Method of producing derivatives of 4-(aroylamino)-pyperidine butanamide or their stereo isomers, or

专利摘要:
The use for the manufacture of a medicament for the treatment of diarrhea of a compound of formula wherein Ar is thienyl, halothienyl, furanyl, halofuranyl, pyridinyl, aminopyridinyl, thiazolyl, imidazolyl or a radical of formula and Ar1 and Ar2 are, each independently, phenyl or halophenyl; the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions; novel compounds of formula (I).
公开号:SU1620049A3
申请号:SU874202790
申请日:1987-06-29
公开日:1991-01-07
发明作者:Анри Поль Ван Даль Жорж；Франсуа Вламинк Фредди；Мария Соммен Франсуа；Анна Жозеф Де Клэйн Мишель
申请人:Жансен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:

HK6K7-C (0) -C (C6H5) 2-A1k-1I-CH2-CH (OK1) -SK- (CH2) 2
where R is —NRa — C (0) —Ar; R, - H, C, -C4-alkyl, C-C-alkylcarbonyl; E „- H, Cj-Cf-alkyl; Ar - thienyl, halohydrofuran, pyridinyl, amine opiridinyl, thiazolyl, imidazolyl, K3, R, RJ (independent) - H, .- alkyl, С, - (4 alkylkoxy, halo, OH, CN, Shg, Shg, mono- and d C -Sf-alkyl) amino, P-C alkylcarbonylamino, C -Sf-alkylcarbonyl, aminosulfonyl, C-04-alkylthio, benzenexy, phenoxy, CFj, prolenyloxy, -alkylcarbonyloxy; Alk - - (CH) g-;
(0) -C (C6He) 2-AlK K-CH2 CH (OR1) -CH (NHR2HCH2) 2
with Ar - C (0) -OH (III) or its functional derivative in an inert solvent, followed by isolation of the target product in free form or in the form of the desired salt. If necessary, the compound f-ly I, where one of R, R4
-CH2-CH (CH3) -; R6 and R7 are C-C4 alkyl or (R6 + is pyrrolidinyl or 4-morpholinyl, provided that when R and R7 are CH3, then Ar Ј gHg1 or their stereoisomers or their pharmaceutically acceptable acid addition salts, possessing anti-diarrhea activity, which can be used in medicine. The goal is to create new active and low-toxic substances of the indicated class. Synthesis is carried out by the reaction of the compound f-ly
ka
4 X
(OR1) -CH (NHR2HCH2) 2
or R, y is KH, or is acylated with the corresponding anhydride or acyl halide to form ((—O-alkylcarbonylamino groups; or reductive N-alkylation of the carbonyl reagent under H atmosphere is carried out in the presence of Pd / C to give di
- (C (-0 4 -alkyl) amino groups, or compound f-ly I, where one of R-, 1C
either Kg-- N0a, or DI or DX, restore or hydrodegalo-dirutot or debenzilir
The invention relates to the preparation of new pyridine derivatives, namely, 4- (aroylamino) -piperidine-butanamide, their stereoisomers and acid addition salts, which have anti-diarrhea activity,
The aim of the invention is to create, on the basis of known methods, a method of obtaining new compounds, derivatives of piperidine, with high pharmacological activity and low toxicity.
Example 1. To a stirred and cooled solution for 4 hours, trans 4-amino 3 oxy ™ I5I, $ - trimethyl -Ob, Sb Diphenyl -1 -piperidinebutanamide at 120 hours, CBS1 was added 1.26 parts of HjN-diethylethanamine. A solution of 2.3 h of 3- (three fluoromethyl) -benzoyl chloride in 85 parts of chloroform of methane is added dropwise to the mixture. After the addition was complete, the reaction mixture was left overnight with stirring at room temperature. A solution of sodium carbonate in water was added. The separated organic layer was washed with water, dried, filtered and evaporated. The residue was dissolved in 2,2-oxibispropane, the precipitated substance was filtered off, dried in vacuum at 60 ° O, and 4.9 parts (86.3%) of TpaHC-3 oKcH N9W, | - trimethyl oил, diphenyl - {4- Ј (3-trifluoro methyl) benzoyl amino -1 -piperidine butanamide, t, mp, 140, (compound 1).
Similarly, the compounds shown in Table 2 were also prepared. 1, and compound 24, To a stirred and cooled (on an ice bath) solution of 4 parts of trans-4-amino-3-hydroxy-U, 11, jf-trimethyl-o /, amp 6-diphenyl- 1-piperidinbutanamitsa in 60 hours trichloromethane was added a suspension of 2.32 parts of 2-amino 3-pyridinecarbonyl chloride monohydrochloride in 45 parts of trichloromethane. Stirring was continued for 15 minutes in an ice bath. 2.7 hours were added dropwise at a temperature below 10 ° C, H, I-diethyl hydrogen in the presence of Pd / C to produce W or H or OH group, The new compounds are more active than the known analogues and have lower toxicity, 5 tab.
five
0 5
0
0 35 40 45
Q
ethanamine. After the addition was complete, stirring was continued for 30 minutes at room temperature. The organic layer was washed with sodium carbonate solution in water and water, successively dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90: 5 10 by volume) as eluent. Pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60 ° C, yielding 1 part (19.3%) of trans 4- -Sh 2-amino-3-pyridinyl) carbonyl amino7-3-hydroxy-Sh, K, -trimethyl- , - dphenyl-1-piperidinebutanamide, so pl. 209.2 ° C.
Similarly, cis 3-CI-I, II, H, Y-trimethyl-c, -diphenyl-4-J J z- (trifluoromethyl) benzoyl amino -1 -1-niperidinbutanamide ethanediolate (it 1), m.p. 206.3 ° C) (compound 28).
Example 2 To a solution of 4 parts of 2- (phenylmethoxy) benzoic acid, stirred and cooled in an ice-bath, in 90 hours. SNH3-s was first added with part of II 5-diethylethanamine and then 1.6 hours of ethyl chloroforic acid (carbon-chloro, 1 g of dates) at a temperature below. After stirring for one hour while cooling in an ice bath, the mixture thus obtained was added dropwise to a cooled solution with 5.94 parts of trans-4-amino-3-hydroxy-I, L, X (- trimethyl, o (-Diphenyl-2-piperidine-butanamide at 90 h, CHClg at a temperature below 5 ° C. After the addition was completed, the reaction mixture was left overnight with stirring at room temperature. The organic layer was washed with water, sodium carbonate solution in water and again with water , dried, filtered, and evaporated. The residue was purified by chromatography on a silica gel column. eat using mixture
51
trichloromethane and methanol (95: 5 by volume) as the mobile phase. Pure fractions were collected and the eluent was evaporated. The residue was cured in 2,2-oxybiopropane. The product was filtered off, dried in vacuum at 60 ° C, and 3.7 parts (40.7%) of tpans-3-hydroxy-H, M, -trimethyl-o (, y-4- | Ј2- (phenylmethoxy ) benzoyl amino-β-piperidinebutanamide, mp 149.0 ° C (compound 29).
Similarly, the compounds shown in Table 2 were also prepared. 2
Similarly, the following compounds were also obtained: trans (acetyl amino) -2- (acetyloxy) benzoyl amino V -1 -1- 4- (dimethyl amino) -1 -1-methyl 4-oxo-3,3-diphenylbutyane | -3- -piperidinol acetate (ester), so pl. 156.4 C (compound 40) and trans-3-hydroxy-K, I, U-trimethyl-o, phenyl-4-G (3-hyenyl) carb onylamino -1-piperidine butanamide, hemihydrate, m.p. 194.4 ° C (compound 41).
Example 3. To a stirred solution of 3.95 parts of trans-4-amino-3-оке -key-NjN, -trimethyl-oЈ, oygdiphenyl-1-piperidinebutanamide and 1.78 h, 4-amo-5 cyano-2 -Oxybenzoic acid in 150 parts. CHC1 $ was added 3.1 parts of N, N-methane-tetraylbis (cyclohexanamine) and left under stirring at room temperature for two days. The reaction mixture was acidified with an aqueous solution of acetic acid. The separated organic layer was washed with water, dried, filtered and evaporated. The residue was taken up with acetonitrile and the precipitate was filtered off. The filtrate was purified by chromatography on a silica gel column using trichloromethane-methanol (90:10 by volume) as an eluent. Pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off, dried, and 0.55 parts (10%) of monohydrate-4- (ами-amino-5-cyano-2-oxibenyl) amino-3-OKCH-K, N, V-trime were obtained. - thyl-0 /, 0b-diphenyl-1 -piperidinebutanamide, so pl. 211.4 C (compound 42).
Example 4. 2.8 parts of NK-diethyl-ethanamine were added to a solution of 1 parts of 5H, 10H-diimidazo (1.5a, I1, 5J-dj-β-pyrane-5,10-dione at 36 hours P, I-dimethylformamide. The suspension thus obtained is added dropwise to
200496
a stirred and heated (70 ° C) solution of 3.95 parts of trans-4-amino-3-hydroxy-N, N, / P-trimethyl-N, N-diphenyl-1-peep e-redinbutanamide at 18. h K, G-dimethylformamide. At the end of the addition, the reaction mixture was left overnight with stirring at 70 ° C. After evaporation, the residue was purified by chromatography on a silica gel column using a mixture of trichloroethane and methanol (90:10 by volume) as eluent. Pure fractions were collected and the eluent was evaporated. The residue was purified by chromatography
15 graph (high performance liquid chromatography) on a silica gel column using a mixture of trichloromethane / methanol / methane, saturated with ammonia in a ratio of 90: 9: 1
20 volume as eluent. The pure fractions were collected and the elution solvent was evaporated. The residue was pulverized and evaporated again. 1.13 parts (23%) of trans-3-hydroxy25 -4p III-imidazol-5-yl) carbonylamino-K, 1O-trimethyl-, 0 (-Diphenyl- 1-iperidine butanamide, mp 155.0 ° C (compound 43).
Example 5.K stirred
30 and cooled (below 5 ° C) solution of 3.95 parts of TpaHC 4-aMHHO-3-OKCH-N, Njf-trimethyl-o, 0,-diphenyl -1-piperidine butanamide in 52 parts of trichloromethane CHCJ-3 drop by drop a solution of 2.03 parts of 1-methyl-2H-3,1-benoxoxin 35 -2.4 (W) -dione was added in 48 parts of CHjCl. After the addition is complete, the mixture is stirred for 32 hours at room temperature. Separated organic layer
. washed with 5% aqueous solution 40
sodium hydroxide and water, dried,
filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture
& e trichloromethane - methanol (96 .: 4 by volume) as the mobile phase. Pure fractions were collected and the eluent was evaporated. The residue was dissolved in trichloromethane. Organic layer
The CQ was washed with a 5% aqueous solution of sodium hydroxide and water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered, dried in vacuum at 60 ° C and obtained 0.5 part (9.4%) of trans-3-hydroxy-K, H, y-trimethyl- (methylamino) benzoyl amino--tf D-diphenyl-1 -piperidinebutanamide, t. pl. 240.3 ° C (compound 44).
Example 6, To a stirred solution of 11.9 h, trans-4-amino-3-hydroxy-N, N, Y-trimethyl-p (, o6 diphenyl-1 - -piperidine in 180 parts of trichloromethane CHClO was added a solution of 5, 8 h. 5-mex-2X-3,1-benzoxazine 2,4- (1H) -dion at 45 h, NN-dimethylformamide at 50 ° C. Mixing was continued
2 h at 50 ° C. After evaporation, the residue was suspended in water. The product was filtered and purified by silica gel column chromatography using a trichloromethane-methanol mixture (95: 5 by volume), saturated with ammonia as the mobile phase. The first fraction was collected and the eluent was evaporated. The residue was suspended in 2,2-oxy-bis-propane. The product was filtered, dried and the first fraction was obtained 7.60 h, trans-4-G (2-amino-6-methoxybenzoyl) amino | v
-Z-hydroxy-N, N, $ -trimethyl-Y, III-diphenyl- /
-1 piperidnnutamida. The second fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered, dried and the second fraction was obtained; 1.23 parts of trans-4- Ј {2-amino-6-methoxybenzoyl) amino-3-hydroxy-K, W, р) p-trimethyl-o, oi-diphenyl-1-piperidinebutanamide. The total yield of 8.83 CV (54.1%) of trans 4-Ј (2-amino-6-methoxybenzoyl) amino 3-hydroxy-N, N 5U-trimethyl, o-diphenyl-1-piperidinbutanamide, t. . 175.1 C (compound 45),
Similarly, were also obtained;
trans-4- | (2-aminobenzyl oyl) amine G - -13-OKCH-N, N, (trimethyl-, in (.-diphenyl -1 -1-piperidinbutanamide, monohydrate, T. pl. 164.5 C (compound 46 );
trans-4- (2-amino 5-chlorobenzoyl) aminoI - 3-hydroxy-N, N, V - trimethyl o (, b-di-phenyl-1-piperidinebutanamide, mp 183.1 ° С (compound 47);
trans-4- Ј (2-amino-4-nitrobenzo-amino-T-3-hydroxy-Y-trimethyl-Obb-diphenyl-1-piperidinebutanamide (compound 48); „
trans-3-hydroxy-4-J 2-methoxy-6- (methylamine) benzoyl amino} -N, ED, | -trimethyl-O aOC-diphenyl-1-piperidinbutanamide, t. pl. 159.1 ° C (compound 49)
Example 7. a) To a stirred and cooled solution of 3.1 parts of (+) - (behind, trans) -4-amino-3-hydroxy-I, N, Ј-trimethyl-o (, o1-diphenyl-1 -piperidine-butanamide at 114 o'clock and 0.94 4.fc W, H-diethylethanamine dropwise to
0
5 Q 5
five
0
A solution of 3.8 parts of 3- (trifluoromethyl) benzoyl chloride in 75 hours, trichloromethane was added. After the addition was complete, the mixture was left overnight with stirring at room temperature. The reaction mixture was washed with an aqueous solution of sodium carbonate and water. The separated organic layer was dried, filtered and evaporated. The residue was cured in 2.2; -ox "t bipropane and crystallized from Cn-Si-acetonitrile-2.2-Oxybispropane. The product was filtered, dried and received 1.3 hours (29.3%) of (-) - (ZA- -trans) -3-hydroxy-N, / G-trimethyl -, - -diphenyl-4-1 3- ( trifluoromethyl) silt aMHHoj-1-piperidinbutanamide, so pl. 197.7 ° C.VD1 | 5 -25.02 ° (with 1% in ethanol) (compound 55). b) 11.5 parts of (-) - (ZA, trans) -3-ox-II, N, X-trimethyl- s (Xdiphenyl-4- | P (trifluoromethyl) benzoyl amino -1 -1-piperidinbutanamide recrystallized three times from acetonitrile. The product was filtered, dried
and received 6.7 hours (59.0%) (-)),
. FOR, trans-3-hydroxy-N, H, 1P-trimethyl-p (, 0 (-diphenyl-4- 3- (trifluoromethyl) benzoyl amino-U-piperidinbutanamide, t, pl. 215.10 C; -41 , 68 ° (in ethanol) (compound 56); Similarly, the following were also obtained:
(+) - (3B, trans) -3-hydroxy-N, H, | - three methyl-o /, Јx-diphenyl-4- {3- (trifluoromethyl) benzoyl amino} -1-pkperidinbutan-amide, t. pl. 2p5.9 ° C, o (65 +36, b ° 1 (in ethanol) (compound 57) and (+) (x), 3B, trans-3-hydroxy-N, K, y-trimethyl-, L -diphenyl-4- (trifluoromethyl) benzoyl Pamino-1-piperidinebutanamide, mp 215.0 ° C. · Qo (a) + 43.47 ° (in ethanol) (compound 58).
Example 8 "To a stirred and cooled (below 10 ° C) solution
, 9 h, Ј1 (U), 3B, t. S-ns -4-amino-3-hydroxy- -N, N,) p-trimethyl-c (, amp 6-diphenyl-1-piperidinebutanamide and 2, 9 h. N, N flH3Tttrt- ethanamine at 300 h. Trichloromethane
a solution of 5.21 parts of 3- (trifluoromethyl) benzoyl chloride in 150 hours, trichloromethane was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then
 washed with sodium carbonate solution, dried, filtered and evaporated. The residue was purified by COPL chromatography.
15
Use silica gel using trichloromethane-methanol (95: 5 o volume) as eluent. Pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. The salt was filtered and dried for 48 h at pu 100 ° {J in vacuo. 4.56 h (32.8%) of (-) - Q (v) 3B monochlorohydrate (JQ trans-3-hydroxy-H, H,) (-ggmethyl-o, -diphenyl-4- {Ј3- (trifluoromethyl) benzoshL of amino-1-piperidinebutanamide, t. 209.6 ° C, EXJ§) -37.62 ° (s-1% i ethanol) (compound 59).
Similarly, it was also received:
(+) - Ј. (Y), FOR, trans-3-hydroxy-N, K, Y-trimethyl-o (, 0-diphenyl-4-Gr-(tritormethyl) benz oshl amino | - G-piperi-20 inbutanamide, so pl 146.00 Cjjj 5gg + 21.44 ° (in ethanol) (compound 60).
Example 9. To mix a solution of 2.72 parts of trans-4-Ј (2-amino-25-but-6-methoxybenzoyl) amino 1-3-hydroxy--N, N, / f-trimethyl-o (, oЈ- diphenyl-1-piperidinebutanamide in 20 parts of acetic acid was added 0.5 parts of acetic anhydride. The reaction mixture was poured on with stirring overnight at room temperature, then evaporated, and the residue was purified by chromatography on a silica gel column using a mixture of trichloromethane — metha-35 nol, saturated with ammonia (95: 5 by volume), as eluent “Pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2, -oxibispropane. The product was filtered out, 40 was discharged, dried at 80 ° C, and 2.45 parts (83.5%) of trans-4- {2- (acetylamino) -b-methoxybenzene Lamino-C-C- si-H ,, | -trimethyl - (, o-diphenyl-1-pi-pern dinbutanamide, mp 146.5 ° C 45 (compound 61).
Similarly, were also obtained:
cis-4- (5-acetylamino) -2-methoxybenzoyl amino.-3-methoxy-i, 11 Jf-tri-SQ methyl-od, b diphenyl-J-piperidino-butan amide, t. pl. 122.9 & C (compound 62) j trans-4-J 4- (acetylamino) -2-methoxybenzoyl amino-3-hydroxy-S, S, / P-trimethyl.-O, o diphenyl-1 -piperidinebutane-amide, t. pl. 193.88C (compound 63); trans-4- Ј4- (acetylamino) -5-chloro-2-methoxybenzoyl amino-3-hydroxy-H, W,
G-trimethyl-o, N-diphenyl-1-piperidine55
five
0
5 о 5 0 5
Q
five
butanamide, so pl. 147, (compound- 64).
Example 10. To a stirred solution of 6.52 parts of cis-4-Ј (5-amino-4-chloro-2-methoxybenzoyl) amino-3-methoxy-N, K, Y-trimethyl-p-diphenyl - - 1-pineridin-butanamide in 195 parts of dichloromethane was added 2.6 parts of butanoyl chloride. After stirring for 15 minutes, 2.94 parts of N, N-α-diethylamine were added. The contents of the reactor were left overnight at room temperature. The reaction mixture was sequentially washed with sodium carbonate solution and water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using trichloromethane-methanol mixture saturated with ammonia (95: 5 by volume) as eluent. Pure fractions were collected and the eluent was evaporated. The residue was stirred at 2,2-oxybispropane. The product was filtered off, dried, and 3.39 parts (46.5%) of cis-4- Ј 4-chloro-2-methoxy-5- - Ј (1-oxobutyl) amino benzenoam amino-3-MeTOKCH- were obtained. N, N (-trimethyl-o about Difnasht-H-piperidinbutanamide, t. Pl. 130,7tfC (compound 65).
Example 11. A mixture of 2.3 h trans-4-Ј (4-amnno-2-methoxybenzoyl) amino} -3-hydroxy-M, K, Y-trimethyl - (, oЈ-diphenyl-1-piperkdinbutanamido, 2 h polyoxymethylene, one part of a 4% solution of thiophene in methanol and 120 hours of methanol were hydrogenated at normal pressure and temperature with 2 hours of a 10% catalyst of palladium on coal. After uptake of the calculated amount of hydrogen, the catalyst was filtered and the filtrate was evaporated. The residue was crystallized from acetonntrile. The product was filtered, dried in vacuum at 50 ° C and received 0.91 h (39.7%) of trans-4-4-4 (dcmethylamino)) -2-methoxyb nzol amino | -3-hydroxy-N, N, y-trimethyl-a (- DI- phenyl-1-piperidinbutanamida, mp 210,9 ° C (compound 66)...
Example 12. A mixture of 4 parts of trans-4- 1 (4-fluoro-2-nitrobenzoyl) amino - -3-hydroxy-K, H, -trimethyl-o D-diphenyl--1-piperidinbutanamide, 1 h A 4% solution of thiophene in methanol and 200 parts of methanol were hydrogenated at normal pressure and room atmosphere with 2 parts of a 5% platinum-on-carbon catalyst. After absorption of the calculated amount of 111620049
The hydrogen of the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in acetonitrile. The organic layer was evaporated again, and the residue was crystallized from a mixture of acetonitrile and a few drops of water. The product was filtered, dried, and 1.93 parts (51.8%) of trans-4- -H (2-amino-4 fluorobenzoyl) amino-3-hydroxy-N, W Jf-trimethyl- t (, o6- diphenyl-1 - -piperidinebutanamide, monohydrate, mp 127.0 ° C (compound 67),
Similarly, were also obtained
trans-4- (3-amino-2-hydroxybenzoyl) amino-3-hydroxy-M, M, U trimethyl o (, o-diphenyl-1-piperidinbutanamide, m.p., 157.2 ° С (compound 68 );
12
filtered, dried and received 16,2,4. (100%). cis-4- (5-amino-2-me-TOKCn6eH3omr) aMHHo-3-MeTOKCH-N, N,) jl-trimethyl-o /, o-diphenyl-1 piperidine-butanamide, so pl. 189.0 ° 0 (compound 74).
Similarly, were also obtained:
trans-4-C4-amino 2-methoxybenz osht) amine o-Z-oKCH-NjN,)) 1-trimethyl- - 0 (, 0b-diphenyl-1 - piperidinebutanamide a, t. pl. 212 C . (compound 75);
cis-4-ts4-amino-2-methoxybenzo.,. (yl) AmingG-3-hydroxy-H, K., K-trimethyl-o (, O-diphenyl-1-piperidine butanamide, mp 151.2 ° C. (Compound 76).
Example 14. A mixture of 2.7 h, trans-3-hydroxy-N, N, y-trimethyl-X, 0 (-di10
trans-4- (2-amino-4-chlorobenzoyl) 20 Phenyl-4- | Ј2- (Р11-СН О) benzoyl1-amshsh amine-L-3-oxy-N, N, Y-trimethyl-o (, o-di

phenyl-1-piperidinebutanamide, t. pl.
197.0 ° C (compound 69);
trans-4-p2-amino-3-chlorobenzene) aMHHo j-3-OKCH-N, N, Y trimethyl-5, & (- -diphenyl-1-piperidinbutanamide, monohydrate, t „pl. 130.9 C ( compound 70);
trans-70 (2-amino-5 methylbenzoyl) amino-3-hydroxy-I, N, / 0-trimethyl- | U, (α- -diphenyl-1-piperidinbutanamide, t.p. 216.8 ° C (compound 71);
trans-4-Ј (2,4-diaminobenoyl) amino-3-hydroxy-N 5N, Jf t-trimethyl-diphenyl-1-piperidinebutanamide, t, pl. 136.1 ° C (compound, 72);
trans-4-2-amino-3-methoxybenzoyl) amino-3-hydroxy-W, N, Y-trimethyl p (, 0 (, - diphenyl-1 -rkperidine butanamide, hemihydrate, mp 169.5 ° C (compound 73)
Example 13, A mixture of 17.3 parts of cis-4- (5-amino-4-chloro-2-methoxybenzoyl) -amine) methoxy-III, U, Y-trimethyl- .O D-diphenyl-1 -piperidine butanamide, 5 parts of calcium oxide and 250 hours, 2-methoxyethanol was hydrogenated at normal pressure and 50 ° C with two parts of a 10% palladium-on-carbon catalyst. After absorption of the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane — methanol, saturated with ammonia (95: 5 by volume) as eluent. Pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. Product, from 25
thirty
-1-pipericinbutanamide and 120 parts of methanol were hydrogenated at normal pressure at room temperature with 2 hours of catalyst — 10% palladium on carbon. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane - methanol (95: 5 but by volume) as elgoent. The pure fractions were collected and the eluent was evaporated. The residue was dissolved in methylbenzene and the solvent was evaporated again. The residue was suspended in a mixture of 2.2 (-oxibispropane and a few drops of acetonitrile. The product was filtered, dried in vacuum at 70 ° C and obtained 1.3 hours, (63.0%) trans-3 hydroxy-4- (2-hydroxybenzoyl) aMHHOj-H, K,} C-trimethyl-o (-diphenyl-piperidinebutanamide, mp 154.3 ° C (compound 77).
Pharmacological testing. The beneficial pharmacological properties of the compounds of formula (l) and their pharmaceutically acceptable acid addition salts are shown in tests for ricin oil and tail withdrawal.
Reactions to ricin oil in rats. Female Wistar rats fixed at night. Each animal was treated orally with a dose of the test compound. One hour after administration, animals received 1 ml of ricin oil through the mouth. Each animal was kept in a separate cage and an hour after the introduction of the ricin
45
50
55
12
filtered, dried and received 16,2,4. (100%). cis-4- (5-amino-2-me-TOKCn6eH3omr) aMHHo-3-MeTOKCH-N, N,) jl-trimethyl-o /, o-diphenyl-1 piperidine-butanamide, so pl. 189.0 ° 0 (compound 74).
Similarly, were also obtained:
trans-4-C4-amino 2-methoxybenz osht) amine o-Z-oKCH-NjN,)) 1-trimethyl- - 0 (, 0b-diphenyl-1 - piperidinebutanamide a, t. pl. 212 C . (compound 75);
cis-4-ts4-amino-2-methoxybenzo-,. (yl) AmingG-3-hydroxy-H, K., K-trimethyl-o (, O-diphenyl-1-piperidine butanamide, mp 151.2 ° C. (Compound 76).
Example 14. A mixture of 2.7 h, trans-3-hydroxy-N, N, y-trimethyl-X, 0 (-di0
0 Phenyl-4- | Ј2- (P11-CH O) benzoyl1 Phenyl-4- | Ј2- (P11-CH O) benzoyl1
0
-1-pipericinbutanamide and 120 parts of methanol were hydrogenated at normal pressure at room temperature with 2 hours of catalyst — 10% palladium on carbon. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane - methanol (95: 5 but by volume) as elgoent. The pure fractions were collected and the eluent was evaporated. The residue was dissolved in methylbenzene and the solvent was evaporated again. The residue was suspended in a mixture of 2.2 (-oxibispropane and a few drops of acetonitrile. The product was filtered, dried in vacuum at 70 ° C and obtained 1.3 parts (63.0%) of trans-3 hydroxy-4-( 2-hydroxybenzoyl) aMHHOj-H, K,} C-trimethyl-o (-diphenyl-piperidine butanamide, mp 154.3 ° C (compound 77).
Pharmacological testing. Useful pharmacological properties of the compounds of formula (l) and their pharmaceutically acceptable acid-, additive salts are shown in tests for ricin oil and tail withdrawal.
Reactions to ricin oil in rats. Female Wistar rats were fixed overnight. Each animal was treated orally with a dose of the test compound. One hour after administration, animals received 1 ml of ricin oil through the mouth. Each animal was kept in a separate cage and an hour after the introduction of the ricin
five
0
five
131620049
the oils observed the presence or absence of diarrhea. U values
50
those obtained in experiments with ricin oil on rats and experiments on tail removal were calculated based on the results of testing at least five animals, and even ten animals were used for a number of the most interesting compounds, given as a dose value per milligram per kilogram of body weight, in which the diarrhea is determined in 50% of the animals tested,
Tail withdrawal test.
Male Wistar rats were fixed overnight. A dose of the test compound was orally administered to each animal. The rats so treated were stirred into separate isolated cages. At various times after administration, the lower part of the tail, 5 cm long, was placed in a cup filled with water at a constant temperature of 55 ° C. A typical tail pull response was evaluated within 10 seconds after immersion. The values of AU 0 are defined as the dose of the test compound, the method of suppressing in 50% of the tested: animals typical reaction of withdrawing: tail over a period of time
calculated 10 seconds. These values are GD .- „
BO
for the proposed compounds are given in table. 3
R
In tab. 5 shows a comparison of the pharmacological activity of some derivatives of general formula (l) and compounds similar in structure, and Table. 4 - data on the toxicity of the proposed compounds in comparison with Loperamide, a known antidiarrheal agent,
From the comparative data it can be seen that, despite the considerable similarity of the chemical structure, the proposed compounds are superior in their activity and safety to the known compounds.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining 4- - (aroylamino) -piperidinebutanamide derivatives,
of general formula O ",
C-N-R7 .OR, O
I / H
РЪ-С-А1к-К VN-C-Ar
- /
Pb
R,
AT ,
. 14 in one before. G, -C,
-alkpch or
V c - C f-al to il to ar 0 onil;
- hydrogen or 0-C4 alkyl;
- tiepil, halonduranyl,
pyridinyl, aminopyridinyl, thiazolyl, imidazolyl or a group of the formula
R,
ten
five
0
five
0
five
where FU, R4 and R-. each independently
is selected from the group consisting of hydrogen,. -appa tz, G, -C, -apkyloxy, halogen, hyaroxy, cyan. npt by.). Mono- and UH (C, fj.-a; iKim) aMUHO, C / - G A, -. iKapCion ,, С 4 -Г -;: - iK-tlcapcownr-, amsjusulfopil s С, -С1 ..- -с; ЧЧИЛТ1.о, б о -: gloxp, fene, jc r: i, g pt; f -r opi; atil a 5 propsnlox h (-P0 ll-cnctcrbonnloxy; Alk is a group-SG-C1 7- or
-r: ir. ;;) -:
R, and R-, - C – C – G Lch t, 1, and b, in the e-oopaavior ptglroln- dpnnlnip p. And h-mora-olinigny) rlpkal; with the proviso that when K and R7 OPA methyl 5 -l-ne is a phenyl or i-a umo 5-point solution: -. 1GM,
or their stereoisomers, their phpma-- acidic acid-adduct salts, about tl and h ao sh and - with the fact that the compound common foo II
ABOUT
45
c - N6-R7
/ oRi
РЪ-С-А1к-г 1 РЪ
ygn
To
subjected to interaction with carbolic acid of the general formula III
About SI-C-AG
or its corresponding functional derivative in an inert solvent and isolate the desired product in free form or in the form of a pharmaceutically acceptable acid addition salt, or, if necessary, route the compound of general formula I, in which one of the substituents recovers the compound of formula I in which one of the substituents R, R or R5 is a nitro group, with hydrogen in the presence of a catalyst, such as palladium on activated carbon, to give a compound of formula I, where one of said substituents represents
Lei EZ,. or R is a JQ is an amino group, a hydrodegalo-halogenated n-group, corresponding to the anhydrous compound of formula I, where .. one of the reed or acyl halide, with the obtained substituents 1C, or Es, predisposed of the compound of formula I, where one is halogen in the atmosphere of these substituents is SC-C-alkylcarbonylamino; reductive N-alkylation of the compound of formula I is carried out, where one of the substituents R ", R or Rg represents an amino group, the corresponding carbonyl reagent in a hydrogen atmosphere in the presence of a catalyst such as palladium on charcoal, to give a compound of formula I, wherein one of said substituents prev
is di- (alkyl) amino
C-N-R4 yOH O
-A to / -C
X restores a compound of formula I in which one of the substituents R, R or R5 is a nitro group, with hydrogen in the presence of a catalyst such as palladium on activated carbon, to give a compound of formula I where one of these substituents is
Doda in the presence of a catalyst, such as palladium on carbon, to obtain a compound of formula I, where one of these substituents is hydrogen, debenerate a compound of formula I, in which one of the substituents R, or Rs is a benzyloxy group, hydrogen in the presence of a catalyst; such as palladium on carbon, to give a compound of formula I, where one of these radicals is a hydroxyl group.
i.
Table
trance
17
C-N-R, OH O, -A1 to X) Y c Ar
1620049
18
Continuation of table 1
Compound
O CH, B I 3 C-N-CH3OH O
- c-ch2-CH-N (-KH-C
CH3
9 9nz
s-tch-sn3
C-CH2-CH2Table 3
Table.4
1 ™ ™ 1 ™
LDL (inside),
mg / kg
226
98.4
21
Compound
Known
C NOCH5 O
F-O-C- (CH2) 3-NQ-NH-C
II
C-0-C2H5 OCH3 About C1 C- (CHj) 3 jQ-NH-C- -NH2
DOS,
13
F e C-N-CH
9 fHa
Och, o
(3 V /
SNG-SNG-SNG-G O-n-s-O-kN
esne nd
OCH3C1
I
-CH-CH2CHr O-WH-C
 t
n
Proposed
oh,
f-N-cH3 it is about Y-with-sn2-sn-k () - mn-ssn
sn,
I 3
с-к-ч: н,
, - - -a / OH O C1
-s-sn2-sn-m () - kn-ssn,
sn.
ten
-lSf-CH3OH O Cl k
-CH2-CH-N (} - NH-C-Q
CH, .trans
1620049
22 Table 5
ED50, mg / kg body weight (experience with ricin oil)
C1
-one%
ten
tjUf
YU
,
13
Cie
ten
ten
n
DOS
 3 cis
.CF,
0.15
trance
0.31
trance
0.04

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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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CA1183847A|1981-10-01|1985-03-12|Georges Van Daele|N-benzamide derivatives|US5130312A|1987-07-17|1992-07-14|Janssen Pharmaceutica N.V.|Substituted N-benzamides|

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NZ225152A|1987-07-17|1990-04-26|Janssen Pharmaceutica Nv|Heterocyclically substituted piperidinyl benzamides as pharmaceuticals|

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US5041454A|1987-09-25|1991-08-20|Janssen Pharmaceutica N.V.|Novel substituted N-benzamides|

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US4975439A|1987-09-25|1990-12-04|Janssen Pharmaceutical N.V.|Novel substituted N-benzamides|

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CA1317940C|1987-09-25|1993-05-18|Georges H. P. Van Daele|Substituted n-benzamides|

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TW294595B|1992-11-20|1997-01-01|Janssen Pharmaceutica Nv|

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JP3235913B2|1993-07-30|2001-12-04|エーザイ株式会社|Aminobenzoic acid derivative|

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US5585387A|1994-10-07|1996-12-17|Torcan Chemical Ltd.|Prepration of cisapride|

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JP2009529047A|2006-03-07|2009-08-13|アレイバイオファーマ、インコーポレイテッド|Heterobicyclic pyrazole compounds and uses thereof|

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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US88206786A| true| 1986-07-03|1986-07-03|

---