Method of producing derivatives of phenylacetic acid or their salts

专利摘要:
Compounds of general formula I <IMAGE> (wherein R1 is optionally substituted polymethyleneimino or dialkylamino; A is substituted CH2; and R2, R3, and W are as defined in the specification) and tautomers, optical enantiomers and salts thereof. The new compounds have valuable pharmacological properties, particularly a hypoglycaemic effect. Processes for the preparation of the new compound and pharmaceutical compositions containing them are described.
公开号:SU1170969A3
申请号:SU833608901
申请日:1983-06-27
公开日:1985-07-30
发明作者:Грель Вольфганг；Гурнаус Рудольф；Грисс Герхард；Заутер Роберт；Руппрехт Экард；Кэлинг Иоахим；Эйселе Бернхард
申请人:Др.Карл Томэ,Гмбх (Фирма)；
IPC主号:

专利说明:

moreover, the substituents may be the same or different, and the alkyl part may contain 1 to 3 carbon atoms, or containing 1 or 2 nitrogen atoms a heteroaryl group with 4, 5, 8 or 9 carbon atoms; RJ and R are the same or different, mean a hydrogen atom or alkyl groups with 1-5 carbon atoms or together with a carbon atom mean a phenylalkyl group with 1-4 carbon atoms in the alkylidene part, W is a carboxyl group or an alkoxycarbonyl group with a total number of carbon atoms 2-6, in which the alkyl part may be substituted by a phenyl group and, starting from the B-carbon atom, may be substituted by one or two hydroxyl groups, an alkoxy group, an alkanoyloxy group, a dialkylamino group, an alkylenimino group or a pyri a dincarbonyloxy group, each alkyl portion may contain 1 to 3 carbon atoms, and an alkylene amino group may contain 4 to 6 carbon atoms, an alkenyloxycarbonyl group with a total atom number. carbon from 4 to 6, an alkyl group with 1–3 carbon atoms, hydroxymethyl, formyl, cyano. 1170969 or so, (II) where or by an introduction where the box of the nose and the box are as in and in aminocarbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, 2,2-bis .- (carboxyT-ethyl, alkoxycarbonylmethyl, 2- alkoxycarbonylethyl, 2-alkoxy-: carbonylether or 2-, 2-bis- (alkoxycarbonyl) -ethyl group, and the alkoxy group can be 1 to 3 carbon atoms, their salts, differing in that the compound of general formula A, R, have the indicated values, its complex with lithium or magnesium halo, if A denotes one of the educed vinylidene The group provides interaction with the compound of the general formula (III) -Co-CH, - / 7Vw RJ has the indicated meanings; N has the meaning given for W or means a protected carilic group, or its reactive derivative, such an acid chloride or anhydride, with a protective removal by grouping the target product in a rimmed form or as a salt.
The invention relates to a process for the preparation of new derivatives of phenylacetic acid, in particular to a method for the preparation of derivatives of phenylacetic acid of the general formula A-NH-CO-CHj where R is a straight chain alkylenimino group with 4-9 carbon atoms, unsubstituted and / or mono- or disubstituted alkyl groups with 1-3 carbon atoms, or - dialkylamino group with 1-5 carbon atoms in each alkyl part; hydrogen, chlorine or bromine, hydroxyl group 3 carbon atoms} an alkyl group on a carbon atom, a hydrogen atom or a halogen group of the formula RK-Re. i- / - chRR is an alkyl group with 1–3 carbon atoms, unsubstituted or substituted by an alkoxy group with 1–3 carbon atoms or a phenyl group, an alkyl group with 4–7 carbon atoms, an alkenyl group with 3–5 carbon atoms, cyano- or an alkylenimino carbonyl group with 4-6 carbon atoms in the alkylene part, an aminocarbonyl group unsubstituted or mono- or disubstituted with an alkyl group or phenylalkyl group with 1-3 carbon atoms in the alkyl part, an aryl group with 6 or 10 carbon atoms, unsubstituted or mono- or disubstituted with gal atoms ogen, alkyl, hydroxyl, alkoxy, phenylalkoxy, alkyl sulfenyl, alkylsulfinyl and / or alkylsulfonyl groups, the substituents may be the same or different, and the alkyl part may contain 1-3 carbon atoms, or containing 1 or 2 atoms a nitrogen heteroaryl group with 4,5,8 or 9 carbon atoms. RjH, the same or different, means a hydrogen atom or alkypyl groups with i-5 carbon atoms or, together with a carbon atom, means a philylalkyl group with 1-4 carbon atoms in the alkyl part. 4 W - carboxyl group or alkoxycarbonyl group with 2-6 total carbon atoms, in which the alkyl part can be replaced by a phenyl group and, starting from the fi-carbon atom, can be replaced by one or two hydroxyl groups, alkoxy group, alkanoyloxy group, dialkylamino group with an alkylenne group or a pyridinecarbonyloxy group, each alkyl portion may contain 1 to 3 carbon atoms, and an alkyl amino group. may contain 4-6 carbon atoms, an alkenyloxycarbonyl group with a total number of carbon atoms from 4 to 6, an alkyl group with 1-3 carbon atoms, a hydroxymethyl, a formyl group, a cyano group, an aminocarbonyl, carboxymethyl, 2-carboxysethyl, 2-carboxyethenyl, 2,2- a bis (carboxy) -ethi1na. alkoxycarbonylmethyna, 2-alkoxycarbonylethanes, 2-alkoxycarbonylstenyl or 2,2-bis- (alkoxycarbonyl) -ethyl group, and the alkoxy group can be 1-3 carbon atoms of their salts. lower content sa hara in the blood wiliness. The aim of the invention is the method of studying new derivatives of phenylacetic acid, which have a greater activity in reducing blood sugar by urs. The method is illustrated by the following examples. Example 1. Complex ethyl p (4-methylphenyl) -2-p-leinobenzyl-aminocarbonyl Methylnanoic acid. To 4.2 g (15 mmol) (4-methylsilyl) -2-piperidinobenzylamine and g (16.5 mmol) of 4-ethoxycarbonyl-acetic acid, dissolved in 0 ml of acetonitrile, add alternately 4.7 g (18 mmol) triphosphine, 3 g (30 mmol) of triethyl and 1.5 ml (15 mmol) of carbon tetrachloride. The reaction mixture is stirred for 2 hours at 50, then concentrated and after acidification with 5N. hydrochloric acid is extracted with ethyl acetate and acetic acid. Then the acidic aqueous phase is extracted several times with methylene chloride)). The methylene chloride extracts are washed with a nari bicarbonate solution and dried over magnesium sulphate and concentrated. The residue thicken rubbed with ethanol and sucked off.
Yield 4.55 g (65% of theory); m.p. 177-178 C.
Calculated,%: C 76.57; H 7.28; N 5.95.
Found,% s C 76,19; H 7.16; N 5.82.
The following compounds are prepared in analogy to Example 1: (3-methylphenyl) -2-piperidinobenzyl J-aminocarbonylmethyl-benvoic acid ethyl ester
The output of 48% of theory, so pl. 159160С.
Calculated,% C 76.57; H 7.28; N 5.95
Found,%: C 76.80; H 7.35; N 5.76;
ethyl ester 4 - ((2-Methylfensh1) -2-piperidinobenzylJ-aminocarbonylmethyl-benzoic acid
The output of 35.4% of theory, so pl.196198 C.
Calculated,%: C 76.57; H 7.28; N 5.95
Found,%: C 76.65; H 7.35; N 5.90;
ethyl ester (4-methoxyphenyl) -2-piperidinobenzyl} -aminocarbonylmethyl-benzoic acid
The output of 45% of theory, so pl. 167168 ° C.
Calculated,%: C 75.05; H 7.04; N 5.76
Found,%: C 73.72; H 6.99; N 5.62;
ethyl ester (4-benzyloxyphenyl) 2-piperidinobenzyl; | -aminocarbonylmethyl j-benzoic acid
Output 96% of theory, so pl. 154155 0.
Calculated,%: C, 76.84; H 6.81; N 4.98
Found,%; C, 76.82; H 6.68; N 5.03; .
ethyl 4-fN-p- (45-fluorophenyl) -2-pipericinobenzyl1-aminocarbonylmethyl1-benzoic acid ethyl ester
Output 58% of theory so pl. 174176 S.
Calculated,%: C 73.40; N. 6.58; to N 5.90
Found,% t С 73.55; H 6.72; N 5.91}
ethyl ester 4-fN- e - (2-fluorophenol) -2-piperidinobenzylJ-ami5 nocarbonylmethyl-benzoic acid
Output 83% of theory, so pl. 173175 0.
Calculated,%: C 73.40; H 6.58; N 5.90
0 Found,%: C 73, bG; H 6.62; N 5.85;
Complex methyl ester (4-chlorophenyl) -2-piperidobenzoyl-aminocarbonyl-benzoic acid 5 Exit 57% of theory, so pl. 178 -
181 ° C ..
Calculated,%; C, 70.94; H 6.36; N 7.51; C1 7.22
Found,%: C 71.10; H 6.56; 0 N 5.26; C1 7.11;
ethyl ester (V- (3-chlorophenyl) -2-piperVDD) benzyl-aminocarboxymethyl benzoic acid
Output 71% of theory, so pl. 1535.
Vmsleno,%: C, 70.94; H 6.36; N 5.71; C1 7.22
Found,%: C 70.86; H 6.26; N 5.65; C1 7.25 0 (2-chlorofensh1) -2-piperidinobenzylZ-aminocarbonylmethyl-benzoic acid ethyl ester
Output 66% of theory, so pl. 196198 Since ..
5 Calculated,%: C, 70.94; H 6.36; N 5.71; C1 7.22
Found,%: C, 70.90; H 6.30; N 5.61; C1 7.10
ethyl ester (4-Me0 tilmercaptophenyl) -2-piperncinobenol. zyl aminocarbonylmethyl-benzoic acid.
Output 84% of theory, mp, 173 175 C.
5Calculated,%: C 71.68; H 6.82;
N 5.57; S 6.38
Found,% C 71.92; H 6.97; N 5.45; S 6.21; 7 complex ethyl ester of 4-fN-5-chloro (2-chlorophenyl-2-pipervdinobenzyl-aminocaronylmethyl 7-benoic acid. Yield 92% of theory, m.p. 213215 0. Calculated,%: C, 66.28; H 5.75; N 5.33; C 13.49; Found,%; C 66.45; H 5.86; N 5.25; C 13.51; ethyl ester 4-CN-t2-nHne rvdino - (2-PIRVDSH1) -benzylJ-amine carbonic1methyl7-benzoic acid; Yield 51% of theory, mp 158159 C. Calculated,%: C 73.50; H 6.83; N9.18 Found,% s C 73.40; H 6.95; N 9.10; ethyl ester 2-pipe ndino-c- (3-pyridyl) -benzylJ-amine carboxymethyl-benzoic acid; Yield 85% of theory, mp 172 Calculated ,%: C 73.50; H 6.86; N 9.18; Found,% C 73.42; H 6.76; N 9.25; layer 4-N-2-pipa RVDIN07 "/ - (4-pyridyl) -benzyl J-amine carbonylmethyl / -benzoic acid 4-N-ethyl ethyl ester; Yield 20% of theory, mp 150152 C. Calculated,%: C 73, 50, H 6.83; N 9.18; Found: C 73.61; H 6.91; N 9.15; ethyl ester (6-chloro-o-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl j-benzoic acid Output 12% of theory, so pl. oil Calculated,%: molar peak m / e 490/492 Found molar peak m / e 490/492; (4-chloro-o-phenyl-2-pipervdinobenzyl) aminocarbonylmethyl-1-benzoic acid ethyl ester 37% yield from theory, m.p. 148150 C. Calculated,%: C, 70.94; H 6.36; N 5.71; C1, 7.22; Found: C, 70.81; H 6.25; N 5.61; C1 7.12; ethyl ester 4-CN - (- 3-chloro-o-phenyl-2-pyrvidinobenzyl) -aminocarbonylmethyl-benzoic acid 74% of theory, so pl. 176178 S. 69 Calculated,% “C H 6.39; N 5.71; C1, 7.22; Found,% C, 70.59; H 6.25; N 5.68; C1 7.16; 4-CN- (6-methyl-o (-phenyl-2-piperchcinobenzyl) -aminocarboxymethyl-benzoic acid ethyl ester. Yield: 65% of theory, mp: oil. The molar peak m / e 470 was calculated. Mole was found. ny peak m / e 470; ethyl (5-methyl-o-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid ethyl ester. Yield 48% of theory, mp. 171173. Calculated,% C 76.57; H 7.28; 5.95. Found,% C 76.75; H 7.35; N 5.72; ethyl ester 4-fN- (4-methyl-o-phenes-1-2-piperidinobenzyl) -aminocarbonylmethyl - benzoic acid. Yield 76% of theory, mp 133135 ° C. Calculated, -% C 76.57; H 7.28; N 5.95. Found,% C 76.51; H 7.16; N 5.83; s false ethyl ether (5-methoxy-o-phenes-1-2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid. Yield 10% of theory, mp. 122125 C. Calculated; molar peak m / e 486 Found; molar peak m / e 486 ; ethyl ester of 4-fY- (6-methoxy-o-phenes 1-2-piperidinobenzyl) aminocarbonylmethyl 3-benzoic acid. Yield 97% of theory, mp: oil. Calculated molar peak .m / e 486 Found molar peak m / e 486; ethyl ester 3-chloro-4- (Y- (o (-phenyl-2-piperidinobenzyl) -aminoCarbonylmethylZ-benzoic acid. Yield 42% of theory, mp. 175176 ° C. Calculated,% C 70.93; H 6.36; N 5.71; C1 7.22. Found: C 70.65; H 6.36; N 5.50; C1 7.29; ethyl ester (2-dimethylamino-0-phenylbenzyl) -aminocarbonylmethyl-benzoic acid. Yield 67% of theory, etc. 116118 C. Calculated,% C 74.97; H 6.77; N 6.73 Found, 7.1 C 75.13; H 6.60; N 6.78; ethyl ester 4- K- (2-di-n-propylamino-o-phenylbeneyl) -amoynocarbonylmethyl-benzoic acid Yield 76% of theory, mp 138139 C. Calculated, 7.1 C 76 , 24; H 7.68; N 5.93 Found,% J C 76.41; H 7.79 ; N 5.81; ethyl ester 4-H-2-octa hydro-1H-azonino) -0-phenylbenzyl-amino Lcarbonylmetyl benzoic acid 71% yield of theory, m.p .: Oil Calculated: molar peak m / e 498 Found molar peak m / e 498; complex ethyl ester 4-tN-t5-xlop 2- (2-methylpiperidino) - o -feiylbenzylZ-aminocarbonylmethylZ-benzoic acid The yield of 36.5% of theory, so pl. 17 Calculated,% s C 71,24; H 6.58; N 5.54; C1 7.01 Found: C 71.45; H 6.68; N 5.59; C1 7.20; ethyl ester (3,3-dimethylpipervidino) - oi-phenylbenzyl-aminocarbonylmethyl) -benzoic acid Yield 91% of theory, so pl. 146148 S. . Calculated% s C 76,82; H 7.49; N, 5.78; Found: C, 76.91; H 7.55; N 5.61. Example 2 y- (4-chloro) phenyl) -2-piperi dinobenzyl2-aminocarbonylmethyl benzoic acid ethyl ester. To a solution of 6.02 g (20 mmol) (4-chlorophenyl) -2-piperidinobenzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform are added dropwise with ice-cooling. BQP 5 g (22.1 mmol) ) 4-ethoxycarbonyl-fenshgatt1lchloride in 20 ml of chloroform, stirred for 2 h at room temperature, added to water and extracted with chloroform. The extracts are dried and concentrated. The residue is chromatographed on silica gel with toluene and ethyl acetate 5: 1. Output g (57% of theory), t. So pl. 178-181 p. Calculated,%: C, 70.94; H 6.36; N 5.71; C1, 7.22; Found: C, 71.09; H 6.47; N 5.61; C1 7.10. Analogously to Example 2, 4-N-5-chloro-2- (3-methylpiperidino) -oi-phenylbenzyl-J-aminocarbonylmethyl-benzoic acid ethyl ester is obtained. Output 54% of theory, so pl. 178180s Calculated,%: C 71.24; H 6.58; N 5.54; C1 7.01 Found,%: C 70.91; H 6.64; N 5.75; C1 7.01. Example 3 4-Sy-in - (4-Methylphenyl) -2-piperidinobenzyl-aminocarbonylmethyl-benzoic acid. 4.4 g (9.35 mmol) of (4-methylphenyl) -2-pipervdinobenzyl-3-aminocarbonylmethyl-benzoic acid ethyl ester is dissolved in 150 ml of ethanol with heating. Then 20 ml of 1N sodium hydroxide are added and stirred for 3 hours at 50 ° C. To the reaction mixture is added 20 ml of 1N. hydrochloric acid and remove the excess standard by condensation in an evaporator. The remaining aqueous suspension is filtered and the precipitate is rinsed with water. Then recrystallized from acetonitrile. Output 2.45 g (59.3% of theory), so pl. 226-228 ° C. Calculated,%: C 75.99: H 6.83; N 6.33. Found: C 75.60; H 6.75; N 6.29. Analogously to Example 3, the following is obtained: Cm-Co - (3-methylphenyl) -2-piperidinobenzyl-aminocarbonylmethyl-benzoic acid 72% yield from theory, m.p. 202203 ° C. . Calculated,%: C 75.99; H 6.83; N 6.33. Found: C 75.64; H 6.91; N 6.37; 4-N-ai- (2-methylphenyl) -2-piperidinobenzyl-aminocarbonylmethyl 3-benzoic acid. Output 42.6% of theory, so pl. 285290 C. Calculated,%: C 75.99; H 6.83; N 6.33; Found: C, 76.05; H 6.98; N 6.25; .
II1170969.12
(4-methoxyphenyl) -2-piperncin- Yield 98% of theories, t. mp, 303 benzyl-aminocarbonylmethylJ-benzoine.  . acid.  Output 72.4% of theory, t. square  22  Calculated,%: C 73.34; H 6.59; N 6.11% found {C 73.22; H 6.61; N 6.13; 4-CN-tv - (4-benzyloxiphenyl) -2-pipone rvidobenzium 3-aminocarbonylmethyl benzoic acid.  Output 57% of theory, t. square  219221 C.  Calculated% С 76.38; H-6.41; N5.24%;%; C 76.05; H 6.44; N 5.24: (4-Fluorophenyl) -2-piperidino zylZ-aminocarbonylmethyl-3-benzoic acid.  Output 75% of theory, t. square  238240 C.  Calculated,%; C, 72.63; H 6.09; N 6.27; Found: C, 72.98; H 6.29; N 6.32: 4-tN- oi- (2-fluorophenyl) -2-piperidino, benzyl-aminocarbonyl-methyl-benzoic acid Output 87% of theory, t. square .  280283C.  Calculated,%: C, 72.63; H 6.09; N 6.27; Found: C, 72.70; H 6.10; N 6.32; (4-chlorophenyl) -2-piperdino benzyl-aminocarbonylmethyl 3-benzoic acid Output 89% of theory, t. square  241242 s.  Calculated. %: C 70.05; H 5.88; N 6.05; C1. 7.66; Found: C, 69.74; H 6.05; N 6.01; C1 7.64;  4-CN- (3-chlorophenyl) -2-piperidino benzyl-aminocarbonylmethyl} benzoic acid 53% yield of theory, t.  square  223225 C.  Calculated,%: C 70.05; H 5.88; N 6.05; C1 7.66; Found: C, 70.28; H 5.98; N 5.78; C1 7.84; 4-СЫ-Сс -chlorophenyl) -2-piperidinobenzylJ-aminocarbonyls IJ-benzoic acid Calculated,%: C 70.05; H 5.88; N 6.05; C1, 7.66; Found: C, 69.88; H 6.05; N 5.87; C1 7.74; - (4-metsh1merkaptofenil) -2-pipertstsinobenzyl} -aminocarbons1metnp} -benzoic acid Output 84.86% of theory, t. mp 225227 ° C.  Vytseleno,%: C 70,86; H 6.37; N 5.90; S 6.75 Found,%: C 70.34 ,; H 6.37; N 5.68; S 6.82; 4- nb-chloro-o (;-(. 2-chlorophenyl) -2-piperidinobenzyl-aminocarbonylmethyl-benzoic acid. Yield 90% of theory, t. square  317320 ° C.  Calculated,%; C 65.19; H 5.27; N 5.63; C1, 14.25; Found: C, 64.87; H 5.34; N 5.69; C1 14.22; 4-N-C2-pipervdino-oi- (2-pyridshI) -benzyl-aminocarbonylmethylZ-benzoic acid. Yield 81% of theory, t. square  160161С.  Calculated,%: C, 72.71; H 6.34; N 9.78 Found: C 72.43; H 6.39; N 10.00; 4-f N-2-pipercincin-o (1- (3-chiridip) -benzylJ-aminocarbonylmethyl-benzoic acid.  Output 72% of theory, t.  square  252253 ° C.  Calculated,%: C, 72.71; H 6.34; N 9.78 Found: C 72.56; H 6.53; N 9.60; 2-piperid ino-oi- (4-pyrvdil) -benzyl-aminocarbylnylmethyl-benzoic acid.  Output 68.5% of theory, t. square   (decomposition).   Calculated,%: C, 72.71; H 6.34; N 9.78 Found: C 72.31; H 6.29; N 9.63; (6-chloro-o-phenyl-2-pipsridinobenzsh1) -aminocarbonylmethyl. 1-benzoic acid Yield 82% of theory, t. square  91944.  Calculated,%: C 70.04; H 5.88; C1 7.66 13 1 Found: C 69.61; H 5.77; N 5.96; C1 7.78; (4-chloro-o; -phenyl-2-piperidinobe. nzil) -aminocarbonylmethylZ-benzoic acid Yield 61% of theory, t.  square  221223 S.  Calculated,%: C, 70.05; H 5.88; N 6.05; C1, 7.66; Found: C, 69.73; H 5.89; N 5.87; C1 7.52; (3-chloro-phenes1-2-pipervdinobenzylJ-aminocarbonylmethylbenzoic acid Acid 83% of theory, t. square  210213 S.  Calculated,%; C, 70.05; H 5.88; N 6.05; C1 7.66; Found: C, 70.31; H 6.03; N 5.90; C1 7.79; (6-metsh1 - {) - phenyl-2-piperidino-benzyl) aminocarbonylmethyl-benzoic acid.  .  Output 64% of theory, t. square  165170 ° C (sintering starts at Calculated,%: C 75.99; H 6.83; N 6.33; Found,% 5C 75.73; H 6.96; N 6.14; (5-methyl-o-phenyl -2-piperidinobenzyl) aminocarbonylmethyl benzoic acid.  Output 97% of theory, t. square  243245 S.  Calculated,%: C 75.99; H 6.83; N 6.33. Found: C 75.60; H 7.01; N 6.31; (4-methyl-y-phenyl-2-piperidinobenzyl) -aminocarboxymethyl-benzoic acid.  Output 96% of theory, t. square  202203 С, Calculated,%: С 75.99; H 6.83; N 6.33; Found: C, 76.04; H 6.78; N 6.23; (5-methoxy- (1-phenyl-2-pipervdinobenzyl) -aminocarbonylmethyl-benzoic acid.  n The yield of 27% of the theory ,, ,,: Calculated% C 73 34- H 6 59 „,. .     L "PE" -, "" Found,%: C 72.92; H 6.68; N 5.99; (6-methoxy-in-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid 6914 Yield 51.5% of theory, t. square  9095 ° C.  Calculated,%: C 73.34; H 6.59; N 6.11 Found, Z: C 73.03; H 6, A2; N 5.86; 5-chloro-2- (3,5-cis-dimethylpiperidino) -B-phenyl 1-benzyl-aminocarbonyl-methyl-benzoic acid Yield 81% of theory, tons , 253255 ° C.  Calculated,%: C, 70.93; H 6.36; N 5.71; C1, 7.22; Found: - C, 70.63; H 6.51; N 5.73; Cl 7.36; 4- {s- (2-dimethylpamino-in phenyl-benzyl) -aminocarbonylmethyl-benzoic acid.  Output 83% of theory, t. square  183184 ° C.  Calculated,%: C, 74.20; H 6.23; N, 7.21; Found: C, 74.31; H 6.27; N 7.16; (2-di-n-propylamino-in-phenylbenzyl) -aminocarbonylmethyl-D-benzoic acid 79% of theory yield, t.  pl, 202204 0.  Calculated,%: C 75.64; H 7.26; N 6.30 Found,% s C 75.74;  H 7.31; N 6.15; 4-H-C5-chloro-2- (2-methyl-piperidino) - -c-phenes1-benzyl-aminocarbonylmethyl-benzoic acid 52% yield of theory, t. square  280282 0.  Calculated,%: C 70.50; H 6.13; N 5.87; C1, 7.43; Found: C, 70.14; H 6.10; N 5.75; C1 7.45; 4-y-5-chloro-2- (3-metstypiperdino) -o-phenylbenzyl-aminocarbonylmethyl benzoic acid 66% of theory yield, t, pl.  246248С.  Calculated,%: C 70.50; H 6,  N 5.87; C1, 7.43; Found,% C, 70.16; H, 6.07; N 5.87; C1 7.30; / Hm Go / -h t h - / 4-1Y-12- (3,3-dimelpipervodino) -o (-phenylbenzyl-aminocarbonylmethyl-benzoic acid,.  Yield 59% of theory, t. pl. 238240 C.  Calculated,%: C 76.28; H 7.07; N 6.14; Found: C, 76.38; H 7.28; N 6.11;  3-chloro-4-K- (o-phenyl-2-piperidinobezyl) -aminocarbonylmethyl-benzoic acid 56% yield of theory, t. pl, 236239C.  Calculated,%: C 70.04; H 5.88; N 6.05; C1, 7.66; Found: C, 69.88; H 5.77; N 5. , 86;  C1 7.81; M-C2- (3,5-cis-diphenylpiperidino) -5-nitro-o-phenylbenzyl-aminocarbonylmethyl-benzoic acid Yield 81% of theory, t. square  255 ° C (decomposition).  Calculated,%: C 69.44; H 6.23; N 8.38 Found: C 68.95; H 6.44; N 8.53; (octahydro-1H-azonino) -.  - about phenylbenzyl. } -aminocarbonylmethyl-benzoic acid Yield 64.5% of theory, t.  pl, 23.  Calculated,%: C 76.56; H 7.28; N 5.95.  Found,%: C 76.50; H 7.30; N 5.94 (5-6xy-o6-phenyl-2-piperzcinobenzyl) aminocarbonylmethyl benzoic acid.  Output 71% of theory, t.  square  98УГС.  Calculated,%: C, 72.95; H 6.35; N 6.30 Found,%: C 72.98; H 6.40; N 6.47.  . Example 4  4-s-Co / - (4-Methyl-phenyl) -2-piperidinobenz aminocarbonylmethyl-cinnamic acid.  It is obtained by alkaline saponification of 4-Sy-ethyl- (4-methylphenyl) -2-piperidinobenzyl-aminocarbonylmethyl-1-cinnamic ethyl ester as in Example 3.  Output 84% of theory, t. square  173MB C.  Calculated,%: C 76.90; H 6.88; N 5.98.  Found,%: C, 77.24; H 7.01; N, 5.64. Analogously to Example 4: (o-phenyl-2-piperidinobenzyl) aminocarbonylmethyl 3-cinnamic acid.  Output 75% of theory, t. square  177180С, Calculated,%: С 76.62; H 6.65; N 6.16; Found; C 76.75; H 6.57; N 6.07.  Example 5  (4-Methylphenyl) -2-piperzzinobenzyl7-aminocarbonylmethyl-benzonoyl.  Prepared from (4-methyl-phenyl) -2-piperidinebenzylamine and 4-cyano-phenylacetic acid as in Example 1.  .  Output 64% of theory, t. square  144146 ° C.  i Calculated,%: C 79.40; H 6.90; Ы 9.92 Found,%: C 79.10; H 6.90; N 9.78.  Analogously to Example 5, 4-fN- (o-phenyl-2-piperchcinobenzyl) -aminocarbonylmethyl-benzonitrile is obtained.  Output 53% of theory, t. square  178181 ° C.  Calculated,%: C 79.18; H 6.65; N 10.26 Found,%. : C 78.84; H 6.55; N 10.24.  Example 6  4 - {(2-methoxy-1- (2-piperdinophenyl) -ethyl 3-aminocarbonylmethyl 3-benvoic acid ethyl ester.  To a solution of 0.55 g (2.34 mmol) of 2-methoxy-1- (2-pipervdinofenil) -ethylamine in 5 ml of acetonitrile, 0.49 g (2.34 mmol) of 4-ethoxycarbonyl-phenylacetic acid, 0 , 73 g (2.78 mmol) of three |) enylphosphine, 0.50 ml (3.66 mmol) of triethylamine and 0.23 g (2.34 mmol) of carbon tetrachloride and stirred for 20 hours at room temperature.  Then, vacuum under vacuum and distribute between ethyl acetate and water.  Dry the organic extract and filter and evaporate in vacuo.  The residue obtained by evaporation is purified by chromatography on a column of silica gel (toluene and acetone 10/2).  Output 0.45 g (45% of theory), t.  square  122-123C.  Calculated,%: C, 70.73; H 7.60; N, 6.60; Found: C, 71.04; H 7.48; N 6.39.  Analogously to Example 6, the following compounds are obtained: 4- (1- (3-chloro-J71 -2-pyperidinophenyl) -1-6wl1) -amiocarbonylmethyl1-benzoic acid ethyl ester, ethyl ester 55% of theory, t.  square  141143 S.  .  AT. Calculated,%: C 68.33; H 7.28; C1 7j76; N 6.13 Found,% j C 68.30; H 7.16; Cl 8.03; N 6.20; 4- (1- (6-chloro-2-piperid11Nophenyl) -1-butyl) aminocarbonylmethyl benzoic acid ethyl ester.  Output 73.9% of theory, t. square  7982 C.  Calculated,% C 68.33; H 7.28; C1 7.76; N 6.13; Found; C 68.45; H 7.24; Cl 7.80; N 6.09; False 4- (1- (4-bromo-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoic ethyl ethyl ester Output 62.1% of theory, t. square  116118 ° C.  Calculated% 5 C 65.27; H 6.63; Br 15.93; N, 5.58; Found: C, 62.53; H 6.48; Br 15.98; N 5.66; ethyl 4- (1- (4-nitro-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl) benzoic acid ethyl ester 74.6% of theory, t. square  127130 0.  Calculated,%: C, 66.79; H 7.11; N 8.99 Found;%; C, 66.88; H 7.08; N 9.15; 4- (1- (3-methyl-2-piperidino) ethyl ester. phenyl) -1-butyl) -aminocarbonyl-benzoic acid.  Yield 68% of theory, t. square  145147С.  Calculated,%: C, 74.28; H 8.31; N 6.42.  Found,%: C, 74.40; H 8.30; N 6.41; complex ethyl ester 4-. t (1- (4-methyl-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid V-code 54.7% of theory, t. square  113lU C. .  Calculated,%: C, 74.28; H 8.31: „D2 Found,%: C 74.23; H 8.30; . .  / her.  ethyl 4-C (1- (5-methyl-2-piperiinoinophenyl) -1-butyl) aminocarbonylmethyl benzoate.  69 18 Output 67.9% of theory, t. square  149 ISOc.  Calculated,% С 74.28; H 8.31; N 6.42 Found,% C 74.38; H 8.21; N 6.49; complex ethyl ether. 4-f (1 (6m ethyl-2-piper1 Zdinofensh1) -1-butyl-aminocarboxyethyl j-benzoic acid, Yield 47% of theory, t. square  9293 C.  Calculated,%: C, 74.28; H 8.31; N 6.42 Found,% C 72.50; H 8.46; N 6.48; ethyl 4-f (1- (2-pyropolydinophenyl) -butyl) -aminocarboiylmethyl-benzoic acid ethyl ester 57.3% of theory, t. pl, 122125s.  Calculated,% g C 73.50; H 7.90; N 6.86; Found: C 73, 63; H 8.07; N 7.01; ethyl ester of 4- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylImethyl) benzoic acid, yield 71.5% of theory, t. square 127128 C.  Calculated,%: C 73.90; H 8.11; N 6.63 Found: C 73.90; H 8.06; N 6.72; 4- (1- (2- (4-methylpiperchicnophenyl) -1-butyl) aminocarbonylmethyl benzoic acid ethyl ester. h Output 51.1% of theory, t. square  153155 s.   Calculated,%: C, 74.28; H 8.31; N 6.42; Found: C, 74.55; H 8.33; N 6.45; ethyl ester of 4- (1- (2-hexahydroazepinophenyl) -1-butyl) -aminocarbonylmethyl benzoic acid. Yield 42.7% of theory, t. square  145147 C.  Calculated,%: C, 74.213; H 8.31; N 6.42; Found: C, 83.98; H 8.26; N 6.58; rf, f.   4- (1- (3-fluoro-2-pipervdinofensh1) -1-butyl) complex ethyl ester; 1-aminoconoxybenzene: J-benzoic acid. Yield 55% of theory, t. square  128-130s  Calculated,%: C, 70.88; H 7.55; N 6.36 Found: C 71.14; H 7.57; N 6.49; a complex methylone effect of 4- (1- (2-pip picinophenyl) r1-butyl) -aminocarbonyl of methyl-benzoic acid 63.2% of theory, t. square 147148 0.  Calculated,%: C 73.50; H 7.90; N 6.86 Found,% s C 73.66; H 7.88; N 6.80; 4- (1- (2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid n-butyl ester; 50.9% of theory, t. square  117 (ether).  Calculated,%: C, 74.63; H 8.50; N 6.22; Found: C, 74.49; H 8.46; N 6.14; ethyl ester of 3-chloro-4- (1- (2-piperidinophenyl) -2-butyl) -amino carbonylmethyl} -benzoic acid Yield 14.9% of theory, t. square  20 ° Calculated: m / e 456/458 (1 chlor) Found m / e 456/458 (1 chlorine); ethyl ester of 4- (1- (2-pipa rvdinophenyl) -4-penten-1-yl) amino bonilmethylZ-benzoic acid 18.9% of theory, t. square SW505 ° C.  Calculated,%: C 74.62; H 7.89; N 6.45; Found: C 75.01; H 8.10; N 6.26; 4- (1- (3-chloro-2-piperdinophenyl) -1-ethyl) -aminocarbonylmethyl-benzoic acid ethyl ester. Yield 58.0% of theory, t. square  166 168С.  Calculated,%: C, 67.20; H 6.81; C1 8.27; N 6.53; Found: C 67.17; H 6.85; C1 8.17; N 6.45 Example 7.  4 - {(1- (5-nitro-2-pipercincinophenyl) -1-butyl) aminocarbonylmethyl-benzoic acid ethyl ester.  To a stirred solution of 15.1 g (54.4 mmol) of 1- (5-nitro-2-piperdinofenes1) -1-butylamine and 8.46 ml (61.4 mmol) of triethylamine in 55 ml of methylene chloride are added dropwise m solution of 14.6 g (64.6 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 20 ml of methylene chloride for 30 minutes, and the temperature does not exceed 30 C.  Then it is stirred for 2 hours at room temperature, 300 ml of methylene chloride is added and extracted twice with shaking, each time with 50 ml of water.  The organic phase is dried over.  sodium sulfate, filtered and evaporated in vacuo.  The red-brown, oily residue is purified by chromatography on a column of silica gel (toluene / acetone 10/1).  Output 17.7 g (69.7% of theory), t. square  135-137 ° C (ether).  Calculated,%: C, 66.79; H 7.11; N, 8. Found;%: C, 66.73; H 6.99; N 9.09.  Analogously to Example 7, the following compounds are prepared: ethyl 4- (1- (2-piperdinophenyl) -1-butyl) -aminocarbonyl-methyl-benzoic acid ethyl ester. Output 80.2% of theory, t. square  127129C.  . Calculated,%: C 73.90; H 8.11; N 6.63 Found: C 73.98; N. 8.26; N 6.89; ethyl 4- (1- (4-hydroxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl j-benzoic acid ethyl ester 13.5% of theory, t. square  178180 C.  Calculated,%: C 71.21; H7.81; N 6.39; Found: C 71.27; H 7.82; N 6.40; ethyl 4- (1- (5-hydroxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoic acid ethyl ester 37.4% of theory, t. square  188190 ° C.  Calculated,%: C 71.21; H 7.81; N 6.39.  Found,%: C 71.34; H 7.89; N 6.38.  Example 8  4-11 (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl J-phenylacetic acid.  3.0 g of 15.45 mmol) p-phenylene-diacetic acid and 10 ml of thionyl chloride are heated with 90 ml of heat for 90 min and evaporated under vacuum.  The crude diacid chloride is dissolved in 00 ml of methylene chloride.  To this solution, a solution of 3.6 g (15.45 mmol) of 1- (2piperidinophenyl) -1-butylamine a is added dropwise at 10-15 ° C.  By the course of 2 hours, the mixture is evaporated under vacuum at room temperature and the residue is distributed between 100 ml of cold 5% sodium hydroxide and ethyl acetate.  Filter through kiz gur and separate the organic phase.  The alkaline water phase is adjusted by semi-centered hydrochloric acid to a pH value of 5.5 and extracted with egylacetate.  Dry over sodium sulfate, filter, and evaporate the filtrate under vacuum.  The residue is purified by chromatography on a column of silica gel (chloroform / methanol 20 / l), Yield 0.10 g (1.6% of theory), t.  square  136-1 OC (acetonitrile and ether).  Calculated,%: C 73.50; H 7.90; N 6.86.  Found,%; C, 73.17; H 8.10; N 6.85.  .  Example 9  4- (2-methyl-1- (2-piperidinophen nip) -1-propen-1-yl) aminocarbonyl methyl benzoic acid ethyl ester.  To a solution of 6.17 g (26.8 mmol) of freshly prepared isopropyl- (2-piperidinophenyl) -thethymeine, 5.58 g (26.8 mmol 4-ethoxycarbonylphenylacetic acid 8.43 g (32.2 g) were added to 62 ml of nitrile acetic acid). mmol) triphenylphosphine 11.2 ml (80.4 mmol) of triethylamine and 2.6 ml (0.0268 mol) of four-chlorinated carbon and stirred for 20 hours at room temperature. Then evaporated under vacuum and partitioned between ethyl acetate and water. The dried and filtered extra ethyl acetate is evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (toluene / ethyl acetate 5 / l)  Output 3.0 g (26.6% of theory), t, pl.  82-84 C (ether).  Calculated% 1 C 74.26; H 7.67; N 6.66; Found: C, 74.20; H 7.49; N 6.56. Analogously to Example 9, the following compounds are obtained: ethyl 4- (1- (2-psh1e rvdinophenyl) -1-penten-1-yl) -amino carboxymethyl-benzoic acid ethyl ester. 16% of theory, m, pl, 9497 C (ethanol), Calculated,%: C 74.62; H 7.89; N 6, AZ Found,%: C 74.75; H 7.71; N 6.24; ethyl ester of 4- (1- (2-piperidinof NILE) -1-hexene-1-yl) aminocarbonylmethyl-benzoic acid.  . The output of 27.4% of theory, t. mp, 83-85 ° C (ethanol).  Calculated% C 74.97; H 8.09; N 6.24; Found: C, 75.42; H 7.95; N 6.00; ethyl ester 4-f (1- (2-piperon adinophenyl) -1-buten-1-yl) aminocarbonylmethyl j-benoic acid.  Output (lipophilic isomer in the form of E) 4.1% of theory, t, pl.  20s, Vomsilo: m / e 420, Found; m / e "420.  Yield (lipophilic isomer in the form of Z) 51.9% of theory, t. square  115117 C (ethanol).  Calculated,%: C, 74.26: H, 7.67; N 6.66 Found: C 73.85; H 7.59; N 6.44; 4- C (2-phenyl-1- (2-piperdinophenyl) -e-ten-1-n) -aminocarbonylmethyl-benzoic acid ethyl ester.  Output (lipophilic isomer in the form of E) 4% of theory, t. . square  75-77 C (ether / petroleum ether).  Calculated% s from 76.90; H 6.88; N, 5.98; Found:% t C, 77.31; N N 5.93 Yield (lower amount of lipophilic isomer in the form of Z) 42.7% of theory, t, pl.  157-160 C (ethanol).  Calculated,%: C 77.19; H 6.95; N 6.02; 4- (3-phenyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl 1-benzoic acid ethyl ester.  Output 62.6% of theory, t. square , Calculated: m / e 482 Found: m / e 482; 4-C (1- (2- (3,3-dimethyl-piperidino) -phenyl-1-buten-1-yl) -amino-carbonylmethylJ-benzoic acid ethyl ester.   . .  Output 33% of theory, t. square  113116 C (ethanol).  Calculated,%: C, 74.97; H 8.09; 6.24; Found-,%: C 75.37; H 7.93; 6.03; 4- (1- (6-methyl2-piperidino phenate) -1-buten-1-yl) aminocarbonylmethyl benzoic acid ethyl ester.  Output 60.4% of theory (in the form of t. square  95-96 C.  Calculated,%: C 74.62; H 7.89; . N 6.45.  m / e 434; m / e 434.  Found,%; C, 74.44; H 8.00; N 6.59.  Example 10  Ethyl 4- (1- (2-piperidino-phenyl) -1-butene-1-yl) aminocarbonylmethyl} benzoic acid ethyl ester.  Heat a stirred solution of 19.0 g (82.46 mmol) of freshly prepared (2-piperidinophenyl) propyl ketmina and 11.5 ml (82.46 mmol) of triethyl amine in J90 ml of water-free toluene to 85 ° C, then a solution of 18.7 g (82.46 mmol) of 4-ethoxide of c-carbonyl-phenylacetic acid in 95 ml of anhydrous toluene is added dropwise over 10 minutes and stirred for 95 minutes at 95 ° C.  It is then cooled to a temperature of 20 ° C and extracted twice with shaking.  The organic phase is dried over sodium sulphate, filtered and dried under vacuum.  Purify the residue by repeated chromatography on a column (toluene / acetone 20/1 and 50/1).  Yield (fat soluble isomer, type E) 11.2 g (23.6% of theory), t. square  20 ° С (yellow, viscous honey-colored oil).  Calculated,%: C, 74.26; H 7.67; N 6.66.  Found,%: C 73.90; H 7.92; N 6. 91.  Yield (lower amount of lipophilic isomer in the form of Z) 15.9 g (33.5% of theory), t. square  114-116С.  Found,%: C 74.02; H 7.69; N 6.85.  Example 11  4- (1- (2-11iperi: dinophenyl) -1-butyl) aminocarbonyl THnJ-benzoic acid.   Mix the mixture with 1.2 g. (2.84 mmol) of 4-T (1- (2-piperidinophenyl) -1-butyl) ethyl aminocarbonylmethyl 3-benzoic acid ethyl ester and 4.26 ml of 1 N.  soda lye in 12 ml of ethanol for 1 h at 60 ° C, neutralized with 4.26 ml of 1 N.  hydrochloric acid and ethanol is evaporated.  Spread it between ethyl acetate and water.  The organic extract is dried, filtered and evaporated under vacuum.  The residue is crystallized from ethanol.  Yield 0.50 g (44.6% of theory), t. square  213-215C.  Calculated,%: C 73.07; H 7.66; N 7.10 Found,% s C 73.18; H 7.51; N 7.10.  Analogously to Example 11, the following compounds are obtained: C (1- (2-piperidinophenyl) -1-pentyl) aminocarbonipmethyl benzoic acid  Output 70.2% of theory, t. square  213215 ° C (acetone).  Calculated,%: C 73.50; H 7.90; N 6.86; Found: C, 73.71; H 7.70; N 6.90; 4- (1- (2-piperidinophenyl) -1-hexyl) aminocarbonylmethyl benzoic acid.  Output 72.6% of theory, t. square  197200 ° C (acetone).  Calculated,%: C 73.90; H 8.11; N 6.63. Found: C 73.83; H 7.93; N 6.77; 4- (2-phenyl-1- (2-piperidinophenyl) -1-ethyl) aminocarbonylmethyl benzoic acid.  Output 68.7% of theory, t. pl, 214215 ° C (ethanol).  Calculated,%: C 75.99; H 6.83; N 6.33. Found:% 75.70; H 6.60; N 6.32; 4- (3-phenyl-1- (2-piperidinophenyl) -1-propyl) aminocarbonylmethyl benzoic acid. Yield 67.7% of theory, t. square  167170 ° C (ethyl acetate).  Calculated,%: C, 76.29; H 7.06; N 6.14; Found: C, 76.56; H 7.06; N 6.23; 4-G2-methoxy-1- (2-piperidinophenyl) -1-ethyl) -aminocarbonylmethyl3-benzoic acid, yield 60.8% of theory, t. square  19b198 ° C (ether).  Calculated,%: C 69.68; H 7.12; N, 7.07. Found: C, 59.72; H 6.52; N 6.71; 2511709 A-C (th (2-piperidinophenyl) -A-penten-1-yl) -aminocarbonylmethyl j-benzoic acid X 0.67 H, jO.  Output 30.7% of theory, t. square  193197С (ether and petroleum 5 ether).  Calculated,% j C 71,74; H 7.38; N 6.69 Found% {C 71.63; H 7.21; N 6.34; "O 4-C (1 (2- (3,3-dimethylpiperidino) -phenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid.  Output 48.2% of theory, t. square  168170С (petroleum ether). 15 Calculated,%: C 73.91; H 8.11; N 6.63 -Naiyeno,%: C 73.51; H 7.89; N 6.32; 4- (1- (3-methyl-2-piperidinophenyl) -20 -1-butyl) aminocarbonylmethyl benzoic acid. .  Output 53% of theory, t. square  179182 ° C.  Calculated,% C 73.50; H 7.90; 25 N 6.86; Found: C 73.50; H 7.82; N 4- (1- (4-methyl-2-piperidinofenches :)) - 1-butyl) -aminocarbonylmethyl-benzo-zoic acid The yield of 85.6% of theory, t. square  170172 ° C.  Calculated,%: C 73.50; H 7.90; N 6.8635 Found: C 73.25; H 7.64; N 6.89; 4- (1- (5-methyl-2-biparvdinophenyl) -1-butsh1) -aminocarbonylmethyl-benzoic acid „40 Exit 62.1% of theory, t. square  219,221 ° C. .  Calculated,%: C 73.50; H 7.90; N 6.86; Found:% C 73.20; H 7.74; 45 N, 6.89; 4- (1- (6-methyl-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl1-benzoic acid x 0.3.  Output 89% of theory, t. square  158- 50 160С, Calculated,% С 72.53; H 7.93; N 6 77 Found: C 72.40; H 7.91; N, 6.92; 55 4- (1- (3-chloro-2-pn1eridinophenyl) -1-butyl) -aminocarbonylmethyl1-benzoic acid.  926 Yield 70% of theory, t. square  189g.  Calculated,%: C, 67.20; H 6.81; C1 8.27; N 6.53%; C, 67.30; H 6.85; C1 8.36; N 6.58; 4- (1- (4-chloro-2-piperidiiophenes) -1-butyl) -aminocarbonyl-benoic acid.  Output 57.8% of theory, t. square  188189 C.  Calculated,%: C, 67.20; H 6.81; C1 8.27; N 6.53; Found: C, 66.90; H 7.00; 8.22; N 6.53; 4- (1- (5-chloro-2-piperdinophenyl) -1-butyl) -aminocarbonylmethyl-benoic acid. Yield 81.6% of theory, t. square  226229 C.  .  Calculated,%: C, 67.20; H 6.81; C1 8.27; N 6.53; Found: C 67.17; H 6.59; C1 8.51; N 6.60; 4- (1- (6-chloro-2-piperdinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid.  Vpsod 69.4% of theory, t. square  150153 ° C.  Calculated,%: C 67.20 :.  H 6.81; C1 8.27; N 6.53. Found,%: C 67.18; H 6.19; C1 8.42; N 6.77; 4- (1- (4-bromo-2-piperdinophenyl) -1-butyl) aminocarbonylmethyl) 3-benzoyl „and acid.  Output 84.4% of theory, t. square  198201 ° C.  Calculated,%: C 60.89; H 6.17; Br 16.88; N, 5.92; Found: C, 60.88; H 5.98; Br 17.20; N 5.98; 4- (1- (5-brom-2-piperidinofenes I) -1-butyp) -aminocarbonyl-benzoic acid.  Output 90.7% of theory, t. square  232235 ° C.  Calculated,%: C 60.89; H 6.17; Br 16.88; N, 5.92; Found: C, 60.97; H 6.13; Br 16.85; N 5.90; 4- (1- (4-nitro-2-piperdinofensh1) -1-butyl) -aminocarbonylmethylj-benzoy "acid Yield 70.9% of theory, t. square  188,190 C.  Calculated,%: C 65.59; H 6.65; N9.56 271170 Found;%: C 65.30; H 6.44; N 9.53; 4- (1- (5-nitro-2-piperidinofeyl) -1-butyp) aminocarbonylmethyl 1-benzoic acid.  Output 90.7% of theory, t. square  225227 ° C. .  Calculated,%: C 65.59; H 6.65; N 9.56 Found: C 65.80; H 6.61; N 9.72; 4- (1- (4-hydroxy-2-piperdinophenyl) -1-butyl) aminocarbonylmethyl} benzoic acid X 0.5 Yield 85.7% of theory, t. square  softening, starting from 70C (foam).  Calculated,%: (x 0.5): C 68.71; H 7.45; N 6.68 Found: C 68.63; H 7.55; N 6.26; . 20 - (1- (5-hydroxy-2-piperidinophenyl) -1-butyl) -aminocarboxymethyl benzoic acid, Yield 89.3% of theory, t. square  186190 0.   None,%: C, 70.22; H 7.37; N 6.82 Found: C 70.31; H 7.58; N 6.51; 4-C (1- (4-methoxy-2-piperdinophenyl) -1-butyl) aminocarbonylmethyl-benzoic acid.  .  The yield of 78.6% of theory, t. square  185187 s.  Calculated,%: C, 70.73; H 7.60; N 6.60. 35% found: C, 70.46; H 7.77; N 6.56; A- (1- (6-methoxy-2-piperidinophenyl) -1-butsh1) -aminocarbonylmethyl-benzoic acid 0 Exit 75% of theory, t. square  184185 ° С (decomposition).  Calculated,%: C, 70.73; H 7.60; N, 6.60; Found: C, 70.52; H 7.50; J} 5 70 A- (1- (2-pyrrolidinophenyl) -1-butyl) aminocarbonylmethyl 1-benzoic acid.  Output 64.5% of theory, t. square  200-50.  Vmsleno,%: C, 72.61; H 7.42; N, 7.36; Found: C, 72.64; H 7.50; {J at 38 4- (1- (2- (4-methyl-piperidinophenyl) -1-butsh1-aminocarbonylmethyl-benzoic acid 6928 Exit 81.4% of theory, t. square  197201 ° C.  Calculated,%: C 73.50; H 7.90; N 6.86; Found: C, 73.90; N. 8.06; N 7.00; 4- (1- (2-hexahydro-eepinophenyl) -1-butsh1) -aminocarbonylZ-benzoic acid.  Output 65.6% of theory, t. square  199202 C.  Calculated,%: C 73.50; H 7.90; N 6.86 Found: C 73.50; H 7.90; N 6.76; 4- (1- (4-fluoro-2-piperidinophenyl) -1-butsh1) -aminocarbenylmethyl-benzoic acid.  Output 87.1% of theory, t. square   Calculated,%: C 69.88; H 7.09; N 6.79 Found: C 70.25; H 7.02; N 7.12; 4-t (1- (5-ft-2-piperidinofenes I) -1-butyl) -aminocarbonylmethyl 1-benzoic acid.  Output 53.9% of theory, t. square  200202 C.  Calculated,%: C 69.88; H 7.09; N 6.79 Found: C 69.67; H 7.24; N 6.90; H-chloro-4- (1- (2-piperidinofensh1) -1-butyl) aminocarbonylmethyl-benzoic acid.  Yield 51% of theory, t. square  165168.  Calculated,%: C, 67.20; H 6.81; 6.53.  / 428/430 (1 chlorine), - m / e 428/430 (1 chlorine. ) Found,%: C, 66.92; H 6.69; 4- (1- (3-methyl-2-piperidinophenyl) -1-ethyl) -aminocarbonylmethyl-benzoic acid, yield 79% of theory, t. square   .  Calculated,%: C 72.60; H 7.42; N, 7.36; Found: C, 72.75; H 7.58; N 7.30; 4- (1- (3-chlorop-2-piperidinophenyl) -1-ethyl-aminocarbonylmethyl-benzoic acid Yield 54% of theory, t. square  192195С (75% aqueous ethanol).  29 Calculated,%: C 65.91; H 6.28; C1 8.84; N 6.99 Found, Z: C 66.00; H 6.44; C1 8.67: N 6.78, Example 12, 4- (2-Methyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethyl benzoic acid.  A mixture of 3.5 g (8.3 mmol) of ethyl 4- (2-methyl-1- (2-piperidinophenyl) -1-propan-1-yl) aminobenzene by i-benzoic acid and 12.5 ml 1 and 12.5 ml 1 and H, sodium liquor in 35 ml of ethanol for 2 h at 60 ° C.  12.5 ml of hydrochloric acid are neutralized, evaporated under vacuum, and partitioned between ethyl acetate and water.  The dried organically filtered extract is evaporated under vacuum.  The residue is crystallized from ethanol.  Output 2.4 g (73.6% of theory), t, pl.  188-19GS.  Calculated,%: C 73.44; H 7.19; N 7.14, Found,%: C 73.60; H 7.19; N, 7.02. Analogously to Example 12, the following compounds were prepared: (E) -4- (1- (2-piperidinophenyl) -1-butene-1-yl) -aminocarbonylmethyl-benzoic acid.  Output 71.5% of theory, t. square  188-190 0.  Calculated,%: C 73.44; H 7.19 N 7.14 Found: C 73.15; H 7.13; N 7.10.  Olefin Proton: H-NMR (CDCl 6 6.42 ppm h ; (Z) -4- (1- (2-piper dinophenyl) -1-buten-1-yl) -aminocarb nylmethyl benzoic acid.  Output 57.8% of theory, t. square  17-175 C (ethanol).  Calculated,%: C 73.44; H 7.19; N, 7.14; Found: C, 73.54; H 6.97; N.  Olefin Proton: H-NMR (CDCl i 5.60 ppm h ; (E) -4- (2-phenyl-1-piperidinophene-1) -ethen-1-yl) amino-carbonylmethyl j-benzoic acid X to 0.4 N. , 0, Output 33.2% of theory, t. square  16 167 ° C (ether and petroleum ether).  9.  30 Calculated,%: (x 0, A): C 75.11; H 6.48; N 6.26; Found: C, 75.22; H 6.39; N 6.26, Olefin Proton: H-NMR (CDC1): 6 7 6.9 million, h; (Z) -4- (2-phenyl-1- (2-piperidinophenyl) -.  -ethen-1-yl) -aminocarbonylmethylJ-benzoic acid x 1 HjO.  Output 72% of theory, t. square  182185 ° C (methanol).  Calculated,%: (x 1 HjO): C 73.34; H 6.60; N 6.11, Found,%: C 73.55; N. 6.45; N 6.00, Olefin Proton: H-NMR (CDClj): 6 6.50 ppm. h ; 4- (3-phenyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonylmethylJ-benzoic acid.  The output of 48.3% of theory, t. square  162164 C (simple ether) in the Z-form.  Calculated,%: C 76.63; H 6.65; N, 6.16; Found: C, 76.30; H 6.47; .  N 6.31.  . Olefinovy proton: H-NMR (CDC1,): J-l, 80 million h; 4-L (1- (2- (3,3-dimethyl-piperidinophenyl) -1-butene-1-yl) aminocarbonylmethyl benzoic acid.  Output 64.1% of theory, t. square  152153 ° C (ethyl acetate) in the Z-form.  Calculated,%: C, 74.26; H 7.67; N 6.67 Found: C 73.93; H 8.57; N. 6.50 Olefin Proton: H-; NMR (CDClj): 6 5.55 ppm. h  5 (Z) -4- (1- (6-methyl-2-piperidinophenyl) -1-butene-1-yl) aminocarbonylmethyl 13-benzoic acid.  The output of 53.3% of theory, t. square  142145 ° C.  Calculated,%: C 73.66; H 7.44; N 6.89 Found: C 73.56; H 7.73; N 7.15.  Olefin Proton: H-NMR (CDClj): 6 5.38 ppm h  Example 13  (+) - 4-C (1- (3-piperidinophenyl) -1-byyl) ethyl aminocarbenyl methyl benzoic acid ethyl ester.  To a stirred solution of 2.58 g (11.1 mmol) of (+) (2-piperidinophenyl) -1-butylamine (. -j, j 87C; its 86 (liquid chromatography
after adding () -1-phenylethyl-isocyanate) to 26 ml of acetonitrile, 2.31 g (11.1 mmol) of 4-ethoxycarbonyl-phenyl-acetic acid, 3.50 g (13.3 mmol) 5 triphenylphosphine, 4.60 ml (33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol) of carbon tetrachloride. After 14 hours at 20 ° C and after 1.5 hours, they are embedded in a vacuum and distributed between water and ether. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified by chromatography on column 5 on silica gel (toluene: acetone 6: T).
The output of 2.63 g (56% of theory), so pl. 188-120 ° C.
Calculated,%: C 73.90; H 8.11; 20 N 6.63
Found,%: C 74.02; H 7.97; N 6.51
oiJ5 9.2 (with 1; methanol).
Analogously to Example 13, 25 (-) - 4- (1- (2-piperidinophenyl) -1-butyl) -aminocarbonyl-3-benzoic acid ethyl ethyl ester is obtained. 1-butylamine x 1.4 HC1 to - 20.0 ° 30 (s 1, methanol).
M.p. 90-100 C; its 80 (liquid chromatography after addition of base with (+) - 1-phenethyl isocyanate) .35
The output of 52.6% of theory, so pl. 115UOC.
Calculated,%: C 73.90; H 8.11; N 6.63
Found,%: C 73.83; H 8.01; 40 N 6.47.
 -9.0 (s 1, methanol).
Example 14. Ethyl ester of (+) - 4-t (1- (2-piperidinophenyl) -1-butsh I) -aminocarboxylate lJ-benzoyl 45 eoic acid.
1, C g (3.27 mmol) of dihydrochloride () -1- (2-piperidiNophenyl) -1-butylamine, Cc / +18.7 50 (s 1, methanol) are suspended; m.p. Starting with 115C decomposition; its 91.6 (liquid phase chromatography after the reaction of the base with (+) - 1-phenethyl-isocyan-. TOM in 6 ml of methylene chloride); add 1.5 ml with stirring 1.4 ml (10 (10 mmol)) triethylamine and then a solution of 0.82 g (3.64
(3.64 mmol) of 4-ethoxycarbonylphenylacetic acid chloride in 2.4 ml of methylene chloride, the reaction temperature rising from 22 ° C to 38 ° C. Then it is stirred for 6 hours at room temperature and extraction is carried out by shaking: twice with 10 ml of water, once with 10 ml of 2 N. hydrochloric acid and once with 10 ml of water.
The organic phase is dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (toluene: acetone 6/1).
Output 0.53 g (38.2% of theory), so pl. 120-122C.
Calculated,%: C 73.90; H 8.11; N 6.63
Found:% C 73, H 7.98 N 6.61.
 9.0 (s 1, methanol).
Example 15. () -4- (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoate.
2.0 g (4, 73 mmol) ethyl () -4- (1- (2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid ethyl ester is stirred in the melt at 65 ° C for 2.5 hours , 2 (from 1), methanol) in 20 ml of ethanol together with 7.0 ml 1 and. sodium liquor. Cool and add 7.0 ml of 1N hydrochloric acid. The slowly precipitated crystals are filtered off, washed with water and dried at Torr.
Output 1.65 g (88.2% of theory), so pl. 185-187C.
Calculated,%: C 73.07; H 7.66; N 7,10
Found,%: C 72.90; H 7.80; 7.17 ..
 7.9 ° (s 1, methanol).
Analogously to Example 15, (-) - 4- (1- (2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid is obtained.
Output 80% of theory, so pl. 187190С.
Calculated,%: C 73.07; H 7.66; 7.10
Found,%: C, 72.98; H 7.44; 7.22. -7.9 (with 1, methanol).
PRI me R 16.  4- (1- (2-Piperidinophenyl) -1-butyl) -aminocarbonylethyl-benzonitrile.  33 Prepared from 1- (2-piperidinophenium -1-butylamine and 4-cyanophenylacetic acid as in Example 6.  Output 57.3% of theory, t. square  14 148C.  Calculated,%: C 76.76; H 7.78; IN 11.19.  Found,%: C 76.46; H 7.81; N 1-1,10.  Analogously to Example 16, 4- (1- (2-piperidinophenyl) -1-butyl) -amioxycarbonylmethyl-3-4-tolyl-cyclic acid is obtained.  Output 60.4% of theory, t. square  150-153C.  Calculated,%: C 79.08; H 8.85; N 7.68 Found: C 78.97; H 8.58; N 7.77.  Example 17  4- (1- (2-piper (inophenyl) -1 -butyl) aminocarbonylmethyl-truncate acid.  4- (2-piperid nophenyl) -1-butyl) -aminocarbonyl-methyl 3-radical acid is obtained by alkaline saponification of a layered ethyl ester with analogous to example 11.  Output 64% of theory, t. square  180183 ° C.  Calculated,%: C, 74.26; H 7.67; N 6.66; Found: C, 74.03; H 7.47; N 6.80.  , Example 18.  (1- (2 -PI peridinophenyl) -1-butyl) -aminocarbonylmethyl-phenyl-propionic acid.  Alkaline saponification of (2-piperidinophenyl) -1-butyl) aminocarbonyl methylphenylpropionic acid ethyl ester is obtained as in Example 11.  Yield 50% of theory, t. square  131-133 Calculated,%: C 73.90; H 8.11; N 6.63 Found: C 73.82; H 8.07; N 6.41.  Similar to the examples given, the following compounds 5 4- - (4-hydroxy-phenyl) -2-piperi dinobenzyl-aminocarbonylmethyl-beic acid, t. square  202-2p4s.  ethyl ester (5-hydroxy-ot-phenyl-2-piperidino-benzyl-aminocarbonylmethyl-benzoic acid, t. square  191-193 C; 6934 4-CH-e / -4-methyl-phenyl) -2-piperidinobenzyl} -aminocarbonylmethylj-benzyl alcohol, t. square  144-146 ° C; 4-N-c / -phenyl-2-piperidinobenzyl) -aminocarbonylmethyl-benzyl alcohol, t. square  143-145C; (4-methyl-phenyl) -2-piperidinobenzyl-aminocarbonylmethyl3-benzaldehyde, t. square  144-146 0; 4-N-o-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl-benzaldehyde, t. square  168-170 ° C; - (4-methyl-phenyl) -2-piperidinobenzyl-aminocarbonylmethyl-benzaldehyde, t. square  145-146 0; (o-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl-benzaldehyde, 1t. square - 7D ° C; (4-methyl-phenyl) -2-piperidinobenzyl-aminocarbonylmethyl3-cinnamic acid ethyl ester, t. square  17b-180s; ethyl ester (o / -phenyl-2-piperidinobenzyl) -aminocarbonyl-.  methyl cyric acid, t. square  159161 ° C; ethyl ester (3-methyl-phenyl) -2-piperidinobenzyl} -aminocarbonylmethyl} -benzoic acid, t. square  158-159 ° C; (j, 5-cis, -dimesh1-piperidino) -5-nitro-o-phenyl-benzyl-aminocarbonylmethyl-benzoic acid, ethyl ester ethyl, t. square  170173С; (4-methyl-phenyl) -2-piperidinobenzyl} -aminocarbonylmethyl2-benzoic acid, t. square  226-228 C; 4- N- 2- (2-methyl-piperidino) - / -phenyl-benzyl-aminocarbonylmethyl-benzoic acid, t. square  246-248 C, 4- (3-methyl-piperidino) -c-phenyl-benzyl-aminocarbonylmethyl-benzoic acid, t. square  228-230C; (4-methyl-phenyl) -2-piperidinobenzyl ethyl ester.  -aminocarbonylmethyl-benzoic acid, t. square  175-177 ° C; 4-N-foi- (4-methyl-phenyl) -2-piperidinobenzyl3-aminocarbonylmethyl-benzoic acid ethyl ester, t. square  177-179C; (5-methyl-c6-phenyl-2-piperidino-benzyl) aminocarbonylmethyl benzoic acid ethyl ester, t. square  170-173C; ethyl 4-N-5-chloro-o- (2-chloro-phenyl) -2-pipotridinobenzyl 3 3. 5-aminocarbonylmethyl 3-benzoic acid, t.  square  ZIS-ZISC; 4- (H-5-chloro -2- (3,5-cis-dimethyl-piperidino) -ti-phenyl-benzyl) -amino-carbonylmethyl-3-benzoic acid ethyl ester, m. square  188-191 С 3- 4-СН - ({/ - (A-metsh-1-phenyl) -2-1 Shh Ridinobenzyl) -aminocarbonylmethyl-13-phenylC-propionic acid, t. square  146-148C} 3-G4-CH With phenyl-2-piperidinoben zyl) aminocarbonylmethyl} phenyl-pro-pionic acid, t. square  97-99 ° C; sodium salt of 4-Cm- {in (-methyl-phenyl) -2-piperidinobenzyl) aminocarb nsh1methyl 1-benzoic acid, t. square  295-300 s; ethanolamine salt of ((4-methyl-phenyl) -2-piperidinobenzyl) aminocarbonylmetl3-benzoic acid, m. square  188-191С; diethanolamine salt. W- (4-methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid, m. square 178-180 ° C; triethanolamine salt ((-methyl-fensh1) -2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid. lots, t. square  160-165 ° C, ethylene diamine salt of (e / - (4-methyl-phenyl) -2-piperidinobenyl) aminocarbonylmethyl-benzoic acid, t. square  160-163 ° C; (5-methoxy-c | 1-phenyl-2-shsheridinobenzyl) aminocarbonylmethyl benzoic acid ethyl ester, t. square  123-125 ° C; (E) (2-Piperidinophenyl) -1-butene-1-yl) aminocarbonylmethyl benzoic acid ethyl ester, t. square  20 ° C; WITH. FALSE (Z) -4-f (1- (2-piperidinophenyl) -1-butene-1 -yl) amino-carbonylmethyl benzoic acid ethyl ester, t. square  115-117C; ethyl ester of (E) - and (g) -4- (1- (6-methyl-2-piperidinophenyl) -1 buten-1-yl) -aminocarbonylmethyl 3-benzoic acid E is an ester.  Calculated: m / e 434; found: m / e - 434.  Z-ester.  Found; m / e -434, 4- (1- (2-piperidinophenyl) -1-butyl-aminocarbonylmethyl-benzoic acid ethyl ester, t. mp 126-128C; 6936 ethyl 4-f (1- (2-piperidinophenyl) -1-pentyl) -aminocarbonylmethyl benzoic acid ethyl ester, t.  square  117-120 ° C (ether); ethyl 4- (1- (2-piperidinophenyl) -1-hexyl) aminocarbonylmethylX-benzoic acid ethyl ester; t. square  SE-PO S (ether); 4-C (2-phenyl-1- (2-piperidinophenyl) -Ifethyl) aminocarbonylmethyl-D-benzoic acid ethyl ester, t. square  161-162C (ethanol); ethyl 4- (3-phenyl-1- (2-piperidinophenyl) -1-propyl) aminocarbonylmethyl benzoate.  t. square  118-119 s (ethanol); ethyl ester 4-C (1- (2; - (3,3-dimethyl-piperidinophenyl) -1-butyl) aminocarbonylmethyl 3 benzoic acid, t. square  140-141 ° C (ethanol); 4- (1- (2- (3,3-dimethyl-piperidinophenyl) -1-butene-1-yl) aminocarbonylmethyl benzoic acid, m. square  152153С (ethyl acetate) in the form of (Z); (Z) -4-t1- (6-methyl-2-piperidinophenyl) - 1 -butene-1 -yl) -aminocarbonylmethyl-benzoic acid, t.  square  142KZ C; 4- (1- (4-amino-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid X 0.5, t. square  11812a C; ethyl 4-f (1- (4-amino-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoic acid ethyl ester, - t. square  145-146 with (ether and petroleum ether); 4- (1- (5-amino-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl-benzoic acid, t. square  227-230 s; ethyl 4- (1- (5-α-amino-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid ethyl ester, m. square  162-165 C.  .  ethyl 4- (1- (5-chloro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl 3-benzoic acid ethyl ester, t. square  137-140 ° C (ether); ethyl 4- (1- (4-chloro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoic acid ethyl ester, t. square  123-125 ° C; complex ETILE. YOU ester 4- (1- (5-bromo-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl} benzoic acid, t. square  140-142 t; 37 ethyl ester of 4- (1- (4-fluoro-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid, t. square .  1 10-1 ethyl 4- (1- (5-fluoro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoate, ethyl ester, m. square  127-129 ° C; 4- (, 1- (4-fluoro-2-piperidinophenyl) -ethyl) aminocarbonylmethylbenzoic acid, t. square  172-175 ° C; ethyl ester of 4- (1- (4-methoxy-2-piperidinophenyl) -1-butyl-aminocarbonylmethyl benzoic acid, t. square  115-117 ° C; ethyl 4- (1- (5-methoxy-2-pigyridinophenyl) -1-butyl-aminocarbonylmethyl-benzoic acid ethyl ester, t. square  142-145С; (2,3-dioxy-propyl) ester 4-G (1- (2-piperidinophenyl) -1-butyl) l-aminocarbonylmethyl benzoic acid, t. square  120-122 ° C; (2-hydroxy-ethyl) -4-t (1- (2-piperidinophenyl) -1-butsh1) -amino carbonylmethyl benzoic acid, t. square  125-1270С; 4- (1-piperidinophenyl) -1-butyl) -amine carbonylmethyl-benzoic acid (2-methoxy-ethyl) ester, m. square  120-123 ° C; 4- (1- (2-piperidichophenyl) -1-butyl) aminocarbonylmethyl j-benzoic acid (2-nicotinoyloxy-ethyl) ester; t. square  32-135 ° C; 4- (1- (2-piperidinophenyl) -1-buty-aminocarbonylmethyl-D-benzyl alcohol, t. square  152-154 ° C; 4- (1- (2-piperidinophenyl) -1-buty-aminocarbonylmethyl} -benzaldehyde, t. square  UZ-US C; ethyl 4- (1- (2-p-peridinophenyl) -1-butyl) aminocarbonate methyl 3-cinnamic acid ethyl ester, t. square  135 137 C (ether and petroleum ether); (2-pyridinophenyl) -1-butyl) aminocarbonylmethyl-phenyl-propionic acid ethyl ester, t. square  98-99C (petroleum ether); ethyl ester of 4- (oi-amine carbonyl-2-piperidinobenzsh1) -aminocarbonylmethyl J-benzoic acid, t. square  160-162 ° C (acetone); ethyl ester of 4- C (o-cyano -2-piperidinobenzyl) aminocarbonylmethyl-isoic acid, t. square  114-11 ether / petroleum ether; 9 4- (o (cyano-2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid, t. square  176-180 ° C (decomposition)} C (1 (2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl J-benzoic acid X HjSO, t. square  192-197 ° C (decomposition); 4- (1- (2-piper. idinophenyl) -1-butyl) -aminocarbonylmethylJ-benzoic acid X 0.5 Hj50 to 1.5, t. square  18Q-185 ° C; decomposition at 207-210 C.  Example 19  4-tN-Coi- (4-oKCH-phenyl) -2-piperidinobenzyl-amino. carbonylmethyl benzoic acid.  1.1 g (2 mmol) (4-6eHyloxy-phenyl) -2-piperidinobenzyl) aminocarbonylmethyl-benzoic acid is suspended in 200 ml of ethanol and catalytically debenzylated at 50 ° C and a hydrogen pressure of 5 bar in the presence of 0.4 g 10% Palladium on coal.  Then the catalyst is filtered off, concentrated and recrystallized from acetonitrile.  Yield 720 mg (66.7% of theory), t. square  202204 s.  Calculated,%: C, 72.95; H 6.35; N 6.30 Found: C 72.65; H 6.17; N 6.20.  Analogously to Example 19, (5-oKCH-o-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid ethyl ester was prepared.  Output 93% of theory, t. square  191-193C. .  Calculated,%: C 73.70; H 6.82; N, 5.93; Found: C, 73.52; H 6.57; N 5.61.  PRI me R 20.  4-CN- o (4-MeTHn-phenyl) -2-piperidinobenzyl-amino-carbonylmethyl-benelyl alcohol.  .   2.5 g (5.3 mmol) of ethyl ester (. - (4-methyl-phenyl) -2-piperidine-benzo-I-aminocarbonyl-methyl-be. In addition, in portions of the suspension, 0.5 g (13.2 mmol) of lithium aluminum hydride is added in portions to 50 ml of absolute tetrahydrofuran.  Then it is stirred for 30 minutes at room temperature, decomposed by addition.  sodium liquor and filtered from sodium aluminate formed.  The filtrate is concentrated and the residue is recrystallized from toluene.  Output 0.98 g (43% of theory), t. square  144-146 ° C.  Calculated,%: C 78.47; H 7.53; N 6.54.  Found,%: C 78.20; H 7.39; N 6.58.  Analogously to example 20, 4- -phenyl-2-piperidinobenzyl) -aminocarbonidmethyl3-benzyl spi is obtained. Yield 31.5% of theory, t. square  143 145 ° C.  Calculated,%: C 78.23; H 7.29; N 6.76 Found: C 78.13; H 7.30, N 6.62. Example 21  4-Sy-S - (- Meti-phenyl) -2-piperidinobeneyl 3-aminocarbonylmethyl J-benzaldehyde.  8.85 g (20 mmol) (4-me-phenyl) -2-piperidinobenzyl-aminocarbonylmethyl-3-benzoic acid and 3.25 g (20 mmol) of the NN-carbonyl dime of dazol are heated under refluxing in 100 ml of absolute tetragvd rofuran for 2 hours  Then cry and, after adding 50 ml of pyridine and 3.7 g (20 mmol) of 4-toluenesulfonic acid hydrazine, are boiled again for 2 hours under reflux.  Then it is poured onto ice water, sucked off and the precipitate is dried.  The toluenesulfonic acid hydrazide thus obtained of the carbonic acid used is mixed with 20 g of sodium carbonate free from water and then heated for 2 hours to a temperature of 50 ml of ethylene glycol.  Then served on water and extracted with chloroform.  Condensed extracts are used on silica gel with toluene and ethyl acetate 5: 1 as a solvent.  Output 1.73 g (21% of theory), t. square  144-146 ° C.  Calculated,%: C 78.84; H 7.09; N, 6.57; Found: C, 78.95; H 7.19; N 6.50.  Analogously to example 21, -phenyl-2-piperidinobenzyl) -aminocarbonylmethyl-benzaldehyde is obtained. Yield 29% of theory, t. square  168170 C.  Calculated,%: C 78.61; H 6.84; N 6.79 Found: C 78.60; H 7.00; N 6.72.  Example 22   - (4-Methyl-phenyl) -2-piperidinobenzylJ-aminocarbonylmethyl-benzaldehyde.  0.5 g (1.2 mmol) - (4-methyl-phenyl) -2-piperidinobenzyl-1-aminocarbonylmethyl-benzyl alcohol is added to a suspension of 0.4 g (1.5 mmol) of pyridine chlorochromate in 2 ml of chloroform.  After 12 hours at room temperature, they are mixed simple) with 1m ether, filtered, and the condensed filtrate is purified by chromatography on a column of silica gel (solvent: toluene and ethyl acetate 5: 1).  Output 0.3 g (60% of theory), t. square  145-14bS  Calculated,%: C 78.84; H 7.09; N 6.57; Found: C 78.97; H 7.12; N 6.57. - In analogy to Example 22, 4- N- (o6-phenyl-2-piperidinobenznl) aminocarbonylmethyl-benzaldehyde is obtained.  The yield of 40% of theory, t. square  .  Calculated,%: C 78.61; H 6.84; N 6.79.  Found,%: C 78.59; H 6.87; N 6.61.  PRI m e r 23.  Ethyl 4- (4-methyl-phenyl) -2-pn-meridinobenzyl} -aminocarbonylmethyl-cinnamic acid ethyl ester.  427 mg (1 mmol) (/ (4-methyl-phenyl) -2-piperidinobenzyl-J-aminocarbonylmethyl-benzaldehyde was added to the ether solution of 450 mg (2 mmol) of diethylphosphonoacetic acid ethyl ester and 100 mg (2 mm) of 50% sodium hydride.  After stirring overnight, it is mixed with water and extracted with chloroform and purified by chromatography on a column with toluene and ethyl acetate: 1 as a solvent.  Yield 0.18 g (36% of theory),. square  176-180 ° C.  Calculated,%: C 77.39; H 7.31; 5.64 Found: C 77.64; H 7.25; 5.71.  Analogously to Example 23, 4-to- (oi-phenyl, 2-piperidinobenzyl) aminocarbonylmethyl-trinic acid ethyl ester is obtained.  The output of 28.6% of theory, t. square  159-161c.  Calculated,%: C 77.14; H 7.10; N, 5.80; Found: C, 77.28; H, 7.21; N 5.65.  Example 24  4-N-Co6- (4-Methyl-phenyl) -2-piperidinobenzyl-3-carbonylmethyl-cinnamic acid.  It is obtained by alkaline saponification of (4-methyl-phenyl) -2-g1Iperidinobene-ethyl-aminocarbonylmethyl-cyanoic acid ethyl ester as in Example 3.  Output 84% of theory, t. square  173176 ° C.  Calculated,%: C 76.90; H 6.88; N5.98 Found: C, 77.24; H 7.01; N5,64.  Similar to example 24.  sex / tea (c-phenyl-2-piperidinobenzyl) "aminocarbonylmethyl-cinnamic acid.  Output 75% of theory, t. square  177180 ° C.  Calculated,%: C 76.62; H 6.65; H 6.16 Found,%: C 76.75; H 6.57; N 6.07.  Example 25  Ethyl ester (5-chloro-o (. - (2-chloro-phenyl -2-piperidinobenzyl-aminocarbonyl methyl benzoic acid.  10 mmol of (2-chlorophenyl) -5-nitro-2-piperidinobenzyl-aminocarbonyl-methyl-benzoic acid ethyl ester is dissolved in 50 ml of dimethylformamide and, after the addition of nickel, Rene is hydrogenated at 6 bar hydrogen pressure.  The catalyst is then filtered off, the filtrate is concentrated and the residue consisting of 1: 5-amino-o - (2-chloro-phenyl -2-piperidinobenzyl-aminocarbonyl methyl-benzoic acid ethyl ester) is concentrated in 100 ml of concentrated hydrochloric acid.  When cooled by ice, a solution of 1.0 g (14 mmol) of sodium nitrite in 10 l of water is added and stirred for 1 h at 0–5 ° C.  The reaction mixture is then added dropwise to a solution of 3 g of copper (1) chloride in 25 Mfi of concentrated hydrochloric acid.  After 1 hour, additional stirring is applied with sodium hydroxide solution and extracted with chloroform.  Condensed chloroform extracts are purified by chromatography on a column on silica gel in a solvent consisting of toluene and ethyl acetate 5: 1, yield 1.5 g (28.6% of theory), t. square  213-215C.  Calculated,%: C, 66.28; H 6.75; N 5.33; C1 13.49.  Found,%: C, 66.40; H 5.91; N 5.41, C1 13.40.  Analogously to Example 25, 4- {L-5-chloro-2- (3, 5-cis-dimethylpiperidino) -0-phenylbenzyl) -aminocarbonylmethyl-ben, 1-o-acid, ethyl ester is obtained.  Output 28% of theory, t. square  18819Т ° С.  Calculated,%: C 71.72; H 6.80; N 5.40; C1, 6.83; Found: C, 71.95; H 6.85; N 5.35; C1 6.77.  PRI am 26. .  3-C4- N- (o -4-Methyl-phenyl) -2-piperidinobenzyl). -aminocarbonylmethyl j-phenyl-propionic acid.  0.91 g (2 mmol) of 4-C4- (o (- (4-methyl-phenyl) -2-piperidinobenzyl) -aminocarbonylmethyl-cinnamic acid is dissolved in 50 ml of methanol and after adding 0.5 g of palladium (10% -carbonized) is catalytically hydrogenated at room temperature and a hydrogen pressure of 3 bar.  After uptake by hydrogen, the catalyst is filtered off and recrystallized from a small amount of acetal nitrile.  The output of 0.68 g (74% of theory), t. square  146-148 ° C.  Calculated,%: C 76.57; H 7.28; N 5.95.  Found,%: C 76.41; H 7.19; N 5.61 Analogously to example 26, receive (o (. -phenyl-2-piperidino-benzyl) -aminocarbonylmethyl-phenyl-propionic acid.  Yield 65% of theory, t. square  97Calculated,%: C 76.30; H 7.06; N 6.13; Found: C, 76.25; H 6.95; N 5.91.  Example 27  The sodium salt of 4-N-pt (- (4-methyl-phenyl) -2-piperidinobenzyl) aminocarbonylmethyl} -benzoic acid.  442 mg (1 mmol) (oL- (4-Methyl-phenyl) -2-piperidinobenzyl) -aminecarbonylmethyl-benzoic acid is dissolved in 25 ml of ethanol and mixed with 1 ml of 1N sodium hydroxide.  Then concentrated under vacuum, mixed with 20 ml of acetone, sucked in about the precipitate and washed with ethyl acetate acetic acid Yield 410 mg (85% of theory), t. square  295-300С.  Calculated,%: C, 72.40; H 6.29; N, 6.03; Found: C, 72.15; H, 6.46; N 5.93.  Analogously to Example 27, the following is prepared: ethanolamine salt of 4-t4 - ((-phenyl) -2-piperidinobeneyl) aminocarbonylmethyl-D-benzoic acid.  Output 75% of theory, t. pl, 188191 C.  Calculated,%: C 71.55; H 7.41; N 8.34 Found,%: C 71.16; H 7.48; N 8.52; diethanolamine salt of (N- (4-methyl-phenyl) -2-piperidinobenzyl) aminocarbonylmethyl benzoic acid.  Output 81% of theory, t. square  178180С.  : From 70.7. 0; H 6.86; Calculated by; N, 7.73; Found: C, 70.25; H 6.75; N 7.58; the triethanolamine salt of (oi- (4-methyl-phenyl) -2-piperidinobenzyl) aminocarbonylmethyl3-benzoic acid from the theory, t. square 160 Yield 165 ° C.  Calculated: C 69.01; H 7.67; N 7.10 C 68.91; H 7.64; Found, 7, N 7.45; ethylene diamine salt of (ei- (4-methyl-phenyl) -2-piperidinobenzyl) aminocarbonylmethyl benzoic acid.  Yield 65% of theory, t. mp, 160163C, 1: C, 71.69; H 7.62; Calculated, N11.15 Found,%: C 72.04; H 7.80; N 10.96, 8, Ethyl complex Example 4-CN- (5-MeTOKcn7c 7deHKn-2-nHn Ridinobenzyl) -aminocarbonylmethylJ-benzoic acid ester 472 mg (1 mmol) of ethyl 4-Cm- (5-hydroxy-) xs-phenyl-2- 69. The 44 pipene, reedinobenzyl) aminocarbonylmethyl benzoic acid is dissolved in 25 ml of absolute dimethylformamide.  After the addition of 50 mg of 50% sodium hydride, the mixture is stirred for 30 minutes.  0.5 g of methylene iodide is then added dropwise and stirred overnight.  Then it is fed to ice water and extracted with methylene chloride.  Condensed extracts are purified by chromatography on a column of silica gel with toluene and ethyl acetate 4: 1 as diluent. Exit 260 mg (53% of theory), t, pl.  123-125C.  %: C, 74.05; H 7.04; Calculated N 6.76.  Found,%: C 73.86; H 6.95; N 5.61, Example 29.  Ethyl ester of (E) - and (2) -4- (1- (2-piperidinophenyl) -1-buten-1-yl) -aminocarbonyl-.  methyl benzoic acid.  1.0 g of Z-ester is heated in a preheated oil bath with a temperature of 230 ° C for 30 minutes.  After cooling, the product obtained is purified by silica gel column chromatography (toluene / acetone 20 / L).  Output (complex E-ester) 0.365 g (36.5% of theory), t, pl,, Output (complex Z-ether) 0.380 g (38.0% of theorist), t, al, 115-117C, When heating for 3.5 hours of the complex (E) -ether with a catalytic amount of iodine in benzene, according to thin-layer chromatography (toluene) and acetone 10 / l, a mixture of complex (E) - and (Z) -ether 1/1 is obtained. get complicated ethyl. ether (E) and - (Z) (6-methyl-2-piperidinophenyl) -1-butene-1-yl) aminocarbonylmethyl j-benzoic acid.  From complex (Z) -ether, a mixture of complex (E) - and (Z) -ether 1/1 is obtained according to thin-layer chromatography. Top spot (E).  Calculated,%: / e 434; Found: m / e 434.  Bottom spot (Z), Found,%: / e 434, note e. p 30.  Sodium salt of - (1- (2-piperidinophenyl) -1-butyl) aminobenzoyl methyl-benzoic acid X 0.5 HjO, 10.0 g (25.35 mmol) of (2-piperidinophenyl) -1-butyl) 45 is dissolved.  α-aminocarbonylmethyl 3-benzoic acid at 200 ml of ethanol and 25.35 ml of 1N sodium hydroxide are added.  It is then evaporated under vacuum to dryness and the residue is dissolved by heating in a steam bath in a minimum amount of ethanol.  The mixture is cooled in an ice bath, filtered off from precipitated crystals, washed with ether and dried at 140 ° C and pressure of 15 Torr.
The yield is 9 g (85.3% of theory), m.p. 280-285 0 (decomposition; softening begins at 255 ° C.
Calculated,%: (0.5): from 67.74; H 6.87; H 6.58
Found,%: C 67.86; H 7.13; N 6.49.
EXAMPLE 31. 4 (1- (4-amino-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid X 0.5 HjO.
0.60 g (1.365 mmol) of 4- (1- (4-nitro-2-piperidinophenyl) -g 1 -butyl) aminocarbonylmethyl-benzoic acid is hydrogenated for 3 hours at 25 ° C and 1 bar of hydrogen on O, 1 g palladium and coal (10%). Filtered from. catalyst over diatomaceous earth and evaporated under vacuum. The residue is crystallized from ether.
Output 0.41 g (73.2% of theory), so pl. 118-120s.
Calculated,%: (x 0.5 H, j0): C 68.87; N. 7.71; N 10.04
N-found,%: C 68,62; H 7.64; N 10.08.
Analogously to Example 31, the following compounds are prepared: ethyl 4 - {(1- (4-amine -2-pi-pentine OOF)) - 1-butyl) -aminocarboxylate methyl benzyl acid ethyl ester.
The output of 81.7% of theory, so pl.145146 ° C (simple ether and petroleum ether).
Calculated,%: C 71.37; H 8.06; N 9 ,, 60
Found,%: C, 71.50; H 8.08; N 9.68;
4- (1- (5-amino-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl J-benzonic acid
Output 64% of theory, so pl. 227230 0.
Calculated,%; C, 70.39; H 7.63 N 10.26
7096946
Found,%: C 70,54; H 7.4; N 10.36;
- Compound ethyl ester, 4- (1- (5-amino-2-piperidinophenyl) -1-butyl) -aminocarbonyl methyl J-benzoic acid.
Output 84.3% of theory, so pl. 162165 ° C.
Calculated,%: C 71.37; H 8.06;
to N 960: Found,%: C 71.58; H 7.83; N 9.65.
Example 32, Compound ethyl (1- (5-chloro-2-piperidinophenyl) 1-butyl) aminocarbonylmethyl j-benzoic acid.
From g (4.57 mmol) of 4- (1- (5-amino-2-piperidinophenyl) -1-butyl) amino-carbonylmethyl benzoic acid ethyl ester in 4.8 ml of half-concentrated hydrochloric acid and 0.315 g (4.57 g mmol) of sodium nitrite in 1.66 ml of water gives a solution of a diazonium salt, which has an OS temperature. This solution is added dropwise at 0-5 ° C to a stirred mixture of 0.59 g (5.94 mmol) of copper chloride (.1) and 2.4 ml of concentrated hydrochloric acid and then heated in a bath having a temperature of 50 ° C. After the formation of a gas has been completed (about 15 minutes), the reaction mixture is cooled, fed to ice and concentrated ammonia is extracted four times, 5 each time with 100 ml of ethyl acetate. The combined organic extracts are extracted by shaking with water, dried, filtered and evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (toluene / ethyl acetate 10/1),
Output 0.80 g. (40% of theory), mp, 137-140 ° C (ether),
Calculated,%: C 68,32; H 7.27; 5 C1 7.75; N 6.13
Found n,%: C 68.42; H 7.09; C1 8.06; N 6.05.
In analogy to Example 32, the following compounds are prepared:
0 ethyl 4-t (1- (4-chloro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoate
The output of 21.9% of theory, tpl, 123125 C.
5 Calculated,%: C 68.32; H 7.27; C1 7.75; N 6.13
Found,%: C 68.70; H 7.18; C1 7.77; N 6.08; ethyl ester 4-f (1- (5-6pOM -2-peryridinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid Yield 53.8% of theory, so pl. 140 142 ° C. Calculated,%: C 62.27; H 6.63; Br 15.93; N, 5.58; Found: C, 62.39; H 6.78; Br 15.85; N 5.59; ethyl ester of 4- (1- (4-fluoro-2-piperidinofensh1) -1-butyl) -aminobenzoic acid IH-benzoic acid Yield 21.6% of theory, so pl. 110. Calculated,%: p. 70,88; H 7.55; N 6.36 Found: C: 71.01; H 7.53; N 6.21. In addition, 40% of 4 - ((1- (4-hydroxy-2-pip, rvdinophenyl) -1-butyl) -aminocarbonyl methyl benzoic acid ethyl ester (solid foam); ethyl ester 4-1 ( 1- (5-fluoro -2-piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoic acid. Output 2% of theory, mp 127129 0. Found: m / e 440. Found: m / e 440. 4- C (1- (4-fluoro-2-piperidinophenyl) -ethyl) aminocarbonylmethyl 2-benzoic acid. Yield 16.9% of theory, mp. 172. Calculated,%: C 68.73; H 6, 55; N 7.29; Found: C 68.78; H 6.62; N 7.31. Example 33. Ethyl ester. 4- (1- (4-methoxy-2-piperidinophenyl) -1-butyl ester ) -aminocarbonylmet w13-benoic acid., To 548 mg (11.4 mmol) of sodium hydride (50% in oil) in 10 ml of absolute dimethylformamide, a solution of 5.0 g (11.4 mmol) is added dropwise with stirring and at a rotate temperature. 4-C (1- (4-hydroxy-2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-benzoic acid ethyl ester) in 45 ml of absolute dimethylformamide. Then the supplement is stirred for 15 minutes and solution 0 is added, 71 ml (11.4 mmol of methyl iodide in 8 ml of absolute dimethylformamide. Then it is stirred for 2 more hours, at room temperature, evaporated under vacuum and distributed between water and ether. The ether phase is dried, filtered and evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (toluene and acetone 20/1). Output 1.8 g (34.9% of theory), so pl. 115-117C. Calculated,%: C 71.65; H 8.02; N 6.19. Found,%: C 71.47; H 7.86; N 6.19. Analogously to Example 33, 4-C (1- (5-methoxy-2-pyridinophenyl) -1-butyl) aminocarbonylmethyl.-Benzoic acid ethyl ester is obtained. The output of 68.4% of theory, so pl.142145 ° C. Calculated,%: C 71.65; H 8.02; N 6.19. Found: C 71.87; H 8.06; N.6,38. Example 34. Complex (2-nicotinoyloxy-ethyl) -ether-4- (1- (2-piperidinophenyl) -butyl) -aminocarbonylmethyl} -benzoic acid. To a stirred solution of 2.0 g (4.56 mmol) of (2-hydroxyethyl) 4- (1-2-piperidinophenyl-1-butyl) -aminobenzenemethyl-benzoic acid ester in 40 ml of methylene chloride and 0.7 ml- ( 4.81 mmol) of triethylamine is quickly added dropwise a solution of 0.7 g (4.68 mmol) of nicotinic chloride in 20 ml of methylene chloride. Then it is stirred for 2.5 hours at 20 ° C, extracted by shaking with water, dried and the organic phase is filtered and evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (toluene / acetone 5/1). Output 1.1 g (44% of theory), so pl. 132-135 ° C. , Calculated,%: C 70.70; H 6.86; N, 7.73; Found: C, 70.82; H 6.82; N 7.91. Example 35 4- (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl benzyl alcohol. To a stirred suspension of 0.68 g (17.95 mmol) of lithium aluminum hydride in 25 ml of absolute tetrahydrofuran is added dropwise at an internal temperature of 0 ° C with a solution of 5.0 g (11.83 mmol) of ethyl ester 4 (1 - (2-piperidinophenyl) -1-butyl) aminocarbonylmethylJ-benzoic acid in 75 ml of absolute tetrahydrofuran. Then it is stirred for 20 hours at room temperature, cooled to 0 ° C, and this quantity of 4 N is slowly added dropwise. sodium hydroxide solution until a filtered precipitate is obtained, and it is filtered and boiled several times with ether. The combined organic solutions are evaporated under vacuum. The residue is partitioned between water and ether. The ether phase is dried, filtered and evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (toluene / acetone 5/1). Output 1, 0 g (22% of theory), „So pl. 152-154 p. Calculated,%: C 75.75; H 8.48; N, 7.36; Found: C, 75.90; H 8.45; N, 7.28. Example 36. 4- (1- (2-Piperi dinofila) -1-butyl) -aminocarbonylmethyl-benzaldehyde. 6.6 g (62 mmol) of sodium carbonate are heated with 62 ml of ethylene glycol in a 170 ° C bath and 6.2 g (11 mmol) of N-4- (1- (2-piperidinophenyl) are added with vigorous stirring for 1 min. A) -1-butsh1-aminocarbonylmetho1t-benzoyl 3 -N-tosyl-hydrazine (mp.195 ° C decomposition), and gas formation is observed intensively. It is then heated for 2.5 minutes at and immediately vyshivaet on ice. It is extracted with ether, dried, filtered and the ether solution is evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (chloroform and acetone 20/1). Output 2.2 g (52.9% of theory), so pl. 142-145p. Calculated,%: 76,16; H 7.99; Found,% C 76.26; H 7.96; N 7.37. Example 37. Ethyl ester of 4- (1- (2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-basic acid. To 0.60 g (12.5 mmol) of sodium hydride (50% in oil) in 15 ml of absolute dimethylformamide, a solution of 2.80 g (12.5 mmol) of diethylphosphonate ethyl ether is added dropwise at room temperature. uksuskoy acid in 10 ml of absolute dimethylformamide. Then it is stirred for 15 minutes (until the end of gas formation) and. a solution of 2.4 g (6.34 mmol) of 4-g (1- (2-piperidinophenyl) -1-butyl) aminocarbonyl J-benzaldehyde in 10 ml of absolute dimethylformamide is added dropwise. Then it is stirred for 2 hours at room temperature, evaporated under vacuum and distributed between water and ether. The ether phase is dried, filtered and evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (toluene and acetone 10/1). Output 0.85 g (29.9% of theory), so pl. 135-137 ° C (ether and petroleum ether). Calculated,%: C, 74.97; H 8.09; N 6.24; Found: C, 74.91; H 7.89; .N 6.29. About p and me R38. 4- (1- (2-Piperidinophenyl) -1-butyl) aminocarbonylmethyl-Cinnamic acid Alkaline saponification of ethyl 4- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylMeT nj-cinnamic acid is obtained as in Example 11. Yield 64% of theory, mp, J80183 ° C. Calculated,%: C, 74.26; H 7.67; N 6.66. Found,%: C 74.03; H 7.47; N 6.80. Example 39. 3- 4- (1- (2-piperidinophenyl) -1-butyl) amino-carbonylmethyl J-phenyl-propionic acid ethyl ester. 0.60 g (1.34 mmol) of 4- (1- (2-piperidinophenyl) -butyl3-aminocarbonylmethyl-cinnamic acid ethyl ester) is hydrogenated in 10 m of ethanol at 0.20 palladium and carbon (10%) at 5 bar at room temperature and hydrogen pressure, then filtered and evaporated under vacuum. Yield 0.53 g (88% of theory), mp 98-99 ° C (petroleum ether). Calculated,%: C 74.63; H 8.50; N 6.22 51%: C 74.64; H 8.58; Found, N 6.23. 19 is obtained. Similar to the example rtltcuiui pchpi jy IlUJiy IdlUl 3 (; (4 (1. (2.piperidinophenyl A) -1-buty 1-aminocarbonylmethyl 3-phenyl J-propionic acid, O. Output 63% of theory, mp C. 73.90; H 8.11; Calculated, N 6.63 C 73.96; H 8.30; Found,% N 6.56. Example 40. (1- (2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl 3-phenyl-7-propionic acid. Obtained by alkaline saponification of ethyl ester ( 1- (2-pi peridinophenyl) -1-butyl) -aminocarbo, nylmethyl-phenyl-propioic acid as in example 11. Yield 50% of theory, mp.% CZ: 73.90; H 8.11; Calculated , N 6.63 8.07; Found,%: C 73.82; H N 6.41. Example 41. Ethyl 4- (c-cyano-2-piperidinobenzsh-aminocarbonylmethyl-benzoic acid ethyl ester .. mg (1.22 mol) of ethyl ester 4 (o-aminocarbonyl-2-piperidinobenzyl) -aminocarbonyl. Benzoic acid in 0.22 ml of pyridine is added in two portions with 234 mg (1.22 mol) of 4-toluenesulfonyl chloride and heated to. After the same 2 hours, the same amount of pyridine I and 4-toluo sulfochloride are added over 2 hours. and heated for 1 hour at. Then left for two days at which 2N ammonia is added and extracted with chloroform. A solution of chloroform two times After drying and filtering, the solution is evaporated under vacuum. The residue is purified by chromatography on a column of silica gel (chloroform and methanol 10/1. The yield is 114-117 / C (ether and petroleum ether). Calculated ,%: C 71.09; H 6.71; N 10.36; Found,%: C 70.79; H 6.56; N 10.10. 69. 52 Example 42. 4-С (1- (2 -Piperidinophenyl) -1-butyl) -amoynocarbonyl methyl -benoneic acid x Hj 80 .. to a solution of 1.0 g (2.53 mmol) h j „A – G (1- (2-steridinophenyl) - 1-butsh1) aminocarbonylmethylJ-benzoic acid i. -YAMINLI-YAPPOIIGTMRTIP TSG1RNCHPINPI IfKr.TTri in 50 ml of ethanol was added 5 ml (2, 50 mmol) of 1 N, sulfuric acid, are evaporated under vacuum to dryness and dissolved with acetone. Output 0.80 g (65% of theory), so pl. 192-197 with (decomposition). Calculated,%: C 58.53; H 6.55; .N 5.69; S 6.49; Found; C 58.05; H 6.54; N 5.49; S 6.35. Analogously to Example 42, 4-C (1 (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl j-benzoic acid x 0.5 I, 80 x 1.5 is obtained Get half of the amount of sulfuric acid as in example 42. The output of 59.3% of theory, so pl. 180-. , decomposition at 207-210 ° C. Calculated%: C 61.26; H 7.28; N 6.95; S 3.40 Found: C 61.28; H 6.99; N 6.10; S 3.23. And p imper 43. 4-CT- (2-piperidinofenes1) -1-butene-yl) -amino-carboxymethyl-benzoic acid ethyl ester. To a suspension of 4.76 g (12.5 mmol) of the iodomagnesium-propargyl (2-piperidinophenyl) -chetimino complex in 30 Htn methylene chloride, while stirring, a solution of 3.16 g (14 mmol) of 4-ethoxycarbonyl-phenacetyl chloride was added dropwise in 10 ml of methylene chloride. At the same time, the internal temperature rises to 30 ° C. Stirring is continued for 2 hours at room temperature, then water is added with stirring and extracted with methylene chloride. The resulting methylene chloride solution is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue obtained after evaporation is purified by chromatography on a column of silica gel (20/1 ratio of toluene to acetone). The output of 1.05 g (20% of theoretical) of the specified ester in E-form, so pl. 20C (yellow honey-colored oil). Calculated,%: C, 74.26; H 7.67; N 6.66; Found: C, 74.31; .H 7.92; N 6.54. In addition, 1.37 g (26% of theoretical) of the indicated ester is obtained in the Z-form, m.p. 114 116. Found,%: C, 74.11; H 7.55; N 6.36. . Example 44. Example 1 is repeated with the difference that the initial ketimino-compound is used as a complex with lithium. You get: 1.15 g (22% of theory) of the target product in the E-form, so pl. from 1.32 g (25% of the theory) of the target product in the Z-form, mp, 114-11 ° C. I (As indicated, the novel compounds of general formula (1) have the ability to lower blood sugar levels. The following compounds have been investigated. A) (Z) -4- (1- (2-piperidinophenyl) -1-buten-1-yl) -aminocarbonylmethylJ-basic acid; B) (Z) -4- (1- (2-piperidinophenyl) -1-buten-1-yl) aminocarbonylmethyl benzoic acid ethyl ester; B) (E) -4- (1- (2-piperidinophenyl) -1-butene-1-yl) aminocarbonylmethyl-3-isoic acid; . D) 4- (2-methyl-1- (2-piperidinophenyl 1-propen-1 -yl) -aminocarbonylmethyl-benzoic acid; D) ethyl ester of (Z) -4- (1- (2-piperidinophenyl) -1 -hexen-1-yl) -aminocarbonylmethylj-benzoic acid; E) (Z) -4- (3-phenyl-1- (2-piperidinophenyl) -1-propen-1-yl) aminocarbonyl methyl benzoic acid; G) (Z) -4- (1- (3,3-dimethyl-piperidine phenyl) -1-buten-1-yl) amino carbonylmethyl benzoic acid; 3) 4- (1- (2-pyrrolidinophenyl) -1-butyl) aminocarbonylmethyl J-benzoic acid; I) (±) -4- (1- (2-piperidinophenyl) -1-buyl) aminocarbonylmethyl benzoic acid; K) (+) - 4- (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl-benzoic acid; L) ethyl ester (+) - 4- (1- (2-piperidinophenyl) -1-butyl) -amino carboyl methyl benzoate acid; M) 4- | (1- (2-Hexagidroazepiophenyl) 954 -1-butyl) -aminocarbonylmethyl-benzoic acid; H) N-4- (1- (2-piperidinophenyl) -1-gensyl) aminocarbonylmethyl benzoic acid; O) 4- (3-phenyl-1- (2-piperidinophenyl) -1-propyl) aminocarbonylmethyl benzoic acid} P) 4- (2-methoxy-1) (2-piperid 11Nophenyl) -1-ethyl) aminocarbonylmethyl - benzoic acid; P) 4 C (α-cyano-2-piperidinobenzyl) -aminocarbonylmethyl 7-benzoic acid; C) 4-C (1- (2-piperidinofensh1) -1-butsh1) -aminocarbonylmethyl-benzyl alcohol; T) 4 (1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl-phenylacetic acid; U) 4- (1- (2-piperidinophenyl) -1-butyl) -aminocarbonylmethyl-truncated acid; O) p1- (2-piperidinophenyl) -1-butyl) aminocarbonylmethyl-benzoic acid (2,3-dioxy-propyl) ester; X) 4-t (1- (4-fluorop-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl benzoic acid; C) 4-C (1- (4-methoxy-2-piperidinophenyl) -1-butyl) -aminocarbonyl-benzoic acid; (H) 4- (1- (2-octahydroazonin-6-phenyl) -1-ethenyl) -aminocarboxymethyl, 7-benzoic acid; B) 4- (1- (3-chloro-2-piperidinophenyl) -1-ethyl) -aminocarbonylmethyl-benzoic acid; J) 4- (1-t3-methyl-2-piperidinophenyl) - 1-ethyl) -aminocarbonylmethyl-benzoic acid; L) ((4-methyl-fensh1) -2-piperidnnobenzyl) -aminocarbonylmethyl-benzoic acid; E) 4- (ci - (3-methyl-phenyl) -2-piperidinobenzyl) aminocarbonylmethyl-benzoic acid; S) 4 - ((4-fluorophenyl) -2-piperidinobenzyl) aminocarbonylmethyl benzoic acid; I) 4-C (o (2-fluoro-phenyl) -2-piperidinobenzyl) aminocarbonylmethyl benzoic acid; 4- (ol ;-( 4-chlorophenyl) -2-piperidineobenzSHl) -aminocarbonyl methyl benzoic acid; AB) 4- (oC- (3-chloro-phenyl) -2-piperidium
nobenzyl) aminocarbonylmethylJ-benvoic acid;
AB) 4- (2-piperidino-ot- (2-pyridyl) benzyl) -aminocarbonyl methyl benzoic acid; AH) 4-C {2-piperidino-o - (4-pyridyl) benzyl) aminocarbonylmethyl benzoic acid;
AD) 4- (6-chloro-o-phenyl-3-piperidinobeneyl) aminocarbonylmethyl benzoic acid;
AE) 4- (o-phenyl-2-piperidinobenzyl) aminocarbonylmethyl 3-cinnamic acid;
AJ) 3-4- (c-phenyl-2-piperidinobenzyl) aminocarbonylmethyl-3-phenyl-propionic acid;
A3) 4- (4-chloro-N-phenyl-2-piperidinobenzyl) aminocarbonylmethylJ-benzoic acid;
AI) 4-C (6-metsh1-about phenyl-2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid;
AA) 4- (4-methyl-c-phenyl-2-piperidinobenzyl) aminocarbonylmethylJ-benzoic acid;
AL) 4 (phenyl-2-piperidino-benzyl) aminocarbonylmethyl 3-benzaldehyde; . AM) 4- (2- (2-methyl-piperidino) -o-phenylbenzyl) aminocarbonylmethyl benzoic acid;
AH) 4-f (2- (3-methyl-piperidne) -c / -phenyl-benzyl) -aminocarbonyl-methyl-benzoic acid;
AO) 4- (3-chloro-phen-1-2-piperidinobenzyl) -aminocarbonylmethyl-benzoic acid.
The effect of the test compounds on the blood sugar level was determined on female rats weighing 180220 g, which were not given 1 hour 24 hours before the start of the experiment. The test compounds immediately prior to the start of the experiment: 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 plexus. At the same time, up to 50 ml of blood were subjected to release from protein with 0.5 ml 0.33 n. perchloric acid, followed by centrifugation. In the residue, glucose was determined by the Technocinase method using an analytical photometer. Statistical evaluation was performed for the Student with a p of 0.05 as the limit of significance. The research results are shown in Table. one.
Table 1
57
.Note. The sign (+) is a dose of 10 mg / kg; n.s - according to statistics
not significantly.
On female and male mice weighing neither (suspension in 1% methylene cello 20-26 g, a single dose of toxic delupose was investigated) with a subsequent substance following oral administration and administration for 14 days.
M70969
58 Continuation of the table, 1 B s with physiologically tolerable salts with; suitable for the treatment of diabetes. Comparative experience. Known compounds: (2-anilino-benzoylamino) -ethyl-benzoic acid} A-C2- (2-ethylamino-benzoylamino) -ethyl} -benzoic acid; complex methyl 4-C2- (2-ethylamino-benzosoIlamino) -ethylJ-benzoic acid ester, and (2-ethylamino-5-chloro-benzoylamino) -ethylZ-benzoic acid. These compounds were tested for blood sugar lowering activity. It was found that the known compounds do not show statistically significant (active activity at a dose of 5 mg / kg. Comparative results show that at doses of 5 mg / kg and less obtained by the proposed method, new derivatives of phenylacetic acid have the best activity to reduce blood sugar than known compounds of similar structure.

权利要求:
Claims (2)
[1]
1. or 2 nitrogen atoms a heteroaryl group with 4,5,8 or 9 carbon atoms _f 50
RjH R ^ - the same or different, mean a hydrogen atom or alkyl groups with 1-5 carbon atoms or together with a carbon atom mean 55 f ^ nipalkylidene group with 1-4 carbon atoms in the alk
W is a carboxyl group or an alkoxycarbonyl group with a total number of carbon atoms
1 to 4 carbon atoms in the alkylidene part,
W is a carboxyl group or an alkoxycarbonyl group with a total number of carbon atoms
2-6, in which the alkyl part can be substituted by a phenyl group and, starting from the β-carbon atom, can be substituted by one or two hydroxyl groups, an alkoxy group, an alkanoyloxy group, a dialkylamino group, an alkyleneimino group or a pyridinecarbonyloxy group, each alkyl part may contain 1-3 carbon atom, and the alkyleneimino group may contain 4-6 carbon atoms, an alkenyloxycarbonyl group with a total number of carbon atoms from 4 to 6, an alkyl group with 1-3 carbon atoms, hydroxymethyl, formyl group, cyano group PPA, aminescarbonyl, carboxymethyl, 2-carboxyethyl,
2-carboxyethenyl, 2,2-bis .- (carboxyl-ethyl, alkoxycarbonylmethyl, 2-alkoxycarbonyl ethyl, 2-alkoxycarbonyl-ethyl or 2-, 2—-bis- (alkoxycarbonyl) -ethyl groups, and the alkoxy group may mean 1- 3 carbon atoms, or their salts, characterized in that the compound of General formula (II)
A-NH R.
where A, R ₃ h R ₂ have the indicated meanings, or its complex with lithium or magnesium halide, if A means one of the above vinylidene groups, is reacted with a compound of the general formula (III)
Н0 ~ СО
X where R ₃ has the indicated meanings;
N has the meanings given for W or means a protected carboxyl group, or a reactive derivative thereof, such as chloroacetone or anhydride, followed by removal of the protective group and isolation of the desired product in free form or in the form of a salt.
The invention relates to a method for producing new derivatives of phenylacetic acid, in particular to a method for producing derivatives of phenylacetic acid of general formula 5 where R ₃ is an unbranched alkyleneimino group with 4-9 carbon atoms, unsubstituted and / or mono- or disubstituted by alkyl groups with 1-3 carbon atoms , or . dialkylamino group with 1-5 carbon atoms in each alkyl part;
R ₂ - an atom of hydrogen, fluorine, chlorine, bromine or iodine, hydroxyl, trifluoromethyl groups, nitro group, amino group, piperidinotrup3
1170969 4 pa, alkyl, alkoxyl alkyl sulfonyl, alkyl, sulfinyl, alkyl sulfonyl groups, phenylapoxy group, alkanoyloxy group, alkanoylamino group, alkylamino or dialkylamino groups, each alkyl group may contain 1-3 carbon atoms; Щ R ₃ is an alkyl group with 1-3 carbon atoms, a hydrogen or halogen atom A is a group of the formula or
R ₄ is an alkyl group with 1-3 carbon atoms, an unsubstituted or substituted alkoxy group with 1-3 carbon atoms or a phenyl group, an alkyl group with 4-7 carbon atoms 20, an alkenyl group with 3-5 carbon atoms, a cyano or alkyleniminocarbonyl group with 4-6 carbon atoms in the alkylene part, an aminocarbonyl group unsubstituted or mono- or disubstituted with an alkyl or phenylalkyl group with 1-3 carbon atoms in the alkyl part, an aryl group with 6 or 10 35 carbon atoms, unsubstituted or mono- or disubstituted with halogen atoms a, alkyl, hydroxy, alkoxy, fenilalkoksilnoy, 40-alkyl sulphenyl, alkylsulphinyl and / or alkylsulphonyl groups, wherein the substituents may be the same or different and the alkyl portion 45 may comprise 1-3 carbon atoms, or comprising
[2]
2-6, in which the alkyl part may be substituted by a phenyl group and, starting from the β-carbon atom, may be substituted by one or two hydroxyl groups, an alkoxy group, an alkanoyloxy group, a dialkylamino group, an alkyleneimino group or a pyridinecarbonipoxy group, each alkyl part may contain 1-3 carbon atom, and alkyleneimino group. may contain 4-6 carbon atoms, an alkenipoxycarbonyl group with a total number of carbon atoms from 4 to 6, an alkyl group with 1-3 carbon atoms, methyl hydroxide, formyl groups, cyano group, aminocarbonyl, carboxymethyl, 2carboxyethyl, 2-carboxyetheniphenic, 2,2- bis (carboxy) ethyl. alkoxycarbonylmethyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycarbonylethylene or 2,2-bis (alkoxycarbonip) ethyl groups, and alkoxy may mean 1-3 carbon atoms, or their salts.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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BE764238A|1971-03-17|1971-09-13|Lilly Industries Ltd|PHENYLALKYLAMINE DERIVATIVES|

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NL7305171A|1973-04-13|1974-10-15|

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DE3100575A1|1981-01-10|1982-09-02|Dr. Karl Thomae Gmbh, 7950 Biberach|"NEW BENZOESAEURS, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS"|US5312924A|1983-12-30|1994-05-17|Dr. Karl Thomae Gmbh|Phenylacetic acid benzylamides|

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DE3347565A1|1983-12-30|1985-07-11|Thomae Gmbh Dr K|NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF|

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GB8903592D0|1989-02-16|1989-04-05|Boots Co Plc|Therapeutic agents|

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FR2763590B1|1997-05-22|2000-03-24|Synthelabo|ACID DERIVATIVES [[[ AMINO] CARBONYL] ALKYL] - AROMATICS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION|

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PE20050630A1|2003-06-09|2005-09-22|Boehringer Ingelheim Int|HETEROCYCLIC COMPOUNDS AS PAPILLOMA VIRUS INHIBITORS|

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EP2364977A1|2010-01-26|2011-09-14|Reuter Chemische Apparatebau KG|Process for the enantiomeric enrichment of 3-methyl-1--1-butylamine|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE19823225188|DE3225188A1|1982-07-06|1982-07-06|Novel phenylacetic acid derivatives, their preparation and pharmaceuticals containing these compounds|

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DE19823225155|DE3225155A1|1982-07-06|1982-07-06|Novel N-benzylamides and their salts, their preparation and pharmaceuticals containing these compounds|

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