (fr) | 2011-06-22 | 2012-12-27 | Purdue Pharma L.P. | Antagonistes de trpv1 comprenant un substituant dihydroxy et leurs utilisations |
WO2013021276A1 (fr) | 2011-08-10 | 2013-02-14 | Purdue Pharma L.P. | Antagonistes du trpv1 comprenant un substituant dihydroxy et leurs utilisations |
EP2604599A1 (fr) | 2007-04-27 | 2013-06-19 | Purdue Pharma LP | Antagonistes de TRPV1 et utilisations de ceux-ci |
US8518947B2 (en) | 2009-12-14 | 2013-08-27 | Sanofi | (Heterocycle/tetrahydropyridine)-(piperazinyl)-1-alcanone and (heterocycle/dihydropyrrolidine)-(piperazinyl)-1-alcanone derivatives, and use thereof as p75 inhibitors |
US8580790B2 (en) | 2009-12-14 | 2013-11-12 | Sanofi | (Heterocycle/condensed piperidine)-(piperazinyl)-1-alkanone or (heterocycle/condensed pyrrolidine)-(piperazinyl)-1-alkanone derivatives and use thereof as p75 inhibitors |
US8703962B2 (en) | 2008-10-24 | 2014-04-22 | Purdue Pharma L.P. | Monocyclic compounds and their use as TRPV1 ligands |
US8759362B2 (en) | 2008-10-24 | 2014-06-24 | Purdue Pharma L.P. | Bicycloheteroaryl compounds and their use as TRPV1 ligands |
US8921373B2 (en) | 2010-06-22 | 2014-12-30 | Shionogi & Co., Ltd. | Compounds having TRPV1 antagonistic activity and uses thereof |
WO2015105772A1 (fr) | 2014-01-09 | 2015-07-16 | Bristol-Myers Squibb Company | Antagonistes sélectifs de nr2b |
US9763940B2 (en) | 2011-12-20 | 2017-09-19 | Sanofi | Therapeutic use of P75 receptor antagonists |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0481744A1 (fr) * | 1990-10-19 | 1992-04-22 | JOHN WYETH & BROTHER LIMITED | Dérivés de pipérazine |
WO1994008983A1 (fr) * | 1992-10-17 | 1994-04-28 | John Wyeth & Brother Limited | Derives d'amide |
WO1996002525A1 (fr) * | 1994-07-20 | 1996-02-01 | Pierre Fabre Medicament | Nouvelles piperazides derivees d'aryl piperazine, leurs procedes de preparation, leur utilisation a titre de medicament et les compositions pharmaceutiques les comprenant |
-
1996
- 1996-02-02 FR FR9601275A patent/FR2744448B1/fr not_active Expired - Fee Related
-
1997
- 1997-01-31 CA CA002244940A patent/CA2244940A1/fr not_active Abandoned
- 1997-01-31 WO PCT/FR1997/000195 patent/WO1997028140A1/fr not_active Application Discontinuation
- 1997-01-31 BR BR9707261A patent/BR9707261A/pt not_active Application Discontinuation
- 1997-01-31 CN CN97192737A patent/CN1212690A/zh active Pending
- 1997-01-31 NZ NZ331221A patent/NZ331221A/xx unknown
- 1997-01-31 EP EP97902419A patent/EP0886636A1/fr not_active Withdrawn
- 1997-01-31 JP JP9527373A patent/JP2000504004A/ja active Pending
- 1997-01-31 AU AU16070/97A patent/AU1607097A/en not_active Abandoned
-
1998
- 1998-08-03 MX MX9806246A patent/MX9806246A/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0481744A1 (fr) * | 1990-10-19 | 1992-04-22 | JOHN WYETH & BROTHER LIMITED | Dérivés de pipérazine |
WO1994008983A1 (fr) * | 1992-10-17 | 1994-04-28 | John Wyeth & Brother Limited | Derives d'amide |
WO1996002525A1 (fr) * | 1994-07-20 | 1996-02-01 | Pierre Fabre Medicament | Nouvelles piperazides derivees d'aryl piperazine, leurs procedes de preparation, leur utilisation a titre de medicament et les compositions pharmaceutiques les comprenant |
Cited By (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998031669A1 (fr) * | 1997-01-15 | 1998-07-23 | Pierre Fabre Medicament | Nouvelles arylpiperazines derivees de piperidine comme medicaments antidepresseurs |
FR2758327A1 (fr) * | 1997-01-15 | 1998-07-17 | Pf Medicament | Nouvelles arylpiperazines derivees de piperidine |
WO2003053927A1 (fr) * | 2001-12-21 | 2003-07-03 | Taisho Pharmaceutical Co.,Ltd. | Dérivé de piperazine |
US7473698B2 (en) | 2002-07-03 | 2009-01-06 | H. Lunbeck A/S | Secondary amino anilinic piperidines as MCH1 antagonists and uses thereof |
US7572812B2 (en) | 2003-07-24 | 2009-08-11 | Purdue Pharma, L.P., Usa | Therapeutic agents useful for treating pain |
US8178560B2 (en) | 2003-07-24 | 2012-05-15 | Purdue Pharma L.P. | Therapeutic agents useful for treating pain |
EA009480B1 (ru) * | 2003-07-24 | 2008-02-28 | Еуро-Селтик С. А. | Гетероарил-тетрагидропиридины и их применение для лечения или профилактики боли |
EA010852B1 (ru) * | 2003-07-24 | 2008-12-30 | Еуро-Селтик С. А. | Пиперидиновые соединения и фармацевтические композиции, их содержащие |
WO2005009987A1 (fr) * | 2003-07-24 | 2005-02-03 | Euro-Celtique S.A. | Composes de piperidine et compositions pharmaceutiques les contenant |
KR100896499B1 (ko) * | 2003-07-24 | 2009-05-08 | 유로-셀띠끄 소시에떼 아노님 | 통증 치료 또는 예방에 유용한헤테로아릴-테트라하이드로피페리딜 화합물 |
EP2067776A1 (fr) | 2003-07-24 | 2009-06-10 | Euro-Celtique S.A. | Composes de piperidine et compositions pharmaceutiques les contenant |
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WO2005009988A1 (fr) * | 2003-07-24 | 2005-02-03 | Euro-Celtique S.A. | Composes de 4-heteroaryle-tetrahydropiperidyle utiles pour le traitement ou la prevention de la douleur |
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WO2009150387A1 (fr) * | 2008-06-13 | 2009-12-17 | Sanofi-Aventis | Derives de 2-oxo-alkyl-1-piperazin-2-one, leur preparation et leur application en therapeutique |
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FR2932481A1 (fr) * | 2008-06-13 | 2009-12-18 | Sanofi Aventis | Derives de 4-{2-°4-phenyl-3,6-dihydro-2h-pyridin-1-yl!-2- oxo-alkyl}-1-piperazin-2-one, leur preparation et leur application en therapeutique. |
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EA019924B1 (ru) * | 2008-06-13 | 2014-07-30 | Санофи-Авентис | Производные 2-оксоалкил-1-пиперазин-2-она, их получение и их применение в терапии |
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US8518947B2 (en) | 2009-12-14 | 2013-08-27 | Sanofi | (Heterocycle/tetrahydropyridine)-(piperazinyl)-1-alcanone and (heterocycle/dihydropyrrolidine)-(piperazinyl)-1-alcanone derivatives, and use thereof as p75 inhibitors |
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US8921373B2 (en) | 2010-06-22 | 2014-12-30 | Shionogi & Co., Ltd. | Compounds having TRPV1 antagonistic activity and uses thereof |
US10450308B2 (en) | 2011-06-22 | 2019-10-22 | Purdue Pharma L.P. | TRPV1 antagonists including dihydroxy substituent and uses thereof |
US9273043B2 (en) | 2011-06-22 | 2016-03-01 | Purdue Pharma L.P. | TRPV1 antagonists including dihydroxy substituent and uses thereof |
WO2012176061A1 (fr) | 2011-06-22 | 2012-12-27 | Purdue Pharma L.P. | Antagonistes de trpv1 comprenant un substituant dihydroxy et leurs utilisations |
US9630959B2 (en) | 2011-06-22 | 2017-04-25 | Purdue Pharma L.P. | TRPV1 antagonists including dihydroxy substituent and uses thereof |
EP3173411A1 (fr) | 2011-06-22 | 2017-05-31 | Purdue Pharma L.P. | Antagonistes de trpv1 comprenant un substituant dihydroxy et leurs utilisations |
US9394293B2 (en) | 2011-08-10 | 2016-07-19 | Purdue Pharma L.P. | TRPV1 antagonists including dihydroxy substituent and uses thereof |
US9873691B2 (en) | 2011-08-10 | 2018-01-23 | Purdue Pharma L.P. | TRPV1 antagonists including dihydroxy substituent and uses thereof |
WO2013021276A1 (fr) | 2011-08-10 | 2013-02-14 | Purdue Pharma L.P. | Antagonistes du trpv1 comprenant un substituant dihydroxy et leurs utilisations |
US9763940B2 (en) | 2011-12-20 | 2017-09-19 | Sanofi | Therapeutic use of P75 receptor antagonists |
WO2015105772A1 (fr) | 2014-01-09 | 2015-07-16 | Bristol-Myers Squibb Company | Antagonistes sélectifs de nr2b |
Also Published As
Publication number | Publication date |
---|---|
CN1212690A (zh) | 1999-03-31 |
CA2244940A1 (fr) | 1997-08-07 |
AU1607097A (en) | 1997-08-22 |
FR2744448B1 (fr) | 1998-04-24 |
EP0886636A1 (fr) | 1998-12-30 |
FR2744448A1 (fr) | 1997-08-08 |
MX9806246A (es) | 1998-11-29 |
BR9707261A (pt) | 1999-07-20 |
JP2000504004A (ja) | 2000-04-04 |
NZ331221A (en) | 2000-01-28 |
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