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    • 专利摘要:
    The method of producing carboxylic acid amides of the general formula PV HA — CH — CO — CH 2 / RI NR where R and R together with the nitrogen atom form an alkylenimino group with 4-5 carbon atoms, which can be substituted by one or two methyl groups, or in which one a methylene group may be substituted by a carbonyl group, or in which one ethylene group may be a zo-phenylene group, an alkenylamino group with 4-6 carbon atoms, a saturated or partially saturated azabicycloalkyl group with 6-10 carbon atoms, heptamethyl- imino-, ok ametilenimino-, nonametilenimino- or dekametilenimino- group; R, is a hydrogen or halogen atom or methyl I A — methylene or ethylene, unsubstituted or substituted by methyl, ethyl or isopropyl, methoxycarbonyl, carboxyl or phenyl, or etheville; V is methyl, unsubstituted or substituted by OXI, carboxy or alkoxycarbonyl group containing only 2-4 carbon atoms; (dimethyldixolanine) methoxycarbonyl or carboxyl group and its alkyl esters containing 1-4 carbon atoms in the alkyl part, or their optically active antipodes or their sodium salts, characterized in that the compound of the general formula § O) Where A and R RO has the indicated meanings or if A is ethenyl, its tautomer or its. complex with a magnesium halide, is reacted with a carboxylic acid of the general formula HOOC-CH2, where W. has the meanings for W or not: it denotes or denotes a carboxyl group protected by benzyloxy group or its anhydride or acid halide in an organic solvent in the presence of
    公开号:SU1253429A3
    申请号:SU3369254
    申请日:1982-01-06
    公开日:1986-08-23
    发明作者:Грелл Вольфганг；Грисс Герхард；Заутер Роберт；Хурнаус Рудольф；Руппрехт Экхард；Каубиш Николаус；Кэлинг Йоахим
    申请人:Др.Карл Томэ Гмбх (Фирма)；
    IPC主号:
    专利说明:

    activator selected from the group consisting of N, N -carbonyldinimidazole, triphsnilphosphine, thionyl chloride and triethylamine followed, if necessary
    The invention relates to the synthesis of new biologically active chemical compounds, specifically to a process for the preparation of novel amides of aromatic carboxylic acids, having a shortage of sugar in the blood by action.
    The purpose of the invention is to develop a better way to obtain carboxylic acid amides, which have a stronger effect reducing blood sugar levels.
    Example 1. Ethyl ether of (+) 4-1tt- (2-piperidiophenyl) ethyl j-aminocarbonylmethyl benzoic acid.
    To a solution of 290.9 mg (1.40 mmol) of 4-ethoxycarbonylphenyl acetic acid in 6 ml of tetrahydrofuran was added 231.4 mg (1.43 mmol) of N, N-Kap-. bo yldiimidazole and then heated in the absence of moisture for 90 t-tc with reflux condenser. After cooling to room temperature, 0.385 ml (L 2.78 mmol) of triethyl is added: on (dried over potassium hydroxide, potassium oxide) and J60 mg (1.30 mmol) of hydrochloride (+) 1- (2-piperid-). nofe nile) ethyl amine tls; 242 ° C (decomposition); - +14.8 (methanol)} together with 2 ml of tetrahydrofuran. Then it is stirred in a warm oil bath (50 ° C) for 4 hours. It is evaporated in vacuo and the residue from evaporation is partitioned in chloroform and water, the chloroform extract is dried over sodium sulfate, filtered through a glass frit and evaporated in vacuo to dryness. The residue obtained is purified by chromatography on a column of silica gel (chloroform / methanol 6: 1). Output: 229 mg (44.7% of theoretical), t.pcs. 89-90 ° С (simple ether), f.p ° +8,2 (с 1; м-- tanol),
    Found,%; C 73.20; H 7.68; N 7.14 (m / e 394).
    removing the protective radical and introducing the desired product in free form, in the form of optically active antipodes or in the form of sodium salt.
    Calculated,%: C 73.07; H 7.66; N 7.10 (t / e 394),
    Example 2: Ethyl - (4-chloro-2-pipet idinophenyl) ethyl J-aminocarbonylmethyl benzoic acid
    To a solution of 5.5 g (0.023 mol) of 1- (4-chloro-2-piperidinophenyl) ethyl amine, 4.8 g (0.023 mol) of 4-ethoxycarbonylphenyl acetic acid, 7.3 g (0.028 mol) of triphenylphosphine and 3.2 ml (0.023 mol) of triztilamine in 50 ml of acetonitrile were added 2.3 ml (0.023 mol) of carbon tetrachloride and stirred for 24 hours at room temperature. It is then evaporated in vacuo and partitioned into 100 ml of water and ethyl acetate. The combined organic extracts dried over sodium sulfate are filtered, evaporated in vacuo, and the residue is purified from evaporation by a chromatograph of 1 g of silica gel column (toluene / ethyl acetate 4/1). Yield: 6.1 g (62% of theory), t. Pl. 126-128 ° C.
    Found,%: G 67.43; H 6.97; C1 8.16; N 6.40.
    Calculated,%: C, 67.20; H 6.81;
    C1 8.27; N 6.53.
    Froze Ethyl ether
    4-1- (2-piperidinofensh1) ethenyl aminocarbonylmethyl benzoic acid.
    In a solution of 10.9 g (0.0539 mol) of freshly prepared (2-piperidinophenyl) methyl ketimin in 110 ml of acetonitrile, stirred, 11.2 g (0.0539 mol) of 4-ethoxycarbonylphenylacetic acid, successively added, 17 g ( 0.0647 mol) triphenylphosphine, 22.6 ml (0.162 mol) of trinethylamine and 5.2 ml (0.0539 mol) of carbon tetrachloride. The clear solution formed over time is stirred for 20 hours at 20 ° C. It is filtered from the precipitate formed
    (Triphylamine hydrochloride and evaporate the filtrate in vacuo. Evaporation residue is purified by chromatography on a column of silica gel (toluene / acetone 10: 1). Yield: 15 g (70, j% of theoretical), mp 112-115 C ( ether).
    Found,%: C 73.28; H 7.32; N 6.96.
    Calculated,%: C 73.44; H 7.19; N 7.14,
    Example4. 4- {f1- (2-piperidinofensh1) ethyl amino carbonylmethide} benzoic acid ethyl ester,
    In a stirred solution of 49.6 g
    (0.243 mol) 1- (2-piperidinofensh1) ethylamine (so kip. 100-t07 G; so pl. Dihydrochloride 234-237 ° C with decomposition) and 37.3 MP (0.267 mol) of triethyl amine in 245 ml of methylene chloride drop by drop, easily cooled with ice, at a internal temperature of 20-30 ° C, a solution of 60.6 g (0.267 mol) of 4-thi-cicarbonylphenethyl chloride in 120 ml of methyl chloride is added. Then continue stirring for another 2 hours at room temperature. The precipitate injected is filtered, washed once with methylene chloride and the combined methylene chloride phases are shaken twice with water, once with 10% aqueous ammonia, twice with water, once with 100 ml of 3% hydrochloric acid to twice with water. Dry the ти tylene chloride phase over sodium sulfate, filter, and evaporate in vacuo. Evaporation residue is crystallized from ether, course: 88.8 g (92.7% of theoretical
    N
    N
    , nn 148-150 ° C Found,%
    7, 17. Calculated
    7,10. Example
    C, 73.30; H 7.58; : C, 73.07; H 7.67;
    five.
    Ethyl ether
    (2-Piperidinophenyl) etheiyl - aminocarbonyl methyl benzoic acid
    To a stirred solution, 2.02 g (0.010 mol) of freshly prepared meth- 1- (2-piperidinophenyl) ketimine and 1.53 ml (0.011 mol) of triethylamine in 10 ml of methylene chloride are dropped, cooled with ice, at an internal temperature for 15 minutes a solution of 2.49 g (0.011 mol) of 4-ethoxycarbonylphenacetyl chloride in 10 MP of methylene chloride is added. Stir for an additional 20 hours at 20 ° C and
    then
    ten
    2534294
    pour the reaction mixture into the cold
    sodium bicarbonate solution. It is extracted several times with methylene chloride, the organic extract is extracted once with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue from evaporation is purified by chromatography on a column of silica gel (toluene-acetone 50: 1). Output: 1.86 g (47.7% of theoretical), t.
    pp (ethanol).
    15
    20 - 25 io |
    five
    g
    five
    "1day,%: C 72.95; H 6.98; N7.22 t / e 392).
    Calculated, 7,14 (m / e N
    %: C, 73.44; H 7.19; 392).
    EXAMPLE 6 Ethyl ester of (2-piperidinophenyl) ethenyl J-aminocarbonyl methyl benzoic acid.
    To a suspension of 2.20 g (6.24 mmol) of the iodomagnesium- methyl- (2-piperidinophenyl) ketimino complex in 15 ml of methylene chloride, drop by drop, with stirring, a solution of 1.55 g (6.86 mmol); 4-ethoxycarbonylphenacetyl chloride in 5 ml of methylene chloride. At the same time, the internal temperature rises from 20 to. Stir for 2 more hours at room temperature, add water while stirring and extract with methyl chloride several times. The methylene chloride solution is washed three times with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue from evaporation is purified by chromatography on a column of silica gel (toluene / acetone 50: 2). Yield: 1.1 g (45.8% of theory), mp. 115- (ethanol).
    Found.%: C 73.30; H N 7,16,
    Calculated%: N 7,14.
    PRI me R 7. (5-Chloro-2- -piperidinophenyl) ethyl} amnnocarbonylmethyl | benzoic acid.
    To a solution of stirring, 1 g (5.55 mmol) of 4-carboxyphenylacetic acid and 1.32 g (5.55 mmol) of 1- (5-chloro-2-sh1peridi-iophenyl) ethnlamine in 10 ml of absolute pyridine is added 0.4 ml (5.55 mmol) of thionyl chloride, the internal temperature rises from to, the dark brown reaction mixture is stirred for 3 hours at 20 ° C and then evaporated in vacuo. Evaporation residue, 7; 06; C, 73.44; H 7.19;
    five
    limit in water (pH = 3 after addition of 2N hydrochloric acid) and chloroform. The organic extract is dried and filtered and then evaporated in vacuo. The evaporation residue is purified by chromatography on a column of silica gel (chloroform / methanol 10: 1). Output: 1.06 g (48% of theory), mp, 212-214 ° C (proto-epher).
    Found,%: C 65.79; H 6.01; C1 8.69; N 6.87.
    Calculated,%: C 65.91; H 6.29; C1 8.85; N 6.99.
    Froze 4-I 1- (2-Piperidinophenyl) ethyl aminocarbonylmethyl | benzoic acid,
    To a solution of 0.30 g (1.11 mmol) of 4-benzyloxycarbonyl-4 phenylacetic acid in 20 ml of anhydrous tetrahydrofuran was added 0.19 g (1.17 mmol) of N, N -carbonyldiimide-eol and then, without Access moisture is heated for 1.5 hours under reflux. Then, 0.20 (1.00 mmol) -1 - (2 - PIP erid and n o phenyl) ethylamine is added at an internal temperature of 50 ° C and heated at this temperature for another 4 hours.
    The successively obtained reaction solution is hydrogenated after adding 0.30 g of palladium on carbon (10%) to it at 50 ° C and a hydrogen pressure of 5 bar.
    After 5 hours, the catalyst is filtered off on silica gel and evaporated in vacuo. The residue obtained after evaporation is purified by chromatography on a column of silica gel (chloroform / methanol 10: 1). All: 0.22 g (60% of theoretical yield), t. Pl. 163-165 ° C
    When m. P 9. Sodium salt of 4 - {{1- (2-piperidinophenyl) ethyl amino carbonylmette-yl} benzoic acid x 0.6 НО.
    8.4 g (0.0229 mol) 4- | 11- (2-piperidinophenyl) ethyl aminocarbonylmethyl} benzoic acid is dissolved in 80 ml of ethanol at 60-65 0, 22.9 ml of 1N is added, stirred. soda lye and continue to stir for another 30 minutes. The mixture is then cooled to 20 ° C, and a precipitate is obtained. It is cooled to 0 ° C, filtered and the precipitate is washed with cold ethanol and ether. The resulting precipitate with t.gsh. 250-251 С recrystallized534296
    It is made of ethanol / water (7: 3). Output: 7.2 g (78.6% of theoretical), so pl. 253-255 C.
    Found,%: C 66.10; And 6.64; 5 N 7.13.
    Calculated,%: (x 0.6): C 66.18; H 6.61; N 7.02.
    Example 10. 4- (2-Piperidinophenyl) ethyl amino-0 carbonylmethyl} benzoic acid ethyl ester.
    Example 4 is repeated with the difference that instead of 4-ethoxycarbonylphenylacetyl chloride, 4-ethoxycarbonylphenacetylbromide or 4-ethoxy- 15 sycarbonylpheneacetic anhydride is used.
    The yield of the target product is 92.5 and 92.0%, respectively.
    Similarly, the following compounds are obtained- 20 dineni:
    Methyl ester of 4- (5-chloro-2-pyrrolidinobenzyl) aminocarbonylmethyl benzoic acid, yield 68.1% of the theoretical, so pl. -139-141 ° С (methanol).
    Found,%: C 65.46; H 5.91; C1 9.26; N 7.41.
    Calculated,%: 65,19; H 5.99 ;. C1 9.17; N 7.24. 30 Methyl 4-j ester 1- (5-chloro-2-pyrrolidinophenyl) ethyl) aminocarbo7 „„ nylmethylIbenzoic acid, yield
    58.3% of theoretical, so pl. 133-135 ° C (methanol).
    35% found: C 66.24; H 6.19; C1 8.75; N 7.13;
    Calculated,%: C 65.91; H 6.29; C1 8.84; N 6.99,
    Methyl ester 4-G (5-chloro-2-piperidinobenzyl) aminocarbonylmethyl benzoic acid, yield 75.1% of the theoretical, so pl. 123-125 ° C (ether).
    Found,%: C 66.05; H 6.13; 45 C1 8.86; N 7.21.
    Calculated,%: C 65.91; H 6.29; C1 8.84; N 6.99.
    Methyl ether 4- | 1- (5-chloro-2- -piperidinobenzyl) aminocarbonyl - 50-ethyl | benzoic acid, yield 70.4% of theoretical, so pl. 142-144 C (simple ether).
    Found,%: C, 66.50; H 6.49; C1 8j44; N 6.86.
    55. Calculated,%: C, 66.57; H 6.56; C1 8.55; K 6.75.
    Methyl ether 4- | {1- (5-chlorop-2-piperidinofeiyl) ethyl aminocarbonylmethyl benzoic acid, yield 69.5% of theoretical, mp, 147-149 ° С (ether).
    Found,%: C 66.33; H 6.54; C1 8.67; N 6.85.
    Calculated,%: G 66,57; H 6.56; C1 8.55; N 6.75.
    Methyl ester of 4- (1- (5-chloro-2- (3-methylpiperidino) phenyl) ethyl-aminocarbonylmethyl} benzoic acid, yield 54.3% of theoretical, t, mp 160-162 C (methanol).
    Found,%: C 67.27; N 6.81; C1 8.13; N 6.45.
    Calculated,%: C, 67.20; N 6,8t; C1 8.27; N 6.53.
    Methyl ether 4- | 1- (5-chloro-2- (3,5-yis-dimethyl-piperchlocha) -phenyl) ethyl aminocarbenzylmethyl | benzoic acid, yield 44,% of theoretical, so pl. 190-193 C (methanol).
    Found,%: C 67.50; H 7.05; C1 8.25; N 6.48.
    Calculated,%: C 67.78; H 7.05; C1 8.00; N 6.32.
    Methyl ester (5-chlorop-2-piperidinophenyl) propyl-a: IIHocaponylmethyl benzoic acid, yield 65.9% of theoretical, so pl. 142- (simple air).
    Found,%: C 67.45; H 6.63; C1 8.38; N 6.63.
    Calculated,%: C, 67.20; H 6.81; C1 is 8.26; N 6.53.
    Methyl ester 4 | 1- (5-chloro-2- -piperidinophenyl) -2-methylpropyl) aminocarbonylmethyl} benzoic acid, yield 61.4% of theoretical, so pl. 156-158 ° C (ether).
    Found,%. C, 67.80; H 7.17; C1 7.89; N 6.28.
    - TG
    Calculated,%: C 67.78; H 7.05; C1 8.00; N 6.32.
    Found,%: C 68.10; H 7.30; N 6.28.
    Calculated,%: C 68,32; H 7.28; N 6.13.
    5 Methyl ester of 4- | t2- (5-hl-pi-peridinophenyl) -2-ppstn-aminocaponylbenyl-methylbut:; zoic acid, output 84.4% of the theoretical, so pl. 166 164 e. To Found, w / e: 428/430 (1 chlorine).
    Calculated t / e: 428/430 (1 chlorine
    Methyl ester of 4- (5-metsh1-2-pi peridinobenzyl) aminotsarbonone methyl benzoic acid, yield 32.9% of theoretical 15, so pl. 124-126 ° C (paral ether (acetone).
    Found, w / e: 380.
    Calculated t / e: 380.
    Methyl ether (2-piperi 20 dinophenyl) ethyl aminocarbonylmethyl. benzoic acid, yield 82% of the theoretical, so pl. 107-108 ° C.
    Found,%: C 72.79; H 7.38; N 7.53.
    2 $ Calculated,%: C 72.60; H 7.42; N 7.36.
    Ethyl ester of 3- | I1- (2-pJiperidi nophenyl) 3 | ty aminocarbonylmethyl | desoic acid, yield 47% of theoretical 30, so pl. ,
    Found,%: C 73.30; H 7.58; N 7.17.
    Calculated,%: C 73.07; H 7.67; N 7.10.
    Ethyl ester of (2- (1,2,3,4-tetrahydroisoquin-2-yl) -phenyl) ethyl) aminocarbonylmethyl 1-benzoic acid, yield 43,% of theoretical, m.p. 142-144 p. 40 Found,%: C 75.64; H 6.75; N 6.35.
    Calculated,%: C 75.99; H 6.83; N6.33.
    4- {l1- (2-Piperidinophenyl) ethyl
    35
    Methyl ester 4-I 1- (5-hpor-2- - - t - (hexahydro-1H-azepino)) - ethid1 "ami.nocarbonshetil} toluene, yield
    aminocarbonylmethyl benzoic acid, yield 41.7% of theoretical, so pl. 146-147 s (methylene chloride / id / petrol ether).
    Found,%: G 66.90; H 6.66; G1 8.30; N 6.39.
    Calculated,%: C 67.19; H 6.81; C1 8.27; N 6.53. Methyl ether (5-chloro-250
    59% of theoretical, so pl. 136- /,.
    Found,%: G 78.58; H 8.16 ;, N, 8.26.
    Calculated,%: G 78.53; H 8.39; N 8.33.
    Ethyl ester of (2- (1,2,3,6-tetrahydropyridino) -phenyl) -ethyl 1a nocarbonylmethyl} benzoic acid.
    - (octahydro-1N azonino) phenyl) et13135 yield 63.4% of the theoretical.
    aminocarbonylmethyl} -benzoic acid, yield 38% of theoretical, t, pl. 184-185 G (chloroform / toluene);
    m.p. 125-127 G (ether). Found,%: G 73.38; H 7, l5; N 7.13.
    Found,%: C 68.10; H 7.30; N 6.28.
    Calculated,%: C 68,32; H 7.28; N 6.13.
    5 Methyl ester of 4- | t2- (5-chloro-pyperidinophenyl) -2-semicon-amino-carobonylmethyl without: zoic acid, yield 84.4% of the theoretical, so pl.162-1644 e. To Found W / e: 428/430 (1 chlorine).
    Calculated t / e: 428/430 (1 chlorine).
    Methyl ester of 4- (5-metsh1-2-piperidinobenzyl) aminosarbonate methyl benzoic acid, yield 32.9% of theoretical 5, so pl. 124-126 ° C (patrol ether (acetone).
    Found, w / e: 380.
    Calculated t / e: 380.
    Methyl ether (2-piperi. 0 dinophenyl) ethyl aminocarbonylmethyl. benzoic acid, yield 82% of theoretical, so pl. 107-108 ° C.
    Found,%: C 72.79; H 7.38; N 7.53.
    $ Calculated,%: C 72.60; H 7.42; N 7.36.
    Ethyl ester of 3- | I1- (2-pJIperidinonophenyl) 3 | ty aminocarbonylmethyl | benzoic acid, yield 47% of theoretical, so pl. ,
    Found,%: C 73.30; H 7.58; N 7.17.
    Calculated,%: C 73.07; H 7.67; N 7.10.
    Ethyl ester of (2- (1,2,3,4-tetrahydroisoquin-2-yl) phenyl) ethyl) aminocarbonylmethyl 1 benzoic acid, yield 43,% of theoretical, m.p. 142-144 p. 0 Found%: C 75.64; H 6.75; N 6.35.
    Calculated,%: C 75.99; H 6.83; N6.33.
    4- {l1- (2-Piperidinophenyl) ethyl
    five
     - - t am. nocarbonshetil} toluene, yield
    am.nocarbonshetil} toluene, output
    59% of theoretical, so pl. 136- /,.
    Found,%: G 78.58; H 8.16 ;, N, 8.26.
    Calculated,%: G 78.53; H 8.39; N 8.33.
    Ethyl ester of (2- (1,2,3,6-tetrahydropyridino) -phenyl) -ethyl-1-aminocarbonylmethyl} benzoic acid.
    yield 63.4% of theoretical.
    yield 63.4% of theoretical
    m.p. 125-127 G (ether). Found,%: G 73.38; H 7, l5; N 7.13.
    91253429П)
    Calculated,%: C 73.44; H 7.19 | Found,%: C 7j, 20; H 7.79,,
    N .N 6.70.
    Ethyl ether (5-chloro-pipa- Calculated,%: C 73.51, H 7.90,
    Ridinophenyl) ethyl aminocarbonylmethyl N 6.86.
    benzoic acid, yield 68% of the 4- (2-piperidiretic) butyl ester, mp 95-97 ° C (ethanol) .nophenyl) ethyl aminocarbonylmethyl | ben Found,%: C 67.75; H 6.76, zoic acid, yield 49% of Theorem 8.22; N 6,24, ticheskogo, so pl. 148 ° C (ether /
    Calculated,%; C, 67.20; H 6.81; toluene). C1 8.27; N 6.53. tO Found,% C 74.10; H 7.99;
    Ethyl ether (5-fTor-2-N 6.70.
    -piperidinofensh1) ethyl aminocarbonylj Calculated,%: C 73,90j N 8,11
    benzoic acid, yield 47.3% from N 6.63,
    theoretical, so pl. 138-140 ° С (pro-ethyl ester 4- | 1- (5-chloro-2-pisthe ester) .15 peridinophenyl) ethyl} aminocarbonyl Found,%: C 70.10; H 7.10; Tyl} benzoic acid, yield 41% of
    N 6,87, theoretical, so pl. 130-133 ° C
    Calculated,% g C 69.88; H 7.09; (ether). N 6,79. Found,%: C 66.90; H 6.65;
    Methyl ester 4- {12- (1- (2-steter-2oC1 8.32 N 6.67.
    yes1 | ofenyl) ztil) aminocarbonyl ethyl} benzene,%: C 67.21; H 6.81
    zoic acid, yield 90% of theorem C1.2 8.26 j N 6.53. ticheskogo, so pl. 129-131 C. Butyl ester 4- (1- (5-chloro-pipaIaido,%: C 72.61; H 7.77; ridinophenyl) ethyl amine carboxymethyl)
     N7,52..25 benzoic acid, yield 30.7% of
    Calculated,%: C 73.06; H 7.67; theoretical, m.p. 115-118 ° C. N 7.10. Found,%: C 68.20; H 7.23,
    Ethyl ester 4- (1- (5-chloro-2-C1 7.68; N 5.95.
    (2-mvtil-piperidino) -phenyl) -ethyl Calculated: C 68.33, H 7.27j
    aminocarbonylmethyl benzoic acid 530Cl 1 7.75; N 6.12. . yield 71.3% of theoretical, t. (2,2-Dimethyl-dioxolan-4-yl) -mill. . methyl ester (2-piperidino) Found, and / e: 442/444 (1 chlorine), phenyl) ethyl} a shnokarbonn: lmetilJenzoyu Calculated, w / e: 442/444 (1 chlorine), acid, output 30.5% of the theoretic ; YOU air 4- | 1- (2-hexahydonic, m.p., 110-1 (simple
    azepinophenyl) ethyl aminocarbonsh1-me-ether),
    . tyl} benzoic acid, yield 68% of Found,%: C 69.80, H 7.50,
    theoretical so pl. | 45,148 ° C (to-N 5.76, (w / e 480). Louol).
    Found,%: C 73.35; H 8.04; 0 Calculated,%: C 69.98, And 7.55,
    N 6.89 KoN 5.83. (Ha / e 480).
    Calculated,%: C 73.50; H 7.90; Benzyl ether (2-piperidi f 6,86, .nophenyl) ethylRamnnocarbonyl-methyl |
    Ethyl ester of 2 .- (2-methyl-benzoic acid, yield 44.8% of tepirrolidino) -phenyl) ethyl aminocarbo-. Theoretical, mp, 146-147 ° C. nylmethyl) benzoic acid, yield Found%: C 72.19, H 7.33;
    72.0% of the theoretical, t. Ш1. 94-N 7.01. Calculated,%: C 72.60: H 7.42J
    N 7.36. Found,%: C 73.25; H 7.67; tert-Butyl ether (2-pi,. t, p7 m 7 AA Reed оФе ™ l) etsh1 aminocarbosylmethyl%
    . Calculated,%: C 73.07; H 7.66, benzoic acid, yield 19.7% of those T7O2, orthic, t, Sh1. 125-127 ° С (prospect (, t / Ether),
    isopropyl ether (2-piperidinophenyl) ethyl aminecarboxylic acid} 55 Found,%: C-74.20 j H 8.09,
    benzoic acid, yield 45% about t of theo-N 6.77,
    retic, t. pl, 141-143 ° C (simple Calculated,%: C 73.90; H 8; 1i;
    that ether) .N 6,63.
    II 125342912
    Ethyl ester A- {C1- (3-methyl-2-Found,%; C 72.75; H 7.65;
    -piperidinophenyl) phenyl J ethylaminocar-N7.11.
    bonilmethyl benzoic acid, outputCalculated,%: C 72.60, H 7.42;
    .39.5% of theory, mp, 160-N 7.36.
    M64 ° C (cyclohexane). Ethyl ester 4-1 (2-piperidino Found, tp / e 408.benzgvdril) -aminocarbonylmex1 benCalcined, t / e: 408. acid, yield 87 4% of the theorem Ethyl ester (3-chloro-pip- ™ esco, t PL 160- t62 С
    Ridinophenyl) ethyl 1 aminocarbonylmethyl R b
    benzoic acid, yield 52.6% of those— "
    Oretic, t. ™. 132-V35 C (pros: dy; shlesko,%: C 76.29; H 7.06,
    w | MO§.
    fprtt PRETI 01
    „I / 00 // 1P / l Ethyl ether 4-U5-chlorot2-piperi Haido, ha / e: 428/430 (1 chlorine) .., - t, / 00 // OL / -4 chdinobenzhydryl) aminocarbonylmethyl 1 Calculated, tn / e: 428/430 (1 chlorine) .., - j. exactly
    „, / / (Г4 / о 5 benzoic acid, yield 78% of (- 4-) 1- (2-piperipyl) teo ester, s ,,,
    h t 1 7.retichnogo, so pl, 202-204 C.
    dinophenyl) ethyl aminocarbonylmethyl n - 7 g 7n ";
    benzoic acid from dihydrochloride6 5 45
    (-) 1- (2-piperidinophenyl) -ethylamine "
    (mp 239-242-С (decomposition), - otl,
     -19.6 (with 1, methanol), yield 422. „5.71.
    41.1% of theoretical, t.p. 77-, f 4-С (1- (4-piperidi79 C (ether / cyclohexane), GY5 nophenyl) ethyl aminocarbonylmethyl} ben -6,2 Ms 1, methanol). acids, 39% yield of theorem - „7. p 70 A7 H 7 7; ticheskogo, so pl. 118-120 s.
    Found,%: C 72.67, H 7.75 ,. ny „„ „A 7. g 7i on-n 7 7оN 6.82 (ffl / e 394). . ,%: C 73.20, H 7.78,
    Calculated,%: C 73.07; H 7.66, N 7.11.
    N 7.10 (m / e 394). Calculated,%: C 73.07; H 7.67,
    Ethyl ester 4- (1- (4-methyl-2- and 7.10.
    -piperidinophenyl) ethyl aminocaronyl Ethyl ester of 4- (2-pyrrolidinomethyl} benzoic acid, yield 48.2% benzhydryl) aminocarbonylmethyl benot theoretical, so pl. 120-122 C. zoic acid, yield 57% of the theoretically determined,%: C 73.61; H 7.95; ticheskogo, so pl. 163-165 C.
    N6.73. Found,%: C 75.45; H 6.52;
    Calculated,%: C 73.50, H 7.89; j 6.86. 5 Calculated,%: C 75.99, H 6.83,
    Ethyl ester 4- (1- (2- (4-methyl-go1-6.33.
    peridinophenyl) ethyl) aminocarbonyl; me-ethyl ester of 4-K2-hexamethylene benzoic acid, yield of 55.8% imino-benzhydryl) aminocarboxymethyl
    from theoretical, so pl. 125-128 ° Sbenzoic acid, yield 68% of those (ether). Oretic, so pl. 151-154 C.
    Found,%: C 73, AOR; H 7.99; Found: C, 76.43; H, 7.19;
    N 7.20. N 01.
    Calculated,%: C 73.50; And 7.90; Calculated,%: C, 76.56; H, 7.28;
    N 6.86. N 5.95.
    Ethyl ester (2-piperidyl- Ethyl ester of 4- (5-metsh-I-2-piperidophenyl) ethyl-Jaminocarbonylmethyl-jen-hydribenyl) and inocarbonyl-benzoic acid, yield 71% of theorem of benzoic acid; yield 71% of theorem of benzoyl acid; m.p. 147-148 ° C. Of the retic, t. Mon. 116.5-117 seconds
    Found,%: C 73.54; H 8.04; (ethanol / petroleum ether).
    N 6.95.50 Found: C 73.48; H 7.62;
    Calculated,%: C 73.06; H 7.67; N 7.15
    N 7.10. Calculated,%: 73.07; H 7.66,
    4- {11- (2-Piperidinophenyl) 7,10.
    aminocarbonsch1methyl | -phenylacetic acid-ethyl 4- {G1- (5-methyl-2lot obtained from 1- (2-piperidino-55-piperidinophenyl) ethyl aminocarbonyl) phenyl) etch1amine ip-phenylene-diuksus-methyl benzoic acid, 20 , 2%
    Noah acid, yield 27% of theoreti-theoretical, t. Pieces. 132-132 5 s
    ical, t.p. 186-189 C. (ethanol).
    13 125342914
    Found,%: C 73.49; H 7.74; Found; G: 73.75; H 7.43;
    . N 6.94. .N 6.77.
    Calculated,%: 73,50; H 7.90; Vmsleno,%: C 73.86, H 7.43,
    N 6.86. N 6.89.
    4- 1- (2- (1,2,3,4, 1- (5-chloro-2-pi5, 6,7,8-octahydro-isoquinolin-2 yl) -peridinophenyl) ethenyl} aminocarbonylphenyl ethyl ester) ) ethyl aminocarbonylmethyl ben-methyl benzoic acid, yield 39.5%
    Zoyka acid, vkod 35% from theo-theoretical, t. Gsh. 142-145 С
    retic, t, pl. T15-117 S. (ethanol),
    Found,%: C 75.18, H 7.3. Found,%: C 67.51; H 6.37,
    N 5.89. .C1 8.36; N 6.49.
    Calculated,%: C 75, AOR; H 7.67, Calculated,%: C 67.51; H 6.37,
    N 6.27, C1 8.30; N 6.56.
    Ethyl ester 4- | 1- (3-gshperidi-4- (5-chlorop-2-pyrrolidinobenzyl) - nophenyl) ethyl Jaminocarboylmethyl} ben 15 aminocarbonylmethyl benzoic acid, 24% yield of theoretical, output 84, yield 84% from theoretical, tical, m. pl. 164 ° C. t, pl. 208-210® C (ethyl acetate).
    HaftoeHo,%: C 72.80, -H 7.48; Found,%: C 64.70, H 5.68,
    N 7.13, C1 9.58; N 7.60.
    Calculated,%: C 73.07, H 7.66, Calculated,%: C 64.42, H 5.68, N 7.10 ° C 9.51; N 7.51.
    Ethyl ether (6 chloro-2-4-I 1- (5-chlorop-2-pyrpreplidine) I -piperidinophenyl) ethyl a i-onocarbonyl-ethyl aminocarbonylmethyl benzoin methyl benzoic acid, yield 17% acid, yield 81.1% of theoretical - from theoretical, t, pl. 120 ° С-.25 th, t, pl. 202-204 s (ethyl acetate).
    Found,%: C 67.96; H 6.56; Found: C 65.02; H 6.12
    CS 8.80; N 6.67 (m / e 428/30). C1 9.32 N 7.10.
    Calculated,%: C, 67.20; H 6.81; Vmsleno,%: C 65.20J H 5.99;
    , C1 8.26, N 6.5.3 (ta / e 428/30). C1 9, | 7 ;, N 7.24.
    Ethyl ester 4- {and- (6-methyl-2- about 4- (5-chlorop-2-piperidinobenzyl) -piperidinofenes I) ethyl a mnocarbonylnoncarbonylmethyl benzoic acid, methdBenzoic acid, yield 3.5% yield 78% of theoretical t. pl. from theoretical, so pl. ..164-166 ° C. Found,%: C, 73.80., N. 7.61, Nagycheyo,%: C, 65.50, H, 5.76;
    N 7.01 (m / e 408). , .C1 9.24, N 7.36.
    Calculated,%: C, 73.49; H, 7., 89; . Calculated,%; C 65.19 ,. H 5.99;
    .. N 6.85 (ha / e, 408). C1 9.17; N 7.24.
    Ethyl ether (2- (3-azabi-4- (1- (5-chlorop-2-piperidinobenzyl) - cyclo 3,2,2 nonan 3-yl) phenylethyl) - aminocarbonyl ethyl benzoic acid, amino; rbomidmethyl benzoic sour yield of 81.1% of theoretical,., ,, yield 0.5% of theoretical, mp 213 216 ° C (acetone / simple ...,, pl, ... ether).
    Found, t / e: 434. Found,%: C, H 6.40,
    Calculated, t / e: 434.Cl 9.00, - N 7.04.
    Ethyl ester 4- {1- (6-chloro-2-) Calculated,%: C 65.90, H 6.29;
    -piperidinophenyl) ethensh1 aminocarbo-Cl 8.84; N 6.99.
    Nylmethyl benzoic acid, yield 4- {G1- (5-chloro-2-piperidnofensh1) 37% of theoretical, so pl. 102-ethyl aminocarbonylmethyl benzoin
     105 C. acid, yield 84.9% of theoretical Found,%: C 67.86; H 6.39: go, so pl. 213-215 ° C (ether)
    C 8.58; N 6.23 (ha / e 426/28). Found,%: C 66.18; And 6.19;
    . C1 8.88, - N 7.12. . .
    % S, 67.5i; H 6.37; Calculated,%: C 65.91, H 6.29;
    C1 8.30; N 6.56 (ha / e 426/28). C1 8.85; N 6.99.
    Ethyl ester (6-methyl-2-. (5-Chloro-2- (3-methyl-1-taper-piperidinofenesh1), E. amino aminocarbonyl d) phenyl) ethnol aminocarbonylmethyl,
    .nylmethyl benzoic acid, yield. benzoic acid, yield 69.2% of
    41% of theoretical, t, pl. 116-theoretical, t, pl. 208-210 ° C
    t18 C, (ethyl acetate).
    15 1253429.16
    Found,%: C 66.36, H 6.77, acid, yield 82.9% of theoretical 8.58, N 6.80 of whom, t, tt. 227-229 C (acetone) ,.
    Calculated,%: C, 66.57; H, 6.56; Found,%: C, 66.03; H 6.66,
    C1 8.55; N 6.75. .C1 8.67; N 6.59.
    4- E1- (5-Chloro-2- (3.5-14M: -dimethyl-Calculated,%: C 66.57; H 6.56;
    -piperidino) phenyl) etSh1 aminocarbo-Ct 8.55; N 6.75.
    nilmethyl} benzoic acid, yield 4- | (1- (2-Piperidinophenyl) ethyl llami- 82.2% of theoretical, mp 212-nocarbonylmethyl benzoic acid, 2.14 C (ether)). output 85% of theoretical t. pl.
    Found,%: C 66.95, H 6.69, 170-172 C.
    C1 8.43, N 6.68. Found,%: C 71.94, H 7.03;
    Calculated,%: C 67.20, AND 6, 7.72.
    C1, 8.26, N, 6.53. Calculated,%: C, 72.11; H 7.15,
    4- {1- (5- Chlor-2 pnperidinophenyl) -N 7.64.
    propyl aminocarbocylmethyl benzoin j 4- {12- (2-Piperidinofensh1) propyl
     acid, yield 81.5% of theoretical-aminocarbonylmethane 1} benzoic acid, whom, so pl. 200-203 ° С (simple, ether = 72.7% of theoretical).
    Found,%: 0.66.74; H 6.35; t. square 213-215 C.
    C1 8.59; N 6.45. Found,%: C 72.52, And 7.31,
    Calculated,%: C, 66.57; H 6.56; 20 7.45.
    C1 8.55; N 6.75. Viteisleno,%: C 72.61, H 7.42,
    4- | t (5-Chloro-2-piperidinophenyl) -N 7.36.
     -2-methylpropyl amknocarboshshmetil-4-1 (5-l1methyl-2-piperidinobenzyl) benzoic acid, yield 82.7% from amino aminocarbonylmethyl} benzoic acid,
    . theoretical, so pl. 236-240 ° C25 yield 64.6% of theoretical,
    (ethyl acetate), t. square 120-122 ° C,
    Found,%: C 67.19; H 6.56; Found: C, 72.42; H 7.38,
    C1 8.14; N 6.39. N 7.45 (m / e 366).
    Calculated,%: C, 67.20; H 6.81; Calculated,%; 72.11 H 7.15;
    C | 8.27, N 6.53.30 7.64 (m / e 366).
    (5-Chloro-2- (hexahydro-1H-t. Pl. Hydrochloride of 266 ° C (de-azepino) phenyl) ethyl aminocarbonylbenzene).
    T1sh) benzoic acid, yield 81.2%; Found: G 65.00; H 6.62,
    from theoretical, so pl. 202-204 ° CC1 9.40, N 7.00.
    (chloroform / toluene). Calculated,%: C 65.58, H 6.76,
    Found,%: C, 66.60, H, 6.37; C1 8.80; N 6.95.
    C1 8.50, N 6.59. (2-Hyperidinofeamine) propyl Calculated,%: C, 66.58; H 6.56, aminocarbonylmethyl benzoic acid,
    C1 8.55; N 6,75. Output 68.5% of theoretical,
    (5-Chloro-2-octahydroazotsinot-t. Pl. 2t3-215 C.
    phenyl) ethyl aminocarbonylmethyl} ben-Found,%: C 72.43; H 7.25
    zoic acid, yield 44.4% of theo-N 7.40.
    retick, tgag. 196-t97 G (Chloro-Calculated,%: C 72.61; H 7.42,
    forms / petroleum ether) .N 7.36.
    Found,%: C 67.10; H 6.97; 4- (2-Pyprolidinebenzyl) aminocap- N 6,37.bonylmethyl Zenzoic acid, yield
    Calculated,%: C 67.19; H 6.81; 55% of the theoretical, so pl. 212N6, 53.215 ° C (methanol).
    4- {|; 1- (5-Chloro-2- (octahydro-1H-Found;%: C, 70.97; H, 6.91,
    - ozono) fekyl) ethyl 1 amino nocarbosh1me-N 8.15. tyl} benzoic acid, yield 74.7%
    from theoretical, so pl. 204 206 Calculated,%: C 70.99; H 6.55;
    (ethyl acetate / petroleum ether) .N 8.28.
    Found,%: C 67.50; H 7.03; 4- {11- (2-11 errolidinophenyl) 6.04. Aminocarbonylmethyl} benzoic acid.
    Calculated,%: C 67.78; H 7.05; yield 25% of theoretical, so pl.
    N6.32.; 155-157 C (acetone / ether).
    (5-Chloro-2-piperidinoPhenyl) Found:%: C 71,22; H 6.75;
    prog1Sh17amnnokarbonilmetsh1} benzoia N 8.42.
    17 1253A2918
    Vyisleno,%: C 71.57, H 6.86; Calculated,%: C 72, H 6.64;
    N 7.95.N 7.69.
    4- (2-Piperidinobenzyl) aminocar-4- | 2- (5-Chloro 2-piperidinophenyl) bonilmetf benzoic acid, yields ethyl aminocarbonylmethyl} benzoine
    60.4% of theoretical, so pl. 175-acid, 75% yield of theoretically 177 C (acetone). .go, t. PL „192-195 s (ethyl acetate).
    Found,%: C 71.48; H 7.00; Found,%: C, 66.39; H 6.17;
    N 8.09. C1 8.45, N 6.78.
    Calculated,%: C 71.57, H 6.86; Calculated,%: C 65.91, H 6.29;
    N 7.95., 0 Cl 8.84, N 6.99.
    4- | 12- (2-Piperidinophenyl) ethyl -4- {1 (5-Ftop-2-piperidinophenyl) - aminocarbonylmethyl} benzoic acid, ethyl amocarbonylmethyl 1} benzoic
    yield 60.4% of theoretical; t. acid; yield 52.9% of theoretical. 1b4-166 ° C (ethyl acetate). Of which, t. Pl. 174-1Tb C (ethyl acetate).
    Found,%: C, 72.35; H, 7.18; Found,%: C, 68.30: H, 6.48.
    N 7.76. to 7.45
    Calculated,%: C 72.11; H 7.15i Calculated,%: C 68 73 H 6 5-;
    N 7.64N 7.29.
    (2- (2-Methyl-piperidino) fe-4-C (5-Methyl-2-piperidinbenznl) nsh1) eth1} aminocarbonylmethyl} benzo-aminocarbonyl methylbenzoic acid,
    on acid, yield 90.9% of theorem-yield 53.9% of theoretical,
    tichesky, t. pi. 171-173 ° C (petro-t. Pl. 120-122 ° C (ethanol),
    leuyl ether / acetone). Found,%: C 72.45; H 7.04,
    Found,%: C 72.30; H 7.39; "7.64 (ha / e 366).
      „Р79А1 н7 / о-25 Calculated,%: С 72.11; H 7.15i
    Calculated,%: C, 72.61; H, 7.42, 7.64 (m / e 366).
     , 4- | 12-Hydroxy-1- (2-piperidinophenyl) (2-Metsh1-piperidinophenyl) methyl aminocarbonylmetrySh1} benzoine
    ethyl Aminocarbonylmethyl} benzoic acid, yield 65% of theoretical acid, yield 86 3% of theoretical, so pl. 155-157 with decomposition
    whom 170-173 C (petroleum (petroleum ether / acetone).
    ether / acetone), Found, t / e: 382.
    Found,%: C 72.20, H 7.28, Calculated, w / e; 382.
    : „.: 4- (1- (5-Chloro-2- (2-metsh1-piperiCalculated,%: C 72.61, H 7.42, but) fensh1) ethylZaminocarbonylmethyl} / 1g. / ,,„: l 40 benzoic acid, yield 64.1% of
    4- | M2-Piperidinofensh1) -2-me-theoretical, so pl. 195-1984
    tylpropyl aminocarbonsh1metsh1} benzoi / h
    acid, yield 68% of theoretical,%; C 6.01, H 6.25;
    who, t. pl. 215-21 / С (acetone). „. “About%, qn
     Found,%: C 73.10; H 7,. 6.57, H 6.56,
    C1 8 54 N 6 75.
    Calculated,%: C 73.06; H 7,67,4- {1- (2- (4-Metsh1-piperidino) fe / "Nnil) eth1 aminocarbonylmethyl} benzoy4- {1- (2-Hexahydroazepinophenyl) - acid, output 67.7% of the etiorectl aminocarbonsteammethyl benzoin “173-175 ° C (chloroform).
    acid, yield 68 5 from theoretical-found,%: C 72,20; H 7.36;
    who, t. pl. 174-17b C (ethyl acetate) .m at iS
    Found% i C 72.36; H 7.34;
    N 7.38. Calculated,%: C 72-, 6i; H 7.421
    Calculated,%: C 72.61, H 7.42.50 r, ..
     7.36.2- (1- (2-Piperidinophenyl) ethyl ami4-C1-2 (2- (1,2,3,6-tetrahydropyranocarbonylmethyl} benzoic acid,
    dino-feshl) ethylaminocarbonylmethyl - yield 70% of theoretical,.
    benzoic acid, 68.2% yield; square 135 ° C (decomposition).
    theoretical, so pl. 158-160 C55 Found: C 72.29; B 7.03;
    (ethyl acetate) .N 7.37.
    Found,%: C 72.20, H 6.66, You are sisleno,%: C 72.10: H 7 15
    N 7.74, N 7.64
    19125342920
    (2-Piperidinoflein) ethyl amine ethyl aminocarbonylmethyl1) benzoic
    nocarbonylmethyl} benzoic acid, acids, yield 99% of theoretical solution 86% of theoretical, mp 205, so pl. 70 ° C (decomposition). 207 C. Found,%: C 73.00, H 7, | 6
    Found,%: C 72.30, H 7.29, N 5.98 (m / e 418).
    N 7.71. Calculated (x 0.5 N.O.),%: C 73.05;
    Calculated,%: C 72, I, H 7.15 ;; n 7.30 N 6.54 (ha / e 418).
    N 7.64. (4-Hpor-2-piperidinofeshsh) (2- (1,2,3,4-tetrahydro-iso-ethn-1 aminocarbonsylmethyl benzoyl quinolin-2-yl) phenyl) ethyl aminocarbonyl- | o acid, output 82.1% of theoreticalmethyl | Benzoic acid, the output of 59% of whom, so pl. 200-202 Co from theoretical, so pl. 207-209 C. Found,%: C 66.06, H 6.40;
    Found,%: C 75, AOR; H 6.29, C1 9.01, N6.93. N 6,67. Calculated,%: C 65.91, n b, 29.
    Calculated,%: C, 75.34; H, 6.32; Cl, 8.84; N 6.99.
    N 6.76. 4- | 1- (4-Metsh1-2-piperidinophenyl)
    4- 1- (3-Piperidinophenyl) ethyl-ethyl aminocarbonylmethyl benzoine
    aminocarbonylmethyl benzoic acid, acid, yield of 66.5% of theoretical yield 33% of theoretical, so pl. 206-someone, so pl. 110-115 ° Co. . 20 Found: C 72.50; H 7.52;
    Found,%: C 72.04; H 7.14; N 7.46.
    N 7.57. Calculated,%: C 72.60; H 7.42;
    - -N 7.36.
    Calculated,%: C 72.09; H7.15; 4-: (2-Piperidino-benzgvdrnl) 7.64.25 nocar & onylmethyl benzoic acid,
    4-I1- (6-Chloro-2-piperidinofensh1) - 88% of the theoretical output, mp.232 ethyl 1-aminocarboxymethyl | benzene 234 ° С
    acid, yield 35% of theoretical; Found,%: C 75.16; P 6.52;
    go, so pl. 148-150 pp. -Jf
    Found,%: C 65.45, H 6.36; subtracted,%: C 75.68, and b, 59,
    Calculated,%: C 65.91; H 6.28;
    Ct8.84, N6.98, 4- (5-Chloro-2-lipepJ-dino-benzgid-4- {1- (6-Metsh1-2-piperidinophenyl) -ryl) aminocarbonylmethyl benzoate ethl aiiobaraxo-methyl benzene acid, 78.5% yield from theoretical acid, yield 33% of theoretical m. Pl. 255-260 S. go, so pl. 170 ° C. Found,%: C 70.50; H 6.76,
    Found,%: C 72.45; H 7.34, 7.36, N6.06. N 7.32. Calculated,%: C 70.05, - H 5.88,
    Calculated,%: C 72.60; H 7.41; C1 7.66; N 6.03. . . 4- | C | - (4-Piperidinophenyl) ethyl ami4- | .1- (2-Octagidro-isoindole-2- nocarbonylmethyl} benzoic acid,
    -yl) phenyl) ethyl aminocarbonylmethyl -the output of the theoretical, so pl.208- "
    benzoic acid, yield 64% of theo-210 ° C.
    retic, so pl. 130 ° C ..,: Found,%: C 72.24, H 7.26;
    Found,%: C 73.60; H 7.47; N 7 54 N 6.72.
    Calculated,%: C 73.86, H 7.43; Calculated,%: C 72.11, H 7.15f
    N 6,89.N 7,64.
    (2- (DecaHydro-isoch11nolina - (+) 4- | 1- (2-Piperidufensh1) ethyl -2-yl) phenyl) ethyl aminocarbonylmethyl | - ° aminocarbonsImetsh Jbenzoine acid-benzoic acid, 71% of women and women, get 71% of the number of women and women; , 3 N O, yield 40% of theoretical, so pl. 220-221 S., t pl. with decomposition
    Found,%: C, 74.45; H 7.50, (isopropanol / simple zfir), og.1
    N 6.58 (ha / e 420). -t-7.3 (c 1 "methanol).
    Calculated,%: C, 74.25; H 7.66; 55 Found,%: C 70.90, H 7.22;
    N 6.66 (m / e 421). N 7.42 (m / e 366).
    Hemihydrate 4-Ul- (I, 2,3,4,5-, 6,7, -Calculated (x 0.3),%: C 71.02;
    8-octahydro-isoquinolin-2-yl) phenyl) -H 7.25; N 7.52, (m / e 366).
    21,125342922;
    Sodium salt (-) (2-pipa-Found,%: C 72.13, H 7.25,
    Ridinophenyl) ethyl aminocarbonylmethyl} -N 7.75.
    benzoic acid, yield 50% of the Theo-Calculated,%: C 72.11, H 7.15;
    retic.n 7.64.
    Found, s / e: 366.5 (5-Methyl-27PIperidinophenyl Vypshleno, t / e: 366. Aminocarbonylmethyl benzoic acid T.GO1. Sodium salt 190 C (time, yield 56.6% of theoretical,
    position). square 215-217 C (ethanol).
    (2-Piperidinofensh1) ethynyl -Found,%: C 72.71, H 7.49,
    . Aminocarbonylmethyl benzoic acid, S, N 7.25.
    yield 53.6% of theoretical, Vyisleno,%: C 72.61, H 7.42
    m.p. 158-160 C (ethanol) .N 7.36.
    Found%: C 72.40, H 6.34, (- Carboxy-2-piperidinobenN 7.51, zil) aminocarbonylmethyl benzoyl
    Calculated,%: C 72.51; H 6.64, fs acid x 0.66, yield 72.2% of
    N 7,69. theoretical, so pl. 235-240 ° С
    (5-Chloro-2-piperidinophenyl) decomposition (methanol / chloroform).
    ethenyl aminocarbonylmethyl} benzoyl; Found: C, 64.64; H 6.23;
    acid, yield 78.7% of theoretical-N 6.61.
    who, t. pl. 198-200 ° C (acetone) .20 Calculated (x 0.66),%: Found,%: C 65.74, And 5.72, C 64.69, H 6.33, N6.85.
    C1, 9.37, N, 7.10. Sodium salt monohydrate is 4%,%: C 66.24; H 5.81; - {C1- (2-piperidinofeneshl) etshl amine-C1.8.8V; N 7.02ocarbonylmetallone} benzoic acid, 4- {11- (6-Hpor-2-piperidinophenyl) -25 yield 48.6 % of theoretical,. etheiyl | amynocarbonsh1methyl benzoin t. pl. 245-250 C. acid, yield 39% of the theoretical-Found,%: C 65.40, H 6.83J go, so pl. .N 6.72,
    Found,%: C 66.48; H 5.84; Calculated (x 1 N.O.),%: C 65.01;
    ei 8.88, N6.85 (w / e 398/400). No. 6.69, N6.89.
    Calculated,%: C 66.24, H 5.81; 4- (1- (2-Piperidinophenyl) ethylZS1 8.88; N 7.02 (ha / e 398/400). Aminocarbonylmethyl | benzoic acid 4- | G1 - (6-Methyl-2-piperidinophenyl) -ta, yield 52% of theoretical,
    ethenyl aminocarbonylmethyl} benzoic m.p. 169-t71 C.
    acid, yield 49% of theoretical ,, Found,%: C 71.84; H 6.87;
    city square 128-130 C.N. 7.72.
    Found m / e; 378.Calculated,%: 72, It, And 7.15;
    W isleeno, w / e: 378.N 7.64.
    , (2- (4-Oxo-piperidino) fe4- 1- (2- (2-Methyl-pyrrolidino) phenyl) eth11 ananinocarbonylmethyl benzo
    )) ethyl aminocarbonylmethyl benzoic acid, yield 32% of the theoretical acid, yield 62% of the theoretical, so pl. G77-180 C from razlocheskogo, t. Sh1. 169-172 S. agenium (acetone / petroleum ether).
    Found,%: C 71.96, H 6.82, i
    N 7.51. Found:% C 69.62; H 6.41;
    Calculated,%: C, 72.11, H, 7.15; N, 7.50.
    N 7.64. Calculated,%: C 69.46; H 6.36;
    (2-Pryleidinophenyl) propyl —N 7.36.
    aminocarbonylmethylbenzoic acid-4- {1- (2-11piperidinophenyl) methyl amite, you} {71.4% of the theoretical, “nocarbonylmethyl benzene sprint
    m.p. 208-210 C (ethanol). 39% output from the theoretical, t.Sh1.104
    Found,%: C 72.30; H 7.44; 106 ° C. .
    N 7.45. Found,%: C 74.80, H 7.80;
    Calculated,%: C, 72.61; H 7.42; N 7.80.
    N 7.36. Calculated,%: C, 74.96; H 8.00;
    (2-Piperidinophensht) ethyl 1- N 7,94.
    Acinocarbonylmethyl benzoin is a sour-lowering sugar content
    one, the yield of 62% of the theoretical, blood effect of the new researched
    m.p. 163-164 s.odes were determined on rats weighing
    180-220 g, which for 24 hours before the start of the experiment did not give food. Immediately before the start of the experiment, the test compounds were suspended in 1.5% methylcellulose, and the suspension was administered using a gastric probe.
    Blood was taken immediately before application of the test compound and then 1, 2, 3 and 4 hours after application from the retroorbital venous spheny. At the same time 50 μl of blood were subjected to release from protein with 0.5 MP 0.33 n. perchloric acid, followed by centrifugation. In the residue, glucose was determined by the hexokinase method using an analytical photometer. Statistical evaluation was discounted by Student with a p of 0.05 as the limit of significance.
    The following new compounds have been investigated:
    A) 4- (2-pyrrolidinobenzin) aminocarbonylmethyl benzoic acid,
    B) 4-I 1- (2-pyrrolidinophenyl) am-nocarbonylmethyl I benzoic acid,
    B) (5-chloro-2-pyrrolidinophenyl) - ethyl aminocarbonylmethyl benzoic acid
    D) 4- (2-piperidinobenzyl) aminocarbonylmethyl benzoic acid;
    E) 4- I 1- (2-piperidinophenyl) ethenyl-aminocarbonylmethyl 1 benzoic acid,
    E) 4- | 1- (6-chloro-2-piperidinophenyl) -ethenyl amine-carboxymethyl benzoic acid;
    G) (6-methyl-2-piperidinophenyl) - ethenyl aminocarbonylmethyl | benzoic acidJ
    3) (2-piperidinophenyl)
    aminocarbonylmethyl benzoic acid,
    I) (2-piparidinofensh1) ethyl aminocarbonylmethyl-benzoic acid ethyl ester
    K) ethyl ether (+) 4-- | 1-C2-piperi dinofen w) ethyl aminocarbosyl 1-methyl benzoic acid;
    L) (2,2-Dimethyl-dioxolane-4-sh1) -methyl ester of (2-piperidide, .nophenyl) ethyl a-p -carbonylmethyl | - benzoic acid;
    M) 4- | 1- (2-piperidinophenyl) aminocarbonylmethyl-toluene;
    H) 4 - {f 1- (2-piperidinophenyl) aminocarbonylmethyl 1 benzyl alcohol;

    Jq ts 20
    25
    0

    ,
    five
    i) (2-piperidinophenyl) ethyl 1-aminocarbonylmethyl 3-phenylacetic acid,
    P) (4-chloro-2-piperidinophenyl) -ethyl amine-carboxylic methyl} benzoic acid;
    C) (5-chloro-2-pyperidinophenyl) - ethyl minocarbonylmethyl benzoic acid;
    T) (6-chloro-2- -piperidinofekyl) ethyl aminocarbonobylmethyl benzoic acid ethyl ester
    U) 4- {(1- (5-fluoro-2-piperidinophenyl) - ETSh1 aminocarbonylmethyl | benzoic acid
    f) 4- {G1- (4-methyl-2-piperidinofenes1) ethyl aminocarbonylmethyl benzoic acid;
    X) 4-1- (5-methyl-2-piperidinophenyl) ethyl aminocarbonylmethyl} benzoic acid;
    C) 4- fG 2- (2-piperidnofeshsh) -2-previous aminocarbonylmet1t | benzoic acid,
    H) 4- {H1- (2-piper {adinophenyl) -2-methylpropyl aminocarbonylmethyl-benzoic acid;
    W) 4-C (2-piperidinobenzgidrtt) a№1NO- carbonylmethyl benzoic acid
    y) 4- (f1- (2- (1,2,3,6-tetrahydro-pyridino) phenyl) ethyl amine-carbonylmethyl benzoic acid,
    E) 4 - {(1- (2- (3-methyl-piperidino) phenyl) ethyl 1 yminocarbonyl methyl benzoic acid,
    S) 4- (2-hexahydro-eepinophenyl) - ethyl aminocarbonylmethyl benzoic acid
    and known compound (AB)
    4-G2- (2-ethylamino-5-chloro-benzoylamino) ethyl 1-benzoic acid.
    The results of the experiment are given in
    the table shows a percentage of
    compared with the control.
    The data in the table indicate that the new compounds have a better blood sugar level, CHiiHammiiM, than the known compound. Due to the low activity at a dose of 25 mg / kg, the activity of the known compound was not determined by IB doses of 10 and 5 mg / kg,
    Acute toxicity suggests gh compounds and a known compound is determined in experiments on white mice.
    Each compound was administered orally as a suspension in methylcellulose at a dose of 500 mg / kg to five female mice.
    and five males. After 14 days, the number of dead animals is determined. Result: in all cases, no animals died.
    Thus, the proposed method allows to obtain new compounds of the indicated general formula, which have a high glucose lowering activity.
    1 h 2 h
    -46 -38 -44 -46 -45 -46 -39 -34
    n.sV n, s. n.s. n, s.
    -42 -32 -26 -33 -41 -35 -24 -17 -40 -32 -31 -17
     Dose 20 mg / kg. p.So according to statistics is not significant.
    Editor V. Petrash
    Compiled by M. Bibikova
    Tehred V.Kadar Proofreader S.Shekmar
    4633/60
    Circulation 379 Subscription
    VNIIPI State Committee of the USSR
    for inventions and discoveries 113033, Moscow, 4/3, Raushsk nab.
    Production and printing company, Uzhgorod, st. Project, 4
    -45 -39 -35 -31 -48 -36 -33 -20 -29 -18 n.s. n.s.
    权利要求:
    Claims (1)
    [1]
    A process for preparing carboxylic acid amides of general formula wherein R 1 and R 2 together with the nitrogen atom form alkileniminogruppu with 4-5 carbon atoms which may be substituted with one or two methyl groups or in which one methylene group may be substituted by carbonyl groups I ct , or in which one ethylene group may be substituted by an o-phenylene group, an alkenyleneimino group with 4-6 carbon atoms, a saturated or partially saturated azabicycloalkyl group with
    6-10 carbon atoms, heptamethyleneimino, octamethyleneimino, nonamethyleneimino or decamethyleneimino group;
    R 3 is a hydrogen or halogen atom or methyl;
    A is methylene or ethylene, unsubstituted or substituted by methyl, ethyl or isopropyl, methoxycarbonyl, carboxyl or phenyl, or ethenyl;
    W is methyl, unsubstituted or substituted by an hydroxy, carboxy or alkoxycarbonyl group containing only 2-4 carbon atoms; (dimethyldixolanine) methoxycarbonyl or carboxy group and its alkyl esters containing 1-4 carbon atoms in the alkyl part, or their optically active antipodes or their sodium salts, characterized in that the compound of the general formula
    B ^ γΑ - ΝΗ 2
    Bg
    Where A and R have the indicated meanings or if A is ethenyl, its tautomer or its. complex with magnesium halide, is reacted with a carboxylic acid of the general formula hooc-ch 2 hQ W1 where W ( has the values indicated for W or • means a carboxyl group protected by a benzyloxy group, or with its anhydride or halide in an organic solvent in the presence of, if necessary
    SU „about 1253429 AZ of activator selected from the group consisting of Ν, Ν * -carbonyldiimidazole, triphenylphosphine, thionyl. chloride and triethylamine, at 1-50 ° C followed by, if necessary, removal of the protective radical and isolation of the target product in free form, in the form of optically active antipodes or in the form of sodium salt.
    类似技术:
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    同族专利:
    公开号 | 公开日
    ES513781A0|1983-04-16|
    CS228910B2|1984-05-14|
    ES8304070A1|1983-02-16|
    IE52260B1|1987-08-19|
    FI820061L|1982-07-11|
    CA1176246A|1984-10-16|
    JPS57145850A|1982-09-09|
    GB2090834A|1982-07-21|
    IE820039L|1982-07-10|
    DE3100575A1|1982-09-02|
    NO820047L|1982-07-12|
    KR880001773B1|1988-09-13|
    GB2090834B|1984-11-28|
    KR830009071A|1983-12-17|
    EP0058779A2|1982-09-01|
    AU7928982A|1982-07-22|
    ZA82111B|1983-09-28|
    ES8305749A1|1983-04-16|
    AT9464T|1984-10-15|
    ES508587A0|1983-02-16|
    DD204478A5|1983-11-30|
    PL135033B1|1985-09-30|
    EP0058779B1|1984-09-19|
    DK536581A|1982-07-11|
    IL64733D0|1982-03-31|
    DE3166213D1|1984-10-25|
    NZ199449A|1985-09-13|
    AU557959B2|1987-01-15|
    PT74261A|1982-02-01|
    HU186024B|1985-05-28|
    PL234661A1|1982-09-13|
    EP0058779A3|1982-11-17|
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    DE102008046995B4|2008-09-12|2010-08-26|Stada Arzneimittel Ag|2-ethoxy-benzoic acid|
    EP3573972A1|2017-01-27|2019-12-04|Genfit|Rorgamma modulators and uses thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19813100575|DE3100575A1|1981-01-10|1981-01-10|"NEW BENZOESAEURS, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS"|
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