Method of producing alpha, alpha-diphenyl-1-4-aryl-4-oxy-1-piperidinebutaneamide-n-oxides or stereoi

专利摘要:
Novel alpha , alpha -diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, N-oxides of formula <CHEM> wherein R is hydrogen or methyl; Ar<1> and Ar<2> are, each independently, phenyl or halophenyl; Alk is -CH2-CH2- or -CH2-CH(CH3)-; R<1> and R<2> are, each independently, hydrogen, C1-6alkyl, phenylmethyl or 2-propenyl or R<1> and R<2> combined with the nitrogen atom bearing said R<1> and R<2> may form a pyrrolidinyl, piperidinyl, C1-6alkylpipridinyl, 4-morpholinyl or 2,6-di(C1-6alkyl)-4-morpholinyl radical; Ar<3> is phenyl being optionally substituted with up to 3 substituents selected from the group consisting of C1-6alkyl, C1-6alkyloxy, halo and trifluoromethyl; the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are anti-diarrheal agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
公开号:SU1443798A3
申请号:SU864028251
申请日:1986-10-08
公开日:1988-12-07
发明作者:Валс Лауренс；Пауль Кауманс Людвиг
申请人:Жансен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:


N |
CD 00
 CM
The invention relates to the field of production of new heterocyclic compounds - pyridine derivatives, in particular, to a process for the preparation of compounds of the general formula
or their stereoisomers, where Alk is CHj-CH - or —CH —CHCHCH-z) R-1 and R,.,. C-C-alkyl;
 phenyl, possibly having up to. 2 substituents selected from halogen and trifluoromethyl with antidiarrheal action.
The aim of the invention is to create, on the basis of known methods, a method of producing new compounds possessing valuable pharmacological properties.
Example 1. A mixture of 26.5 g of 4- {4-chlorophenyl) -4-hydroxy-N, N-dimethyl- -0 /, o (-diphenyl-1-piperidinebutanamide, 17.1 g of a 30% peroxide solution Hydrogen H / jO, 200 g of methanol and 315 g of methylbenzene are stirred first for 20 hours at 60 ° C and then for 96 hours at 70 ° C. The reaction mixture is evaporated. The residue is purified by capillary chromatography (HPLC). high pressure chromatography) on silica gel using a mixture of trichlorome methane, methanol and methanol saturated with ammonia (90: 9: 1 by volume) as eluent. The pure fractions are collected and the solvent is evaporated. The current is crystallized from a mixture of 2,2-oxy-bis-propane and a small amount of methanol. The product is filtered and dried in a tap for drying with methylbenzene for 30 minutes at reflux temperature, 2.0 g (7%) of trans-4- ( 4-chlorophenyl) -4-hydroxy-N, M-dimesh1-o (, c-biphenyl-1-piperidine-butanamide-H-oxide, t.pcs 149.7 ° C.
PRI mme R 2. A mixture of 21.5 g of 4-t4-xnop-3- (trifluoromethyl) -phenyl-4-hydroxy-N, N-dimetsh-1, o / -difensh1-1-piperidinobutanamide, 8 , 6 g of a 30% hydrogen peroxide solution and 260 g of 4-methyl-2-pentanone are mixed in
0
five
0
five
0 5 о з п
24 hours at 80 ° C. After cooling in an ice bath, the precipitated product is filtered and dried, yielding 10.4 g (46%) (A) -4-: 4-chloro-3- (trifluoromethyl) phenyl} -4 -oxy-K, N-diphenyl-1-piperidinebutanamide-N-oxide, so pl. 185.3 C.
PRI me R 3. A mixture of 20 g of 4-C4-chloro-3- (trifluoromethyl) phenyl-4-hydroxy-N, N-dimethyl-in, "α-diphenyl-1-piperidine butanamide, 8 g of 30% a solution of hydrogen peroxide and 240 g of 4-methyl-2-pentanone is stirred for 24 hours at. The reaction mixture is cooled in an ice bath. The precipitated product is filtered off and the filtrate is evaporated. The residue is purified by capillary chromatography on silica gel using a mixture of trichloromethane and methanol (90:: 10 by volume) as eluent. Collect the second fraction and eluent enter. The residue is further purified by capillary chromatography (HPLC) on silica gel using a mixture of hexane, trichloromethane, methanol and ammonium hydroxide (45: 50: 5: 0.05 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2-oxibispropane. The product is filtered off and dried, to obtain 1.2 g of (B) -4-C4-HLOR-3- (trifluoromethyl) phenyl-4-hydroxy-K, N-dimesh1-o (, o / - diphenyl-1-piperidinbutanamide-S -oxide-sesquihydrate, mp 152.9 ° C.
Example 4 .. To a stirred solution of 133.0 g of 4- (4-chlorophenyl) -4-OKcH-N, N-dimethyl-o / s (-diphenyl-1-pyperidinbuganamide in 2000, 4-methyl-2 -pentanone was added 57.0 g of 30% hydrogen peroxide solution. The whole was stirred for 20 hours at 80 C. After cooling overnight, the precipitate was filtered (filtrate 1 was set aside) and boiled in 4-methyl -2-pentanone. The undissolved part is filtered off and the filtrate, together with filtrate 1, is evaporated. The residue is purified by capillary chromatography on silica gel using a mixture of trichloromethane and methane . La (90:10 by volume) as eluent second fraction was collected and the eluent was evaporated The residue was purified twice:. First using capillary chromatography on silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90: 9: 1 by
volume) as eluent, and then using capillary chromatography on silica gel, using a mixture of trichloromethane, hexane, methanol and methanol saturated with ammonia (45: 45: 9:: 1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2 - oxybispropane. The product is filtered off and dried, yielding 2.3 g of cis-4- (4-chlorophenyl) -4-hydroxy-H, N-dimethyl-o /, o (diphenyl-1-piperidinebutanamide-N-oxide, T. Ш1. 146, б С.
Example5. A mixture of 23 g of 4- (4-chlorophenyl) -4-hydroxy-N, H dimethyl-c /, diphenyl-1-piperidinebutanammund, 12 g of a 50% aqueous solution of hydrogen peroxide, 200 g of methanol and 320 g of methylbenzene
stirred for 24 hours at 60 ° C. The test compound was administered intravenously. The reaction mixture was evaporated. The residue was purified by capillary chromatography (YACD) over silica gel using a mixture of trichloromethane, methanol and methanol as the eluent, saturated with 25-2 hours after the introduction of the castor oil with ammonium (90: 90: 1 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2-oxy-bis-propane and a slight dropping at the desired dose. After one hour, each animal is given 1 ml of castor oil orally. Each animal is kept in a separate cage and later.
note the presence or absence of diarrhea. The value is determined as a dose in mg / kg body weight, at which diarrhea was not observed in 50% methanol spray. Product of filtered animals.
They are dried in a nebulizer with methylbenzene to obtain 1.5 g (6%) of trans-4- (4-chlorophenyl) -4-hydroxy-N-dimethyl-s, c-biphenyl-1-piperidinebutanamide-N-oxide . Melting point 150 ° C. Sample 4. In a stirred solution of 20 g of 4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-d, o (-diphenyl-1-piperidinebutanamide and 192 g of 4% methyl hydrogen peroxide solution are added to 260 g of 4-methyl-2-p.thanone. The entire solution is stirred for 96 hours at 80 ° C. After cooling overnight, the precipitate is filtered and dried. The residue is purified by capillary chromatography ( LSHVD) over silica gel using a mixture of trichloromethane, methanol and methanol saturated with ammonium (90: 90: 1) as eluent. The purified fractions are collected and the eluent is extracted. tail traction. The product is filtered and dried and 1.3 parts (5%) of trans-4- (4-chlorophenyl) -4-hydroxy-NN-dimethyl-ci (, dJ-1-piperidinobutanamide-N-oxide) are obtained. Melting point 150 ° C.
Example. To a cooled (0 ° C) and mixed solution of 20 g of 4- (4-chlorophenyl) -4-hydroxy-H, N-dimethyl-oi, diphenyl-1-piperidinobutanamide and 200 g
ED50 in mg / kg body weight is defined as the dose of the test compound, which suppresses in 50% of the test animals the occurrence of a typical gigantic reaction — withdrawal (pressing) of the tail for more than 10 s. The aforementioned EDDM values obtained for the compound of the invention and for 4- (4-chlorophenyl) -4-oxy-N, trichloromethane are added a mixture of 10 g of 3-chloroperbenzoic acid and 300 g of trichloromethane. Thus, the mixture was stirred for 4 hours in an ice bath. The reaction mixture was stirred for 4 hours in an ice bath. The reaction mixture is successively washed with a solution of potassium carbonate and water,
whereupon the organic layer is separated, evaporated, and dehydrated, and 2.1 parts (9%) of trans-4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-o, c / -1 -piperidinbutanamide are obtained -N-oxydol. Melting point 150 ° C.
Pharmacological testing. Test with castor oil on rats. Five female Wistar rats bind at night. To animal
The test compound is administered intravenously, 2 hours after the injection of castor oil.
in the right dose. After one hour, each animal is given 1 ml of castor oil orally. Each animal is kept in a separate cage and later.
The test compound is administered intravenously, 2 hours after the injection of castor oil.
note the presence or absence of diarrhea. The value is determined as a dose in mg / kg body weight, at which diarrhea was not observed in 50% of the test.
The ED value for the proposed compound and for the known 4- (4-chlorophenyl) -4-occ-N, N-dimet p-o (, o (-diphenyl-1-piper1-schsinbutanamide (loperamide)) is given in the table .
The test for the emergence of the tail pinching effect in rats. Five female Wistar rats bind at night. Each animal dose is administered an intravenously necessary dose of the test compound. The animals treated in this way are placed in cages for the individual to remain stationary,
5 After the test compound is injected, 5 cm of the lower part of the tail is immersed in a cup filled with water at a constant temperature of 55 ° C. 10 seconds after immersion, observe typical
50 Reaction - pushing the tail. The ED50 values in mg / kg body weight are defined as such a dose of the test compound, which suppresses in 50% of the test animals the occurrence of a typical gigantic reaction — withdrawal (retraction) of the tail for more than 10 s. The mentioned EDdm values obtained for the compound of the invention and for 4- (4-chlorophenyl) -4-oxy-N, N514437986
dimethyl-c, o-diphenyl-1-piperidinebutane, the same indicators for the preceding
amide (ie, loperamide) are also listed in the table.
From these values of ED ,,, it can be concluded that the preceding compound suppresses the occurrence of a typical reflex - tail tail, while compound (I) does not show such activity.
Determination of toxicity.
The test compound was introduced to the Wistar female rats in various doses. Values are defined as a dose in mg / kg body weight, 15 which is lethal to 50% of the test animals. The mentioned LD5o values obtained for the compound of the invention and for 4- (4-chlorophenyl) -4-oxy-N, N-dimethyl-o /, o (-diphenyl-1-piperidinebutan-20 amide (i.e., loperamide), Based on these values, it can be concluded that the compounds of the proposed method show lower toxicity.
Defining the boundaries of safety and antidiarrheal specific action.
The safety margin for an antidiarrheal effect is defined as 30 ratio of LDU values to ED 50 in the test with castor oil. Anti-diarrheal specific action is defined as the ratio of ED 5d obtained in a test with 35 tail wringing to the value of ED JP obtained in a test with castor oil. These values are also listed in the table.
Both the safety margin for anti-diarrheal action and the specific anti-diarrhea effect of the compounds of the invention are superior to

权利要求:
Claims (1)
[1]
compounds. Invention Formula
The method of obtaining o /, difensh1-4-aryl-4-hydroxy-1-piperidinebutanamide-N-oxides of the general formula
-N-r
HE
C-A1K-T (
/ Ag O
or their stereoisomers,
where Alk is the -CH2-CH2 group. or CHg-CH (CH3) -; (C,.) Is alkyl; Ar - phenyl, possibly having
up to 2 substituents selected from halogen and trifluoromethyl,
characterized in that
piperidine derivative of general formulas
R
and R OH
about RI
II I
C-N-R
Oc-Alk-NO
ABOUT
subjected to N-oxidation with a 10-50% solution or 3-chlorobenzoic acid in a reaction-inert solvent.
compounds. Invention Formula
The method of obtaining o /, difensh1-4-aryl-4-hydroxy-1-piperidinebutanamide-N-oxides of the general formula
-N-r
HE
C-A1K-T (
/ Ag O
or their stereoisomers,
where Alk is the -CH2-CH2 group. or CHg-CH (CH3) -; (C,.) Is alkyl; Ar - phenyl, possibly having
up to 2 substituents selected from halogen and trifluoromethyl,
characterized in that
piperidine derivative of general formula
R
and R OH
about RI
II I
C-N-R
c-Alk-NO
ABOUT
subjected to N-oxidation 10-50% solution or 3-chlorobenzoic acid in a reaction-inert solvent.

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KR101315751B1|2011-05-30|2013-10-10|주식회사 엔지켐생명과학|New method for producing Loperamide oxide monohydrate|

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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US78656685A| true| 1985-10-11|1985-10-11|LV920227A| LV5042A3|1985-10-11|1992-11-27|Method of obtaining alpha, alpha-diphenyl-4-aryl-4-oxy-1-piperidinbutanamide -N-oxide or stereoisomers thereof|

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LTRP373A| LT2086B|1985-10-11|1993-02-26|-DIFENIL-4-ARIL-4-OXY-1-PIPERIDINBUTANAMIDO-N-OXIDE OR ITS STEREOIZER|