GB1574419A - Piperidine compounds - Google Patents
Piperidine compounds Download PDFInfo
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- GB1574419A GB1574419A GB4713977A GB4713977A GB1574419A GB 1574419 A GB1574419 A GB 1574419A GB 4713977 A GB4713977 A GB 4713977A GB 4713977 A GB4713977 A GB 4713977A GB 1574419 A GB1574419 A GB 1574419A
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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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Description
(54) PIPERIDINE COMPOUNDS
(71) We, ANPHAR S.A., a Spanish Body
Corporate of Calle Terida No. 9, Madrid,
Spain, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to new therapeutically useful piperidine derivatives, to processes for their preparation and pharmaceutical compositions containing them.
The new piperidine derivatives of the present invention are those compounds of the general formula:
[wherein R represents a halogen atom or a hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy or aralkyloxy (preferably phenyl(lower)alkyloxy, e.g. benzyloxy) group, or a lower acyloxy group in which the acyl moiety is derived from a carboxylic acid (preferably a lower alkanoyloxy, e.g. acetoxy, group): R' represents a hydrogen atom or an amino, lower alkylamino, di(lower)alkylamino or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid (preferably a lower alkanoylamino group), R2 represents a nitro or trifluoromethyl group, or a lower alkylthio group, or R1 and R2 together form a triazo group (i.e. --HNN-N==N-): R3 represents a hydrogen atom or a lower alkyl or lower alkenvl group. or a cycloalkyl or cycloalkenyl group having from 3 to 7 carbon atoms in the ring, or a phenyl group;
R4 represents a cycloalkenyl group having from 3 to 7 carbon atoms in the ring optionally substituted by a lower alkyl or lower alkenyl group; R5, R6 and R7 each represent a hydrogen atom, a lower alkyl, lower alkenyl (e.g. -CH2-CH=CH2) or a benzyl group, and W represents a single bond or a lower alkylene (e.g. -CR2- or -CR2. CR-) or lower alkenylene (e.g.
-CH=CM- or -CH2-CH=CR-) group] and pharmacologically acceptable acid addition, alkali metal, alkaline earth metal and quaternary ammonium salts thereof.
The qualification "lower" as applied herein to alkoxy, alkenyloxy, alkynyloxy, alkyl, alkenyl, alkylene, alkenylene, alkylthio, acyl, acyloxy and alkanoyl groups means that the group in question contains at most 6 carbon atoms. It is to be understood
that the cycloalkenyl groups within the definitions of R3 and R4 may have one, two or three double bonds as is appropriate for the number of carbon atoms in the ring. The cycloalkenyl groups may be, for example,
cyclopentenyl, cyclohexenyl and cycloheptenyl with one double bond present,
cyclohexadienyl (preferably cyclohexa
1,4 - dienyl optionally substituted by a
lower alkyl group), and cycloheptatrienyl.
Preferred compounds of general formula
I are those of the more specific formula:
[wherein R' represents a halogen (preferably chlorine) atom or a hydroxy, lower alkoxy (preferably methoxy or ethoxy), allyloxy, propargyloxy, acetoxy or benzyloxy group; R' represents a hydrogen atom, an amino group or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid (preferably acetamido) and R2' represents a nitro or methylthio group, or R'' and R2' together form a triazo group; R3' represents a hydrogen atom or a lower alkyl (preferably methyl) group; R4' represents a cyclohexenyl (preferably cyclohex - 3 - enyl) or a cyclohexadienyl (preferably cyclohexa - 1,4dienyl) group optionally substituted by a lower alkyl (preferably methyl) group, R5, R6' and R7' each represent a hydrogen atom or a lower alkyl (preferably methyl or ethyl) group and W' represents a methylene group or, preferably, a single bond] and pharmacologically-acceptable acid addition salts thereof.
Of outstanding importance are those compounds of general formula II wherein
R' represents a lower alkoxy (preferably methoxy or ethoxy), allyloxy or propargyloxy group, R'' represents an amino group, R2 represents a nitro group, R3' represents a hydrogen atom, R4' represents a cyclohex - 3 - enyl group or, preferably, a cyclohexa - 1,4 - dienyl group optionally substituted by a methyl group,
R5', R6' and R7' each represent a hydrogen atom, and W' represents a methylene group or, preferably, a single bond.
Especially preferred compounds of the present invention are N - (I - cyclohexa 1',4' - dienylmethylpiperid - 4- yl)- 2methoxy - 4 - amino - 5 - nitrobenzamide,
N - [1 - (2 - cyclohexa - 1',4' - dienylethyl)piperid - 4 - yl] - 2 methoxy - 4 - amino - 5 - nitrobenzamide, N - (1 - cyclohexa - l',4' - dienylmethylpiperid - 4 - yl) - 2 - ethoxy - 4 - amino 5 - nitrobenzamide, N - [1 - (4 - methylcyclohexa - 1,4 - dienyl)methylpiperid - 4 - yli - 2 - ethoxy - 4 - amino - 5 - nitrobenzamide and N - [1 - (4 - methylcyclohexa - 1 A - dienyl) - methylpiperid - 4 yll - 2 - methoxy - 4 - amino - 5 - nitrobenzamide, and their pharmacologicallyacceptable acid addition salts.
According to a feature of the present invention, the compounds of general formula I are prepared by the process which comprises reacting a reactive derivative of a benzoic acid of the general formula:
(wherein R, R' and R2 are as hereinbefore defined) with a piperidine derivative of the general formula:
wherein the various symbols are as hereinbefore defined. The reactive derivative of the said benzoic acid may be a halide (preferably chloride), an alkyl ester (preferably methyl ester), an anhydride or a mixed an hydride.
The reaction is preferably carried out in the presence of an inert organic solvent, for example benzene, toluene, chloroform, tetrahydrofuran, N,N-dimethylformamide or dioxan, at a temperature between -5" and 120"C.
Halides of the benzoic acids of general formula III can be prepared by reaction of the acid with thionyl chloride or a phosphorus halide in the presence of an inert organic solvent such as benzene, toluene or a halogenated hydrocarbon.
Mixed anhydrides of the benzoic acids of general formula III can be prepared by the reaction of the acid with, for example, an alkyl chloroformate in the presence of an organic nitrogen-containing base, e.g. triethylamine, in an inert organic solvent, e.g. tetrahydrofuran, N,N-dimethylformamide or methylene chloride, and at a temperature between -20" and +25"C.
Esters and anhydrides of the benzoic acids of formula III, which may be employed as starting materials in the aforementioned process, can be prepared from the benzoic acids by methods known per se.
By the term methods known per se as used in this specification is meant methods heretofore used or described in the chemical literature.
The piperidine derivatives of general formula IV wherein R7 is a hydrogen atom can be prepared by reduction of corresponding 4-piperidone oximes with lithium aluminium hydride in the presence of diethyl ether or tetrahydrofuran. The piperidine derivatives of general formula IV wherein R3 or/and R4 is or are a cyclohexadienyl group can be prepared from the corresponding compounds of general formula IV wherein R3 or/and R4 is or are a phenyl group by reduction with lithium in liquid ammonia or a lower alkylamine. The piperidine derivatives of general formula IV wherein R7 is a lower alkyl, a lower alkenyl or a benzyl group can be prepared from the corresponding N-acyl substituted compounds by reduction of the carbonyl group therein to methylene using lithium aluminium hydride.
Other piperidine derivatives of general formula IV can be prepared by methods
known per se.
The piperidine derivatives of general
formula I are also prepared, according to a
further feature of the invention, by the direct reaction of a benzoic acid of general formula III wfth a piperidine derivative of general formula IV in the presence of an
appropriate dehydrating agent. Such agents are silicon tetrachloride, a mono-, di- or trialkylsilyl chloride, titanium tetra
chloride, N,N'-dicyclohexylcarbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene - p sulphonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent. The reaction is carried out in an inert organic solvent, e.g. methylene chloride, acetone, pyridine, ethyl acetate or dioxan, at a temperature between 20 and I 1 0 C.
The piperidine derivatives of general formula I wherein R represents a hydroxy group are prepared, according to a further feature of the invention, from the corresponding O-methylated derivatives of general formula I (viz. R represents a methoxy group) by the process which comprises the reaction- of such compounds with boron tribromide or aluminium trichloride using methylene chloride or benzene as solvent medium at a temperature between 20 and 800 C. The O- methylated compounds employed as starting materials in this process may be prepared by processes hereinbefore described using starting materials in which
R represents a methoxy group.
The piperidine derivatives of general formula I wherein R represents a hydroxy group are also prepared, according to a still further feature of the invention, from the corresponding O-acylated derivatives of general formula I, viz. R represents an acyloxy group. In this case the O-acylated derivatives are hydrolysed with dilute hydrochloric acid or with sodium or potassium hydroxide in an aqueousalcoholic solution at a temperature between 20 and 90"C.
In the preparation of those compounds of general formula I wherein the symbol R' represents an amino group, it is sometimes advisable to use as starting material corresponding compounds in which the amino group is protected by an acyl group, the acyl protecting group preferably being acetyl, chloroacetyl, trifluoroacethyl or phthaloyl. After the reaction the N-acylated intermediate products are subjected to acid or alkaline hydrolysis to give the corresponding compounds of general formula I in which R represents an amino group. Acid hydrolysis of the N-acylated compound may be carried out by heating with dilute hydrochloric acid, preferably at the boiling point of the reaction mixture, while alkaline hydrolysis is preferably carried out at a temperature between 20 and 90"C with sodium or potassium hydroxide in an aqueous-alcoholic solution.
The piperidine derivatives of general formula I have as their principal pharmacological properties the ability to antagonise the effects of dopamine or dopaminergic agents of endogenous or exogenous origin and to cause stimulation of serotoninergic mechanisms. In those circumstances where homeostatic control is a balance between dopaminergic and serotoninergic mechanisms these two actions are synergistic and the precise contribution of each one to the final biologicaal response is difficult to determine. As a group they have exhibited activities which may be considered beneficial in the treatment of a variety of cerebral malfunctions as well as obesity and gastrointestinal disturbances in mammals, including man. Their characteristic properties in experimental animals are antagonism of the effects of dopaminergic agents such as apomorphine, induction of catatonia, production of local anaesthesia, stimulation of gastrointestinal transit and induction of both spasmogenic and spasmolytic effects on smooth muscle according to the initial resting tone.
Nevertheless, as within the series antidopaminergic, serotoninergic and local anaesthetic potency do not necessarily run in parallel, the clinical applications of the various derivatives may well be different. As a group they may be useful in the treatment of a variety of conditions affecting the central nervous system such as acute and chronic psychosis, manic psychosis, schizophrenias, serious disturbances of behaviour and nonmelancholic depressive states and migraine, and be effective in the treatment of nausea and vomiting of diverse origin such as that resulting from gastrointestinal disorders, congestive heart failure and post-operative conditions, as well as in the treatment of other ;gastrointestinal disorders such as dyspepsia, flatulance, bile regurgitation, hiatus hernia, peptic ulcer, reflux oesophagitis, gastritis, duodenitis and cholelithiasis. They may also be useful in the treatment of obesity and allied conditions where the administration of an appetite suppressants is warranted.
For therapeutic purposes the compounds of general formula I may be employed in the form of biologically and pharmacologically acceptable inorganic or organic acid addition salts such as sulphates, hydrohalides (e.g. hydrochlorides), phosphates, lower alkanesulphonates, arylsulphonates, and- salts of aliphatic or aromatic acids containing from 1 to 20 carbon atoms which may contain one or more double bonds, or other functional group such as hydroxy, lower alkoxy, amino or keto. e.g. fumarates.
The piperidine derivatives of general formula I wherein R represents a hydroxy group may also form pharmacologicallyacceptable salts with alkali or alkaline earth metals, which salts are formed by reaction of the derivatives of formula I wherein R is a hydroxy group with an alkali metal or alkaline earth metal carbonate or hydroxide using water, methanol or ethanol, as solvent at a temperature between 40 and 100"C.
They may also be used for therapeutic purposes in the form of pharmacologicailyacceptable quaternary ammonium salts such as those salts formed by reaction of the compounds of general formula I with lower alkyl halides or sulphates.
The pharmacologically-acceptable acid addition salts and quaternary ammonium salts of the compounds of general formula I may be prepared by methods known per se.
Also included within the scope of the present invention are pharmaceutical compositions which comprise, as active ingredient, at least one compound of general formula I, or a pharmacologically acceptable acid addition salt, alkali metal or alkaline earth metal salt or quaternary ammonium salt thereof, in association with a pharmaceutically acceptable carrier or diluent. Preferably the compositions are made up in a form suitable for oral, topical, percutaneous or parenteral administration.
The pharmaceutically acceptable carriers or diluents which are admixed with the active compound, or compounds, or salts of such compounds, to form the compositons of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Compositions of this invention are preferably adapted for administration per os. In this case, the compositions for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing one or more compounds of the invention; such preparations may be made by methods well known in the art.
The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents. if desired. Tablets or capsules may conveniently contain between 0.1 and 20 mg, and preferably from 0.1 to 5 mg, of active ingredient or the equivalent amount of an acid addition, alkali or alkaline earth metal, or quaternary ammonium salt thereof.
The liquid compositions adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or an acid addition, alkali metal or alkaline earth metal or quaternary ammonium salt thereof in association with water, together with a suspending agent or flavouring agent.
Compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injection fluid.
The compounds of general formula I or salts thereof may be mixed with other active anti-acid and anti-ulcer agents (excluding anti-cholinergic agents) for oral or, in appropriate cases, for parenteral use.
Useful dosages of the compounds of general formula I for tranquillizing, antiemetic and other gastrointestinal indications appear to lie between 0.5 and 50 mg per day.
The following Examples illustrate the preparation of piperidine compounds of the present invention.
EXAMPLE 1
To a solution of 2- methoxy - 4amino - 5 - nitrobenzoic acid (4.2 g; 0.02 moles) in N,N - dimethylformamide (400 ml) a solution of triethylamine (2.78 ml; 0.02 moles) in N,N-dimethylformamide (5 ml) was added. The mixture was cooled to -5" to -10"C and a solution of ethyl chloroformate (2.2 g; 0.02 moles) in tetrahydrofuran (5 ml) was added. The reaction mixture was stirred at the same temperature for 2 hours and then a solution of 1 - cyclohexa - 1',4' - dienylmethyl - 4 aminopiperidine (3.84 g; 0.02 moles) in tetrahydrofuran (15 ml) was added. After stirring for I hour at -50 to -100C, the temperature was allowed to reach room
temperature overnight. The solvent was removed in vacuo and the residue was poured into an aqueous sodium bicarbonate solution. The resulting solid was exhaustively extracted with methylene chloride, the organic layers washed with an aqueous sodium bicarbonate solution and then with water, dried (Na2SO4) and the solvent removed in vacuo. N - (1 - Cyclohexa - 1',4' - dienylmethylpiperid 4 - yl) - 2 - methoxy - 4 - amino - 5
nitrobenzamide (4.7 g) was obtained and
converted into its hydrochloride bv treatment with a saturated solution of ethanolic hydrogen chloride; the hydrochloride melted at 192 -194 C (dec).
The following compounds were prepared in a similar manner: N - [1 - (I - cyclohexa - 1',4' - dienylethyl)piperid - 4 - yl] - 2 - methoxy - 4 amino - 5 - nitrobenzamide, the hydrochloride of which melts at 219 - 221 C;
N - methyl - N - (1 - cyclohexa - l',4' dienylmethylpiperid - 4 - yl) - 2 methoxy - 4 - amino - 5 - nitrobenzamide, the fumarate of which melts at 205 -207 C (dec); N - (1 - cyclohexa -1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 acetamido - 5 - nitrobenzamide, the fumarate of which melts at 1840--1860C; N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4,5 azimidobenzamide, the fumarate of which melts at 178 -180 C (dec); N - (1 - cyclohexa - l'A' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 5 nitrobenzamide, the fumarate of which melts at 161-163 C; N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - ethoxy - 4 amino - 5 - nitrobenzamide, the fumarate of which melts at 212 -214 C (dec);
N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - allyloxy - 4 amino - 5 - nitrobenzamide, the fumarate of which melts at 198 -200 C; N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - propargyloxy 4- amino - 5 - nitrobenzamide, the fumarate of which melts at 198 -200 C (dec); N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - chloro - 4 amino - 5 - nitrobenzamide, the fumarate of which melts at 201 -203 C (dec); bis[N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - benxyloxy 5 - (methylthio)benzamide] fumarate, m.p.
154 -156 C; N - ( I - cyclohex - 3' - enylmethylpiperid - 4 - yl) - 2 - methoxy - 5 nitrobenzamide, the fumarate of which melts at 201 -203 C;
N - (1 - cyclohex - 3' - enylmethylpiperid - 4 - yl) - 2 - methoxy - 4 acetamido - 5 - nitrobenzamide the fumarate of which melts at 204 -206 C (dec); N - (1 - cyclohex - 3' - enylmethylpiperid - 4 - yl) - 2 - methoxy - 4amino - 5 - nitrobenzamide, the fumarate of which melts at 220 -222 C;
N - [1 - (4 - methylcyclohexa - 1,4 dienyl)methylpiperid - 4 - yl] - 2 - chloro 4 - amino - 5 - nitrobenzamide, the fumarate of which melts at 219 -221 C (dec):
bis{N - [1 - (4 - methylcyclohexa - 1,4
dienyl)methylpiperid - 4 - yli - 2
allyloxy - 4 - amino - 5 - nitrobenzamide) fumarate, m.p. 197-199 C (dec); N - [1 - (4 - methylcyclohexa - 1,4
dienyl)methylpiperid - 4- yl] - 2
ethoxy - 4 - amino - 5 - nitrobenzamide,
the fumarate of which melts at 220-222 C (dec); N - [1 - (4 - methylcyclohexa - 1,4
dienyl)methylpiperid - 4 - yl] - 2
methoxy - 5 - nitrobenzamide, the
fumarate of which melts at 148 -150 C;
N - [1 - (4 - methylcyclohexa - 1,4
dienyl)methylpiperid - 4 - yl] - 2
methoxy - 4 - amino - 5 - nitrobenzamide, the fumarate of which melts at 225 -227 C (dec): N - [1 - (4 - methylcyclohexa - 1,4
dienyl)methylpiperid - 4 - yl] - 2
propargyloxy - 4 - amino - 5
nitrobenzamide, m.p. 185 -187 C; N - (1 - cyclohexa - 1',4' - dienyl
methylpiperid - 4 - yl) - 2 - hydroxy - 4
amino - 5 - nitrobenzamide, the fumarate
of which melts at 233 -225 C dec);
N- (1 - cyclohexa - 1',4' - dienyl
methylpiperid - 4 - yl) - 2 - acetoxy - 4
acetamido - 5 - nitrobenzamide, m.p.
218 -220 C (dec); N - [1 - (2 - cyclohexa - 1',4' - dienyl
ethyl)piperid - 4 - yl] - 2 - methoxy - 4
amino - 5 - nitrobenzamide, m.p. 215 -
217 C; N - [1 - (2 - cyclohexa - 1',4' - dienyl
ethyl)piperid - 4 - yl] - 2 - ethoxy - 4
amino - 5 - nitrobenzamide, m.p. 200
202 C; N - [1 - (2 - cyclohexa - l',4' - dienyl
ethyl)piperid - 4 - yl] - 2 - propargyloxy
4- amino - 5 - nitrobenzamide, m.p.
163 -165 C;
N - ( - - cyclohex - 3' - enylmethyl
piperid - 4 . yl) - 2 - allyloxy - 4 - amino
5 - nitrobenzamide, m.p. 190 -192 C;
N - (1 - cyclohex - 3' - ethylmethyl
piperid - 4 . yl) - 2 - ethoxy - 4 - amino
5 - nitrobenzamide, the fumarate of which
melts at 227 -229 C (dec);
N - ( - - cyclohexa - 1',4' - dienyl methyl - 3 - methylpiperid - 4 - yl) - 2 - methoxy - 4 - amino - 5 - nitrobenzamide, the fumarate of which melts at 192 -194 C
(dec), and
N - ethyl - N - (1 - cyclohexa - 1',4'
dienylmethylpiperid - 4 - yl) - 2
methoxy - 5 - nitrobenzamide, the hydrochloride of which melts at 232 -
234 C (dec).
The fumarates mentioned above were
obtained by adding fumaric acid in
stoichiometric amount to a hot ethanolic
solution of the piperidine base. The
resulting hot solution was cooled and the
fumarate crystallizes.
EXAMPLE 2
A mixture of N - (1 - cyclohexa - 1',4' dienylmethyl - piperid - 4 - yl) - 2acetoxy - 4- acetamido - 5- nitrobenzamide (3.5 g; 0.007 moles) [prepared by the procedure described in Example 11, sodium hydroxide (0.75 g; 0.0155 moles), water (65 ml) and ethanol (35 ml) was boiled under reflux for 3 hours. Then the mixture was diluted with water, neutralized with dilute hydrochloric acid and the solid filtered off, washed with water and diethyl ether to give 2.6 g of N - (1 cyclohexa - 1',4' - dienylmethylpiperid 4 - yl) - 2 - hydroxy - 4 - acetamido - 5 nitrobenzamide, m.p. 2150-2170C (dec).
EXAMPLE 3
A mixture of N - (1 - cyclohexa - 1',4' dienylmethyl - piperid - 4- yl) - 2hydroxy - 4 - acetamido - 5 nitrobenzamide (2.1 g; 0.0050 moles)
[prepared as described in Example 2],
sodium hydroxide (0.40 g; 0.01 moles) water (50 ml) and ethanol (25 ml) was boiled under reflux for 3 hours. Then the mixture was diluted with water, neutralized with dilute hydrochloric acid and the precipitate collected by filtration. This precipitate was washed with water and then with diethyl ether to give 1.8 zg of N - (1 - cyclohexa
1',4' - dienylmethylpiperid - 4 - yl) - 2 - hydroxy - 4 - amino - 5 - nitrobenzamide.
This compound was treated with fumaric acid by the procedure described at the end of Example 1 to give the N - (1 cyclohexa - I ',4' - dienylmethylpiperid - 4 - yl) - 2 - hydroxy - 4 - amino - 5nitrobenzamide fumarate, m.p. 2330-- 235"C (dec).
EXAMPLE 4
A mixture of N - (1 - cyclohex - 3' enylmethylpiperid - 4 - yl) - 2 - methoxy 4 - acetamido - 5 - nitrobenzamide (4.3 g; 0.01 mole) [prepared by the procedure described in Example 1], concentrated hydrochloric acid (5 ml), methanol (40 ml) and water (40 ml) was boiled under reflux for 2 hours. The methanol was removed in vacuo and the mixture made alkaline with an aqueous sodium bicarbonate solution. The solid was filtered off and N - (1 cyclohex - 3' - enylmethylpiperid - 4yl) - 2 - methoxy - 4 - amino - 5 - nitrobenzamide (3.5 g) was obtained. The fumarate was prepared by the procedure described at the end of Example 1, m.p.
220"--222"C EXAMPLE 5
A suspension of N - (1 - cyclohexa l',4' - dienylmethyl - piperid - 4 - yl) - 2 acetoxy - 4 - acetamido - 5 nitrobenzamide (4.56 g; 0.01 mole) [prepared by the procedure described in
Example 1] in ethanol (30 ml), concentrated hydrochloric acid (4.5 ml) and water (60 ml) was boiled under reflux for 2 hours. The mixture was diluted with water, made alkaline with sodium bicarbonate and extracted with chloroform. The organic solution was dried (Na2SO4), the solvent removed in vacuo and the residue triturated with diethyl ether to give a solid which was treated with the stoichiometric amount of fumaric acid in hot ethanol. On cooling and further recrystallization from ethanol, 3.1 g of N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - hydroxy - 4 amino - 5 - nitrobenzamide fumarate were obtained, m.p. 2330--2350C (dec).
EXAMPLE 6
A solution of N - (1 - cyclohexa - 1's4' dienylmethyl - piperid - 4 - yl) - 2methoxy - 4 - amino - 5 - nitrobenzamide (3.8 g; 0.01 mole) [prepared as described in
Example 1] in methylene chloride (70 ml) was added to another solution of boron tribromide (2.84 ml; 0.03 moles) in methylene chloride (20 ml). The mixture was stirred at room temperature for 24 hours and then poured into a mixture of a saturated solution of sodium bicarbonate in water (250 ml) and methylene chloride (100 ml). The decanted organic solution was dried and the solvent removed in vacuo to give a paste which was triturated with petroleum ether. The residue obtained was treated with the stoichiometric amount of fumaric acid in hot ethanol to give 3.2 g of N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - hydroxy - 4 - amino 5 - nitrobenzamide fumarate, m.p. 2330-- 235"C (dec).
EXAMPLE 7
N,N' - dicyclohexylcarbodiimide (4.12 g; 0.02 moles) and 1 - cyclohexa - 1',4' dienylmethyl - 4 - aminopiperidine (3.8 g; 0.02 moles) were added successively to a solution of 2 - methoxy - 4 - acetamido 5 - nitrobenzoic acid (5.1 g; 0.02 moles) in methylene chloride (125 ml). After stirring overnight at room temperature, the insoluble N,N' - dicyclohexylurea was filtered off, the solution was washed with water, dried (Na2SO4) and the solvent remov
EXAMPLE 8
A solution of 2 - methoxy - 4
acetamido - 5 - nitrobenzoyl chloride (8.2 g: 0.03 moles) dissolved in anhydrous tetra
hydrofuran (45 ml) was added little by little to another solution of I - cyclohexa
1',4' - dienylmethyl - 4 - aminopiperidine (5.25 g; 0.028 moles) and triethylamine (3.87 ml; 0.028 moles) in anhydrous tetrahydrofuran (45 ml) at room temperature. On completion of the addition, the mixture was left at room temperature with stirring overnight and then the mixture was concentrated in vacuo, poured into water and extracted with chloroform. The organic solution was dried (Na2SO4) and the solvent removed in vacuo.
The residue was suspended in hot methanol and treated with the stoichiometric amount of fumaric acid to give a solution from which N - (I - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 acetamido - 5 - nitrobenzamide fumarate (12.8 g) crystallized, m.p. 1840--1860C.
EXAMPLE 9
To a solution of N - (1 - cyclohexa
1',4' - dienylmethyl - piperid - 4 - yl) - 2
methoxy - 4 - amino - 5 - nitrobenzamide (1.2 g; 0.0031 moles) [prepared as described
in Example 1] in acetone (40 ml) and
chloroform (40 ml), methyl iodide (1.25 ml;
0.02 moles) was added. After stirring at
room temperature for 15 hours, the solid
was collected and washed with diethyl ether
to give 1.2 g of N - (1 - cyclohexa - 1',4'
dienylmethylpiperid - 4 - yl) - 2
methoxy - 4 - amino - 5 - nitrobenzamide methyl iodide. After recrystallization from a
mixture of water-methanol, it melts at 2l30-2l50C (dec).
The following Examples illustrate pharmaceutical compositions according to the invention.
EXAMPLE 10
50,000 capsules each containing 0.5 mg of N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4amino - 5 - nitrobenzamide hydrochloride were prepared from the following formulation:
N - (1 - cyclohexa - 1',4'
dienylmethylpiperid - 4
yl)- 2 - methoxy - 4
amino - 5- nitrobenz
amide hydrochloride 25 g citric acid 50 g magnesium stearate 5000 g lactose spray dried 11175 g
Pluronic F-68 ("Pluronic is a
registered Trade Mark) 2000 g sodium lauryl sulphate 1750 g
Procedure
The N - (I - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide, citric acid, sodium lauryl sulphate, lactose and Pluronic
F-68 were mixed together and passed through a screen with an opening of 0.6 mm.
The magnesium stearate was added and the mixture encapsulated into gelatine capsules of appropriate size.
EXAMPLE 11
100,000 tablets each containing 1 mg of N - (1 - cyclohexa - l',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide hydrochloride were prepared from the following formulation:
N - (1 - cyclohexa - 1',4'
dienylmethylpiperid - 4
yl) - 2 - methoxy - 4
amino - 5 - nitrobenz
amide hydrochloride 100 g microcrystalline cellulose 1850 g lactose spray dried 9820 g carboxymethyl starch 570 g sodium stearyl fumarate 80 g colloidal silicon dioxide 80 g
Procedure
All the powders were passed through a screen with an opening of 0.6 mm. They were then all mixed in a suituble mixer for 30 minutes and compressed into 125 mg tablets using 6 mm discs and flat bevelled punches. The disintegration time of the tablets was about 60 seconds.
EXAMPLE 12
10,000 suppositories each containing 1 mg of N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide hydrochloride were prepared as follows:
N - (1 - cyclohexa - 1',4'
dienylmethylpiperid - 4
yl)- 2 - methoxy - 4
amino - 5 - nitrobenz
amide hydrochloride 10 g theobroma oil 19990 g
Procedure
The theobroma oil was melted and the active compound suspended in it. The mixture was then poured into appropriate suppository moulds to make 2.0 g suppositories.
EXAMPLE 13
50,000 ampoules each containing 0.5 mg of N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide hydrochloride were prepared from the following formulation: N - (I - cyclohexa - 1',4' dienylmethylpiperid - 4
yl) - 2 - methoxy - 4
amino - 5 - nitrobenz
amide hydrochloride 25 g sodium chloride 500 g water injectable grade q.s. 100 litres
Procedure
The N - (I - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide hydrochloride and the sodium chloride were dissolved in approximately 80 litres of water with slight heating. The solution was diluted with water to 100 litres passed through a bacteriaretaining filter and filled into 2 ml glass ampoules in known manner.
The production of the injectable solution
can take place under sterile conditions. It is also possible to work under normal conditions and then to heat-sterilize the filled ampoules.
EXAMPLE 14
1,000 bottles (capacity 150 ml) each containing 15 mg of N - (1 - cyclohexa 1',4' - dienylmethylpiperid - 4 - yl) - 2 methoxy - 4 - amino - 5 - nitrobenzamide hydrochloride were prepared as follows: N - (1 - cyclohexa - I ',4' - dienylmethylpiperid - 4
yl) - 2 - methoxy - 4
amino - 5 - nitrobenz
amide hydrochloride 15 g sorbitol 70000 g sorbic acid 125 g citric acid 125 g distilled water q.s. 150 litres flavouring agent q.s.
Procedure
The N - (I - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide hydrochloride and the sorbic acid were dissolved in 100 litres of water and then the sorbitol, citric acid and flavouring agent were added with stirring until dissolution. The mixture was diluted to 150 litres and divided amongst the bottles.
Similar compositions to those described in Examples 10 to 14 can be prepared having as the active ingredient piperidine derivatives of general formula I other than N - (1 - cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide. for example other products conforming to that formula mentioned at the end of Example 1 or in
Examples 2 to 9.
Claims (33)
1. Piperidine derivatives of the general formula:
(wherein R represents a halogen atom or a hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy or aralkyloxy group, or a lower acyloxy group in which the acyl moiety is derived from a carboxylic acid, R' represents a hydrogen atom or an amino, lower alkylamino, di(lower)alkylamino or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, and R2 represents a nitro or trifluoromethyl group. or a lower alkylthio group, or R1 and
R2 together form a triazo group; R3 represents a hydrogen atom or a lower alkyl or lower alkenyl group, or a cycloalkyl or cycloalkenyl group having from 3 to 7 carbon atoms in the ring, or a phenyl group;
R4 represents a cycloalkenyl group having from 3 to 7 carbon atoms in the ring optionally substituted by a lower alkyl or lower alkenyl group; R5, R6 and R7 each represent a hydrogen atom, a lower alkyl, lower alkenyl or a benzyl group, and W represents a single bond or a lower alkylene or lower alkenylene group) and pharmacologically-acceptable acid addition and quaternary ammonium salts thereof and when R is a hydroxy group-alkali metal and alkaline earth metal salts thereof.
2. Piperidine derivatives according to claim 1 of the general formula:
(wherein R' represents a halogen atom or a hydroxy, lower alkoxy, allyloxy, propargyloxy, acetoxy or benzyloxy group; R" represents a hydrogen atom, an amino group or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, and R2' represents a nitro or methylthio group, or R" and R2' together form a triazo group; R3' represents a hydrogen atom or a lower alkyl group: R4' represents a cyclohexenyl or cyclohexadienyl group optionally substituted by a lower alkyl group. Ras', R6, and R7' each represent a hydrogen atom or a lower alkvl group and WZ represents a single bond or a methylene group) and pharmacologicallyacceptable acid addition salts thereof.
3. Piperidine derivatives according to claim 1 or 2 wherein W or W' represents a single bond.
4. Piperidine derivatives according to claim 1, 2 or 3 wherein R4' represents the cyclohexa - 1,4 - dienyl group optionally substituted by a lower alkyl group.
5. Piperidine derivatives according to claim 2 wherein R' represents a lower alkoxy, allyloxy or propargyloxy group, R" represents an amino group, R2' represents a nitro group, R3' represents a hydrogen atom, R4' represents a cyclohex - 3 - enyl or cyclohexa - 1,4 - dienyl group optionally substituted by a methyl group, R5', R6' and R7' each represent a hydrogen atom, and W' represents a single bond or a methylene group, and pharmacologically-acceptable acid addition salts thereof.
6. Piperidine derivatives according to claim 5 wherein R' represents the methoxy or ethoxy group.
7. Piperidine derivatives according to claim 5 or 6 wherein W' represents a single bond.
8. N - (1 - Cyclohexa - 1',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide.
9. N - [1 - (2 - Cyclohexa- 1',4' - dienylethyl)piperid - 4 - yl] - 2 - methoxy - 4 - amino - 5 - nitrobenzamide.
10. N - (1 - Cyclohexa - l',4' - dienylmethylpiperid - 4 - yl) - 2 - ethoxy - 4 amino - 5 - nitrobenzamide.
11. N - [1 - (4 - Methylcyclohexa - 1,4 dienyl)methyl - piperid - 4 - yl] - 2ethoxy - 4 - amino - 5 - nitrobenzamide.
12. N - [1 - (4 - Methylcyclohexa - 1,4 dienyl)methyl- piperid - 4 - yl] - 2 methoxy - 4 - amino - 5 - nitrobenzamide.
13. A piperidine derivative conforming to the general formula specified in claim 1 mentioned at the end of Example 1 and other than a compound claimed in claims 8 to 12.
14. The piperidine derivatives conforming to the general formula specified in claim 1 obtained as the product of Example 2 or 3.
15. Ph armacologically-acceptable acid addition salts of a piperidine derivative as claimed in any one of claims 8 to 14.
16. Pharmacologically-acceptable quaternary ammonium salts of a piperidine derivative as claimed in any one of claims 8 to 14.
17. Pharmacologically-acceptable alkali metal and alkaline earth metal salts of a piperidine derivative as claimed in claim 14.
18. N - (1 - Cyclohexa - l',4' - dienylmethylpiperid - 4 - yl) - 2 - methoxy - 4 amino - 5 - nitrobenzamide methyl iodide.
19. Process for the preparation of a piperidine derivative as claimed in claim 1 which comprises reacting a reactive derivative of a benzoic acid of the general formula:
(wherein R, R' and R2 are as defined in claim i) with a piperidine derivative of the general formula:
wherein the various symbols are as defined in claim 1.
20. Process according to claim 19 in which a halide, alkyl ester, anhydride or a mixed anhydride of the benzoic acid is used.
21. Process according to claim 19 or 20 in which the reaction is carried out in the presence of an inert organic solvent at a temperature between -5" and 1200C.
22. Process for the preparation of a piperidine derivative as claimed in claim 1 which comprises reacting a benzoic acid of general formula III depicted in claim 19 with a piperidine derivative of general formula IV depicted in claim 19 in the presence of a dehydrating agent in an inert organic solvent at a temperature between 20 and 110 C.
23. Process for the preparation of a piperidine derivative of the general formula depicted in claim 1 wherein R represents a hydroxy group which comprises reacting a corresponding compound of that formula but wherein R represents a methoxy group with boron tribromide or aluminium trichloride using methylene chloride or benzene as solvent medium at a temperature between 20 and 80 C to convert the methoxy group to hydroxy.
24. Process for the preparation of a piperidine derivative of the general formula depicted in claim 1 wherein R represents a hydroxy group which comprises subjecting a corresponding compound of that formula wherein R represents an acyloxy group to acid or alkaline hydrolysis with dilute hydrochloric acid, or with sodium or potassium hydroxide in aqueous alcoholic solution, at a temperature between 20 and 90"C.
25. Process according to any one of claims 19 to 22 for the preparation of a piperidine derivative of the general formula depicted in claim 1 wherein R' represents an amino group in which the amino group of the benzoic acid reactant of general formula
III depicted in claim 19 is protected by an acyl group, and after the reaction with the piperidine derivative of general formula IV depicted in claim 19 the protecting acyl group of the N-acylated intermediate product is removed by acid or alkaline hydrolysis to give a corresponding compound of the general formula depicted in claim I wherein R' represents an amino group.
26. Process according to any one of claims 19 to 25 followed by the step of converting by a method known per se a piperidine derivative of the general formula depicted in claim 1 thus obtained into a pharmacologically-acceptable acid addition salt.
27. Process according to any one of claims 19 to 25 followed by the step of converting by a method known per se a piperidine derivative of the general formula depicted in claim 1 wherein R represents a hydroxy group into a pharmacologicallyacceptable alkali metal or alkaline earth metal salt.
28. Process according to any one of claims 19 to 25 followed by the step of converting by a method known per se a piperidine derivative of the general formula depicted in claim 1 thus obtained into a pharmacologically-acceptable quaternary ammonium salt.
29. Process for the preparation of a piperidine derivative of the general formula depicted in claim 1, and acid addition, alkali metal, alkaline earth metal and quaternary ammonium salts thereof, substantially as hereinbefore described with especial reference to any one of Examples 1 to 9.
30. Piperidine derivatives of the general formula depicted in claim 1, and acid addition, alkali metal, alkaline earth metal and quaternary ammonium salts thereof, when prepared by a process claimed in any one of claims 19 to 29.
31. A pharmaceutical composition which comprises, as active ingredient, a piperidine derivative as claimed in any one of claims 1 to 14, or a pharmacologically-acceptable acid addition, alkali metal, alkaline earth metal or quaternary ammonium salt thereof, in association with a pharmaceuticallyacceptable carrier or diluent.
32. A pharmaceutical compositon according to claim 31 substantially as hereinbefore described.
33. A pharmaceutical composition according to claim 31 substantially as hereinbefore described in any one of
Examples 10 to 14.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB4713977A GB1574419A (en) | 1977-11-11 | 1977-11-11 | Piperidine compounds |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB4713977A GB1574419A (en) | 1977-11-11 | 1977-11-11 | Piperidine compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1574419A true GB1574419A (en) | 1980-09-03 |
Family
ID=10443877
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB4713977A Expired GB1574419A (en) | 1977-11-11 | 1977-11-11 | Piperidine compounds |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB1574419A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004110995A1 (en) * | 2003-06-17 | 2004-12-23 | Pfizer Limited | N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors |
CN105367486A (en) * | 2015-12-16 | 2016-03-02 | 成都欣捷高新技术开发股份有限公司 | New impurity of cinitapride tartrate and preparation method and application thereof |
-
1977
- 1977-11-11 GB GB4713977A patent/GB1574419A/en not_active Expired
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004110995A1 (en) * | 2003-06-17 | 2004-12-23 | Pfizer Limited | N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors |
EA009881B1 (en) * | 2003-06-17 | 2008-04-28 | Пфайзер Инк. | N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors |
US7378436B2 (en) | 2003-06-17 | 2008-05-27 | Pfizer Inc. | Compounds |
CN105367486A (en) * | 2015-12-16 | 2016-03-02 | 成都欣捷高新技术开发股份有限公司 | New impurity of cinitapride tartrate and preparation method and application thereof |
CN105367486B (en) * | 2015-12-16 | 2019-06-18 | 成都欣捷高新技术开发股份有限公司 | A kind of new impurity of cinbitrate tartrate and its preparation method and application |
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Legal Events
Date | Code | Title | Description |
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PS | Patent sealed | ||
704A | Declaration that licence is not available as of right for an excepted use (par. 4a/1977) | ||
732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
PE20 | Patent expired after termination of 20 years |
Effective date: 19971110 |