CS195701B2 - Method of producing n-benzoyl derivatives of 1-phenylalkyl-4-aminopiperidine - Google Patents

Description

R is C 1 -C 6 alkoxy or C 2 -C 6 alkenoxy, each of R 1 and R 2; are the same or different, hydrogen, halogen, sulfonamido, amino, mono- or di-alkyl of 1 to 6 carbon atoms in each alkyl radical, alkylsulfonyl of 1 to 6 carbon atoms, phthalyl, alkylsulfonamido of 1 to 6 carbon atoms C 6 or C 2 -C 6 acylamino, wherein the radical R 1 is also attached to the 3 or 4 position of the aromatic ring,

R 3 represents a hydrogen atom, an alkyl group having 1 to 6 atoms. carbon or phenyl,

Ar represents a phenyl, benzoyl or thenyl group, and

B is alkyl or. a (C 1 -C 6) alkenyl group wherein the acylamino group represented by R 1 or R 2 or both is represented by the formula

R4 - CONH where

R a represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms optionally substituted with 1 to 3 atoms. chlorine, bromine or fluorine, or an amino or substituted amino group having 1 to 6 carbon atoms in the alkyl moiety or a group of the formula

Re \

• N,. /. Re wherein each of R 5 and R 6 is vo195701

195701. C 1 -C 6 alkyl, or both together with the nitrogen atom to which they are attached, form a five, six or seven membered ring containing optionally another nitrogen atom, wherein the phenyl or benzoyl group R 3 or Ar is optionally substituted

1 to 3 radicals which are identical or different and represent a hydrogen atom, an alkoxy group having 1 to 6 carbon atoms in each alkyl group, a mono- or di-alkylamino group having 1 to 6 carbon atoms in each alkyl residue, a halogen such as fluorine, chloro or bromo, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, or sulfonamido.

R @ 1 and R @ 2 'may furthermore represent hydrogen, halogen such as fluorine, chlorine or bromine, sulfonamido, amino, monoalkyl or C1 -C6 dialkylamino, alkylsulphonyl such as methylsulphonyl, ethylsulphonyl or propylsulphonyl, alkylsulphonamido or alkylsulphonamido; such as, for example, methylsulfonamido-, ethylsulfonamido-, propylsulfonamido- or butylsulfonamido, an ureide or N-alkylureide group such as an N-methylureide or N-ethylureide group, an acylamino group such as acetamido, the acylamino group being optionally substituted with 1 to 3 for example, chloroacetamido or trifluoroacetamido, or mono- or disubstituted amino such as dimethylamino- or 1-piperidylacetamido.

The process for the preparation of the compounds of the formula I according to the invention consists in the catalytic hydrogenation of the pyridine salts of the formula

Or a tetrahydropyridine of formula (111)

^ У-CON CH-B-A г. й ^л dl ') AND__ ^ 0 / —CONh 1- N -CH-e-Ar ⁷ R (III)

X is halogen and

R1 'represents a hydrogen, halogen, sulfonamide, nitro, amino, monoalkyl or dialkylamino group having 1 to 6 carbon atoms in each alkyl radical, alkylsulfonyl group having 1 to 6 carbon atoms, phthalyl C1 -C6 alkylsulfonamido or C2 -C6 acylamino, wherein the radical R @ 1 is bonded at the 3- or 4-position of the aromatic ring.

The hydrogenation is carried out in the presence of a catalyst such as platinum oxide or Raney nickel at a hydrogen pressure of 0.3 to 7.1 MPa at a temperature of 20 to 90 ° C using acetic acid, water, ethanol , methanol or mixtures thereof as solvents. After completion of the hydrogenation, the catalyst is separated by filtration and the product isolated by removal of the solvent and recrystallization.

The invention also provides the preparation of salts of the compounds of formula (I) with biologically and pharmacologically acceptable inorganic or organic salts. acids, including, but not limited to, sulfates, hydrogen halide salts, phosphates, C 1 -C 6 alkanesulfonates, arylsulfonates, C 1 -C 20 aliphatic mono-, di- and trivalent salts, which may contain at least one double bond, an aryl ring or other functional groups such as a hydroxyl group, an amino group or a keto group; and aromatic acid salts in which the aromatic nucleus is optionally substituted by groups such as hydroxy, C 1 -C 6 alkoxy, amino, Mono- or di-alkylaminosulfonamido having 1 to 6 carbon atoms in each alkyl radical.

The invention also provides compositions comprising the active compounds with pharmaceutically acceptable ingredients for oral and parenteral administration. Pharmaceutically acceptable diluents or carriers which are added to the active compound or the compounds or salts thereof to form the compositions of the invention are known; the ingredients used depend, inter alia, on the method of application of the composition. The compositions of the invention may be formulated for oral, external, percutaneous or parenteral administration, but the preferred route of administration is oral. In this case, the oral compositions may take the form of tablets, capsules, pills or effervescent granules, or they may be liquid, such as elixirs, syrups or suspensions. All of these compositions comprise at least one compound produced by the process of the invention. The compositions may be prepared by known pharmaceutical procedures.

The compounds obtained by the method of the invention have anti-dopaminergic properties and abolish the effects of apomorphine in animals, have local anesthetic activity, and have the ability to induce catatonia in rats and mice.

In addition, they encourage animals and humans to come out

R, R2, R3, B and Ar are as defined above, gastric emptying. For example, N- [4--1 H -benzyl] -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide and its salts promote. in humans and animals, gastric emptying at doses from 0.1 mg (100 µg) to 20 mg. The compounds may be used for the treatment of stomach upset and vomiting due to digestive problems, cardiac failure due to pulmonary congestion, postoperative conditions and the like, as well as other gastrointestinal disorders such as dystepsia, bloating, bile throwing, hiatus hernia, peptic ulcer, vasofagitic reflex, gastritis of the duodenum and choletiasis,. as an additive in x-ray of the digestive tract or as neuroleptics and tranquillizers. The compounds produced by the method of the invention cause considerably less central nervous system disorders than chlorpromazine or another phenothiazine antiemetic compound probably due to its more selective antidopaminergic effects.

The following examples illustrate the preparation of the compounds of the invention.

Example 1

3.0 g of Raney nickel W7, i.e. containing alkali, are added to a mixture of 4.5 g of 4- [2'-methoxy-4'-amino-5'-chlorobenzamido] -1-benzylpyridine lumbromide, 300 ml of 90% alcohol and 1.4 ml triethylamine. The mixture was hydrogenated at 70 ° C under 50 psi for 15 hours. Catalyst. The filtrate was distilled under reduced pressure. The residue is stirred with dilute sodium hydroxide solution, washed several times with water, dried and recrystallized from methanol to give 2.3 g of N - [(4-benzyl) piperidyl] -2-methoxy-4-amino-5-chlorobenzamide. mp 193-195 ° C.

In a manner similar to that described in Example 1, the following compounds were prepared:

N- ^[4-t -Ol' methc-dimethoxybenzyl 1) piperidyl] -2-methoxy-4- (amino (5-chlorobenzamide having a melting range of 226-227 ° C, N- [4 '(L n-p-methoxybenzyl) -piperidyl] -2-methoxy-4-amino-b-chlorobenzamide, m.p. 238-239 ° C, N - (- (1-t-m-chlorobenzyl) piperidyl) -2-methoxy 204 DEG-206 DEG C., N- [4 '- [. Beta.-cinnamyl] piperidyl] -2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. to 259 [deg.] C., N- [4- (piperidin-1-yl) -piperidyl] -2-methoxy (4-amino-5-chlorobenzamide hydrochloride, m.p. 264 DEG-266 DEG C., N- [4 '] - (1 '- (2'-Thenyl)) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide, m.p. 231-233 ° C, N- [4'- [Γ-p] hydrochloride N- (4'- (1'-diphenylmethyl) -piperidyl] -2-methoxy-4- (2-chlorobenzyl) piperidyl-4-methoxy-4-amino-5-chlorobenzamide, m.p. amino-5 -chlorobenzamide, m.p. 153-159 ° C,

N- [4‘- (1'-o-methoxybenzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide, m.p. 163-165 ° C,

N- [4'- (1 '- (3', 4 ', 5'-trimethoxybenzyl) piperidyl] -2-methoxy-4-amino-S-chlorobenzamide, m.p. 80-82 ° C, N hydrochloride - [4'- (1'-sec-Phenethyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide, m.p. 247-250 ° C, and N- [4 '- (1'- benzyl) -f

-piperidyl] -2 (methoxy (5-methylsulfonylbenzamide), m.p. 206-208 ° C).

Example 1. a d 2 ‘

A mixture of 3.4 g of 1-benzyl- (4-methoxy-4-aminobenzamide) -1,2,5,6-tetrahydropyridine, 25 ml of water, 25 ml of acetic acid and 0.5 g of platinum oxide is hydrogenated. for 19 hours at 50 [deg.] C. under 0.36 MPa. The catalyst was filtered off, the residue was poured into water, basified with 2N sodium hydroxide solution and extracted with chloroform. The chloroform extracts were dried, distilled under reduced pressure, and the resulting solid residue was dissolved in acetone. A solution of hydrogen chloride in methanol was added sequentially to give 3.1 g of N- [4- [1- (1'-benzyl) -piperidyl] -4-methoxy-4-aminobenzamide dihydrochloride, m.p. 215-217 ° C.

Ί

Example 3

N- [4‘- (1‘-Benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide fumarate of formula

C20H24ClN3O2. C4H4O4

A hot solution of 3.75 g of N- [4 '- (l ^t benzyl) piperidinyl] -2-methoxy-4-Amino-5-chloro benzamide in 130 ml of methanol was added to a hot solution of 1.2 g of fumaric acid in 60 ml acetone and 20 ml methanol. The solution obtained is filtered and allowed to cool, whereupon the product crystallizes. Yield 2.7 g. Melting point: 209-210 ° C.

The following N- [4‘- (1'-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide salts were prepared in a similar manner:

Phosphate formulas

ОюНмСПМзОг. H 3 PO 4, m.p. 224-225 ° C, succinate of formula

C20H24ClN3O2. 166 DEG-168 DEG C., citrate monohydrate of formula

C20H24ClN3O2. C6H8O7. H 2 O, m.p. 86-90 ° C (dec.), Oxalate of formula

C20H24ClN3O2. C2H2O4, m.p. 234-235 [deg.] C, [alpha] -ketoglutarate of the formula

C20H24ClN3O2. C5H6O5, mp 113-115 ° C, malate of formula

C20H24ClN3O2. 170 DEG C. (decomposition) and hydrochloride monohydrate, m.p. 217-219 DEG C .;

Example 4

100,000 tablets of 2.0 mg of N- [4 ‘- (1‘-benzyl) piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate

Ingredients

N- [4 ‘- (1‘-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate200 g microcrystalline cellulose 1870 g spray-dried lactose - 9880g carboxymethyl starch 430g sodium stearyl fumarate 60g colloidal silicon dioxide 60g

Method

All powders are sieved. sieve. with 0.6 mm holes. It is then mixed in a suitable mixer for 20 minutes and recovered. the blends compress 125 mg tablets using flat plate punches with 6 mm bevelled edges. The disintegration time of the tablets is 60 s.

Example 5,

100,000 capsules of 2.0 mg of N- [4‘- (1‘-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate

Ingredients

N- [4 ‘- (1‘-benzyl) -piperidyl] -2-methoxy-4-amipo-5-chlorobenzamide malate 200g corn starch 9600g lactose 10 000 g colloidal silicon dioxide 100g magnesium stearate 100g

Method

All powders are sieved through a 0.6 mm sieve. It is then mixed in a suitable mixer for 20 minutes and mixed. fill 100,000 capsules of suitable size in a filling machine.

Example 6

000 vials of 10 ml volume, containing 44. mg of malate N - [(4-t-benzylpiperidyl)] - 4-methoxy-4-amino-4-chlorobenzamide

Ingredients

N- [4 ‘- (1‘-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate 440 g chlorhexidine acetate 60 g propylene glycol 60 000 g distilled water up to 100 ´ 1

Method

N- [4‘- (1‘-Benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate and chlorhexidine acetate were dissolved in 40,000 g of distilled water with stirring. Propylene glycol is added and the solution is made up to the desired volume with distilled water. The solution is filled with 10,000 10 ml vials using a suitable filler. A calibrated dropper is attached to the vials.

Example 7

000 ampoules of 2.0 ml of N- (4‘- (t-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate

Ingredients

N- [4‘- (1‘-Benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate 20 g

90% lactic acid 400 g

N sodium hydroxide to pH 4.7 water for injections up to 20 liters

Method

N- [4'- (1'-Benzyl) piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate is dissolved with stirring in 15,000 g of water for injection, lactic acid is added, pH is adjusted with 2 N solution sodium hydroxide to 4.7 and make up to volume with water for injection. Filter the resulting solution through a 0,22 μπι membrane filter and divide into 10 000 ampoules.

The vials are sealed and sterilized at 121 ° C in a steam autoclave for 30 minutes.

Claims (1)

5,000 suppositories of 2,5 mg of N- (4 ‘- (1‘-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate Ingredients N- [4 ‘- (1‘-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate 12.5 g theobromine oil 7987.5 g Method The N- [4'- (1'-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide malate is sieved through a 0.4 mm sieve and suspended in theobromo oil, pre-dissolved by minimal heating. . The mixture is filled with suppository forms having a nominal content of 1.6 g; a total of 5000 suppositories are prepared. the subject of the invention A process for the preparation of N-benzoyl derivatives of 1-phenylalkyl-4-aminopiperidine of the formula I wherein R is C 1 -C 6 alkoxy or C 2 -C 6 alkenoxy, each of R 1 and R 2 being the same or different, is hydrogen, halogen, sulfonamido, amino, mono- or di-C 1 -C 6 -alkylamino; C 6 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, phthalyl, C 1 -C 6 alkylsulfonamido or C 2 -C 6 acylamino, wherein R 1 is bonded at the 3- or 4-position of the aromatic ring , R3 represents a hydrogen atom, a (C1-C6) alkyl group or a phenyl group, Ar is phenyl, benzoyl or thenyl, and V represents an alkyl or alkenyl group having from 0 to 6 carbon atoms, the acylamino group represented by R1 or R2 or both being represented by the formula R a is hydrogen, C 1 -C 6 alkyl optionally substituted with 1 to 3 chlorine, bromine or fluorine atoms, or amino or substituted C 1 -C 6 aminoalkyl or alkyl Rs \ N, / Rg wherein each of R 5 and R 6 is hydrogen, C 1 -C 6 alkyl, or both together with the nitrogen atom to which they are attached, form a five, six, or seven membered ring, optionally containing an additional nitrogen atom, the phenyl or benzoyl group R3 or Ar is optionally substituted with 1 to 3 radicals which are identical or different and represent a hydrogen atom, a C1-C6 alkoxy group, a hydroxy group, an amino group, a mono- or di-C1-6 alkylamino group carbon atoms in each alkyl radical, halogen such as fluorine, chlorine or bromine, trifluoromethyl, straight-chain or branched alkyl of 1 to 6 carbon atoms or sulfonamido, characterized in that the pyridine salts of the formula II or the tetrahydropyridines of the general formula are catalytically hydrogenated of formula III R4 — CONH, 185701 kde R, R2, Из, В and Ar are as defined above, X is halogen and R 1 represents a hydrogen atom, a halogen atom, a sulfonamido group, a nitro group, an amino group, a monoalkyl- or dialkylamino group having 1 to 6 carbon atoms in each alkyl radical, an alkylsulfonyl group having 1-6 carbon atoms, a phthalyl group having 2 to 6 carbon atoms, the residue R 1 'being bonded at the 3 or 4 position of the aromatic ring, in the presence of a catalyst such as platinum oxide or Raney nickel, under a hydrogen pressure of 0.3 to 7.1 MPa at a temperature in the range 20 to 90 ° C using acetic acid, water, ethanol, methanol or a mixture thereof as solvent, after completion of the hydrogenation, the catalyst is filtered off and the final product is recovered from the solution by removing the solvent.