The method of synthesis of n-/-4-piperidinyl/benzamides and their pharmaceutically admissible salts

专利摘要:
Novel substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides of formula <CHEM> the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are gastrointestinal stimulating agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
公开号:SU1625331A3
申请号:SU884356607
申请日:1988-09-23
公开日:1991-01-30
发明作者:Анри Поль Ван Даль Жорж；Франсуа Вламинк Фредди；Анна Жозеф Де Клейн Мишель
申请人:Жансен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:

31625JJ
This invention relates to the chemistry of nitrogen-containing heterocyclic compounds, in particular, to a process for the preparation of new M- (4-piperidinyl) benzamides of a general formula I:
ORi Oise L,
- i
ten
Kg
%, 4 and Rr
SRI
de R. - hydrogen, C -C-alkip,
C -C-alkyloxycarbonyl, phenoxycarbonyl, aminocarbonyl, mono- or diC (-C ± -apkyl-aminocarbonyl, pyrrolidinylcarbonyl or piperylidene-nylcarbonyl, - hydrogen or .C, -C 4 alkyl,
A1K-A1K G I
-Y n
h i
ns, s
RU-0-Ј Y, -A1K0 „-С-0-АЖV
KI-C-Y, A1KR "
G /
-U
A1K
(",), about
A, .N-C-Y-A1K (CH,) t RJ,
R and AlK
Have
and
L
v
N-dec
OR
/ V
 RM
(b) (c) (d)
(e) (e)
(g)
(h) (i)
(to)
15
20
- each independently of one another are hydrogen, .- alkyl, C — C-alkyloxy, radical, halo, hydroxyl, amino, trifluoromethyl, mono- or di-C (—C-alkyl, but C — C-alkylcarbonylamino , aminosulfonyl or C1-C4 alkylaminosulfonyl;
R6 is hydrogen, hydroxyl, or C -C l Kil o to forces;
L-radical of the formula:
(but)
thirty
35
40
45
50
55
SSU (
CHSIOT
(l)
0
five
0
0
35
40
45
50
five
where is Alk R7 Rg
and R,
to 41
R13 RU and R16
s
A
R, 7
And R, eC-Cf-alkanediyl or C-C alkenediyl;
oxygen or NR Y - O, NR7
or contact ma}
hydrogen or j-alkyl;
regardless d: beats from each other
hydrogen or C -C alkyl when
provided that Rg and R are not
are alkaline when
R7 is hydrogen;
C-C-alkyl;
phenyl, phenyl halide,
phenyl-C 4 alkyl or
C-Sc.-alkyloxy;
C, -C4 alkyl;
C4-Cf-alkyl, cyclo-C-Cg alkyl, phenyl or substituted
phenyl,
phenyl C, -C4-alkyl, where
C, -Sc., Alkyl radical
substituted by hydroxyl or
C (-C 4.-alkylcarbonyloxy |
each is independently hydrogen, C — Cf-alkyl, hydroxyl, C, —C-alkyloxy, amino, mono- or di-C (-C) -alkylamino, hydroxy-C / C-D-dyl, C ( - SF-alkylcarbonyl, kiloxycarbonyl, aminocarbonyl mono-idi-C - kilome n o car b o nyl
or 2-C (-C.-alkyl-1,3-dioxolan-2-yl, or R5S and in combination with the carbon atom bound to said R15- and Rtg, can form a carbonyl radical or 1.3 -dioxolan-2-ylidene; an integer of 1.2 or 3, O or NR4g, where is hydrogen, C-C -alkip, ysenyl, substituted pheny, n, pyridinyl, pyrimidinyl, C, | - C uf-an kil kilo carbonyl , C kiloxycarbonyl or phenyl C, -C-alkyl,
g is hydrogen or C {-C4-akyl,
or, when A is NR, R17 and R (j, taken together can form a condensed benzene residue which can be replaced by a radical R
ten
scrap halide or C -CF-alkyl, is an integer of 1 or 2; 20 is hydrogen or C —C “j.-alkyl; B is a bivalent radical of the formula - ly —CHH — CHg—, —C / 0 / —CH 2 - or —CH — CHH — CHg — where each hydrogen atom can be independently substituted with C {-C4 alkyl or, when 20 C - C-alkyl, the indicated bivalent radical can also be i a 1,2-benzenediyl, optionally substituted by a halogen radical or C | -C4 al kil ohm; E - bivalent radical
, -, -CH2j-N (R2t) A. Cooking intermediates.
Example 1. To a stirred and cooled (ice-bath) solution of 71.12 hours of pyrrolidine in 210 hours, 70.5 hours of 4-chlorobutanoyl chloride are added dropwise at a temperature below 15 ° C. At completion, stirring is continued overnight at room temperature. Water is added. The product is extracted with dichlomethane. The extract is separated, dried, filtered and evaporated. The residue is dispersed at 266 Pa and so on. 137 C J5 is obtained 45 parts (51%) of 1- (4-chloro-1-oxobutyl) pyrrolidine (intermediate
The compounds listed in Tables 1 and 2, as well as 8- (4-chloro-1-oxobutyl) -1,4-diox2, are prepared in the same way.
or -C% -CH2-CH2-, where each 20 8-azaspiro | 4, 5jfleKaH, bk. 120 C
at 5.34 Pa (intermediate 24).
R
This hydrogen atom can independently be substituted with C (-C-alkyl, or the indicated divalent radical can also be 1,2-benzenediyl, optionally substituted by a halogen radical or C (-C-alkyl, with the indicated Rg, - hydrogen or Cj | -C-alkyl;
22
RZ, H R - each independently is hydrogen or C {-C-alkyl; n and m are both independently 0 or 1;
G is carbonyl, C1-C-alkyloxycarbonylmethylene, alkylcarbonylmethylene, 5.5-dimethyl-1,3-dioxan-2-ylidene or 1,3-dioxolan-2-ylidene;
and substituted phenyl is phenyl, substituted with 1,2 or 3 substituents, each independently selected from halogen, hydroxy, C-C4 alkyl or C-C-alkyloxy, their pharmaceutically acceptable acid addition salts, stereoisomeric forms or N-oxides, which have stimulating properties of the digestive system and can be used in medicine
The aim of the invention is the synthesis on the basis of the known methods of new benzimidazole derivatives, which have a higher biological activity compared with their analogues in structure.
A. Preparation of intermediates.
Example 1. In a stirred and cooled (ice-bath) solution, from 71.12 hours of pyrrolidine, in 210 hours of petroleum ether, 70.5 hours of 4-chlorobutanoyl chloride are added dropwise at a temperature below 15 ° C. Upon completion, stirring continue overnight at room temperature. Water is added. The product is extracted with dichloromethane. The extract is separated, dried, filtered and evaporated. The residue is distilled at 266 Pa and bp. 137 ° C is obtained 45 parts (51%) of 1- (4-chloro-1-oxobutyl) pyrrolidine (intermediate 1)
The compounds listed in Tables 1 and 2, as well as 8- (4-chloro-1-oxobutyl) -1,4-dioxa GO, are obtained in the same way.
0 8-azaspiro | 4, 5jfleKaH, bk. 120 C
at 5.34 Pa (intermediate 24).
Example 2. a) To a stirred mixture of 20 parts of 2-methyl-4- (phenylmethyl) -piperazine, 11.13 parts of carbonate
5 sodium and 120 parts of 2-propanone were added dropwise 16.28 parts of 4-chloro-2-methylbutanoyl chloride. Upon completion, stirring is continued for 45 minutes. The precipitated product is filtered off and
Q is dissolved in dichloromethane. Water and sodium carbonate are added. The organic layer was separated, dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 2-propanol. This salt is filtered off and dried in vacuo at 40 ° C and 16.5 parts (45.5%) of 1- (4-chloro-2-methyl-1-oxobutyl) -2-methyl-4- (phenylmethyl) are obtained. ) -piperazinmonohydrochloride (intermediate 25) o
b) A mixture of 16h. 1- (4-chloro-2-methyl-1-oxobutyl) -2-methyl-4- (phenylmethyl) piperazine monohydrochloride, 200 parts of methanol and 7 parts of the for0 solution
45
Maldehyde (40%) is hydrogenated at normal pressure at 60 ° C for 2 hours.
10% palladium carbon catalyst. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichpormethane and methanol saturated with ammonium (98; 2 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanol and 2,2-oxybispropane and 9 parts (72.6%) of 1- (4-chloro-2-methyl-
oxobutyl) -2,4-dimethylpiperazine mono-hydrochloride (intermediate 26).
Example a) A mixture of 24.2 parts of 3-methoxy-1- (phenylmethyl) -4-piperidinone, 16 parts of N-methylmethanamine, 1 part of a solution of thiophene in methanol and 520 parts of methanol is hydrogenated under normal pressure and 50 ° C 3 h. 10% catalyst palladium on carbon. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 27.3 parts (100%) of cis-3-methoxy-K, M-dimethyl-110
Another portion of 1.5 parts of 2- (methylamino) ethanol is added and stirring is continued for a week at room temperature. The separated organic layer is washed with a solution of 5% hydrochloric acid and water, dried, filtered, evaporated and 7 parts (40.1%) of M- (2-hydroxyethyl) -K-methyl-1-pyrrolidinecarboxamide as a residue are obtained ( intermediate 30) „
b) To a stirred solution of 4 parts of M- (2-hydroxyethyl) -M-mb of tyl-1-pyrrolidinecarboxamide in 22.5 parts of methyl (fellmethyl) -4-piperidinamine (inter-j5 benzene is added 2 , 9 h. Chloride
mediate 27).
b) A mixture of cis-3-methoxy-K, M-dimethyl-1- (phenylmethyl) -4-piperidinamine is hydrogenated at normal pressure and room temperature.
e 5 h. 10% of the catalyst is palladium on carbon. After absorption of the calculated amount of hydrogen, the catalyst is filtered off, the filtrate is evaporated and 17 h is obtained. (100%) cis-3-methoxy-M, N-dimethyl-4-piperidinamine (intermediate 28).
c) Mixed and cooled (ice-bath) mixture of 7.9 parts of cis20
25
thionyl. After adding a few drops of M, M-dimethylformamide, the reaction mixture is slowly heated to the reflux temperature. After stirring for 2 hours at this temperature, the mixture is cooled, completely evaporated and 4.5 parts (100%) of M- (2-chloroethyl and methyl-1-pyrrolidinecarboxamide) are obtained as a residue (intermediate 31).
Similarly, 2- (chloroethyl) -2-pyrrolidinecarboxylate is obtained as a residue.
Example 5 in mixed
3-methoxy-M, K-dimethyl-4-piperidine-30 Solution from 3-methyl-2,4-imidane, 7 parts of NjN-dimethylethanamine, 195 parts of dichloromethane are added dropwise 6.16 parts of 4- chlorobutanoyl chloride (temperature С5 ° С). Then mix for another 30 minutes. The organic layer is washed twice with a saturated solution of sodium chloride, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. Pure fractions are collected, the eluent is evaporated and 13.7 parts (100%) of cis-1- (4-chloro-1-oxobutyl) -3-methoxy-M, N-dimethyl-4-piperidinamine (intermediate 29) „are obtained.
Example4. a) To a stirred solution of 7.5 hours with 2- (methylamino) ethanol in 75 parts of trichloromethane was added 9.8 parts. To the M-diethylethanamine while cooling in an ice-bath with dropwise, add a solution of 13 4 hours of 1-pyrrolidinecarbonyl chloride at 52.5 parts of trichloromethane (isothermal reaction, the temperature increases from -10 to 0 ° C). After the addition is complete, stirring is continued for 6 hours at room temperature.
35
40
solidinedione in 198 parts of NjN-dimethylformamide, 1.6 h are added in portions. 5 dispersion of sodium hydride under nitrogen atmosphere (exothermic reaction, cooling). After the addition is complete, stirring is continued for 1 hour at room temperature. 45.5 parts of 1,2-dibromoethane o are added dropwise. Upon completion of the operation, the entire mixture is stirred for 2 days at room temperature. The reaction mixture is evaporated and the residue is taken up in a mixture of water and dichloromethane. The separated organic layer is dried, filtered and evaporated. The residue was purified by column chromatography over silica gel, using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected, the eluent is evaporated and 35.8 parts (73.6%) of 3- (2-bromoethyl) -1-methyl-2,4-imidazolidinedione are obtained as residue (intermediate 33) “In a similar way, I also get 1 - (3-chloropropyl) -2-imide, 1zopidinone as a residue (intermediate 34); 1- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Sintermediate 35);
45
50
Another portion of 1.5 parts of 2- (methylamino) ethanol is added and stirring is continued for a week at room temperature. The separated organic layer is washed with a solution of 5% hydrochloric acid and water, dried, filtered, evaporated and 7 parts (40.1%) of M- (2-hydroxyethyl) -K-methyl-1-pyrrolidinecarboxamide as a residue are obtained ( intermediate 30) „
b) To a stirred solution of 4 parts of M- (2-hydroxyethyl) -M-mb of tyl-1-pyrrolidinecarboxamide in 22.5 parts of methyl benzene was added 2.9 parts of chloride
thionyl. After adding a few drops of M, M-dimethylformamide, the reaction mixture is slowly heated to the reflux temperature. After stirring for 2 hours at this temperature, the mixture is cooled, completely evaporated and 4.5 hours (100%) of M- (2-chloroethyl) - and-methyl-1-pyrrolidinecarboxamide as a residue are obtained (intermediate 31).
Similarly, 2- (chloroethyl) -2-pyrrolidinecarboxylate is obtained as a residue.
Example 5 in mixed
Solution from 3-methyl-2,4-imide
solidinedione in 198 parts of NjN-dimethylformamide, 1.6 h are added in portions. 50% sodium hydride dispersion under nitrogen atmosphere (exothermic reaction, cooling). After the addition is complete, stirring is continued for 1 hour at room temperature. 45.5 parts of 1,2-dibromoethane o are added dropwise. Upon completion of the operation, the entire mixture is stirred for 2 days at room temperature. The reaction mixture is evaporated and the residue is dissolved in a mixture of water and dichloromethane. t The separated organic layer is dried, filtered and evaporated. The residue was purified by column chromatography over silica gel, using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected, the eluent is evaporated and 35.8 parts (73.6%) of 3- (2-bromoethyl) -1-methyl-2,4-imidazolidinedione are obtained as residue (intermediate 33) “In a similar way, 1 - (3-chloropropyl) -2-imide, 1zopidinone as a residue (intermediate 34); 1- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Sintermediate 35);
916
1- (4-chlorobutyl) -3-ethyl-2-imidazololidinone as a residue (intermediate 36) „
Example a) A solution of 109 h of an бисsis (1,1-dimethylethyl) dicarbonate in 375 parts of trichloromethane is added dropwise to a solution of 40 parts of 4- (methylamino) -1-butanol in 750 parts of trichloromethane (slightly exothermic). The reaction mixture was evaporated, the residue was distilled at 26.6 Pa and 50 hours (67.2%) of (1,1-dimethyl) (4-hydroxybutyl) methylcarbamate (intermediate 37) were obtained.
b) A solution of 50 parts of (1,1-dimethylethyl) (4-hydroxybutyl) methylcarbamate in 91 hours of dichloromethane is added dropwise to a mixture of 150 parts of pyridine dichromate 112 parts of molecular sieves and 1300 parts of dichloromethane at a temperature of 109C. After the addition is complete, stirring is continued for 3 hours at room temperature. The reaction mixture is filtered, washed with 1,1-hydroxyethisne and the filtrate is evaporated. “The residue is purified by column chromatography over silica gel using dichloromethane as the eluent. The pure fractions are collected, the eluent is evaporated with methyl benzene and 35 parts (70%) are obtained 1,1-dimethylethyl) methyl (4-hydroxybutyl) -carbamate as a residue (intermediate 38) In a similar way (1,1-dimethylethyl) methyl (3-oxo-propyl) carbamate is obtained as a residue (intermediate 39);
(1,} -dimethylethyl) methyl (2-oxo-ethyl) carbamate as a residue (intermediate 40).
Example 7. Gaseous tetrachloroethylene was sparged for 3 hours through a solution of 88 parts of 2-amino-3,4,5-trimethoxybenzoic acid in 63 parts of concentrated hydrochloric acid and 525 parts of water (the temperature rises to 40 ° C) . The precipitated product is filtered off, washed with water, dried in vacuum and receive 60.5 hours, (75%) 6,7,8-trimethoxy-2H-8,1-benzoxazin-2.4 (III) -dione, mp 247 , 8 ° С (intermediate 41).
Example, a) A mixture of 43.9 h. 1- (4-chloro-1-oxobutyl) pyrrolidine, 55.1 parts cis-3-methoxy-H- (phenylmethyl) -4-piperidinamine, 37.8 parts I, M-diethyl ethanamine and 900 hours. K, N-dimethylformamide is stirred overnight at 70 ° C. Another portion of 4.4 hours is added.
five
33
0
f) 5 jq
40
d5
35
50
1 Yu
1- (4-chloro-1-oxobutyl) pyrrolidine and stirring is continued overnight at 70 ° C. The reaction mixture is evaporated and the residue is diluted in a mixture of water and sodium carbonate. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and. evaporated. The residue was purified by column chromatography over silica gel, using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. Pure fractions are collected, the eluent is evaporated and 53.1 parts (59.0%) of cis-1-4 (3-methoxy-4-phenylmethylamino-1-pyrididinyl) -1 -1-oxobut-G-pyrrolidine are obtained as residue (intermediate 42 ) „
b) A mixture of 53 parts of cis-1-Ј4- (3-methoxy-4-phenylmethylamino-1-piperidinyl) -1-oxobutyl-pyrrolidine and 200 h, methanol is hydrochemical under normal pressure and at room temperature for 3 hours 10% palladium carbon catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel, using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. Pure fractions are collected, the eluent is evaporated and 28.3 parts (71.4%) of cis-1-4- (4-amino-3-metroxy-1-piperidinyl) -1-oxobutyl | - pyrrolidine are obtained as a residue (intermediate 43).
Similarly, cis-H-2- (4-amino-3-hydroxy-1-piperidinyl) ethyl-M-methyl-1 -pyrrolidine-carboxamide is obtained as residue (intermediate 44).
cis-1- 2- (4-amino-3-methoxy-1-piperidinyl) -ethyl-3-ethyl-2-imidazolidinone as a residue (intermediate -45).
Example 9.a) A mixture of 183.4 h. ethyl cis-3-methoxy-4-phenyl-methylamino-1-piperidinecarboxylate, 144 parts of chloromethylbenzene, 85 parts of sodium carbonate and 720 parts of methylbenzene are stirred for 10 days at reflux temperature. The reaction mixture is filtered. the filtrate is washed 3 times with 400 hours of water, dried, filtered and evaporated. The petroleum ether is added. The whole mixture is cooled until the product remains solid. It is filtered, dried under vacuum.
at 40 ° C, 155 parts (64%) of ethyl cis-4-bis-phenylmethylamino-3-methoxy-1-piperidinecarboxylate are obtained, m.p. 85.2 ° C (intermediate 46).
b) To a stirred mixture of 230 parts of potassium hydroxide and 1600 parts of 2-propanol, 155 parts of ethyl cis-4-bis-phenylmethylamino-3-methoxy-1-piperidinecarboxylate are added. The entire mixture is stirred and refluxed for 7 hours. The reaction mixture is evaporated, water is added and the mixture is evaporated until all traces of 2-propanol are removed. The product is extracted with dichloromethane. The extract is washed twice with a solution of sodium chloride in water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is dissolved in dichloromethane. The solution is washed with a 5% sodium hydroxide solution, filtered, evaporated and 70 parts (55%) of cis-3-methoxy-M, I-bis (phenylmethyl) -4-piperidinamine are obtained as a residue (intermediate 47).
c) through a stirred solution
out of 70 parts of cis-3-methoxy-M, H-bis (phenylmethyl) -4-piperidinamine, in 368 parts of ethanol and 460 hours, water was bubbled with gaseous oxirane for 1.5 hours at room temperature. The product is filtered off, washed with a mixture of ethanol and water (50:50 by volume) and crystallized from acetonitrile. The product is filtered and dried in vacuo to give 50 parts (61.3%) of cis-4-bis-phenylmethylamino-3-meth hydroxy-1-piperidine ethanol (intermediate 48).
d) To a stirred mixture of 5.32 parts of cis-4-bis-phenylmethylamino-3-methoxy-1-piperidineethanol and 96 parts of dichloromethane, 3.63 parts of phenylcarbonyl chloride are added with cooling. The whole mixture is stirred for 35 hours at room temperature. The reaction mixture is evaporated. The residue is cured in 2,2-hydroxy-propane. The product is filtered, dried and obtained 6.4 h. (83.4%) cis-Ј .- (4-bis-phenylmethylamino-3-methoxy-1-pipchridinyl) nylcarbonate monohydrochloride (intermediate 49).
e) To a stirred suspension of 6.4 parts (4-bis-phenylmethylamino0
five
0
five
0
five
0
five
0
five
3-methoxy-1-piperidyl) ethyl phenylcarbonate monohydrochloride in 105 parts of 1,1-hydroxyethane was added 200 parts of ammonia. After 48 hours, the layer of 1,1-oxybisethane is treated with 5% sodium hydroxide solution. The reaction mixture is poured into water. The product is filtered and crystallized from acetonitrile. The product is filtered, dried in vacuo at 50 ° C, and 2.13 parts (38.2%) of (4-bisphenylmethylamino-3-methoxy-1-piperidinyl) ethyl carbamate are obtained, mp. 162.2 ° C (intermediate 50).
f) A mixture of 16.3 parts of cis-Ј2- (4-bisphenylmethylamino-3-methoxy-1-piperidinyl) ethyl carbamate and 200 parts of methanol is hydrochemical under normal pressure and 50 ° C for 2 hours. 10% g palladium carbon catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off, the filtrate was evaporated and 8.5 parts (95.4%) of (4-amino-3-methoxy-1-piperidinyl) ethescarbamate as residue (intermediate 51) were obtained.
B. Obtaining final compounds.
Example 10. A mixture of 2.21 parts of 1- (2-chloroethyl) -Z-ethyl-2-imidazolidicone, 3.13 parts of cis-4-amino-5-chloro-2-methoxy-M- ( 3-methoxy-4-piperidinyl) benzamide, 1.58 parts of sodium carbonate and 90 parts of M, M-dimethylformamide are mixed and heated for 48 hours at 70 ° C. The reaction mixture is evaporated. Water is added and the product is extracted twice with dichloromethane. The combined extracts are washed with water, filtered and evaporated. The residue was purified by column chromatography over silica gel, using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. The first fraction is collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, and 3.08 parts (67.8%) of cis-4-amino-5-chloro-K-1- 2- (3-ethyl-2-oxo-1-imidazolidine) are obtained. ethyl-3-methoxy-4-piperidinyl y-2-methoxybenzamide, m.p. 152.8 С
(compound 1) o
In a similar way, the compounds listed in Table “30”
Example 11. A mixture of 6.3 parts of 1- (3-chloropropyl) -3-ethyl-2-imidazolidinone, 4.75 parts of cis-4-amino-5-chloro-2-methoxy-M- ( 3-methoxy-4-piperidinyl) benzamide, 2.3 parts of sodium carbonate,
0.1 h of potassium iodide and 90 parts of N, N-dimethylacetamide are stirred at 70 ° C for a week. After cooling, the reaction mixture is evaporated. The residue is dissolved in dichloromethane and water. The organic layer is separated, washed twice with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel, using a mixture of trichloromethane and methanol (96: 4 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile with a few drops of water at 0 ° C. The product is filtered off, dried in vacuo at 40 ° C, and 2.83 parts (36.6%) of cis-4-amino-5-chloro- (3-ethyl-2-oxo-2-imidazolidinyl) propyGH are obtained. 3-methoxy-4-piperidinyl -2-methoxybenzamide, m.p. 112.9 ° C (compound 12).
A similar method was obtained for cis-4-amino-5-chloro-i-, G1-Ј4- (3-ethyl-2-oxo-1-imidazolidinyl) butyl-3-methoxy-4-piperidinyl -2-methoxybenzamide, t .pl. 84.2 ° C (compound 13);
Cis-4-amino-5-chloro-I-3-ethoxy-1- 2- (3-ethyl-2-oxo-1-imidazolidinyl ethyl) -4-piperidinyl -2-methoxybene-amide, mp 161, 8 ° C (compound 14).
Example 12. To a stirred solution of 3.00 parts of 1- (4-chloro-1-oxobutyl) pyrrolidine in 67.5 parts of M, M-dimethylformamide was added 1.93 parts of trans-4-amino -5-chloro-K- (3-hydroxy-4-piperidinyl) -2-methoxybenzamide and 1.5 parts of NjN-diethylamine and all stirred for 18 hours at 70 ° C. The reaction mixture is evaporated, the residue is treated with an aqueous solution of sodium carbonate. Product
five
0
0
0
In a similar way, cis; -4-amino-5-chloro-M-, 1-2 (2,5-dioxo-1-imide zolidinyl) ethyl-3-methoxy-4-piperidinyl -2-methoxybenzamide monohydrate was obtained; m.p. 220.4 ° C. (compound 16);
 Ј (4-amino-5-chloro-2-methoxybenzoyl) amino | -3-methoxy-1-pit Q peridinyl ethyl -1-pyrrolidinecarboxy., Lat, m.p. 170.6 ° C (compound 17);
trans-4-amino-5-chloro-2-methoxy-. I-Ј3-methoxy-1 4-oxo-4- (1-pyrrolidinyl) butyl-4-piperidinyl} benzamide monohydrate, mp 101.1 ° C (compound 18);
cis-4-amino-5-chloro-2-methoxy-K-3-methoxy-1-2- (3-methyl-2,5-dioxo-1-imidazolidinyl) -4-pip eridinyl) benz. . rt
amide monohydrate, so pl. 121.0 ° C (compound 19);
cis-4-amino-5-chloro-2-methoxy-ЈЈЈ-3-methoxy-1-4- (4-methyl-1-pipedradinyl) -4-oxobutyl-3-piperidinyl Zbenz-5 amide, Topl. 175.9 ° C (compound 20);
cis-4-amino-5-chloro-N-3-hydroxy-1- 4- (1-pyrrolidinyl) -butyl-4-piperidinyl -2-methoxybenzamide as a residue (compound 21);
cis-4-amino-5-chloro-2-methoxy-H-3-methoxy-1-f2- (4-methyl-1-piperidinyl) -2-oxoethyl | -4 pip eridinshg | b benz-amide hemihydrate, m.p. 140.6 ° C. (compound 22).
Example 13. A mixture of 2.54 parts of 4-chloro-M-methyl-M-phenylbutanamide, 3.14 parts of cis-4-amino-5-chloro-2-methoxy-K- (3-methoxy- 4-piperidinyl) benzamide, 2.45 parts of I, M-diethylethanamine, .0.1 parts of potassium iodide and 90 parts of N, N-dimethylformamide are stirred for 20 hours at 80 ° C. The reaction mixture is evaporated. The residue is treated with water and sodium carbonate. The product is extracted
extracted with trichloromethane. Extract dichloromethane. The extract is dried, filtered off. Washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as the ELENENTENT. Pure fractions are collected and the eluent is evaporated. The residue is recrystallized from acetonitrile and a small amount of water. The product is filtered off, dried and obtained 2.05 H | (40.4%) of cis-4-4-amino-5-chlorout and evaporated. The residue is purified on a chromatographic column v over silica gel, using a mixture of trichloromethane and methanol saturated with ammonia (90:10 by volume) as eluent. The pure fractions are combined and the eluent is evaporated. The residue is recrystallized from acetonitrile. The product is filtered, dried, yield 2.1 h (47.8%)
TRANS-4-amino-4-chloro-P1--3-hydroxy-1- 55 2-methoxybenzoyl (amino) -3-methoxy-I--4-oxo-4- (1-pyrrolidinyl) butyl- | -4-methanol-K-phenyl-1-piperidinebutanamipiperidikil1-2-methoxybenzamide, etc.
174.7 ° C (compound 15).
premonohydrate, so pl. 97.4 ° C. (compound 23).
2-methoxybenzoyl (amino) -3-methoxy-I-methanol-K-phenyl-1-piperidinebutanamide monohydrate, so pl. 97.4 ° C. (compound 23).
The compounds shown in Table 4, as well as
cis-4-amino-5-chloro-M-3-methoxy-1- f 2-Ј-methyl- (1-pyrrolidinylcarbonyl) -aminoTethyl-4-piperidinyl-2-methoxy-benzamide hemihydrate, m.p. 82.7 ° C (compound 45);
cis-4-amino-5-chloro-M-M-Ј4- (hexa-hydro-4-methyl-1H-1,4-diazepin-1-yl) oxobutyl-3-methoxy-4-piperidinyl 1-2- methoxybenzamide (compound 46).
Example 14. A mixture of 4.5 parts of CIS-4-amino-5-chloro-2-methoxy-N- (3-methoxy-4-piperidinyl) benzamide,
2.12 hours, sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone are stirred and refluxed for 15 min1 using an aqueous separator. Then 3.92 parts of 1- (4- chloro-1-oxobutyl) -2,6-dimethylpiperidine and stirring is continued, first three hours at reflux temperature and then overnight at room temperature. Water is added. The product is filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is recrystallized from acetonitrile. The product is filtered off, dried, and 5.25 parts (70.7%) of cis-4-amino-5-xnopo-N-j-4- (2, 6-dimethyl-1-piperidinyl) -4-oxobutyl-3 are obtained. -methoxy-4-piperidinyl -2-methoxybenzamide, t, pl. 202.1 ° C (compound 47).
The compounds listed in Table 5 are prepared in a similar manner, as well as
cis-4-amino-5-chloro-M-мет3-methoxy-1 - j4-OKCo-4 (1-piperidinyl) -butyl 4-piperidinyl -2-methoxybenzamide, m.p. 148.6 ° C (compound 59);
cis-4-amino-5-chloro-2-methoxy-H-p-methoxy-1 -ЈЈ-oxo- (1-piperidinyl) propyl 4-piperidinyl benzamide, mp 194.7 ° C (compound 60 );
cis-4-amino-5-chloro-2-methoxy-M-3-methox-1-3-methyl-4-ox-o-4- (1-piperidinyl) butyl | -4-piperidinyl} benzamide, t. Shea 181.2 ° C (compound 61);
cis-4-amino-5-chloro-2-methoxy-M-3-methoxy-1-5-oxo-5- (1-piperidinyl) penta-4-piperidinyl benzamide, m.p. 162.8 ° C (compound 63);
Cis-4-amino-5-chloro-2-methoxy-and-3-methoxy-1- 3-methyl-4- (2-methyl-1-piperidinyl) -4-oka absorbed 4-piperidinyl benzamidethanedioate (1: 1 / hemihydrate, mp 182.7 ° C (compound 64);
cis-4-amiino-5-hlop oN- Јl (3-ethyl-2,3-dihydro-2-oxo-1H-benzamidazole-1-yl) propyl-3-methoxy-4-piperidine g | - 2-methoxybenzamide monohydrate, so pl. 103.4 C (compound 65) and cis-4-amino-5-chloro-M- / 1-Ј4- (3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1- or) butyl-3-methoxy-4-piperidinyl -2-methoxybenzamide, m.p. 103.4 ° C. (compound 66).
The following compounds were prepared according to the same procedures as described in examples 10-14;
Cis-3-chloro-5-ethyl-6-hydroxy-2-methoxy-N-3-methoxy-1-G4-oxo-4- (1-pyrrolidinyl) -butyl-4-piperidinyl benzamide, m.p. . 91 ° C (compound 67);
CNS-3-bromo-5-chloro-2-hydroxy-6-labels of C-M-3-methoxy-1-oke-4- (1-pyrrolidinyl) -butyl-4-piperidinyl b-amide, t. square 128 ° C (compound 68);
Cis-N-3-methoxy-1-H-oxo-4- (1-pyrrolidinyl) butyl-4-piperidinyl-3- (trifluoromethyl) benzamidethanethioate (1: 1), m.p. 184 ° C (compound 69);
(4-amino-5-chloro-2-methoxybenzoyl) -amino-3-methoxy-1-piperidinyl ethyl carbamate monohydrite, m.p. 167 ° C (compound 70);
cis-5-chloro, ro-2-methoxy-Mr-methoxy-1-4-oxo-4- (1-pyrrolidinyl) b 4-piperidinyl-4 - (methylamine) benzamide mp 170 ° C (compound 71);
cis-4-amino M-1- 2- (3-ethyl-2-oxo 1-imidazolidinyl) ethyl-3-methoxy-4-piperidinyl -2-methoxy-5-tmethylamino) sulfonyl benzamide, m.p. 223 C (compound 72);
cis-4-amino-K-j-2- (dimethylamino) carbonylamino ethyl-3-methoxy-4-piperidinyl-3-methoxybenzamide, m.p. 207 ° C (compound 73);
cis-4-amino-5-chloro-M-butylamino) carbonylamino ethyl-3-methoxy-4-piperidinyl -2-methoxybenzamide (compound 74);
cis-N-f2-G4- (4-amino-5-chloro-2-methoxybenzoyl) amino-3-methoxy-1-piperidine ethyl 1-aminocarbonylbenzene methanol acetate (ether), m.p. 101 C (compound 75);
cis-K-Ј2-Ј4- Ј (4-amino-5-chloro-2-methoxybenzoyl) amino-3-methoxy-1-piperidinyl, 4-dimethyl-1-piperazinecarboxamide, mp 135bC (compound 76);
Cys-b - 2- | 4- (4-amino-5-chloro-2-methoxibenzoyl) amineG-J-methoxy-1 -piperidi- -o (- (hydroxymethyl) benzenecetamide, mp 113 ° C (compound 77);
cis-4-amino-5-chloro-K-1,3- (1,3-di-hydro-1,3-dioxo-3H-isoindol-2-yl) propyl (-3-methoxy-4-piperidinyl) -2- methoxybenzamide, m.p. „208 ° С (compound 78);
cis-4-amino-5-chloro-2-methoxy-K-Ј 3-methoxy-1-3- (4-methyl-2,5-dioxo-4-imidazolidinyl) propyl-4-piperidinyl | benzamide, t .pl. 236 ° C (compound 79);
cis-4-amino-5-chloro-K-1-K 1,4-dioxaspiro) 4.5 dec-8-yl / methylZ-3-methoxy-4-piperidinyl -2-methoxy-
Benzamide, so pl. 188 ° C (compound 80)
(+) - (1) cis (2,4) -I- 1- / 4-acetylcyclohexyl / -3-methoxy-4-piperidinyl 1-4-amino-5-chloro-2-methoxybenzamide, m.p. . 204 ° C (compound 81);
(1,1-dimethylethyl) (4-amino-5-chloro-2-methoxybenzoyl) amino-3-methoxy-1 -piperidinyl e-L-methylcarbamate (compound 82).
Example 15. A mixture of 2.8 h of cis-0 - Ј2-Ј4- (4-amino-5-chloro-2-methoxy-benzoyl) amino-3-methoxy-1-piperidinyl ethylaminocarbonylT-benzamethanol acetate (ester), 1.1 parts of concentrated acetic acid and 28 hours of methanol are stirred for 20 hours at reflux temperature. The reaction mixture is evaporated. The residue is dissolved in water. The solution is treated with ammonia. The aqueous phase is extracted with dichloromethane. The organic layer is washed with water, dried, filtered and evaporated. The residue is recrystallized from methanol. The resulting product is filtered and dried in vacuo at 50 ° C., 0.67 parts (25.7%) of cis-M-p-4- (4-amino-5-chloro-2-methoxybenzoylamino) -3- are obtained. methoxy-1-piperidinyl 1-ethyl 1-p (-hydroxybenzene-acetamide, mp. 227.6 ° C (compound 83).
Example 16. In a stirred solution of cis-4-amino-5-chloro-and-Ј3-hydroxy-1-4-oxo-4- (1-pyrrolidinyl) butyl-4-piperidinyl | -2-methoxybenzamide and 31.5 parts of tetrahydrofuran add 0.7 parts N, K-distiethanamine. The mixture is cooled in an ice bath and a solution of 0.72 h is added dropwise to it.
-
0 0
0
phenylcarbon chloride in 13.5 parts of tetrahydrofuran (slightly exothermic). Then a solution of carbon chloride in 9 parts of tetrahydrofuran is added to the mixture. After stirring the mixture for 30 minutes in a water bath, a solution of 0.07 parts of phenyl carbonate in 9 parts of tetrahydrofuran is added to it. The mixture is stirred for another 30 minutes in an ice bath and then the reaction mixture is drunk on water. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is recrystallized from acetonitrile. After cooling to 0 ° C, the product is filtered off and dried in vacuum at 50 ° C to obtain 1.3 h, (50.5%) cis-4- / 4-amino-5 chloro -2-methoxybenzoyl) amino-11-Ј4-gxo-4- (1-pyrrolidinyl) butyl-3-piperidinylDphenylcarbonate (compound 84).
In the same way receive
cis-pi-p4-amino-5-chloro-2-methoxibibenzoyl) aminoC-1-G2- (3-ethyl-2-oxo-1-imidazolidinyl) ethyl-3 3-piperidine-nsHG | phenyl carbonate (compound 85);
 tc4-amino-5-chloro-2-methoxibenzoyl) amineH} -1-2-methyl- (1 -pyrrole idinylcarbonyl) -amino ethyl-3-piperidine phenylcarbonate (compound 86).
Example 17, In a stirred and cooled (ice on a bath) solution of 3 parts of cis-Ј4-G (4-amino-5-chloro-2-methoxybenzoyl) amine G -1-C2- (3-ethyl-2-oxo -1-imidazolidinyl) ethG | -3-piperidinedigupenylcarbonate in 135 parts of tetrahydrofuran was added a solution of 64 parts of pyrrolidine in 27 hours, tetrahydrofuran. The mixture is then stirred for 1 hour at room temperature. The reaction mixture is poured into water. The resulting product is extracted with di-, chloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is boiled in a mixture of 2,2-hydroxybispropane and a few drops of acetonitrile. The product is filtered and subjected to crystallization from acetonitrile at 0 ° C. The product is filtered again and dried in vacuo at 50 ° C, yielding 1.95 parts (66%) of cis-Ј4- (4-amino-5-chloro-2-methoxybenzoyl) amino- (3-ethyl- 2-oxo-1-imidazolidinyl) ethyl-3-piperidn-1-pyrrolidinecarboxylate, m.p. 214.5 ° C (compound 87).
nineteen
162533G20
the mixture is concentrated. The concentrate is purified by column chromatography on silica gel using a mixture of trichpormethane and methanol, 5 saturated with ammonia (90:10 by volume) as eluent. The purified fractions were combined and the eluent was evaporated. The residue is dissolved in acetonitrile and again evaporated.
In the same way receive
 Ј (4-amino-5-chloro-2-methoxy-benzoyl) amino--1-4-oxo-4- (1-pyrrole idinyl) butyl-D-3-piperidinne-methyl methyl carbamate, t: pl. 214 C (compound 88);
(4-amino-5-chloro-2-methoxy-benzoyl) amino -1-2- (3-ethyl-2-ox-1-imidazolidinyl) ethyl-3-piperidi-10 Crystalline product was filtered by Ldimethylcarbamate, t .pl. 111, / ° C-woo / Sushat si receive 2.45 hours (69.6%)
- J-cis-4-amino-5-chloro-2-methoxy-M-Ј3 (compound 89);
 Ј (4-amino-5-chloro-2-methoxy-benzoyl) amino -1-Ј2-methyl- (1-pyrrolidinyl sarbonyl) amino 3Tnnj-3-rm- пери peridinyl dimethylcarbonate monohydrate, mp. 170.1 ° C (compound 90).
25
Example 18. A mixture of 2.1 parts of cis-4-amino-5-chloro-M-G1-G4- (1,4-dioxa-azaspiro G, 5 Dec-8-yl / 4-oxobu Tyl 1-20 benzamide at 20 h Acetic 3-methoxy-4-piperidinyl -2-methoxy-0.89 parts anhydride
benzamide, 0.74 parts of sulfuric acid and 40 hours of water are stirred for 2 hours at reflux temperature. The mixture is cooled and alkalinized with sodium carbonate while cooling. The extract is washed with water, dried, filtered and evaporated. The residue is recrystallized from acetonitrile. The product is filtered and dried in JQ.
vacuum at 60 ° C to give 1 part (51.9%) of cis 4-amino-5-chloro-2-methoxy-K-3-methoxy-1-4-oxo-4- (4-oxo-1- piperidinyl) butyl-4-pyperidinyl benzamide, m.p. 156.9 C (compound 91).
In the same way receive
cis-4-amino-5-chloro-2-methoxy-N-3-methoxy-1- (4-oxocyclohexyl) -4 piperidinyl benzamide, t „pl. 209.5 ° C (compound 92);
cis-4-amino-5-chloro-2-methoxy-M-3-methoxy-1-X 4-oxocyclohexyl) methyl-4-piperidinyl 1-benzamide, t „pl. 211.6 ° C (compound 93);
cis-M-1- 4- (4-acetyl-1-piperidinyl) -4-oxobutyl-3-methoxy-4-piperidinyl-4-amino-5-chloro-2-methoxybenzamide, t. square 208.6 ° C (compound 94).
methoxy-1-4-oxo-4- (1-pyrrolidinyl) butyl-4-piperidinylZ-benzamide M-oxide, m.p. 140.0 ° C (compound 95).
Example 20. In a stirred solution of 4 hours, cis-4-amino-5-chloro-2-methoxy-N-3-methoxy-1-4-oxo-4- (1-pyrr olidyl) b-2-4- pi pyrid and nile
acids
acetic anhydride
acid. The mixture is then stirred overnight at room temperature. The reaction mixture is poured into water and, with cooling, is treated with ammonium hydroxide. The product obtained is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is cured in a mixture of 2.2 G - oxybispropane and a few drops of acetonitrile. The solid product is filtered and recrystallized from acetonitrile. After cooling to 0 ° C, the product is filtered and dried in a vacuum at 40 ° C to obtain 1.9 parts (42.8%) of cis-4- (acetylamino) -5-chloro-2-methoxy-N- Ј3-methoxy-1- Ј4-oxo-4- (1-pyrrolidinyl) butyl T-4-piperidine benzamide hemihydrate, ToPL. 149.7 ° C (compound 96).
C Pharmacological examples.
The following examples illustrate the ability of the proposed compounds to stimulate the digestive system and accelerate gastric emptying.
40
45
EXAMPLE 21 “Enhancement of contractions caused by submaximal transmural stimulation of the ileal
Example 19. In mixed.
and cooled (ice on the ban) solution 50 muscles of the guinea pig. 3,30, including cis-4-amino-5-chloro-2-labels-non-end segments
C-M-3-methoxy-1-4-oxo-y- (1-pyrrolidinyl) butyl-4-piperidine 6-benzamide in 225 parts of trichormethane is added with acids. Withstand the mixture until reaching ileum.
the guinea pig muscles are suspended vertically with a preload of 1 g in a 100 ml body bath
   -.-l- ..f
1.55 parts of 3-chlorobenzenecarboperoxy (3 /,) and purged with a mixture of gases
95% 0 and 5% COgo Abbreviations are measured
isothermal o Transmural excitation is applied along the entire length of the room temperature and stirred overnight. Then
CIS-4-amino-5-chloro-2-methoxy-M-Ј3
five
benzamide in 20 h. acetic. Add 0.89 parts anhydride
Q
methoxy-1-4-oxo-4- (1-pyrrolidinyl) butyl-4-piperidinylZ-benzamide M-oxide, m.p. 140.0 ° C (compound 95).
Example 20. In a stirred solution of 4 hours, cis-4-amino-5-chloro-2-methoxy-N-3-methoxy-1-4-oxo-4- (1-pyrr olidyl) b-2-4- pi pyrid and nile
acids
acetic anhydride
acid. The mixture is then stirred overnight at room temperature. The reaction mixture is poured into water and, with cooling, is treated with ammonium hydroxide. The product obtained is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is cured in a mixture of 2.2 G - oxybispropane and a few drops of acetonitrile. The solid product is filtered and recrystallized from acetonitrile. After cooling to 0 ° C, the product is filtered off and dried in a vacuum at 5 ° C at 40 ° C, 1.9 parts (42.8%) of cis-4- (acetylamino) -5-chloro-2-methoxy-LY are obtained. Ј3-methoxy-1- Ј4-oxo-4- (1-pyrrolidinyl) butyl T-4-piperidine benzamide hemihydrate, ToPL. 149.7 ° C (compound 96).
C Pharmacological examples.
The following examples illustrate the ability of the proposed compounds to stimulate the digestive system and accelerate gastric emptying.
0
five
EXAMPLE 21 “Enhancement of contractions caused by submaximal transmural stimulation of the ileal
.
guinea pig muscles. End segments
ileal
the guinea pig muscles are suspended vertically with a preload of 1 g in a 100 ml body bath
ft
isothermally Transmural excitation is applied along the entire length of the muscle strip with the help of two platinum electrodes (0.5 mm in diameter), and the anode is passed through the lumen of the iliac muscle, and the cathode is immersed in the bath solution. The tissue is excited by a single rectangular pulse with a duration of 1 m / s, a submaximal voltage and a frequency of 6 per minute. Such impulses are known to contribute to the release of acetylcholine from interstitial nerve endings. After a period of stabilization of 30 minutes, a single dose of the test compound is added to the bath solution and its effect is continued for another 30 minutes. The effect of the drug is expressed as a percentage of the initial value of the reduction before the drug is given.
Table 6 shows the lowest effective concentrations of the test compounds, at which there is a 20% increase in the reduction compared with the reduction before the administration of the preparation.
PRI me R 22. Strengthening contractions caused by subpraximal transmural stimulation of the ileal muscle of the guinea pig.
The end segments of the ileal muscle of the guinea pig are suspended vertically with a preliminary tension of 1 h in a 100 ml thyrodne bath (37.3 ° C) and flushed with a gas mixture of 95% QЈ and 5% C0g. The contraction is measured isothermally. Transmural excitation is caused along the entire length of the muscle strip with the help of two platinum electrodes (0.5 mm in diameter), the anode is passed through the lumen of the iliac muscle and the cathode is immersed in the bath solution. The tissue is excited by single pulses (rectangular) with a duration of 1 m / s and super maximum current (maximum +20 mA) at a frequency of 6 per minute. After a period of stabilization (30 minutes), a single dose of the test compound is injected into the bath solution, which gives a concentration of 0.01 mg / l. After 5 minutes, another dose of the compound is added to obtain a concentration of 0.16 mg / mpo. The effect of the drug is determined as a percentage of the initial contraction value prior to the administration of the drug.
Table 7 shows the percentage increase in reduction compared to
0
five
0
five
0
five
0
five
0
five
with initial concentrations. 0.01 and 0.16 mg / l.
Example 23. Gastric emptying in rats after receiving liquid food.
Rats are deprived of food for 24 hours, placed in separate cages. Water is removed at the beginning of the experiments. The tested food, which consists of a warm suspension of 200 mg of red phenol in 40 ml of distilled water,. administered through a tube into the mouth (0.4 ml / rat) half an hour after intramuscular injection of 0.16, 0.63, 2.5, 10 or 40 mg / kg of the compound of general formula I or saline. The stomach is then removed by laparotomy, a ligature is quickly applied to the pylorus and the esophagus sphincter at the entrance to the stomach and the stomach is removed. The stomach is cut and its contents are extracted with 100 ml of 0.1 M sodium hydroxide solution. The phenol content of this extract is examined colorimetrically at 558 nm in a spectrophotometer. The mean attenuation units 1.41 are obtained from animals that received saline.
Table 8 presents the attenuation unit values with the administration of 0.16, 0.63, 2.5, 10 or 40 mg / kg of the test compound.
Emptying the stomach from liquid food in rats.
The proposed method is described in example 23.
Table 9 shows the individual results in extinction units after subcutaneous administration of 0.16, 0.65, 2.5, 10, and 40 mg / kg of the test compound. Table 9 presents the compounds of general formula I, and table 10 describes the structural analogues of the prototype.
Table 9 clearly shows that the compounds of the invention show an increase in gastric emptying in a wide range of areas, in particular, the content of red phenolic in the stomach is less than 0.65 after administration from 0.63 mg / kg to 10 mg / kg. Table 10 shows that the compounds of the prototype to increase gastric emptying is significantly lower (this effect is significant only for a limited dose range). It is the latter aspect that makes known analogs less applicable as a medicine.
Thus, the proposed method allows to obtain new N- (4-piperidinyl) benzamides, which have valuable pharmacological properties.

权利要求:
Claims (1)
[1]
JQ Invention Formula
The formulation of the preparation of K- (4-piperidinyl) benzamides of the general formula I
 OR, R,
(r
(to)
(l)
162533124
5L
"-" QW
about „or
with O- (Ae1)
Fm) n
where Alk is a Ci-C-alkanediyl or .alcidiyl;
YJ is oxygen or Y is 0, NR or direct bond; R7 is hydrogen or C -C alkyl;
15
and
C8
R-- independently of each other
hydrogen or C-Cf-alkyl with the proviso that Rg and Rg are not hydrogen when R7 is hydrogen; C-Sf-alkyl;
de R | - hydrogen,.-alkyl,
C-C-alkyloxycarbonyl, phenoxycarbonyl, aminocarbonyl, mono- or di-C -C-alkylaminocarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl; RЈ is hydrogen or C -C-alkyl;
R ,, R4. and R
R,
each independently of one another is hydrogen, kil, C —C4-alkyloxy, a radical, halogen, hydroxyl, amino, trifluoromethyl, mono- or di-C -C4 — alkylamino, C -C-alkylcarbonylamino, aminosulfonyl, or kilaminosulfonylj hydrogen, hydroxyl, or C —C.-alkyloxy; radical of general formula
R 4-Yt-A /
. /
LA1Kj-0-C-T, -AUt-,
AJ
RH-C-Y, -A1K- R "7. (CH1% „
A-fi-Y- ("L
About i
Rte-lTV-alk
In o
N-A "
AJ
(but)
(b)
(at)
. (g)
(e) (e)
(g)
(h) (i)
(to)
(l)
0
five
0
five
0
45
50
55
and
RM - RM
C8
R-- independently of each other
hydrogen or C-Cf-alkyl with the proviso that Rg and Rg are not hydrogen when R7 is hydrogen; C-Sf-alkyl;
phenyl, substituted phenyl, phenyl-C-C-alkyl or C-1-alkyl oxy;
. - C-Sf-alkyl;
R is C-Cjj-alkyl, cyclo-C-C is alkyl, phenyl or substituted phenyl;
 - phenyl-C-C-alkyl, where C). is an alkyl radical substituted by hydroxyl or .- alkylcarbonyloxy;
RI
and R is each independently hydrogen, Ci-Cf-alkyl, hydroxyl, C-C-alkyloxy, amino, mono- or di-C-C-alkylamino, hydroxy-C-alkyl, Cf-alkylcarbonyl, C) kiloxycarbonyl , aminocarbonyl, mono- or di-C1-C4 alkylaminocarbonyl or / - C (-Cf-alkyl-T, 3-dioxolan-2-yl, or in combination with a carbon atom bound to said R15- and Rfg, may form a carbonyl or 1,3-dioxolan-2-ylidene radical; an integer of 1.2 or 3;
S A
oxygen or NR ,, Q, where R is hydrogen, C-Cf-alkyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, C (-C.-alkylcarbonyl, C-C alkyloxycarbonyl or phenyl-C (-Sf -alkil;
and each is independently hydrogen or C-C4 alkyl or, when A is NR, Rj (7 and R, taken together, can form
a condensed benzene residue which can be replaced by a halogen radical or C-Cf-alkyl;
t is an integer of 1 or 2;
RJQ is hydrogen or C-Cf alkyl;
B is a bivalent radical of the formula, —C (0) —CH, -, or —CH —CHj — CH -, where each hydrogen atom can independently be substituted with a C — Cf-alkyl, or when C, | —S-alkyl, indicated the bivalent radical may also be 1,2-benzenediyl, optionally substituted by radical by halogen or C-Cf-alkyl;
- a bivalent radical of the formula -CH2-CF2-, -CHЈ-N (R2 () - or, where each hydrogen atom can independently be substituted by Cd-alkyl, or the said bivalent radical can also be 1,2-benzene-diyl, if necessary substituted radical by halogen or C 4-Cf-alkyl, and the specified Rg hydrogen or C-Cf-alkyl;
22 P "
R2j - each independently hydrogen
or C-Sf-alkyl;
m is both independently 0 or 1;
- carbonyl, C.) -Sf-alkyloxy-carbonylmethylene, kilcarbonylmethylene, 5,5-diR (ОR 25
 And I # # + I-C-CH-CH2-CH2-C1
2-Н3С- 4-Н3С- 2-НЭС
methyl-1, J-diokean-2-ylidene or 1,3-dioxolan-2-ylidene substituted phenyl is phenyl substituted with 1,2 or 3 substituents, each independently selected from halogen, hydroxy, alkyl or C - C4-alkyloxy, their pharma-i-chemically acceptable acid addition salts, stereoisomeric forms or N-oxides, characterized in that the N-alkylated piperidine of the general formula
ORi 9nH-lT -N L4
2 R6
subjected to interaction with the reagent of formula III
L - C1,
 where L has the indicated values, in a reaction inert solvent, in the presence of a base and / or iodine salt, if necessary, convert the compounds of the general formula I to one another by means of operations known in the art of group conversion or, if desired, convert the compound of general formula I to a therapeutically active non-toxic acid addition salt by treating with an appropriate acid or, conversely, by converting an acid addition salt to the free base form with an alkali, to isolate the desired product in a rim in the form of a pharmaceutically acceptable acid addition salts, in form of stereoisomeric forms or in the form of N-oxides.
Table 1
n3sN N N
because 135 ° C at 199.5 Pa
T. 95 ° C at 5.32 Pa
because.145 ° C at 239.4 Pa
because.146 ° C at 266 Pa
6
one
8 9
10 11 12 13 14
15
sixteen
one/
3ННН
24-H2N-C (0) -NH
24-BUT-NN
24-СгН50-С (0) -НН
23-Н3МтС (о; -НН
23-BUT-CH2-NN
23-BUT-NN
2H, HH3C24-Methyl-1, 3-HH dioxolan-2-yl
12-С1Н Г0-С (0) -НН
24-M (CH3) g —HH 23-N (CH,) 2-HH
17
, „0
/ -K II A -C-Alfc-V

C6H5-N.
CH3-N- n-C6H ,, - NJT
Q-NCH3-NH H
H H
H
because 95 ° C at 13.3 Pa
tk.129 ° C at199.5 Pa
because 140 ° C at 13.3 Pa
because 172 ° С at 99.5 Pa Pa HC1
Table 2
H H
H H
H
l
- (CK2) -C1.HC1 - (CH-ClfHCl
- (CH -Br-HCl - (CH2) 3-C1 HC1
- (CH2) 3-C1-HC1 - (CH2) 3-C1
OR, OOCHj LN KNU-C -O-W,
M cl
0
l
CHj-N N-CHj-CH.d
Н3СО о
n3со-О-Ј- нснг) 3HjCO
0
O-c-CH |
O-s- (cis) 30 H5C, -L N-CH, -CHjOCH3 OOCHj L-N -im-5 -O-NH, Cl
I
24
SNGS (o) -o- (ch2) 2
0
l
 H
nn -sn, -sn, IITable3
CH3HC1 H20203,5
CH, H O120.0
CH3H O152.2
CjHy Base 176.9
Base
,
IS
TableA
.Base
Base
151.7 200.0
43
n} s-O -c- (cis), o ch3
44 О-с-н- (шгЬ1, 5 Н20
115.8
Base
141.8
(Continuation of table 6
OCHjO OCH3
.-iTjW-C -NHi
CI
cUj-cn, -N N Sing, 0
cH.j-CH2-N N-CHJ-CH,) (
W
OCHj 0 OCH3
L-idJ H c-0- Ha
 Cl
The content of red phenolic in the stomach in extinction units at the dosage
1, 24 1.27
СНзО-О-СНгС) -о-а1г-а1г0, 91
0.870.630.430.45 0.90
0,650,180,19 0,64
Table 10

0.75 0.77
0.75 0.63
0.59 0.62
1.33 0.86
1.07
1.58

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同族专利:

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公开号 | 公开日

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DK529888D0|1988-09-23|

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DE3852085T2|1995-04-06|

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FI884375A0|1988-09-23|

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PT88577B|1992-11-30|

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EP0309043A2|1989-03-29|

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BG60560B1|1995-08-28|

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CN1021652C|1993-07-21|

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KR890005053A|1989-05-11|

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IE882889L|1989-03-25|

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NO172580C|1993-08-11|

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NZ226125A|1990-05-28|

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ES2066781T3|1995-03-16|

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AU610241B2|1991-05-16|

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CN1067889A|1993-01-13|

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AT113936T|1994-11-15|

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AU2232288A|1989-04-06|

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HU203724B|1991-09-30|

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法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US10111587A| true| 1987-09-25|1987-09-25|

---