CA1085855A - N-piperid-4-yl benzamide compounds - Google Patents
N-piperid-4-yl benzamide compoundsInfo
- Publication number
- CA1085855A CA1085855A CA289,550A CA289550A CA1085855A CA 1085855 A CA1085855 A CA 1085855A CA 289550 A CA289550 A CA 289550A CA 1085855 A CA1085855 A CA 1085855A
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- Canada
- Prior art keywords
- methoxy
- amino
- piperid
- chlorobenzamide
- preparation
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the Disclosure There are disclosed certain novel N-substituted benzamides having pharmacological activity including anorexia, vasodilatation and inhibition of gastric acid secretion and ulcer formation. Pharmaceutical compositions containing the active compounds are also disclosed.
Description
i8~S
This invention relates to N-substituted-benzamides and to pharmaceutical compositions containing them.
Canadian application Serial No. 248,237 discloses compounds of the general formula:-R2\
~ 13 (~ ~ CON~I-(CH2)X7 R ~ \(CH ) Z
wherein R represents a Cl-C6 alkoxy or C2-C6 alkenyloxy group, Rl and R2 are the same or different and each represents a hydro-gen or halogen atom, or a sulphonamido, amino, Cl-C6 alkyl-, di-(Cl-C6)-alkyl-amino, alkylsulphonyl, alkylsulphonamido or acyl- -amino group, the symbol Rl being in the 3- or 4-position of the phenyl ring, R3 represents a hydrogen atom or a Cl-C6 alkyl or aryl group, Ar represents an optionally substituted aryl, aroyl or a single ring aromatic heterocyclic group, x represents 0 or l, _ represents 2 or 3, and z represents an integer from l to 6, `
and pharmaceutically acceptable acid addition salts thereof. The compounds are stated to have useful pharmacological properties and, more partieularly, the ability to antagonise the effeets of dopamine or dopaminergie agents of endogenous or exogenous origin.
It has now been found that eertain compounds falling within the scope of the above general formula but not speeifieally disclosed in the prior application possess the aforesaid pharma-eologieal properties and also properties not hitherto diselosed in respeet of eompounds of general formula I.
Aeeordingly, the invention provides an N-piperid-4-yl benzamide of the general formula:
:.,,~' l\
, -, , ~ ~
Rl ~ CON~ CI - Ar IA
[wherein R represents a methoxy, ethoxy or allyloxy group; R
represents an amino, acetamido, methylamino or dimethylamino group; R2 represents a chloro or bromo atom, or an amino group;
R~ represents a hydrogen atom or a methyl group and Ar repre-sents a ~naphthyl group or a phenyl group, optionally substit-uted by a halogen atom, a trifluoromethyl, methyl or nitro group, or by both a chlorine atom an~ a methoxy group], or a pha.rmaceutically acceptable acid addition salt thereof.
10The new compounds of the present invention are thus N-[l-(_-trifluoromethylbenzyl)piperid--4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l-~l-phenylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide, N-[1-~2-methoxy-5-chlorobenzyl)-piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l-~-naphthylmethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l-~p-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chloro- ~ -benzamide, N-[l-~p-r ~ la -8~3S~ii bromobenzyl)-piperid-4-yl~-2-methoxy-4-amino-5-c}llorobenzamide, N (1-(~-fluorobenzyl)piperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide, N~ o-methylbenzyl)piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, N-(l-benzyl-piperid-4-yl)-2-methoxy-4,5-diaminobenzamide, N-~l-(p-nitrobenzyl)-piperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide, N-~l-(l-phenylethyl~piperid-4-yl~~2-methoxy-4-amino-5-bromobenzamide, N-rl-(m-methylbenzyl)piperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide, N-(l-benzylpiperid-4-yl)-2-ethoxy-4-amino-5-chloro-benzamide, N-ll-(l-phenylethyl)piperid-4-yl)-2-methoxy-4,5-diaminobenzamide, N-(l-benzylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide, N-[l-(l-phenylethyl)piperid-4-yl~-2-methoxy-4-acetamido-5-aminobenzamide, N-(l-benzyl-piperid)-2-methoxy-4-methylamino-5-chlorobenzamide, N~ benzylpiperid-4-yl)-
This invention relates to N-substituted-benzamides and to pharmaceutical compositions containing them.
Canadian application Serial No. 248,237 discloses compounds of the general formula:-R2\
~ 13 (~ ~ CON~I-(CH2)X7 R ~ \(CH ) Z
wherein R represents a Cl-C6 alkoxy or C2-C6 alkenyloxy group, Rl and R2 are the same or different and each represents a hydro-gen or halogen atom, or a sulphonamido, amino, Cl-C6 alkyl-, di-(Cl-C6)-alkyl-amino, alkylsulphonyl, alkylsulphonamido or acyl- -amino group, the symbol Rl being in the 3- or 4-position of the phenyl ring, R3 represents a hydrogen atom or a Cl-C6 alkyl or aryl group, Ar represents an optionally substituted aryl, aroyl or a single ring aromatic heterocyclic group, x represents 0 or l, _ represents 2 or 3, and z represents an integer from l to 6, `
and pharmaceutically acceptable acid addition salts thereof. The compounds are stated to have useful pharmacological properties and, more partieularly, the ability to antagonise the effeets of dopamine or dopaminergie agents of endogenous or exogenous origin.
It has now been found that eertain compounds falling within the scope of the above general formula but not speeifieally disclosed in the prior application possess the aforesaid pharma-eologieal properties and also properties not hitherto diselosed in respeet of eompounds of general formula I.
Aeeordingly, the invention provides an N-piperid-4-yl benzamide of the general formula:
:.,,~' l\
, -, , ~ ~
Rl ~ CON~ CI - Ar IA
[wherein R represents a methoxy, ethoxy or allyloxy group; R
represents an amino, acetamido, methylamino or dimethylamino group; R2 represents a chloro or bromo atom, or an amino group;
R~ represents a hydrogen atom or a methyl group and Ar repre-sents a ~naphthyl group or a phenyl group, optionally substit-uted by a halogen atom, a trifluoromethyl, methyl or nitro group, or by both a chlorine atom an~ a methoxy group], or a pha.rmaceutically acceptable acid addition salt thereof.
10The new compounds of the present invention are thus N-[l-(_-trifluoromethylbenzyl)piperid--4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l-~l-phenylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide, N-[1-~2-methoxy-5-chlorobenzyl)-piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l-~-naphthylmethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l-~p-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chloro- ~ -benzamide, N-[l-~p-r ~ la -8~3S~ii bromobenzyl)-piperid-4-yl~-2-methoxy-4-amino-5-c}llorobenzamide, N (1-(~-fluorobenzyl)piperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide, N~ o-methylbenzyl)piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, N-(l-benzyl-piperid-4-yl)-2-methoxy-4,5-diaminobenzamide, N-~l-(p-nitrobenzyl)-piperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide, N-~l-(l-phenylethyl~piperid-4-yl~~2-methoxy-4-amino-5-bromobenzamide, N-rl-(m-methylbenzyl)piperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide, N-(l-benzylpiperid-4-yl)-2-ethoxy-4-amino-5-chloro-benzamide, N-ll-(l-phenylethyl)piperid-4-yl)-2-methoxy-4,5-diaminobenzamide, N-(l-benzylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide, N-[l-(l-phenylethyl)piperid-4-yl~-2-methoxy-4-acetamido-5-aminobenzamide, N-(l-benzyl-piperid)-2-methoxy-4-methylamino-5-chlorobenzamide, N~ benzylpiperid-4-yl)-
2-allyloxy-4-amino-5-chlorobenzamide, N~ -methylbenzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, N-(l-benzylpiperid-4-yl~-2-methoxy-4-acetamido-5-aminobenzamide, N-~1-(2-methoxy-5-chlorobenzyl)-piperid-4-yl~-2-methoxy-4-acetamido-5-aminobenzamide and N-tl-benzylpiperid-4-yl)-2-ethoxy-4-methylamino-5-chlorobenzamide and pharmaceutically acceptable acid addition salts thereof. These compounds have been founcl to possess - in addition to the pharmacological properties mentioned in the earlier patent application -new activi~ies, the most interestin~ of which are anorexia ~mouse spaghetti -~
test) without amphetamine-like stimulation of the central nervous system, vasodilatation ~mouse ear ~est) and inhibition of gastric acid secretion ~pyloric ligature model of Shay) and ulcer foTmation ~phenylbutazone or stress models) in the rat.
These new compounds may be prepared by application of the methods described in the speciication of Application Serial No. 248,237 for the preparation of compounds of general formula I.
Thus, compounds of formula I may be prepared by ~a) reacting a mixed anhydride of a substituted benzoic acid of the general formula: :
;
35~
R~ C2 II
with a piperidine derivative of the general formula:
13 :
H2N ~ N - CH - Ar III
wherein groups R, R1, R2, R3 and Ar are as defined for formula IA above, and if necessary, converting a product of formula IA
to a pharmaceutically acceptable acid addition salt thereof, or vice versa.
The acid addition salts may be prepared by reacting the base in a solvent such as methanol, ethanol, acetone or waterg or a suitable mixture of such solvents, at a temperature between 10C and the boiling point of the , ~
.
, . .-~15 51~
reaction mixture.
The present invention also includes within its scope pharmaceuti-cal compositions comprising one or more of the afore-named compounds, or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier. The pharmaceutical carrier may be a solid, a liquid or a mixture of a solid and a liquid, and the compositions of this invention may be adapted for oral, rectal or parenteral use, the preferred method of administration being ~ os. In this case, the compositions may take the form of tablets, capsules, lozenges, effervescent granules, syrups or suspensions.
Such compositions may be made by methods well known in the art.
The following Example illustrates the preparation in detail of one of the compounds of the invention. Other compounds of the invention may be prepared in a similar manner.
EXAMPLE
N-[l-~m-Trifluoromethylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide To a suspension of 6.0 g of 2-methoxy-4-amino-5-chlorobenzoic acid in 400 ml of anhydrous tetrah~drofuran, a solution of 4.2 ml of triethylamine in 28 ml of tetrahydrofuran was added. The resulting solution was cooled to -10C and then a solution of 2.98 ml of ethyl chloroformate in 25 ml of tetra-hydrofuran was slowly added. The mixture was stirred at the same temperature for half an hour and a solution of 8.58 g of 1-(_-trifluoromethylbenzyl)-4-aminopiperidine in 25 ml of tetrahydrofuran was added. After stirring for 1 hour at -10 to -5C, the temperature was allowed to rise to room temperature and the reaction mixture was left to stand overnight. The mixture was eva-porated to dryness and the residue dissolved in a mixture of chloroform and water. The mixture was made strongly basic with sodium hydroxide solution, the chloroform phase was separated and washed with water, dried ~sodium sul-phate) and evaporated to dryness to yield 9.5 g of the title compound, m.p.
138 - 140C (after crystallisation from acetone/n-hexane). Its hydrochloride melted at 219 - 221C.
S~ , By a similar procedure and using appropriate starting materials and appropriate quantities thereof, the following compounds were prepared:-N-[l-(l-phenylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 282 - 284C;
N-[1-~2-methoxy-S-chlorobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenz-amide, the hydrochloride of which melts at 200 - 203C;
N-[l-~-naphthylmethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 220 - 221C;
N-[l-(~-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 234 - 235C
N-[l-~p-bromobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 242 - 243C;
N-[l-~p-1uorobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride monohydrate of which melts at 256 - 258C ~dec); .
N-[l-~o-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide the hydrochloride of which melts at 186 - 188C;
N-~l-benzylpiperid-4-yl)-2-methoxy-4~5-diaminobenzamide, the hydrochloride monohydrate of which melts at 244 - 246C;
N~ p-nitrobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamade, the hydrochloride of which melts at 223 - 225C;
N-[l-~l-phenylethyl)piperid-4-yl]-2 methoxy-4-amino-5-bromobenzamide, the hydrochloride o which melts at 239 - 241C;
N-Ll-~m-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 217 219C;
N-~l-benzylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide, the hydrochloride o which melts at 271 - 273C;
N-[l-~l-phenylethyl)piperid-4-yl]-2-methoxy-4,5-diaminobenzamide, the dihydro-chloride monohydrate of which melts at 246 - 248C;
N-~l-benzylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide, the fumarate of which melts at 185 - 187aC;
., ~ , .. ..
5~55 Bis{N-[l-(l-phenylethyl)piperid-4-yl]-2-methoxy-4-acetamido-5-aminobenzamide}
fumarate, m.p. 165 - 166C;
N-(l-benzylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, the fumarate of which melts at 221 - 222C (dec.);
N-(l-benzylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide, the hydro-chloride of which melts at 223 - 225C;
N-(l-~-methylbenzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, the fumarate of which melts at 172 - 174C (dec.);
N-(l-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, the fumarate of which melts at 177 - 179C; -N-[1-(2-methoxy-5-chlorobenzyl)piperid-4-yl]-2-methoxy-4-acetamido-5-amino-benzamide, the fumarate of which melts at 182 - 184C (dec.); and N-~l-benzylpiperid-4-yl)-2-ethoxy-4-methylamino-5-chlorobenzamide, the fumarata of which melts at 229 - 231C (dec.).
test) without amphetamine-like stimulation of the central nervous system, vasodilatation ~mouse ear ~est) and inhibition of gastric acid secretion ~pyloric ligature model of Shay) and ulcer foTmation ~phenylbutazone or stress models) in the rat.
These new compounds may be prepared by application of the methods described in the speciication of Application Serial No. 248,237 for the preparation of compounds of general formula I.
Thus, compounds of formula I may be prepared by ~a) reacting a mixed anhydride of a substituted benzoic acid of the general formula: :
;
35~
R~ C2 II
with a piperidine derivative of the general formula:
13 :
H2N ~ N - CH - Ar III
wherein groups R, R1, R2, R3 and Ar are as defined for formula IA above, and if necessary, converting a product of formula IA
to a pharmaceutically acceptable acid addition salt thereof, or vice versa.
The acid addition salts may be prepared by reacting the base in a solvent such as methanol, ethanol, acetone or waterg or a suitable mixture of such solvents, at a temperature between 10C and the boiling point of the , ~
.
, . .-~15 51~
reaction mixture.
The present invention also includes within its scope pharmaceuti-cal compositions comprising one or more of the afore-named compounds, or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier. The pharmaceutical carrier may be a solid, a liquid or a mixture of a solid and a liquid, and the compositions of this invention may be adapted for oral, rectal or parenteral use, the preferred method of administration being ~ os. In this case, the compositions may take the form of tablets, capsules, lozenges, effervescent granules, syrups or suspensions.
Such compositions may be made by methods well known in the art.
The following Example illustrates the preparation in detail of one of the compounds of the invention. Other compounds of the invention may be prepared in a similar manner.
EXAMPLE
N-[l-~m-Trifluoromethylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide To a suspension of 6.0 g of 2-methoxy-4-amino-5-chlorobenzoic acid in 400 ml of anhydrous tetrah~drofuran, a solution of 4.2 ml of triethylamine in 28 ml of tetrahydrofuran was added. The resulting solution was cooled to -10C and then a solution of 2.98 ml of ethyl chloroformate in 25 ml of tetra-hydrofuran was slowly added. The mixture was stirred at the same temperature for half an hour and a solution of 8.58 g of 1-(_-trifluoromethylbenzyl)-4-aminopiperidine in 25 ml of tetrahydrofuran was added. After stirring for 1 hour at -10 to -5C, the temperature was allowed to rise to room temperature and the reaction mixture was left to stand overnight. The mixture was eva-porated to dryness and the residue dissolved in a mixture of chloroform and water. The mixture was made strongly basic with sodium hydroxide solution, the chloroform phase was separated and washed with water, dried ~sodium sul-phate) and evaporated to dryness to yield 9.5 g of the title compound, m.p.
138 - 140C (after crystallisation from acetone/n-hexane). Its hydrochloride melted at 219 - 221C.
S~ , By a similar procedure and using appropriate starting materials and appropriate quantities thereof, the following compounds were prepared:-N-[l-(l-phenylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 282 - 284C;
N-[1-~2-methoxy-S-chlorobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenz-amide, the hydrochloride of which melts at 200 - 203C;
N-[l-~-naphthylmethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 220 - 221C;
N-[l-(~-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 234 - 235C
N-[l-~p-bromobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 242 - 243C;
N-[l-~p-1uorobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride monohydrate of which melts at 256 - 258C ~dec); .
N-[l-~o-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide the hydrochloride of which melts at 186 - 188C;
N-~l-benzylpiperid-4-yl)-2-methoxy-4~5-diaminobenzamide, the hydrochloride monohydrate of which melts at 244 - 246C;
N~ p-nitrobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamade, the hydrochloride of which melts at 223 - 225C;
N-[l-~l-phenylethyl)piperid-4-yl]-2 methoxy-4-amino-5-bromobenzamide, the hydrochloride o which melts at 239 - 241C;
N-Ll-~m-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the hydrochloride of which melts at 217 219C;
N-~l-benzylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide, the hydrochloride o which melts at 271 - 273C;
N-[l-~l-phenylethyl)piperid-4-yl]-2-methoxy-4,5-diaminobenzamide, the dihydro-chloride monohydrate of which melts at 246 - 248C;
N-~l-benzylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide, the fumarate of which melts at 185 - 187aC;
., ~ , .. ..
5~55 Bis{N-[l-(l-phenylethyl)piperid-4-yl]-2-methoxy-4-acetamido-5-aminobenzamide}
fumarate, m.p. 165 - 166C;
N-(l-benzylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, the fumarate of which melts at 221 - 222C (dec.);
N-(l-benzylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide, the hydro-chloride of which melts at 223 - 225C;
N-(l-~-methylbenzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, the fumarate of which melts at 172 - 174C (dec.);
N-(l-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, the fumarate of which melts at 177 - 179C; -N-[1-(2-methoxy-5-chlorobenzyl)piperid-4-yl]-2-methoxy-4-acetamido-5-amino-benzamide, the fumarate of which melts at 182 - 184C (dec.); and N-~l-benzylpiperid-4-yl)-2-ethoxy-4-methylamino-5-chlorobenzamide, the fumarata of which melts at 229 - 231C (dec.).
Claims (46)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of an N-Piperid-4-yl benzamide of the general formula:
IA
[wherein R represents a methoxy, ethoxy or allyloxy group; R1 represents an amino, acetamido, methylamino or dimethylamino group; R2 represents a chloro or bromo atom, or an amino group; R3 represents a hydrogen atom or a methyl group and Ar represents a .beta.-naphthyl group or a phenyl group, optionally substituted by a halogen atom, a trifluoromethyl, methyl or nitro group, or by both a chlorine atom and a methoxy group], or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting a mixed anhydride of a benzoic acid of the general formula:
II
(wherein R, R1 and R2 are as defined above) with a piperidine derivative of the general formula:
III
(wherein R3 and Ar are as defined above), and, if desired, converting the thus obtained compound into a pharmaceutically acceptable acid addition salt thereof, or vice versa.
IA
[wherein R represents a methoxy, ethoxy or allyloxy group; R1 represents an amino, acetamido, methylamino or dimethylamino group; R2 represents a chloro or bromo atom, or an amino group; R3 represents a hydrogen atom or a methyl group and Ar represents a .beta.-naphthyl group or a phenyl group, optionally substituted by a halogen atom, a trifluoromethyl, methyl or nitro group, or by both a chlorine atom and a methoxy group], or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting a mixed anhydride of a benzoic acid of the general formula:
II
(wherein R, R1 and R2 are as defined above) with a piperidine derivative of the general formula:
III
(wherein R3 and Ar are as defined above), and, if desired, converting the thus obtained compound into a pharmaceutically acceptable acid addition salt thereof, or vice versa.
2. A process for the preparation of N-[1-(m-Trifluoromethylbenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chloro-benzamide, which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(m-tri-fluoromethylbenzyl)-4-aminopiperidine.
3. A process for the preparation of N-[1-(1-phenylethyl) piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-ethoxy-4-amino-5-chlorobenzoic acid with 1-(1-phenylethyl)-4-amino-piperidine.
4. A process for the preparation of N-[1-(2-methoxy-5-chlorobenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chloro-benzamide which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(2-methoxy-5-chlorobenzyl)-4-aminopiperidine.
5. A process for the preparation of N-[1-(.beta.-naphthylmethyl) piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(.beta.-naphthylmethyl)-4-aminopiperidine.
6. A process for the preparation of N-[1-(p-methylbenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(p-methylbenzyl)-4-aminopiperidine.
7. A process for the preparation of N-[1-(p-bromobenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(p-bromobenzyl)-4-amino-piperidine.
8. A process for the preparation of N-[1-(p-fluorobenzyl) piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(p-fluorobenzyl)-4-aminopiperidine.
9. A process for the preparation of N-[1-(o-methylbenzyl) piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed an-hydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(o-methylbenzyl)-4-aminopiperidine.
10. A process for the preparation of N-(1-benzylpiperid-4-yl)-2-methoxy-4,5-diaminobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4,5-diaminobenzoic acid with 1-benzyl-4-aminopiperidine.
11. A process for the preparation of N-[1-(p-nitrobenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(p-nitrobenzyl)-4-amino-piperidine.
12. A process for the preparation of N-[1-(phenylethyl) piperid-4-yl]-2-methoxy-4-amino-5-bromobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-bromobenzoic acid with 1-(1-phenylethyl)-4-aminopiperi-dine.
13. A process for the preparation of N-[1-(m-methylbenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(m-methylbenzyl)-4-aminopiperidine.
14. A process for the preparation of N-(1-benzylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-ethoxy-4-amino-5-chlorobenzoic acid with 1-benzyl-4-aminopiperidine.
15. A process for the preparation of N-[1-(1-phenylethyl) piperid-4-yl]-2-methoxy-4,5-diaminobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4,5-diaminobenzoic acid with 1-(1-phenylethyl)-4-amino-piperidine.
16. A process for the preparation of N-(1-benzylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-dimethylamino-5-chlorobenzoic acid with 1-benzyl-4-aminopiperidine.
17. A process for the preparation of N-[1-(1-phenylethyl) piperid-4-yl]-2-methoxy-4-acetamido-5-aminobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-acetamido-5-aminobenzoic acid with 1-(1-phenylethyl)-4-aminopiperidine.
18. A process for the preparation of N-(l benzylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-methylamino-5-chlorobenzoic acid with 1-benzyl-4-aminopiperidine.
19. A process for the preparation of N-(l-benzylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-allyloxy-4-amino-5-chlorobenzoic acid with 1-benzyl-4-aminopiperidine.
A process for the preparation of N-(1-p-methylbenzylpiperid-4-yl) 2-methoxy-4-acetamido-5-aminobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-acetamido-5-aminobenzoic acid with 1-(p-methyl-benzyl)-4-aminopiperidine.
21. A process for the preparation of N-(1-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-acetamido-5-aminobenzoic acid with 1-benzyl-4-aminopiperidine.
22. A process for the preparation of N-[1-(2-methoxy-5-chlorobenzyl) piperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide which comprises reacting a mixed anhydride of 2-methoxy-4-acetamido-5-aminobenzoic acid with 1-benzyl-4-aminopiperidine.
23. A process for the preparation of N-(1-benzylpiperid-4-yl)-2-ethoxy-4-methylamino-5-chlorobenzamide which comprises reacting a mixed anhydride of 2-ethoxy-4-methylamino-5-chlorobenzoic acid with 1-benzyl-4-aminopiperidine.
24. An N-piperid-4-yl benzamide of formula IA as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
25. N-[1-(m-Trifluoromethylbenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, whenever prepared by the process claimed in claim 2, or by an obvious chemical equivalent thereof.
26. N-[1-(1-Phenylethyl) piperid-4-yl)-2-ethoxy-4-amino-5-chloro-benzamide, whenever prepared by the process claimed in claim 3, or by an obvious chemical equivalent thereof.
27. N-(1-(2-Methoxy-5-chlorobenzyl) piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, whenever prepared by the process claimed in claim 4, or by an obvious chemical equivalent thereof.
28. N-(1-(.beta.-Naphthylmethyl) piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, whenever prepared by the process claimed in claim 5, or by an obvious chemical equivalent thereof.
29. N-[1-(p-Methylbenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, whenever prepared by the process claimed in claim 6, or by an obvious chemical equivalent thereof.
30. N-[-(p-Bromobenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chloro-benzamide, whenever prepared by the process claimed in claim 7, or by an obvious chemical equivalent thereof.
31. N-[1-p(-Fluorobenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chloro-benzamide, whenever prepared by the process claimed in claim 8, or by an obvious chemical equivalent thereof.
32. N-[1-(o-Methylbenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chloro-benzamide, whenever prepared by the process claimed in claim 9, or by an obvious chemical equivalent thereof.
33. N-(1-Benzylpiperid-4-yl)-2-methoxy-4,5-diaminobenzamide, whenever prepared by the process claimed in claim 10, or by an obvious chemical equivalent thereof.
34. N-[1-(p-Nitrobenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chloro-benzamide, whenever prepared by the process claimed in claim 11, or by an obvious chemical equivalent thereof.
35. N-[1-(Phenylethyl) piperid-4-yl]-2-methoxy-4-amino-5-bromobenzamide, whenever prepared by the process claimed in claim 12, or by an obvious chemical equivalent thereof.
36. N-[1-m-Methylbenzyl) piperid-4-yl]-2-methoxy-4-amino-5-chloro-benzamide, whenever prepared by the process claimed in claim 13, or by an obvious chemical equivalent thereof.
37. N-(1-Benzylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide, whenever prepared by the process claimed in claim 14, or by an obvious chemical equivalent thereof.
38. N-[1-(1-Phenylethyl) piperid-4-yl]-2-methoxy-4,5-diaminobenzamide, whenever prepared by the process claimed in claim 15, or by an obvious chemical equivalent thereof.
39. N-(1-Benzylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide, whenever prepared by the process claimed in claim 16, or by an obvious chemical equivalent thereof.
40. N [1-[1-Phenylethyl) piperid-4-yl]-2-methoxy-4-acetamido-5-aminobenzamide, whenever prepared by the process claimed in claim 17, or by an obvious chemical equivalent thereof.
41. N-(1-Benzylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, whenever prepared by the process claimed in claim 18, or by an obvious chemical equivalent thereof.
42. N-(1-Benzylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide, whenever prepared by the process claimed in claim 19, or by an obvious chemical equivalent thereof.
43. N-(1-p-Methylbenzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, whenever prepared by the process claimed in claim 20, or by an obvious chemical equivalent thereof.
44. N-(1-Benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, whenever prepared by the process claimed in claim 21, or by an obvious chemical equivalent thereof.
45. N-[1-(2-Methoxy-5-chlorobenzyl)piperid-4-yl]-2-methoxy-4-acetamido-5-aminobenzamide, whenever prepared by the process claimed in claim 22, or by an obvious chemical equivalent thereof.
46. N-(1-Benzylpiperid-4-yl)-2-ethoxy-4-methylamino-5-chlorobenzamide, whenever prepared by the process claimed in claim 23, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4464976A GB1593851A (en) | 1976-10-27 | 1976-10-27 | N-(4-piperidyl)-benzamides and pharmaceutical compositions containing them |
| GB44649/76 | 1976-10-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1085855A true CA1085855A (en) | 1980-09-16 |
Family
ID=10434204
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA289,550A Expired CA1085855A (en) | 1976-10-27 | 1977-10-26 | N-piperid-4-yl benzamide compounds |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5392783A (en) |
| BE (1) | BE860139R (en) |
| CA (1) | CA1085855A (en) |
| CH (1) | CH625219A5 (en) |
| ES (1) | ES463557A2 (en) |
| FR (1) | FR2378762A2 (en) |
| GB (1) | GB1593851A (en) |
| NL (1) | NL7711690A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001036385A1 (en) * | 1999-11-17 | 2001-05-25 | Kissei Pharmaceutical Co., Ltd. | Hydroxyethoxybenzamide derivatives and drugs containing the same |
| TW200800953A (en) | 2002-10-30 | 2008-01-01 | Theravance Inc | Intermediates for preparing substituted 4-amino-1-(pyridylmethyl) piperidine |
| JP2007524641A (en) | 2003-07-11 | 2007-08-30 | セラヴァンス， インコーポレーテッド | Substituted 4-amino-1-benzylpiperidine compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR5916M (en) * | 1966-01-21 | 1968-05-06 | ||
| GB1345872A (en) * | 1970-09-03 | 1974-02-06 | Wyeth John & Brother Ltd | Amino-and acylamino-pyridine and hydropyridine derivatives |
-
1976
- 1976-10-27 GB GB4464976A patent/GB1593851A/en not_active Expired
-
1977
- 1977-10-25 CH CH1295177A patent/CH625219A5/en not_active IP Right Cessation
- 1977-10-25 NL NL7711690A patent/NL7711690A/en not_active Application Discontinuation
- 1977-10-26 BE BE182086A patent/BE860139R/en not_active IP Right Cessation
- 1977-10-26 CA CA289,550A patent/CA1085855A/en not_active Expired
- 1977-10-26 FR FR7733111A patent/FR2378762A2/en active Granted
- 1977-10-26 ES ES463557A patent/ES463557A2/en not_active Expired
- 1977-10-27 JP JP12915777A patent/JPS5392783A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| GB1593851A (en) | 1981-07-22 |
| NL7711690A (en) | 1978-05-02 |
| JPS5392783A (en) | 1978-08-15 |
| ES463557A2 (en) | 1978-11-16 |
| CH625219A5 (en) | 1981-09-15 |
| FR2378762A2 (en) | 1978-08-25 |
| FR2378762B2 (en) | 1980-09-12 |
| BE860139R (en) | 1978-02-15 |
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