• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    Médicaments utiles pour le traitement des états d'anxiété et des troubles pulmonaires, rénaux, cardiovasculaires ou circulatoires, contenant, comme substance active, un composé de formule: dans laauelle R1 est alkvle 1-6 C, phénvle, cvcloalkvle 3-6 C. phénylalkyle, cycloalkylalkyle ou étant H ou alkyle, R5 étant alcényle ou alcinyle, la somme des atomes de carbone de R3, R4 et R5 étant de 2 à 5, R2 a les mêmes significations que R, et non plus la signification dans laquelle n est 0, 1, 2 ou 3, R1 et R2 pouvant en outre former avec l'atome d'azote auquel ils sont rattachés un radical hétérocyclique à 5, 6 ou 7 chaînons pouvant contenir un autre hétéroatome choisi parmi O et N et porter un ou deux substituants, Z est phényle, pyridyle, thiényle, thiazolyl-2 ou phényle substitué, X et Y sont H, halogène, alkyle 1-3 C, alcoxy 1-3 C, nitro ou CF3, A représente N ou CH, B représente N ou CH.
    公开号:SU1255050A3
    申请号:SU833682598
    申请日:1983-12-23
    公开日:1986-08-30
    发明作者:Дюброюк Мари-Кристин；Роже Ле Фюр Жерар；Луи Альбер Рено Кристиан
    申请人:Рон-Пуленк Санте (Фирма)；
    IPC主号:
    专利说明:

    R, and Rj can, in addition, form together with the nitrogen atom to which they are connected a heterocyclic radical with 5, 6 or 7 units, which may contain another heteroatom, selected among nitrogen and oxygen, and carry one or two substituents selected from C -Cj-ankyl groups, hydroxy, OXO-, hydroxyalkyl groups, the apical part of which contains 1 to 3 carbon atoms, - Z, X and Y have the indicated values:
    or A is nitrogen; B - CHJ Z, X and Y groups have the indicated meanings; R (phenyl group, C, -Cj-cycloalkyl, phenylalkyl group, the alkyl part of which contains 1-3 carbon atoms} R, j. Is phenyl group, C-Ce-dicloalkyl, phenylalkyl group, the alkyl part of which contains 1-3 atom carbon, or
    and to obtain a compound of the formulas T, where A, B, X, Y, Z, R have the indicated values, and RI is the group n
    has specified and R
    /P.TT X / T.T t these values, and R is the group lLH2) y –N Where –d
     (SNO) J / CNRsubstantial data prnmst
    j values
    R and R can, in addition, form together with the nitrogen atom to which they are attached, pyrrolidinyl, piperidine morpholine, 1,2,3,6-tetra-hydropyridyl, 2,3,4,5,6,7-hexahyd - roacepinyl, A-oxopiperxins or piperidinadical, substituted by one or two C, -C-alktr groups, or a hydroxy group at position 3 or 4, hydroxyalkyl group, the apkyl part of which contains 1-3 carbon atoms
    amine of general formula IV
    -SHG -O-sn2-SbN
    with a compound of formula V
    CO-W
    in yag
    Y A
    where X, Y, Z, A, B, R,

    n have the indicated meanings; W is an alkoxy group with a lower allele, chlorine or an alkoxycarb niloxy group with a lower allele,
     or R, and R can be different C, -C {, - alkyl groups, such as, for the preparation, the NJL of the compound of formula 1, where A, B, R, Rj, X, Z and Y have. Indicated
    values, the reaction of the amine of general formula II is carried out
    HN
    /
    RI
    R9
    compound of formula III
    CO-W to Y
    where X, U, Z, A, B, R and R have
    specified values; W is an alkoxy group with a lower alkyl, chlorine or an alkoxycarbonyloxy group with a lower alkyl,
    and to obtain a compound of the formula T, where A, B, X, Y, Z, R, have the indicated meanings, and RI is the group of defined values, and R is the group
    Reacamine General Formula IV
    -SHG -O-sn2-SbNb
    uniform formula V
    CO-W
    in yag
    Y A
    X, Y, Z, A, B, R,

    n have the indicated meanings; W is an alkoxy group with a lower alkyl, chlorine or an alkoxycarbonyloxy group with a lower alkyl,
    The resulting bonding is debenzylation.
    This invention relates to a process for the preparation of racemic or stereoisomeric naphthalene or azanaphthalene carboxamide derivatives having biological activity.
    The purpose of the invention is the synthesis of new compounds with pharmacological properties.
    Example 1 Preparation of N, N-flM-ethyl-2-phenyl-4-quinolinecarboxamide,
    30 g of 2-phenyl-4-quinolinecarboxylic acid in 100 ml of thionyl chloride are brought to the boil. After boiling for 1 hour, the thionyl chloride was evaporated, the residue was treated with 100 ml of toluene, which was again evaporated. 100 ml of toluene was added to the resulting residue, then 70 ml of diethyl amine were added with stirring. The mixture is boiled under reflux for 1 hour, then the reaction mixture is poured into 500 ml of water. Decant the organic phase. The aqueous phase is extracted 3 times with 150 mp of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated under reduced pressure. After crystallization of the resulting residue from diethyl ether and recrystallization from isopropyl alcohol, 18 g of K, ethyl 2 phenyl-4-quinolinecarboxamide, melting at
    PRI mme R 2. K, K Diethyl-2- 2-pyridyl-4-quinoline-carboxamide is prepared according to Example 1 from 15 g of 2-2-pyridyl-4-quinoline carboxylic acid, 45 ml of thionyl chloride and 6 ml of diethylamine.
    After recrystallization of the residue from diisopropyl ether, 14.3 g of N N-diethyl-2-2-pyridyl-4 are obtained. . - quinoline carboxamide with m.p. 100 ° C.
    2- 2-Pirndil-4-quinolinecarboxylic acid can be obtained by a known method.
     Froze Preparation of α-pyridyl-4-quinolyl-carbonyl-piperidine.
    3 g of 2-2-pyridyl-4-quinolinecarboxylic acid and 10 ml of thionyl chloride are refluxed for 1 hour. The thionyl chloride is evaporated. The residue is treated with 100 mp of toluene and again evaporated. 20 ml of toluene are then added to the residue, after which 3.5 ml of piperidine are added dropwise and with stirring. Stir for 2 hours at room temperature. The reaction mixture is poured into 50 ml of water, the organic phase is decanted and the aqueous phase is extracted three times with 100 ml of ethyl acetate. The organic phases are combined, permeated three times. 30 ml each time with water, dried over magnesium sulfate and evaporated under reduced pressure.
    After recrystallization of the resulting residue from ethyl acetate, 2.9 g of 1- {2- 2-pyridyl 4-quinolyl-β-carbonyl-piperidine, melting at 158 ° C, are obtained.
    5 S 5
    20
    five
    hell
    five
    five
    Example4. 1- 2-Phenyl-4-quinolyl-carbonyl-piperidine is prepared according to example 3 starting from 8 g of 2-phenyl-4-quinolinecarboxylic acid, 24 ml of thionyl chloride and 8.16 g of piperidine.
    After recrystallization of the residue from diisopropyl ether, 8.7 g of 1- 2-phenyl-4-quinolyl-carbonone-piperidine were isolated, melting at 104 ° C. -
    EXAMPLE 5 4- 2-phenyl-4-quinolyl-carbonyl-morpholine was prepared according to Example 3 starting from 8 g of 2-phenyl-4-quinoline-carboxylic acid. 24 ml of thionyl chloride and 8.3 g morpholina.
    After recrystallization from ethanol, 8 g of 4-2-phenyl-4-chi nolyl - carbosh-w-morpholine are obtained, melting at 124 C.
    PRI me R 6. I, K-Diethyl-2- | 4- -chlorophenyl-4-quinolinecarboxamide receive according to example 3 on the basis of 5 g of 2-4-chlorophenyl-4-quinolinecarboxylic acid, 15 ml of thionyl chloride and 18 ml diethylamine. „
    After recrystallization of the resulting residue from diisopropyl ether, 4.2 g of N, N-diethyl-2-4-chlorophenyl-4j-quinolinecarboxamide, melting at 105 ° C, are isolated.
    2-4-Chlorophenyl-4-quinolinecarboxylic acid can be obtained by a known method.
    Example. N, N-Diethyl-2-4-methoxy-phenyl-4-quinolinecarboxamide is prepared according to Example 3 starting from 5 g of 2-4 methoxy-phenyl-4-quinolinecarboxylic acid, 15 ml of thionyl chloride and 18.4 ml of diethylamine.
    After recrystallization of the residue from diisopropyl ether, 3.8 g of H, K-diethyl-2-4-methoxyphenyl-1-4-xynol-lincarboquamide, melting at 128 ° C, are isolated.
    2 4-methoxy-phenyl-4-quinolinecarboxylic acid can be obtained by a known method
    PRI me R 8, When preparing N, N-diethyl-2-2-chlorophenyl-4-quinoline-carboxamide according to example 3, starting from 5 g of 2-2-chlorophenyl-4-quinoline-carboxylic acid, 15 ml of thionyl chloride and 12.7 ml diethylamine.
    After recrystallization of the residue from diisopropyl ether, 3.2 g of N, N-diethyl-2-2-chlorophenyl-4-quinoline-carboxamide, melting at 130 ° C, are isolated.
    2-C-Chlorophenyl-4 quinoline carboxylic acid can be obtained by a known method.
    EXAMPLE 9, K, K-Diethyl-2- 3-β-trifluoromethyl-phenyl-4-quinoline-carboxamide was prepared as in Example 3 starting from 6 g of 2-3-trifluoro-methylphenyl-4-quinoline carboxylic acid , 18 MP of thionyl chloride and 18.5 ml of di-ethylamine.
    After recrystallization of the residue from diisopropyl ether, 5.2 g of K, K-diethyl-2-3-trifluoromethyl-phenyl-4-quinolinecarbox- are isolated. amide, melted at 100 ° C.
    2-3-Trifluoromethyl-phenyl-4-quinoline-carbopic acid can be obtained by a known method.
    Example 10. K, K-Dietsh1-2- 4-α-fluoro-phenyl-4-quinoline-carboxyMid is obtained according to Example 3 starting from 5 g of 2-4 fluoro-phenyl-4-quinoline carboxylic acid, 15 ml of thionyl chloride and 19.2 ml diethylamine.
    After chromatography of the residue of Tia with silica gel using an eluent formed of a mixture of hexane and ethyl acetate (70:30), and recrystallization of the thus obtained product from diisopropyl ether, 0.86 g of H, K-diethyl-2-4-fluoro-fe - Nil-4-quinoline-carboxamide, melted at 114 C.
    2- 4-Fluoro-fenst-4-quinoline-carboxylic acid can be obtained by a known method.
    Example P. 1- 2-Phenyl-4-quinoline -carbonyl-pyrrolidine is prepared according to Pr1Fleu 3 based on 10 g of 2-phenyl-4-quinoline-carboxylic acid, 30 ml of thionyl chloride and 10.3 ml of pyrrolidine. Thus, after recrystallization of the residue from isopropanol, 5.6 g of 1 -2-phenyl-4-quinolyl carbonyl-pyrrolidine, melted at 128 ° C., are thus isolated.
    Example 12. N, N-Diethyl-6,7-dimethoxy-2-phenyl-4 -: (shlincarbox-amide is obtained according to example 3 starting from 2.5 g of 6,7-dimethoxy-2-phenyl-4- quinoline carboxylic acid, 8 ml of thionyl chloride and 8.2 ml of diethylanin.
    In this way, 2.9 g of N, N- -DIETSH1-6,7-dimethoxy-2-phenyl-4-quinoline-carboxyamide are obtained in the form of an oil, which in acetone is converted into its own
    hydrochloride by adding a solution of hydrochloric acid in ether. After recrystallization and acetone, the substance (hydrochloride) has a melting point of 5 equal to 0 ° C.
    f, 7-dimethoxy-2-phenyl-4-quinoline-carboxylic acid can be obtained by a known method.
    EXAMPLE 13 H, H-Diethyl-6-methyl-2-phenyl-4-quinoline-carboxamide is prepared, according to Example 3, from 3.2 g of 6-metsh-2-phenyl-4-quinoline-car- boic acid, 15 ml of thionyl chloride and 12.5 ml of diethylamine. 5 After recrystallization of the residue from diisopropyl ether, 3.1 g of H, H-diethyl-6-methyl-2-phenyl-4-quinoline carboxamide, melting at 120 ° C., are obtained;
    06-methyl-2-phenyl-4-quinoline carboxylic acid can be obtained by a known method.
    Example 14. N, N-Diethyl-8-nitro-2-phenyl-4-quinoline-carboxamide 5 are prepared according to Example 3 starting from 32 g of 8-nitro-2-phenyl-4-quinoline-carboxylic acid, 9 ml thionyl chloride and 11.5 ml of diethylamine.
    After recrystallization of the residue 0 from a mixture of cyclohexane with ethyl acetate (1: 1), 2.45 g of N, N-diethyl-8-nitro-2-phenyl-4-quinoline-carboxamide, melting at 138 ° C., are isolated.
    8 Nitro - 2-phen1 p-4-quinolinecarboxylic acid can be obtained by a known method.
    Example 15. K-Methyl-Y-l-methyl-propyl -2-2-chlorophenyl-4-quinoline-carboxamide is prepared as in Example 0 3 based on 5.7 g of 2 -2-chlorofene-4-quinolinecarboxylic acid , 15 ml of thionyl chloride and 15 ml of methyl 2-butanamine.
    After recrystallization of the 5th residue from diisopropyl ether, 5 g of N-MeTmi-N- -methylpropyl -2 -2-chlorophenyl-4-xynol synobromide are obtained.
    melt at 118 C. I
    Example 16, N, N-Di-1-methyl-propyl-12-2-chlorophenyl-4-quinoline-carboxamide is prepared according to Example 3 starting from 2.83 g of 2-2-chlorophenyl-4-quinolinecarboxylic acid, 10 ml thionyl chloride and 5.16 g of N-l-methylpropyl -2-butanamine.
    After the first chromatography of the residue on silica gel using a mixture of cyclohexane and ethyl acetate
    7
    (1: 1) as eluant, then after the second chromatography under pressure on silica gel using a mixture of cyclohexane and ethyl acetate (7: 3), 1.8 g of K are obtained as eluant; K-di-1-methylpropyl-2- 2- -chlorophenyl-4-quinolinecarboxamide, melting at 120 ° C.
    Example 17. N-Ethyl-K-l-methyl-propyl -2-2-chlorophenyl-A-quinoline-carboxamide is prepared according to Example 3 starting from 2.8 g of 2-2-chloro-phenyl-4-quinolinecarboxylic acid, in ml thionyl chloride and 4 g of N-α-ethyl-2-butanamine.
    After recrystallization of the residue from diisopropyl ether, 0.9 g of N-ethyl-N-1-methylpropyl -2--2-chlorophenyl-4-quinoline-carboxamide are obtained, melting at 95 ° C.
    Example 18. 1- 2- 2-Chlorophenyl-4-quinolyl-carbonyl-piperidine is prepared according to Example 3 starting from 2.8 g of 2-2-chlorophenyl-4-quinolinecarboxylic acid, 10 ml of thionyl chloride and 3.4 g of piperidine .
    After recrystallization of the residue from ethyl acetate, 2.1 g of - 2-chlorophenyl-4-quinolyl carbonyl-piperidine was isolated, melting at 129 ° C.
    Example 19. N, N-Diethyl-2- 2-β-thiazolyl} -4-quinolinecarboxamide is prepared according to Example 3 starting from 0.8 g of 2 -2-thiazolyl-4-quinolinecarboxylic acid, 20 ml of thionyl chloride and 10 ml of diethylamine.
    After chromatography of the residue on silica gel using a mixture of chloroform and acetate (9: 1) as an eluant, 0.3 g of N, N-α-diethyl-2 -2-thiazolyl-4-quinoline-carboxamide melting at 97 ° C is isolated. .
    2-2-Thiazolyl-4-quinolinecarboxylic acid is obtained by exposing isatin (1.4-1 CG mol) to 2- acetyl-thiazole (1.3-10 mol) in a medium formed of 30 ml of aqueous 6i. potassium hydroxide solution and 10 ml of ethanol at reflux temperature. She has a mp. 250 ° C.
    2-Acetyl-thiazole can be obtained by a known method.
    Example 20. N, N-Diethyl-3-β-phenyl-1-naphthalene-carboxamide is prepared according to Example 3 using 5 g of 3-phenyl-1-naphthalene-carboxylic acid instead of 3 g of 2 -2-pyridyl-42550508
    -quinolinecarboxylic acid, 20 ml of thionyl chloride instead of 10 ml of thionyl chloride and 4.5 ml of diethylamine in 23 ml of pyridine instead of 3.5 ml of piperidine 5 in 20 MP of toluene. After recrystallization from hexane, 3.4 g of N, N-diethyl-3-phenyl-1-naphthalene-p-box amide are obtained, which melt at 65 ° C.
    A 1-phenyl-1-naphthapicarbonyl acid can be made by a known method.
    PRI me R 21. K-Methyl-M-1-methyl-propsh-β-3-phenyl-1-naphthalene-carboxamide, prepared according to example 20 15 based on 4.3 g of 3-phenyl-1-naphthalene-carboxylic acids, 20 ml of thionyl chloride and 1.5 g of N-methyl-2-butanamine in 20 ml of pyridine. After recrystallization from petroleum ether, 2.8 g of N-methyl-K-1-methylpropyl-3-phenyl-1-naphthalenecarboxamide, melting at 125 ° C, are obtained.
    EXAMPLE 22 N, N-Diethyl-2- 2-chlorophenyl-4-quinoline-carboxamide 25 is prepared according to Example 3, starting from 2.16 g of 2rf2-xylope) enyl-4 -.quinazoline carboxylic acid and 10 ml of thionyl chloride, then 10 ml of diethylamine in 20 ml of toluene. After recrystallization from diisopropyl ether, 2.2 g of N, N-diethyl-2-2-chlorophenyl-4-quinazoline carboxamide are obtained;
    Shchegos at 124 S. G
    2-2 Chlorophenyl-4-quinazoline carboxylic acid can be prepared as follows. A mixture of 15 g of N-phenyl-2-chloro-benzamide and 11 ml of thionyl chloride is heated at 90 ° C for 1 h 30 min. The excess thionyl chloride is removed by distillation under reduced pressure, and 7 g of ethyl cyanoformate and 18.2 g of tin tetrachloride are added. Bring to 140 ° C for 10 minutes, cool, pour the reaction mixture into a mixture of methylene chloride and water, wash the organic phase with water, dry it over magnesium sulfate and evaporate to dryness under reduced pressure — Hi-m. By chromatographing the residue on silica gel using a mixture of cyclohexane: ethyl acetate (9: 1), 7 g of product was isolated as eluant, which was treated at reflux with 10 ml of 5N hydrochloric acid. sodium hydroxide and 30 ml of ethanol. The ethanol is removed by distillation under reduced pressure, the residue is treated with water and ether. 2.3 g is obtained by acidifying the aqueous phase.
    35
    40
    five
    0
    2- {2-hprenilT | -4-quinazolinecarboic acid, melted at.
    Example 23. 1 - 2-phenyl-4-sinol-1-carbonyl-piperazine G was prepared as follows.
    30 g of 2-phenyl-4-α-quinolinecarboxylic acid are boiled under reflux for 4 hours in 90 ml of thionyl chloride, the thionyl chloride is evaporated, the residue is treated with 100 ml of diethyl ether and again evaporated. The residue is added in portions to a stirred solution of 51.6 g of ttiperazine in 250 ml of methylene chloride. Stir overnight at room temperature. The solution is then treated with 500 ml of methylene chloride and .400 ml of water, -. The organic phase is separated and the aqueous phase is washed 3 times with 100 ml of methylene chloride. The organic phases are combined, washed with 150 ml of water, sulphate over dried magnesium and evaporated under reduced pressure.
    The residue is taken up in 200 ml of aqueous 0, li, acetic acid solution. The insoluble portion is filtered off, washed 3 times with 20 ml of aqueous 0.1N acetic acid solution. The filtrate and washes were combined and alkalinized by the addition of a concentrated solution of potassium hydroxide, and extracted with 3 times 150 ml of methylene chloride. The organic phase is washed 3 times with 60 ml of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel using toluene / diethylamine (9: 1) as eluent.
    Thus, the creeping wet base was dissolved in ethanol, then converted to its dihydrochloride by adding a solution of hydrochloric acid in ether. After recrystallization from ethanol, 2.4 g of I-2-phenyl-4-quinolyl-α-carbonyl piperazine dihydrochloride are obtained, melting at 250 ° C,
    Example 24, Getting H, ethyl-2- | 4 methyl phenyl-4-quinoline car oxamide,
    To 5.5 ml of diethylamine in 50 ml of anhydrous tetrahydrofuran, 7.2.5 ml of a 1.6 M solution are added at room temperature and under nitrogen.
    five
    butyl lithium in hexane. After stirring for 15 minutes, cooled to 0 ° C, then 5.25 g of ethylyl-2-4-methylphenyl-4-quinoline5 carboxylate are slowly added. Stir for 2 hours at room temperature. Acetic acid is then added slowly, at room temperature and with stirring, until decolorization is complete.
    To obtain a yellow color of the solution, 100 ml of water were added, and tetrahydrofuran was evaporated under reduced pressure and extracted with 3 times 100 mp of ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel using cyclohexane / ethyl acetate.
    0 (80:20) as eluant. After recrystallization of the crude product thus isolated from diisopropyl ether, 1.1 g of N, N-β-DIES1-2-4-methyl-fench-13 -4-quinoline 5 carboxamide, melting at 145 ° C, are obtained,
    Ethyl 2-4-methyl-phenyl-4-quinolinecarboxylate can be obtained by exposure to ethanol. 2- 4-methyl-phenyl-4-quinoline carboxylic acid in
    0 in the presence of concentrated sulfuric acid. It has a mp, 52 ° C,
    2-4-Methyl-phenyl-4-quinoline-carboxylic acid can be obtained by a known method.
    Example 25, .N, N-Diethyl-2-fe-nyl-4-x-nazolinkarbokamid get - according to example 24 on the basis of 2.9 g of ethyl 2-phenyl-4-quinazoline, 3 ml of diethylamine, 10 ml of 1.6 M solution butyl liter in hexane and 10 ml of tetrahydrofuran. After recrystallization from ethanol, 2.2 g of N, N-diethyl-2-phenyl-4-quinazolinecarboxamide, melting at 127 ° C., are obtained.
    Ethyl-2-phenyl-4-quinazoline-carboxylate can be obtained by a known method, avoiding hydrolysis up to 5

    you. It has t, pl, 55-56-C,
    Example 26, 1- (2-phenyl-4-xinazolinyl) -carbonyl | -pyrupidine was prepared as in Example 24 starting from 3 g of methyl 2-phenyl-4-quinazolinecarboxylate, 3 ml of pyrrolidine, 15 ml 1 6 M solution of utility in hexane and 25 tetrahydrofuran. After recrystallization from ethanol, 2.1 g of 1- (2- -phenyl-4-quinazolinyl) -carbonyl-pyrrolidine is obtained, melting at 153 ° C.
    EXAMPLE 27. 1 - C2-Phenyl 4-xi-yazolinyl-Kap6oHHnJ-piperidine is prepared as in Example 24 starting from 3.3 g of ethyl-2-phenyl-4-quinazoline-carboxyl 2.5 ml of piperidine, 1.5 ml 1, 6 M thief trust utility in hexane and 20 ml of tetrahydrofuran. After recrystallization from ethanol, 2.6 g of 1- (2-phenyl-4-quinases olinyl) -carbonyl-piperidine are obtained, melting at 160 ° C.
    EXAMPLE 28 4- (2-Phenyl-4-quinazolinyl) -carbonyl-morpholine was prepared as in Example 24 starting from 3.1 g of ethyl 2-phenyl-4-quinazolinecarboxylate, 2 ml of morpholine, 15 ml 1.6 M solution of butyl lithium in hexane and 20 ml of tetrahydrofuran. After recrystallization from ethanol, 3 g of 4- - (2-phenyl-4-quinazolinyl) -carbonyl - -morpholinal melting at 148 C. are obtained.
    EXAMPLE 29 1- (2-Phenyl-4-quinazolinyl) -carbonyl-4-piperidinol is prepared as in Example 24, starting from 2 g of ethyl 2-phenyl-4-quinazoline carboxylate, 1, 4 g of 4-piperidinol, 18 ml of a 1.6 M solution of utility in. hexane and 30 ml of tetrahydrofuran .. After recrystallization from a mixture of methanol and methylene chloride, 2.1 g of 1- (2-phenyl-4-quinazolinyl) -carbonyl-4-piperidinol is obtained, melting at 209 C.
    EXAMPLE 30 2,3,4,5,6,7-Hexa-hydro-1- ((2-phenyl-4-quinazolinyl) -carbonyl azepine is prepared in Example 24, starting from 3 g ethyl 2-phenyl-4-quinazoline carboxylate, 2.8 ml of 2,3,4,5,6,7-hexahydro-azine, 15 ml of a 1.6 M solution of butyl lithium in hexane and 20 ml of tetrahydrofuran. After recrystallization from ethanol, 2 g of 2,3,4,5,6,7-hexahyd-po-, LD2-phenyl-4-chinazolinyl) -carbo-ynyl-azepine, melting at 140 ° C, are obtained.
     EXAMPLE 31 4-Methyl-1- (2-phenyl-4-quinazolinyl) -carbonyl-piperidine was prepared as in Example 24, starting from 3 g of ethyl 2-phenyl-4-quinazoline-carboxylate, 2 , 95 ml of 4-methyl-piperidine, 15 ml of a 1.6 M solution of butyl lithium in hexane in 20 ml of tetrahydrofuran. After recrystallization from ethanol, 1 g of 4-methyl-1- - (2-phenyl-4-quinazolinyl) -carbonyl - -piperidine is obtained, melting at 138 C.
     ,
    . PRI me R 32. Methyl-1- (2-phenyl-4-quinazolinyl) -carboxy-13-piperidir is prepared as in Example 24 from the
    SOSO12
    from 3: ethyl-2-phenyl-4-quinazoline carboxylate, 3 ml of 3-methyl-piperidine, 15 ml of a 1.6 M solution of butyl lithium in hexane and 20 ml of tetrahydrofuran. After recrystallization from diisopropyl ether, 1 g of 3-methyl-1- (2-phenyl-4-quinazolinyl-carbonyl-piperidine, melting at.
    EXAMPLE 33. 2-Methyl-1- (2- -phenyl-4-quinazolinyl -carbonyl-piperidine was prepared as in Example 24, starting from 3 g of ethyl 2-phenyl-4-quinazoline-carboxylate, 3 ml 2 -methyl-piperidine, 15 ml of a 1.6 M solution of butyl lithium in hexane and 20 ml of tetrahydrofuran. After recrystallization from ethanol, 1.7 g of 2-methyl--1 - (2-phenyl-4-quinazolinyl) -carbonyl - piperidine, melted at 150 ° C,
    EXAMPLE 34 1-C2-Phenyl; -4-quinazolinyl-carbonyl-3-piperidine-methanol was prepared according to Example 24 starting from 3 g of ethyl 2-phenyl-4-quinazo-lincarboxy, lat, 2.9 g of 3-piperidine-methanol, 31 ml of a 1.6 M solution of butyl lithium in hexane and 20 ml of tetrahydrofuran. After recrystallization from ethyl acetate, 1 g of 1- (2- -phenyl-4-quinazolinyl) -carbonyl -3- -piperidine-methanol is obtained, melting ave. Pr 142 ° C.
    PRI me R 35. Preparation of N, N-diethyl-6-chloro-2-4-chloro-phenyl-4-quinoline-carboxamide.
    To 3 ml of diethylamine in 15 ml of anhydrous tetrahydrofuran, 12.5 ml of a 1.6 M solution of butyl lithium hexane are added at room temperature and under nitrogen. After stirring for 1 hour, cool to -65 ° C, then 3.4 g of ethyl 6-chloro-2-4-chlorophenyl-4-quinoline carboxylate are slowly added to 15 ml of tetrahydrofuran. Stir for 2.5 hours at -65 ° C, then add 4 ml of glacial acetic acid, leave the oHHyio reaction mixture so that the temperature of the medium rises to 50 ml of water and leave the temperature to rise to room temperature. Evaporate tetrahydrofuran, extract the insoluble part 3 times with 50 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure.
    13
    The residue obtained is chromatographed on silica gel with cyclohexane: chloroform (50:50) as eluant. After recrystallization from ethyl acetate of the thus obtained crude product, 1.1 g of N, N-diethyl-6-hlop-2- | 4-chlorophenyl-4-quinoline carboxamide, melted at 173 ° C.
    Ethyl 6-chloro-2-4-chlorophen-1-sh-4-quinolinecarboxylate can be obtained by the action of ethanol on 6-chloro-2-4 chlorophenyl-4-hlnolinecarboxylic acid in the presence of concentrated sulfuric acid. It has a mp. .
    6-Chloro-2-4-chlorophenyl 4 quinoline-. carboxylic acid can be synthesized according to a known method.
    EXAMPLE 36. U, K-Diethyl-2-3-β-chlorophenyl-4-quinolinecarbox mid is prepared as in Example 35, starting with 4.3 ml of diethylamine, 20 ml of a CB of M solution of bu-, tillity in hexane and 3 , 2 g methyl 2
    slot in
    the presence of concentrated sulfuric acid. It has a mp. 74 C.
    4-dichloro-phenyl-4-quinoline-5 carboxylic acid can be obtained by a known method.
    EXAMPLE 38 H, K-Diethyl-2- 2-α-fluorophenyl-4-quinolinecarboxamide was prepared as in Example 35 starting from 10 27 M.L diethylamine, 12.5 ml of a 1.6 M solution of butylity in hexane and 2 g of ethyl 2- 2-fluorophenyl-4-quinolinecarboxyl. After recrystallization, the residue from IS diisopropyl ester was isolated with 2 g of N, N-diethyl-2-2-fluorophenyl-4-quinoline-carboxamide, melting at 92 ° C,
    ETSh1-2-2-fluoro-phenyl-4-quinolinecarboxylate can be obtained by the action of ethanol on 2-2-fluoro-phenyl-4-quinolinecarboxylic acid in the presence of concentrated sulfuric acid. It has a mp. 86 p. 2- 2-Fluorophenyl-4-quinolinecarbo 30
    - 3-chlorophenyl-4-quinolinecarboxylate. 25 novol acid can be obtained. Then 3.4 g of H5K-dietary 1-2-2-3 chlorophenyl-4-quinoline-carboxamide is obtained, which is converted to its hydrochloride by adding a solution of hydrochloric acid in diethyl ether to the solution of the product in acetone. After recrystallization from ethanol: diethyl ether (.2: 1), this hydrochloride has a mp. ,
    Methyl-2-3-chlorophenyl-3-quinolinecarboxylate can be obtained by the action of methanol on 2-3-chloro-chloro, bc-quinolinecarboxylic acid in the presence of concentrated sulfuric acid. It has a mp. 101 (.
    2-3-Chlorophenyl-4-quinoline-carboxylic acid can be obtained by a known method:
    Example 37, K, K-Diethyl-2 3,
    35
    40
    by a known method.
    PRI me R 39. Getting - (2-chlorophenyl) -4-quinolyl-carbonyl | - -2,6-dimethylpiperidine.
    5.7 g of 2- 2-chlorophenyl-4-quinolinecarboxylic acid and 15 ml of thionyl chloride are refluxed for 1 hour. The chloride is evaporated, the residue is treated with 40 ml of toluene and again evaporated.
    Then 50 ml of toluene are added to the residue, after which 6.78 g of 2,6-dimethyl-β-piperidine is added dropwise with stirring. The mixture is stirred at room temperature for one hour, the precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue is treated with 50 ml of water and 50 ml of chloroform.
    4-dichlorophenyl-4-quinolinecarboxamide,. The organic phase is decanted and fed according to example 35 from 5 ml of diethylamine, 23 tons of 1.6 M solution of butyl lithium in hexap and 4 g of ethyl -2-13,4-dichlorophene-4-quinolinecarboxyl. After three recrystallisations of the residue from isopropanol, 2.5 g of N, N-diethyl-2- 3,4-dichlorophenyl-3 4-quinoline-carboxy No. was melted at 170 ° C,
     3,4-Dichlorophenyl 4-quinoline-carboxylate can be obtained by the action of ethanol on 4-dichlorophenyl-4-quinoline-carboxylic acid50
    55
    The new phase is extracted with 50 ml of chloroform. The organic phases are combined, dried over magnesium sulphate and evaporated under reduced pressure.
     - - - After recrystallization of the obtained isp-atka from ethyl acetate, I obtain 3.8 g of 1- 2- (2-chlorophenyl) -4-quinoline. -carbonyl -2, b-dimethyl-piperidine, melt at 163 C.
    PRI me R 40. Preparation of K, M-diisobutyl-2-2-chlorophenyl-4-quinolinecarboxamide.
    ,
    55050
    slot in
    14
    the presence of concentrated sulfuric acid. It has a mp. 74 C.
    4-dichloro-phenyl-4-quinoline-5 carboxylic acid can be obtained by a known method.
    EXAMPLE 38 H, K-Diethyl-2- 2-α-fluorophenyl-4-quinolinecarboxamide was prepared as in Example 35 starting from 10 27 M.L diethylamine, 12.5 ml of a 1.6 M solution of butylity in hexane and 2 g of ethyl 2- 2-fluorophenyl-4-quinolinecarboxyl. After recrystallization, the residue from IS diisopropyl ester was isolated with 2 g of N, N-diethyl-2-2-fluorophenyl-4-quinoline-carboxamide, melting at 92 ° C,
    ETSh1-2-2-fluoro-phenyl-4-quinolinecarboxylate can be obtained by the action of ethanol on 2-2-fluoro-phenyl-4-quinolinecarboxylic acid in the presence of concentrated sulfuric acid. It has a mp. 86 C. 2- 2-Fluorophenyl-4-quinolinecarbo25 nova acid can be obtained
    new acid can be obtained
    by a known method.
    PRI me R 39. Getting - (2-chlorophenyl) -4-quinolyl-carbonyl | - -2,6-dimethylpiperidine.
    5.7 g of 2- 2-chlorophenyl-4-quinolinecarboxylic acid and 15 ml of thionyl chloride are refluxed for 1 hour. The chloride is evaporated, the residue is treated with 40 ml of toluene and again evaporated.
    Then 50 ml of toluene are added to the residue, after which 6.78 g of 2,6-dimethyl-β-piperidine is added dropwise with stirring. The mixture is stirred for one hour at room temperature, the precipitate is filtered off and the filtrate is ground under reduced pressure. The residue is treated with 50 ml of water and 50 ml of chloroform.
    The organic phase is decanted and water.
    The new phase is extracted with 50 ml of chloroform. The organic phases are combined, dried over magnesium sulphate and evaporated under reduced pressure.
     - - - After recrystallization of the obtained isp-atom from ethyl acetate, 3.8 g of 1- 2- (2-chlorophenyl) -4-quinoline-.-Carbonyl -2, b-dimethyl-piperidine, melting at 163 ° C. are obtained.
    PRI me R 40. Preparation of K, M-diisobutyl-2-2-chlorophenyl-4-quinolinecarboxamide.
    ten
    20
    15125.5050
    2.8 g of 2- 2-chlorophenyl-4-quinolinecarboxylic acid in 10 ml of thionyl chloride are refluxed for 1 hour. Thionyl chloride is evaporated, the residue is treated with 40 ml of toluene and again evaporated. Then 20 ml of toluene is added to the residue obtained and a solution of 5.16 to diisobutyl amine in 20 ml of toluene is added dropwise with stirring. The mixture is stirred overnight at room temperature, evaporated under reduced pressure, the residue is treated with 50 ml of chloroform and 100 ml of water. The organic phase is decanted, dried over magnesium sulphate and evaporated under reduced pressure.
    The resulting residue is dissolved in 100 ml of ethyl acetate, the organic phase is extracted with 100 ml of 1N. acetic acid solution, washed 4 times with 100 ml of water, dried over magrsh sulphate and evaporated under reduced pressure. The resulting residue is treated with acetone and, after adding a solution of hydrogen chloride in ether, 1.5 g of hydrochloride M, K-diisobutyl-2-1 2-chlorofeil-4-quinolinecarboxamide, melting at.
    PRI me R 41. Obtaining zotyl-L-fensh1-2-fenip-4-quinolinecarboxamide,
    To a solution of 12.8 g of N-methylaniline in 75 ml of methylene chloride, cooled to 0 ° C, 10.7 g of 2-phenyl-4-quinoline-carboxylic acid chloride hydrochloride are added in portions with stirring in 15 minutes. Stir for 2 h 30 min at 10 ° C. The resulting solution is washed with 120 ml of a 20% aqueous solution of acetic acid in water. The acetic acid solution is extracted with 100 ml of methylene chloride. The organic phases are combined, washed 3 times with 100 ml of water, dried over magnesium sulfate and evaporated under reduced pressure.
    After recrystallization of the residue from acetonitrile, 9.1 N-me-; ThylH-phenyl-2-phenig-4-quinoline-carboxamide, melting at 141 ° C is obtained.
    35
    40
    45
    50
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    from am
    ti 15 am from yes to re you pr yes
    3, -hi move read you.
    in the dit nol 3,6 x 1380 gold
    -2 chin ben hlo guide sis
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    25
    pla
    PRI me R 42. Getting K, K-dimethyl-2-phenyl-4-quinoline carboxamide,
    To a stirred solution of 18.9 g of M, H-dimethylamine in 100 ml of methylene-55 chloride, cooled to 0 ° C, 10.7 g of 2-phenacid hydrochloride hydrochloride are added in portions within an hour.
    20

    zo
    35
    40
    five
    0
    -4-quinolinecarboxylic acid. The mixture is stirred at 0 ° C. for one hour. The solution is evaporated under reduced pressure. The residue is treated with 100 ml of methylene chloride. The organic phase is washed 3 times with 100 ml of water, dried over magnesium sulphate and evaporated under reduced pressure.
    After recrystallization of the residue from acetonitrile, 7.9 g of N, N-dimethyl-2-phenyl-4-quinoline-carboxamide are isolated, melting at 158 ° C.
    EXAMPLE 43 K-Methyl-Y-G1-methylpropyl -2-phenyl-4-quinoline-15-amide was prepared according to Example 42 starting from 10.7 g of 2-phenyl-4-quinoline-carboxylic acid hydrochloride and 10.5 g of N-methyl-2-butanamine in 75 ml of methylene chloride. After recrystallization from acetonitrile, 10.1 g of N-methyl-N-methyl-propyl 2-phenyl-4-quinoline carboxamide, melting at 146 ° C., are isolated.
    Example 44. 2-Phenyl-4- (, 2, 3,6-tetrahydro-1-pyridyl) -carbonyl - -quinoline is assigned according to example 41 from 10 g of 1,2,3,6-tetrahydropyridine in 75 ml methylene chloride and 2 phenyl-4-quinolinecarboxylic acid.
    The resulting base is dissolved in diethyl ether, then converted to its hydrochloride by adding a solution of hydrochloric acid in ethanol. After recrystallization from ethanol, 7 g of 2-phenyl-4- (1,2, 3,6-tetrahydro-1-pyridyl) -carbonyl-quinoline is isolated as the hydrochloride having a fuzzy melting point between 130 and 140 ° C.
    EXAMPLE 45 N-Benzyl-M-methyl--2-phenyl-4-quinoline-carboxamide was prepared according to Example 41, starting from 14.5 g of benzylmethylamine in 100 ml of methylene chloride and 9.1 g of 2-phenyl hydrochloride -4-quinolinecarboxylic acid.,
    After recrystallization from acetonitrile, 7 g of K-benzyl-N-methyl-2-phenyl-4-quinoline-carboxamide are isolated.
    25
    five
    melt at 106-110 C.
    Example 46. N-Cyclohexyl-N- -metsch1-2-phenyl-4-quinoline carboxamide is prepared as in Example 41 starting from 9.1 g of 2-feiyl-4-quinoline-carboxylic acid hydrochloride and 13.5 g of W-methyl-cyclohexylamine per 100 ml of methylene chloride.
    After recrystallization of | Ai from acetyltryl, 9.3 g of K of cyclohexes1 of K-methyl 2-phenyl-4-quinolinecarb-, the melt of p1egos are obtained. at.
    Group 47, Preparation of N-etyl-5 N- (4 piperidyl) methyl -2-feiyl 4 -quinolinecarboxamide.
    To a stirred solution of 9.1 g of 2-phenyl-4-quinoline-carboxylic acid chloride and 8.4 ml of triethylamine-10 per 100 ml of toluene, a solution of 7 g of N-ethyl-1-benzyl- is added slowly at room temperature. 4-piperidyl-J-methanamine in 50 ml of toluene. The mixture is stirred for 1 hour at room temperature. The reaction mixture is poured into 100 ml of water, the toluene is evaporated under reduced pressure, then 200 ml of ether are added, the organic phase is decanted, the aqueous phase is extracted with 100 ml of ether The organic cell phases are combined, and they are mixed 2 times with 50 ml of aq., Then they are extracted 3 times with 20 ml of an aqueous 2n solution of hydrochloric acid. The aqueous, acidic 25 phase is washed with ether, adjusted to pH 10 with addition of a condensed solution of sodium hydroxide and extracted 3 times with 150 ml of ether. The ether phase is nicknamed 3 times with 30 ml of water and is heated at a reduced pressure. Then get 12. g No. - ethyl H - (l-benzyl ™ 4-pipera - dil) - letil l -2 phenyl 4-quinolinecarbox-amide a.3, j
    Dibenzylation is carried out as follows.
    To dissolve, 9.6 g (4-g1-inidis1) -methyl 2-phenyl-4-quinolinecarboxamide (200 np ethanol) is dissolved to dissolve. After cooling, 9.2 ml of 4.5 N is added to this solution. ethanol solution of hydrochloric acid, 2.9 g containing 10% pale coal as a catalyst, and 1.7 g sodium acetate. 1 Id1-1p y from under stirring at a hydrogen pressure equal to the normal pressure ™, Lensho (i bar) for 5 hours, According to a flow of 5 hours (then the number of absorbents: hydrogenated hydrogen will be 470 ml) the catalyst is removed by filtration; the solvent is ethanol distilled off under reduced pressure, the residue is treated with 200 MP of water, adjusted to pH 55 with 10 by adding concentrated sodium hydroxide solution and extracted 3 times with 100 im ether. The organic phase is washed 3 times with 50 ml of water, dried over magnesium sulphate and evaporated under reduced pressure. In this way, 5 g of N-ethyl-N- (4-piperidyl) -methyl -2-phenyl-4-quinoline-carboxamide is obtained, which is dissolved in acetone and converted into monohydrochloride by adding a solution of hydrochloric acid in ether. This mono-chlorine hydrate has t, units, 219 C,
    K-Ethyl-1-benzyl-4 piperidyl-methane amine can be obtained by reduction of N-ethyl-1-benzoyl-4-piperidine carboxamide (310 mol) with lithium aluminum hydride (6 X 1.0 mol) in 100 ml of tetrahydrofuran wound,
    Ethyl-1 benzoyl-4-piperidinecarboxazoamide can be obtained by the action of thionyl chloride (6, mol) on 1-benzoyl-4-piperidinecarboxylic acid (4.5) in 100 ml of chloroform and by reaction of the acid chloride thus obtained with 0, 22 moles of ethylamine in 30 ml of toluene,
    1 Benzoyl-4-piperidinecarboxylic acid can be obtained by exposing bsnzoyl chloride (0.85 mol) to 4-piperidinecarboxylic acid (O (, 85 mol) in the presence of 10% potassium carbonate solution (3300 ml) This product is 1- 1meet t, pp,,
    PRI me R 48, Getting N-ztil-N 4-piperidyl -2-fensh1-4-quinoline carboxam.ida,
    To a stirred suspension of 17.5 g of phenyl-4-xnolyn-carboxylic acid chloride 2 in 250 ml of toluene are added slowly 16 ml of triethnlamine; then for 30 minutes a solution of 125.6 g of N-ethyl-1-benzine 4 piperidine amine in .50 ml of toluene. Stir at room temperature for 4 hours.
    The reaction medium is poured into 250 ml of water, the toluene is evaporated by distillation under vacuum and 200 Nm diethyl ether is added. The organic phase is decanted, the aqueous phase is extracted with 2 times 200 ml of dizti-new ether. The organic phases are combined, d.alc., 2 times with 50 ml of water, dried over magnesium sulfate and concentrated by distillation under reduced pressure. The residue is chromatographed on silica gel using; as eluant. a mixture of toluene: di-ethylamine (9: 1), thus semi19
    25 g of N-3TH.n-N-fl-beisyl-A-peep rndyl 2-phenip-D quinolinecarboxamide;
    Debenzylation is carried out as follows.
    To the transferred solution of 17 g of N-STun-N-1-benzyl-4-piperidyl1-2-phenyl-4-quinoline-carboxamide in 340 ml of toluene was added 8 g of 2,2,2-trichloro-ethyl chloroformate. The mixture is heated under reflux for 6 hours, another 1.6 g of 2,2,2-trichloroethyl chloroformate is added and the mixture is heated under reflux for 2 hours. The reaction mixture is poured into 300 ml of water, alkalinized with aqueous 2 and, sodium hydroxide solution, and extracted 3 times with 150 ml of ethyl acetate. The organic phase is washed with 2 times 50 ml of water, dried over magnesium sulphate and concentrated under reduced pressure.
    To the resulting oil was added 450 ml of ethanol, then 200 ml of aqueous 6N potassium hydroxide solution. The mixture is stirred for several minutes, then heated under reflux with stirring for 6 hours. After evaporation of the ethanol under reduced pressure, the reaction mixture is treated with 300 ml of water, then 180 ml of aqueous bn. hydrochloric acid solution and extracted 3 times with 200 ml of chloroform. The organic phase is washed with 2 times 50 ml of water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel using toluene: methanol: diethylamine (9: 1: 1) as the zlutant. Thus, 3.3 g of N-ethyl-N-4-piperidyl -2-phenyl-4-quinoline are isolated. - carboxamide.
    This compound is dissolved in ethanol, then converted to monohydrochloride by adding a solution of hydrochloric acid in ether. The monochlorohydrate has a melting point above 250 C.
    N-Ethyl-1-benzyl-4-piperidinamine can be obtained by reducing H-acetyl-1-benzyl-4-piperidinamine (6.4-10 mol) with lithium aluminum hydride (0.128 mol) in 200 ml of tetrahydrofuran. N-Anethyl-1-benzyl-4-piperidine amine can be obtained by the action of acetyl chloride (1.1510 mol) on 1-benzyl-4-piperidinamine (1.05 h
    ZZPTO;)
    to 10 miles) in 100 ml x.; 1 formformal n sug / guvium with triethyla a (1.03-10 mol).
    I p-meper 49. M - Ethyl-H- 2- (4- -piperidyl) ethyl -2-phenyl-4-quinoline-5 carboxamide.
    To a stirred suspension of 8.3 g of 2-phenyl-4-quinoline-carboxylic acid chloride in 50 ml of toluene are added 6.7 ml of triethylamine, then 0 within 30 minutes a solution of 6 g of N-ethyl-1-benzyl-4- piperidyl-ethanamine in 50 ml of toluene. Stir for 20 hours at room temperature. Pour the reaction mixture into 100 ml of water, evaporate the toluene by distillation under reduced pressure, treat with 200 ml of diethyl ether, add 0.8 ml of triethylamine. The organic phase is decanted, the aqueous phase 20 is extracted with 2 times 100 ml of diethyl ether. The organic phases are combined, washed 2 times with 30 ml of water, dried over magnesium sulphate and evaporated under reduced pressure. Cs-25 chromatographic on silica gel, using as eluant, a mixture of cyclohexane: diethylamine (9: 1). Thus, 9.7 g of N-ethyl- -N-2-1-benzyl 4-piperidyl-ethyl-0 -2-phenyl-4-quinoline-carboxamide are obtained.
    Debenzylation is carried out as follows.
    To a stirred solution of 5.8 g of N-ethyl-N-2-l-benzyl-4-piperidyl-5-ethyl-2-phenyl-4-quinoline-carboxamide in 100 ml of toluene was added 2.6 g of trichloro-ethyl chloroformate. The mixture is heated under reflux for 1 hour. The reaction mixture is poured into 100 ml of water, alkalinized with aqueous 2N. sodium hydroxide solution and extracted with 3 times 100 ml of ethyl acetate. The organic phase is washed with 2 times 30 ml of water, 5 is dried over magnesium sulphate and vacuum under reduced pressure.
    To the resulting oil was added 150 ml of ethanol, then with stirring 64 ml of aqueous 6N. potassium hydroxide solution. The mixture is heated at reflux temperature for 2 hours and then stirred at room temperature for 15 hours. 100 ml of water are added to the reaction medium.
    5, ethanol was evaporated by distillation under reduced pressure, another 100 ml of water was added, then extracted 3 times with 150 ml of diethyl ether and 150 ml
    21
    methklenchloride. The organic phases are combined, extracted 4 times with 25 ml of water each time, with acetic acid solution. The acetic phase is adjusted to pH 10 by the addition of aqueous 2N. sodium hydroxide solution and extracted again 3 times with 50 ml of methylene chloride. The organic phase is washed with 30 ml of water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel using toluene-diethylamine (9: 1) as eluant. 2.2 g of K-ethyl-K-2- (4-piperidyl) -ethyl -2-phenyl-4-quinoline-carboxamide are thus isolated. This compound is converted to ethanol in its
    . monohydrochloride. The latter has about
    T.SH1. equal to 210 C.
    Ethyl-1-benzyl 4-piperidyl-ethane-amine can be obtained by reducing N-ethyl-1-benzoyl-4-pyperidyl-acetamide (2.9 mol) with aluminum hydroxide (5.8-10 mol) in 100 ml of tetrahydrofuran.
    K-Ethyl fl-benzoyl-4-piperidyl-β-acetamide can be obtained by exposure to thionyl chloride (δ 10 mol) to: (1-benzoyl-4-piperidyl) acetic acid (4 10 mol) in 100 ml of chloroform and by exposure in this way the acid chloride obtained per 0.2 mol of ethylamine in 130 ml of toluene,
    (1 -Benzoyl-4-pi1Gleridyl) -acetic acid can be obtained by the action of benzoyl chlord (1.2-10 mol) on the potassium salt of (4-piperidyl) acetic acid (10 mol) at 0 ° С in water (100 ml ). Ong has a mp.
    Example 50. N-ethyl-Nl; 3- (4- -piperidyl) -propyl -2-phenyl-4-quinoline-carboxamide is prepared according to example 48 from 32 g of 2-phenyl-4-quinopine carboxylic acid chloride in 250 ml of toluene, 12.3 ml of triethylamine and 11.4 g of M-ethn-1 - (-bench-1 -4-pt7eridyl) -lropanamine in 50 ml of toluene. Thus, 21 g of H-ztil-H-3- (1-benzyl-4-piperidyl) - -proyl 3 -2 phenyl-quinoline-carboxamide are obtained.
    Debenzylation was carried out as in Example 48, starting from 21 g of N- -ethyl-N-3-1-benzyl- (4-piperidyl) - -prop-2-phenyl-4-quinolinecarboxes
    d in 400 ml of toluene j 9 g of 2,2,2-trichloro-ethyl chloroformate, then 245 ml of aqueous 6N. hydro12 solution



    55050 22
    potassium hydride in .50 ml of ethanol. After chromatography of the residue on the sylcagel using toluene: diethylamine (9: 1) as the eluant, you are 5, 10 g of N-methyl-N-f3- (4-piperidyl) -propyl -2-phenyl- 4-quinolinecarboxamide, which is converted in ethanol to its methanesulfonate by the addition of an ethanolic solution of methanesulfonic acid. Methanesulfonate has. m.p. . N-ethyl-1-benzyl-4-pyperidyl-propanamine can be obtained by reduction of N-ethyl-1-benzoyl-4-piperidyl-propionamide (3.4
    15/10 mol) with lithium aluminum hydride (6.9) in 200 ml of tetrahydrofuran.
    N-ethyl-1-benzoyl-4-piperidyl-β-propionamide can be obtained by the action of thionyl chloride (8.610 mol) on (1-benzoyl-4-piperidyl) propionic acid in 150 ml of chloroform, and by the action of the chloride thus obtained acid to 2.85 mol
    25 ethylamine in 150 ml of toluene.
    N-Benzoyl-4-piperidine propanoic acid can be obtained by a known method. ,
    Example 5 Preparation of N-methyl 30 Tyl-N-P-methylpropyl-3-phenyl-1-iso

    quinolinecarboxamide.
    1.1 g of triethnlamine are added to 2.4 g of 3-phenyl-1-isoquinoline-carboxylic acid in 100 ml of chloroform. Cool to 10 ° C and add 1.21 g of ethyl chloroformate. After stirring for 40 minutes, 1.1 g of H-mets-1-2-butanamine are added and the mixture is stirred at room temperature for 4 hours. The organic phase is washed with aqueous saturated sodium carbonate solution, dried over magnesium sulfate and evaporated under reduced pressure to dryness. The residue is chromatographed on silica gel with cyclohexane: ethyl acetate (7: 3) as eluant and the recovered product is recrystallized from diisopropyl ether. Thus, 1.36 g of K-methyl-K-1-methylpropyl-3-phenyl-1-oquinoline-carboxamide are obtained, melting at 125 ° C. after recrystallization from diisopropyl ether,
    Z-Phenyl-1-isoquinolinecarboxylic acid can be obtained from 1- -methyl-3-phenyl-isoquinoline, using N-bromosuccinimide, first semi-23
    1-dibromomethyl-3-phenyl-isoquinoline is prepared, which is then oxidized with silver nitrate, first in neutral medium, then in basic medium. This acid has a mp. 134 °
    PRI me R 52, Getting - (2-phenyl-4-quinazoline) -carbonyl 4-β-piperidine-ethanol.
    1.7 g of ethyl-phenyl-4-quinazoline carboxylate and 8 g of 4-piperidine-ethanol are heated at 150 ° C for 4 h. After ohg: averages are added water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel with ethyl acetate as eluant and the recovered product is recrystallized from diisopropyl ether. The product is obtained 0.5 g of - (.- -phenyl-4-hknazolinyl) -carbon-4-4-piperidine ethanol, melting at 14b ° C.
    EXAMPLE 53. Preparation of 1- (2- -phenyl-4-quinazolinyl) -carbonyl-4- -piperidinone.
    I, m
    Under an atmosphere of nitrogen and at O C, 37 ml of a 1, 6 M solution of butyl lithium in hexane are not added to 7.5 ml of 1,5-dioxa-8-aza-spiro (4,5) -decane in 30 ml of anhydrous tetrahydrofuran. . After 30 minutes, ethyl b is added to g of 2-phenyl-4-quinazolinecarboxylate as a solution in 30 ml of anhydrous tetrahydrofuran. After 2 hours at room temperature, water is added and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is treated with 100m of acetone and 20 ml of concentrated hydrochloric acid and stirred for 5 hours at room temperature.
    Dilute with water, extract the aqueous phase with methylene chloride, wash the organic phase with 1N. Sodium hydroxide solution, then with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. 1 g of product is obtained which is chromatographed on silica gel using a mixture of toluene di-ethyl; amine (95: 5) as eluant. 4.5 g of product is recovered, which is recrystallized from a mixture of cyclohexane ethyl acetate (1: 1). So about505024
    2.3 g of 1-C2-phenyl-4-quinazolinyl -carbonyl-4-piperidinone, melting at 161 C, is obtained at once,
    EXAMPLE 54 M, K-Diethyl-2-phenyl-8-trifluoromethyl-4-quinoline-carboxamide is prepared according to Example 4 from 10 g of 2-phenyl-8-trifluoromethyl-4- quinoline carboxylic acid, 30 ml of thionyl chloride and 16.2 ml of diethyl 0 amine.
    After chromatography on silica gel with a mixture of cyclohexane: ethyl acetate (70:30) as eluant and recrystallization from a mixture of diiso-15 propyl ether and petroleum ether (8: 3), 9.2 g of N, N-diethyl -2 -fensh-1-8-trifluorometsh-1-4-quinoline-carboxamide, melted at 114 C, 2-Phenyl-8-trifluoromethyl-4-quinoline-20 carboxylic acid can be obtained by a known method.
    The data of elemental analysis are given in the table.
    Pharmacological properties. The means to the receptor sites of the benzo-diazepins are measured by the ability of the products to replace tritium-containing diazels (H-diazepam) in its region (the binding site is expressed in 0 by the Kj value in micromol (dM), which is calculated using the formula LC,
    t
    -5T)
    0
    five
     .1 + C / Kj,
    5 where C is the concentration used
     n-diazepam;
    Kj is an affinity constant characteristic of diazepam. LCjg is the concentration of product that is necessary to obtain 50% inhibition of H-diazepam binding. The affinity of the compounds of the formula I to the receptor receptors of the benzodiazepines is determined on rat brain membranes by the method of MOHLER et al
    The affinity of the compounds of the formula T for receptor sites of the peripheral type is determined on rat kidney membranes.
    The following results were obtained: Affinity for receptor sites of the recust type Products by K; (| cm) for example
    10.05
    30.16
    0
    25
    40, OA
    50.09
    110.13
    240.33
    250.39
    260.09
    270.07 380.31 490.40. 530.27
    Chlordiazepoxides .0.08
    Affinity for receptor cells of the peripheral type
    Products by example
    eight
    ten
    15
    sixteen
    17
    18
    20
    21
    22
    37
    39
    43
    five . Diazepam
    K; (c, M)
    Ro-5-4864
    0,117 0,160 0,031 0,072 0,009 0,360 0,002 0,058 0,270 0,117 0.05 0,100 0,045 0,043 0,004
    Toxicological properties. The residual toxicities of the compounds of formula I were determined orally in the male mouse. LDjQ was calculated after three days of observation by the cumulative method of J.J.REED Mohleretal.
    The compounds of the formula I behave as relatively toxic substances with respect to the mouse, since the LDj0 of the compounds is 200-1000 mg / kg.
    Therapeutic use. The proposed medicinal products containing a compound of formula I or a mixture of stereoisomeric compounds are in accordance with formula I, or the salt ta 1255050
    26
    Any compound or mixture of stereoisomeric compounds with a pharmaceutically compatible acid associated with a pharmaceutically acceptable excipient can be used in human therapy for treating anxiety and lung, renal, cardiovascular or circulatory disorders. They may be filled in the form of tablets, capsules, gelatin capsules, suppositories, solutions for injection or for oral administration, etc.
    The dosage depends on the desired effects and the route of administration used. For example, orally, it can be 10-500 mg of active substance per day with unitary doses, up to 2-100 mg of active substance. Affinity for cerebral receptor centers
    Compounds of K; (shchM) example
    20.39
    70.49
    131
    230.17
    281
    290.64 320.43
    341.05
    360,57
    500,52
    Affinity for Peripheral Receptor Centers
    Compounds K (luM)
    for example
    190.90
    290.90
    300.54
    311.44
    320.38
    330.33 360.29
    440.90
    450.21
    461.62 522
    27
    99.7 99.8
    99.6
    100.3
    100.4
    100.2
    99.7
    99.9
    99.5
    99.6
    100.2
    99.0
    99.6
    99.3
    99.4
    99.4
    20
    2
    22
    23 24
    100.0 100.3
    125505П28
     Table continuation
    Calculated: C 65.59i H 5.47; N 13.50 - O 5.141 S 10.29 Found: C 65.4; H 5.5; N 13.4; O 5.2, S 10.3
    Calculated: C 83.17; H 6.93; N 4.62, O 5.28
    Found: C 83.2; H 6.9; N 4.5; About 5.5
    Calculated: C 83.28 J H 7.26 N 4.42; About 5.05
    Found: C 83.2; And 7.3, N 4.4 O 5.2
    Calculated: C 67,16; H 5.30, N 12.37; Ct 10.46. Found: C 66.9i and 5.3 N 12.4; From 10.6
    one
    t g ;;;;;;;;; ;
    99.7
    Calculated: C 67.74, H 5, P {
    N 7.53; F 15.32
    Found: C, 67.5; H 5.1 N 7.4, F 15.2
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING RACEMIC OR STERIOISOMERIC DERIVATIVES OF NAPHTHALINE- OR AZANAFTALINKARBOKSAMIDOV of the general formula I where A and B are nitrogen;
    R f is a linear or branched C ( -C 6 alkyl group, 'phenyl group, C 3 -C 6 cycloalkyl group, phenylalkyl group, the alkyl part of which contains 1-3 carbon atoms;
    R <is a linear or branched C, C 6 alkyl group, phenyl group, C 3 C 6 cycloalkyl group, phenyl alkyl group, the alkyl part of which contains 1-3 carbon atoms, or a group where n = 0,1,2 or 3;
    R (and R 2 , in addition, can form together with the nitrogen atom to which they are connected, a heterocyclic radical with 5, 6 or 7 units, which may contain another heteroatom selected from nitrogen and oxygen, and carry one or two substituents, selected from C ( -C e -alkyl groups, hydroxy groups, oxo groups and hydroxyalkyl groups, the alkyl part of which contains 1-3 carbon atoms;
    Z is a phenyl group, pyridyl, thi-azolip-2-or phenyl group substituted with one or two substituents taken from halogen atoms, C ^ -C 5 -alkyl, C ( -Cj-alkoxy and trifluoromethyl groups',
    X and Y are hydrogen or halogen, C f -C s alkyl group, nitro or trifluoromethyl group;
    or A is a group CHJ B is nitrogen; X, Y, Z, R ( and R 7 have the indicated meanings;
    either A and B are CH groups; R) is a linear or branched C 2 -C 6 alkyl group, phenyl, C ^ -C G cycloalkyl, phenylalkyl group, the alkyl part of which contains 1-3 carbon atoms;
    R 2 is a linear or branched C ( -C 6 alkyl group, phenyl, C 9 -C b- cycloalkyl, phenylalkyl group, the alkyl part of which has 1-3 carbon atoms, or - (εΗ 2 ) η -θΝ-Η.№ η has the indicated values 1 ,
    SU w, 1255050 AZ
    R ( and R 2 can also, together with the nitrogen atom to which they are attached, form a heterocyclic radical with 5, 6 or 7 units, which may contain another heteroatom selected from nitrogen and oxygen, and carry one or two substituent selected from C 4 -C 5 -alkyl groups, hydroxy-, oxo-, hydroxyalkyl groups, the alkyl part of which contains 1-3 carbon atoms', Z, X and Y have the indicated values *, either A is nitrogen; B is the group CH} Z, X and Y have the indicated meanings; R <“phenyl group, C, -C 6 cycloalkyl, phenylalkyl group, the alkyl part of which is holds · 1-3 carbon atoms} R 2 - phenyl group, C ^ -C 6 cycloalkyl, phenylalkyl group, the alkyl part of which contains 1-3 carbon atoms, or η DG and has the indicated values}
    R <and R 2 can, in addition, form together with the nitrogen atom to which they are attached pyrrolidinyl, piperidine morpholine, 1,2,3,6-tetra. Hydropyridyl, 2,3,4,5,6,7- hexahydroacetinyl, 4-oxo-piperidine or piperidin radical substituted with one or two C ( -Se apkyl groups, or a hydroxy group at position 3 or 1 4, a hydroxyalkyl group, the alkyl part of which contains 1-3 carbon atoms} or R ( and R 2 may be different C, -C ^ -alkyl groups, but with the fact that to obtain a compound of formula 1, where A, B, R ( , R 2 , X, Z and Y have . The indicated values carry out eaktsiyu amine of general formula II
    Hn
    with a compound of formula III Χ ^ ΊΓ CO — W Av A 'where X, Y, Ζ, A, B, Rf and R have
    indicated values;
    W is an alkoxy group with lower alkyl, chlorine or an alkoxycarbonyloxy group with lower alkyl, and to obtain a compound of formula T, where A, B, X, R have the indicated meanings — group — there is an amine reaction of general formula IV —Cy ' K_CH 2 C 6 H 5 'with a compound of the formula V where X, Y, <, η have the indicated meanings;
    W is a lower alkyl alkoxy group, chlorine or a lower alkyl alkoxycarbonyloxy group, and the thus obtained compound is subjected to debenzylation.
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    同族专利:
    公开号 | 公开日
    ES528364A0|1985-01-01|
    DE3372579D1|1987-08-27|
    NO834798L|1984-06-25|
    EP0112776B1|1987-07-22|
    FR2538388A1|1984-06-29|
    JPS59219260A|1984-12-10|
    PT77886A|1984-01-01|
    DK596483A|1984-06-25|
    US4684652A|1987-08-04|
    AU2277683A|1984-06-28|
    AU575797B2|1988-08-11|
    ES8502433A1|1985-01-01|
    GR82358B|1984-12-13|
    AT28401T|1987-08-15|
    EP0112776A3|1984-09-12|
    EP0112776A2|1984-07-04|
    IL70528D0|1984-03-30|
    FR2538388B1|1985-06-21|
    CA1225992A|1987-08-25|
    HU191745B|1987-04-28|
    MA19982A1|1984-07-01|
    ZA839576B|1984-08-29|
    US4711890A|1987-12-08|
    DK596483D0|1983-12-23|
    PT77886B|1986-04-09|
    IL70528A|1987-01-30|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8221758A|FR2538388B1|1982-12-24|1982-12-24|NOVEL NAPHTHALENE- OR AZANAPHTHALENECARBOXAMIDE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS|
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