CA1094059A - Piperidine derivatives - Google Patents
Piperidine derivativesInfo
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- CA1094059A CA1094059A CA271,918A CA271918A CA1094059A CA 1094059 A CA1094059 A CA 1094059A CA 271918 A CA271918 A CA 271918A CA 1094059 A CA1094059 A CA 1094059A
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
ABSTRACT OF THE DISCLOSURE
Piperidine derivatives, and process for their prepar-ation of formula:
1 wherein R represents a lower alkoxy or lower alkenyloxy group;
R1 and R2, which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkyl-amino, di(lower)alkylamino, lower alkylsulphonyl or lower alkyl-sulphamoyl group, or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, the halogen atom or group represented by the symbol R1 being in the 3- or 4-position of the phenyl ring, with the proviso that R1 and R2 do not both represent hydrogen atoms; R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a cycloalkyl group having from 3 to 7 carbon atoms in the ring optionally substituted by an alkyl group containing 1 to 3 carbon atoms, or R4 represents an adamantyl group; and pharmaceutically-acceptable acid add-ition salts and quaternary ammonium derivatives and N-oxides thereof. These compounds find use as agents to antagonize the effects of dopamine, and dopaminergic agents of endogenous or exogenous origin.
Piperidine derivatives, and process for their prepar-ation of formula:
1 wherein R represents a lower alkoxy or lower alkenyloxy group;
R1 and R2, which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkyl-amino, di(lower)alkylamino, lower alkylsulphonyl or lower alkyl-sulphamoyl group, or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, the halogen atom or group represented by the symbol R1 being in the 3- or 4-position of the phenyl ring, with the proviso that R1 and R2 do not both represent hydrogen atoms; R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a cycloalkyl group having from 3 to 7 carbon atoms in the ring optionally substituted by an alkyl group containing 1 to 3 carbon atoms, or R4 represents an adamantyl group; and pharmaceutically-acceptable acid add-ition salts and quaternary ammonium derivatives and N-oxides thereof. These compounds find use as agents to antagonize the effects of dopamine, and dopaminergic agents of endogenous or exogenous origin.
Description
10~ 0~
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 inven-tion are those compounds of the general formula:
~ CONH ~ N-CH-R4 R ~
[wherein R represents a lower alkoxy or lower alkenyloxy group;
Rl and R2, which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkyl-10 amino) di~lower)alkylamino, lower alkylsulphonyl or lower alkyl-sulphamoyl group, or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, including halogen substituted carboxylic acids such as trifluoroacetic acid (pre-ferably a lower alkanoylamino group), the halogen atom or group represented by the symbol Rl being in the 3- or 4-position of the phenyl ring (preferably in the 4-position), with the proviso that R and R2 do not both represent hydrogen atoms; R3 repre-sents a hydrogen atom or a lower alkyl group, and R4 represents a cycloalkyl group having from 3 to 7 carbon atoms in the ring optionally substituted by an alkyl group containing 1 to 3 car-bon atoms, or R4 represents an adamantyl group;] and pharmaceut-ically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides thereof.
The qualification "lower" as applied in this specification to alkoxy, alkenyloxy, alkyl, acyl and alkanoyl groups means that the group in question contains at most 6 carbon atoms.
10~40S9 Preferred compounds of general formula I are those of the more specific formula:
R ~ CONH ~ N-13'R4' 11 R
[wherein R' represents a lower alkoxy ~preferably methoxy or ethoxy) or allyloxy group, Rl represents a hydrogen atom, or an amino, lower alkylamino (preferably methylamino), di(lower)-alkylamino (preferably dimethylamino) or a lower acylamino (preferably lower alkanoylamino, e.g. acetamido or trifluoro-acetamido) group, R2 represents a halogen (preferably chlorine or bromine) atom, or an amino, sulphamoyl or lower alkylsulphonyl (preferably methylsulphonyl) group, R3 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms (prefer-ably methyl) group, and R4 represents a cycloalkyl group option-ally substituted by a lower alkyl (preferably methyl) group] and pharmaceutically acceptable acid addition salts thereof.
Of outstanding importance are N-(l-cyclohexylmethyl-piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, N{l-cyclo-hexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide, N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, N-~l-cyclohexylmethylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide and N-(l-cyclohexylmethylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide, and their pharmaceutic-ally-acceptable acid addition salts.
According to a feature of the present invention, the piperidine derivatives of general formula I are prepared by the process which comprises reacting a reactive derivative r~
109~59 of a benzoic acid of the general formula:
Rl ~ COOH III
R
~wherein R, Rl and R2 are as hereinbefore defined) with a piperidine derivative of the general formula:
~ 1 4 2N ~ N-CH-R IV
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~, anhydride or a mixed anhydride, the N-imidazolamide or acid azide.
The reaction is preferably carried out in the presence of an inert organic solvent, for example benzene, toluene, chloroform, tetrahydrofuran or dioxan, at a temperature between -5 and 120C.
The piperidine derivatives of general formula IV can be prepared by reduction of corresponding piperid-4-one oximes with lit~ium aluminium hydride in the presence of diethyl ether or *etrahydrofuran, or by reductive amination of corresponding piperid-4-ones dissolved in an organic solvent~ e.g. an alcohol containing up to 6 carbon atoms, in the presence of Raney nickel or platinum as catalyst.
Halides of the benzoic acids of genera~ 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 sol-vent, e.g. tetrahydrofuran or methylene chloride, and at a temperature between -20 and +25C. Esters and anhydrides of the benzoic acids of formula III, which may be employed as starting materials in the aforementioned process, can be pre-pared from the benzoic acids by methods known per se, as can also the N-imidazolamides or acid azides of the acids.
The piperidine derivatives of general formula I are also prepared, according to a further fea~ure of the invention, by the direct reaction of a benzoic acid of general formula III with a piperidine derivative of general formula IV in the presence of an appropriate dehydrating agent. Such agents are silicon tetrachloride, a mono-, di- or trialkyl-silyl chloride, titanium tetrachloride, N,N'-dicyclohexyl-carbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene-~-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 llo&.
In the preparation of those compounds of general formula I wherein the symbol(s) R and/or R represent(s) an amino group by the aforementioned processes, it is sometimes advisable to protect the amino group(s) of the A ~
lr~ ~ acid of general formula ~ or derivative thereof before reacting the compound with the piperidine derivative of general formula ~Y~ In this case an N-J~
acyl derivative of the amino-substituted benzoic acid of general formula is initially prepared, the acyl protecting group preferably being acetyl, chloroacetyl, trifluoroacetyl or phthalimido. After the reaction between the lLL
N-acylated compound of general formula ~ or reactive derivative thereof, with the piperidine derivative of general formula ~Y~ the corresponding N-acyl derivative of the compound of general formula I is obtained and that compound is then subjected to acid or alkaline hydrolysis to give the corresponding compound of general formula I in which R and/or R represent(s) 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 room temperature with sodium or potassium hydroxide in an aqueous-alcoholic solu-tion.
The piperidine derivatives of general formula I have as one of their principal pharmacological properties the ability to antagonize the effects of dopamine or dopaminergic agents of endogenous or exogenous origin. They have exhibited activities which may be considered beneficial in the treatment of gastrointestinal and cerebral malfunction in mammals, including man. They have also been shown to be capable of exerting anorectic properties. Their characteristic properties are an antagonism of the effects of the dopaminergic agent, apomorphine, in animals, local anaesthetic activity and the ability to induce catatonia in rats and mice. Consequently, they may be useful in the treatment of nausea and vomiting of diverse origin and as neuroleptic or tranquilizing agents. They may be useful for the treatment of nausea and vomiting resulting from gastrointestinal disorders, congestive heart failure, postoperative conditions, etc., other gastrointestinal disorders such as dyspepsia, flatulance, bile regurgitations, hiatus hernia, peptic ulcer, reflux aerophagitis, gastritis, duodenitis and cholethiasis, and a variety of conditions affecting the central nervous system such as acute and chronic psychosis, manical psychosis, schizophrenias, serious disturbances of behaviour and non-melancholic depressive states and migraine. They may also be useful in the treatment of obesity and allied conditions where the administration of an appetite supressant is warranted.
For therapeutic purposes the piperidine derivatives of general formula I may be employed in the form of non-toxic pharmaceutically-acceptable inorganic or organic acid addition salts such as sulphates, hydrohalides, phosphates, lower alkanesulphonates, arylsulphonates, salts of aliphatic mono-di- or tri-basic acids of from 1 to 20 carbon atoms which may contain one or more double bonds, an aryl nucleus or other functional group such as hydroxy, amino or keto; salts of aromatic acids in which the aromatic nucleus may optionally be substituted by groups such as hydroxy, lower alkoxy, amino, mono-S~,t lp~ah~
or di-(lower)aIkylamino and ~ -groups. They may also be employed in the form of pharmaceutically-acceptable quaternary ammonium salts such as those salts formed by reaction of the piperidine derivatives of general formula I with lower aIkyl halides or sulphates, or in the form of oxygenated derivatives in which oxygen is attached to the nitrogen atom of the piperidine n~cleus, viz. the N-oxides.
The pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides of the piperidine derivatives of general formula I may be prepared by methods known ~ se.
10~4059 Also included within the scope of the present invention are pharma-ceutical compositions which comprise, as active ingredient, at least one piperidine derivative of general formula I, or a non-toxic pharmaceutically-acceptable acid addition salt or quaternary ammonium derivative or N-oxide 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 ad-mixed with the active compound, or compounds, to form the compositions of this invention are well known ~ se and the actual excipients used depend inter a _ on the method of administering the compositions. Compositions of this invention are preferably adapted for administration ~ 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 composi-tions include those liquid and solid diluents which are compatible with the active ingredient, together with, if desired, colouring or flavouring agents.
Tablets or capsules may conveniently contain between 0.1 and ~0 mg of active ingredient or the equivalent amount of an acid addition salt or quaternary ammonium or N-oxide derivative 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 a water-insoluble active compound of the invention or an acid addition salt or quater-nary ammonium or N-oxide derivative thereof in association with water, 10940.~9 together with a suspending agent and flavouring agent.
Compositions for parenteral injection may be prepared from water-soluble salts, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injection fluid.
In another aspect of the invention, the compounds may be mixed ~ith other active anti-acid and anti-ulcer agents (excluding anticholinergic agents) for oral, or in appropriate cases, for parenteral use.
The following Reference ~xample and Examples illustrate the prepara-tion of piperidine derivatives of general formula I.
(a) A solution of l-cyclohexylmethylpiperid ~-one oxime (37.8 g; 0.18 moles) dissolved in anhydrous diethyl ether (250 ml) was added little by little to a suspension of lithium aluminium hydride (14.04 g; 0.36 moles) in anhydrous diethyl ether (200 ml.). On completion of the addition, the resultant mixture was heated to the boiling point and maintained there under reflux for 12 hours and then thoroughly cooled whilst water (14 ml), 15~ (w/v) aqueous sodium hydroxide solution (14 ml) and water (42 ml) wer~ added successively. The mixture was filtered and the ethereal solution was dried (Na2S04) and the solvent removed in vacuo. The product l-cyclohexylmethyl 1-aminopiperidine (31 g) was isolated as a viscous liquid, b.p. 105 -110 & /0,3 mm Hg.
In a similar r.lanner, using appropriate oximes as starting materials, there were also prepared:
l-cyclopentylmethyl-4-aminopiperidine, b.p. 90 -92 & /0.45 mm Hg;
l_cyclobutylmethyl ~-aminopiperidine, b.p. 70 -71 C/0.05 mm Hg;
l-(l-adamantylmethyl)-4-aminopiperidine, m~p. 76 -79 C, and 1-(4-methylcyclohexylmethyl) ~-aminopiperidine, b.p. 127 -130 C/4 mm Hg.
(b) A solution of 1 cyclohexylmethylpiperid ~-one (65 g; 0.33 moles)in a saturated ethanolic solution of ammonia (350 ml) was hydrogenated in the presence of Raney nickel catalyst (6.5 g) at 75 C and 13 atmospheres for 3.5 10~40~9 hours. The mixture was cooled, the catalyst filtered off and the solvent removed by distillation in vacuo. The residue was treated with a saturated ethanolic solution of hydrogen chloride, and the insoluble dihydrochloride was filtered off, treated with an aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was dried (Na2S04) and the solvent removed in vacuo giving l-cyclohexylmethyl-4 aminopiperidine (45.5 g) as a viscous liquid, b.p. 105 - 110 & /0.3 mm Hg.
Also prepared in a similar manner were:
l_cycloheptylmethyl_4_aminopiperidine, b.p. 101- 102 C/0.15 mm Hg, and 1-cyclobutylmethyl-4-aminopiperidine, b.p. 70 - 71 & /0.05 mm Hg.
E~AMPLE 1 Triethylamine (5.6 ml; 0.04 moles) and ethyl chloroformate (3.84 ml;
0.04 moles~ were added successively to a stirred suspension of 2-methoxy-4-amino-5-chlorobenzoic acid (8 g; 0.04 moles) in anhydrous tetrahydrofuran (300 ml) whilst maintaining the temperature between -5 and -lo&. After stirring at this temperature for 0.5 hours, a solution of l-cyclohexylmethyl-4-aminopiperidine (7.85 g; 0.04 moles) in anhydrous tetrahydrofuran (50 ml) was added, the temperature was maintained at -5 to -10 C for 1 hour and then allowed overnight to reach room temperature. The solvent of the mixture was removed in vacuo~ the residue poured into water, extracted with chloroform and the organic layers washed with water. The chloroformic solution was dried (Na2S04) and the solvent removed in vacuo to give a solid which as triturated with a mixture of methanol and diethyl ether. N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-amino-5-chlorobenzamide (8 g) was thus obtained.
The hydrochloride was prepared by addition of a saturated ethanolic solution of hydrogen chloride to a solution of the base in ethanol. Recrystal-lization from ethanol gave a white solid, melting point 225 - 227 C (dec).
Also prepared in a similar ma~mer were:
N-(l-cyclopentylmethylpiperid 1-yl)-2-methoxy-4-amino-5-chlorobenzamide 10940~9 hydrochloride, m.p. 226 - 227 C;
N-(l-cyclobutylmethylpiperid-4-yl)-2_methoxy_4_amino-5-chlorobenzamide hydrochloride, m.p. 240 - 242 C;
N-[l-(l-adamantyl)methylpiperid-4-yl]-2-methoxy_4-amino-5-chlorobenzamide hydrochloride, m.p. 259 - 260 C;
N-(l-cycloheptylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 218- 220C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide hydrochloride, m.p. 229 - 230 C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy 1-acetamido-5-chlorobenzamide hydrochloride monohydrate, m.p. 219 - 221C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-5-chlorobenzamide hydrochloride, ^ ~ sc~lpha,.~
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-5-oulphon~miaobenzamide hydro-chloride, m.p. 237 - 238 C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-trifluoroacetamido-5-chloro-benzamide hydrochloride, m.p. 218 - 220 C (dec);
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-5-methylsulphonylbenzamide hydro-chloride, m.pO 216 - 218 & (dec);
N-[1-(4-methylcyclohexyl)methylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenz-amide hydrochloride, m.p. 229 - 230 C;
N-[l-(l-cyclohexyl)ethylpiperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 225 - 227 C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-ethoxy ~-acetamido-5-chlorobenzamide, the fumarate of which melts at 189 - 191 C;
N-(l-cyclohexylmethy]piperid-4-yl)-2-ethoxy 1-amino-5-chlorobenzamide hydro-chloride, m.p. 242 - 243 C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4,5-diaminobenzamide dihydro-chloride, m.p. 270 - 272 C (dec);
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy_4_dimethylamino-5-chlorobenz~mide, ~? ~c - ~ ~Vc A the fumarate of which melts at ~ a;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, the fumarate of which melts at 216 - 218 C, and N-(l-cyclohexy~ethylpiperid-4-yl)_2_allyloxy_4-amino_5-chlorobenzamide hydro-chloride, m.p. 212 - 214&.
The fumarates of certain piperidine derivatives indicated above were prepared by the procedure described in subsequent Example 9 illustrating the preparation of the fumarate of N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide.
To a solution of l-cyclohexylmethyl-4-aminopiperidine (9.8 g; 0O05 moles) in methyl ethyl ketone (100 ml), a solution of 2-methoxy-4-acetamido-5-chlorobenzoyl chloride (14.4 g, 0.055 moles) in methyl ethyl ketone (100 ml) was slowly added at a temperature between 0 and 5&. The mixture was stirred at the same temperature for 1 hour followed by 4 hours at room temperature.
The precipitated solid was filtered off, washed with methyl ethyl ketone and recrystallized from a mixture of ethanol-water to give N-(l-cyclohexylmethyl-piperid 1-yl)-2-methoxy-4-acetamido-S-chlorobenzamide hydrochloride monohydrate (21 g), m.p. 219_ 221C.
Also prepared in a similar manner was N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy 1-trifluoroacetamido-5-chlorobenzamide hydrochloride, m.p.
218- 220C (dec.).
A mixture of N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-acetan~ido-S-chlorobenzamide hydrochloride monohydrate (10 g; 0.02 moles)~ concentrated hydrochloric acid (6 ml) and water (20 ml) was boiled under reflux for 1.5 hours. The solution was then made a~aline with sodium hydroxide solution and extracted with chloroform. The organic solution was dried (Na2S04) and the solvent removed in vacuo to give N-(l-cyclohexylmethylpiperid 1-yl)-2-methoxy-4-amino-5-chlorobenzamide (7.1 g), m.p. 213- 215 & after recrystallization from methanol.
The base was converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride. The solid obtained melted at 225 - 227& (dec).
A mixture of N-(l-cyclohexylmethylpiperid 1-yl)-2-methoxy ~-tri-fluoroacetamido-5-chlorobenzamide (8.1 g; 0.017 moles), ethanol (25 ml), water (15 ml) and 8N sodium hydroxide aqueous solution (25 ml) was stirred for 12 hours at room temperature. After dilution with water, the mixture was extracted with chloroform and the chloroformic solution dried (Na2S04) and evaporated in vacuo. N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (5 g) was obtained. It was converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride; the hydrochloride melted at 225 - 227 & (dec).
E~AMPLE 5 A mixture of methyl 2-methoxy-4-acetamido-5-chlorobenzoate (25.? g;
0.1 moles~, xylene (80 ml), l-cyclohexylmethyl ~-aminopiperidine (21.6 g;
0.11 moles) and aluminium isopropoxide (5 g) was heated to the boiling point whilst methanol was distilled off as it was formed. When the theoretical quantity of methanol was removed, the xylene was distilled off and the residue was dissolved in 2N hydrochloric acid (200 ml). The aqueous solution was made aIkaline with sodium hydroxide solution, extracted with chloroform and the chloroformic layer evaporated to dryness to give N-(l-cyclohex~lmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (27 g). Its hydrochloride mono-hydrate was prepared by the procedure described in Example 1, m.p. 219 - 221C~
N,N'-dicyclohexylcarbodiimide (10.3 g; 0.05 moles) and l-cyclohex~l-methyl-4-aminopiperidine (9.8 g; 0.05 moles) were added successively to a solution of 2-methoxy-4-acetamido-5_chlorobenzoic acid (12.1 g; 0.05 moles) in methylene chloride (250 ml). After stirring overnight at room temperature, the insoluble N,N'-dicyclohex~lurea was filtered off, the solution was washed with water, dried (Na2S04) and the solvent removed in vacuo. The residue was recrystallized and the product converted into its hydrochloride to give 14.2 g of N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy ~-acetamido-5-chlorobenzamide hydrochloride monohydrate, m.p. 219 - 221C.
To a warm solution of N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (10 g; 0.023 moles) in diethyl ether (300 ml) a solution of methyl iodide (1.8 ml; 0.033 moles) in diethyl ether (25 ml) was added. The mixture was stirred at room temperature for 1 hour and then heated under reflux for 2 hours. An additional amount of methyl iodide (1 g; 0.0023 moles) was added and the reflux of the mixture was kept up for 3 more hours.
The mixture was then evaporated in vacuo and the residue recrystallized from a mixture of diethyl ether-ethanol. N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-acetamido-5-chlorobenzamide methyl iodide (10.5 g), m.p. 209- 211C
was thus obtained.
To a solution of N-(l-cyclohexylmethylpiperid l-yl)-2-methoxy 1-acetamido-5-chlorobenzamide (10 g; 0.023 moles) in glacial acetic acid (50 ml) a 30% hydrogen peroxide solution (6 ml) was added. The mixture was heated for 8 hours at a temperature between 70 and 80 C. Afterwards the solvent was evaporated in vacuo, and N-(l-cyc]ohexylmethylpiperid-4-yl)-2-methoxy ~-acetamido-5-chlorobenzamide N-oxide was obtained as a viscous liquid. After recrystallization from a mixture of aceton and diethyl ether, there was obtained 7.3 g of the N-oxide, melting at 206 - 208 C.
10!~4(~59 E~AMPLE 9 To a hot solution of N~ cyclohexylmethylpiperid ~-yl)-2-methoxy-4-amino-5-chlorobenzamide (5 g; 0.013 moles) in ethanol (30 ml) there was added fumaric acid (1.7 g; 0.014 moles). The hot mixture was stirred until complete dissolution. After cooling N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-amino-5-chlorobenzamide fumarate crystallized: yield 6.3 g, m.p.
229 - 231 C.
The following Examples illustrate pharmaceutical compositions according to the present invention and procedures for their preparation.
E~AMPIE 10 100,000 Tablets each containing 2 mg of N-(l-cyclohexylmethylpiperid -4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride were prepared from the following formulation:
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy ~-amino-5-chlorobenzamide hydrochloride 200 g microcrystalline cellulose 1870 g lactose spray dried 9880 g carboxymethyl starch 430 g sodium stearyl fumarate 60 g colloidal silicon dioxide 60 g Procedur-e:
All the powders were passed through a screen with an opening of 0.6 mm. They were then all mixed in a suitable mixer for 20 minutes and compressed into 125 mg tablets using 6 mm. discs and flat bevelled punches. The disin-tegration time of the tablets was about 60 seconds.
100,000 Capsules each containing 1 mg of N-(l-cyclohexylmethylpiperid -4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride were prepared from the following formulation:
N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 100 g lactose 9000 g sodium lauryl sulphate 370 g corn starch 8000 g alpine talc 530 g Procedure:
The above ingredients were sieved through a 40 mesh sieve, then mix-ed in a suitable mixer and distributed into 100,000 gelatine capsules (180 mg).
10,000 Suppositories each containing 5 mg of N-(l-cyclohexylmethyl-piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride were prepared as follows:
N-~l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 50 g theobroma oil 19950 g Procedure:
. . .
The theobroma oil was melted and the N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-~-amino-5-chlorobenzamide hydrochloride suspended in it. The mixture was then poured into appropriate suppository moulds to make 2.0 g suppositories.
50,000 Ampoules each containing 2 mg of N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-~-amino-5-chlorobenzamide hydrochloride were prepared from the following formulation:
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy ~-amino-5-chlorobenzamide hydrochloride 100 g sodium chloride 500 g water injectable grade q.s. 100 litres _ 15 -10~40~;9 Procedure:
The N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chloro-benzamide hydrochloride and the sodium chloride were dissolved in approximat-ely 80 litres of water with slight heating. The solution was diluted with water to 100 litres, passed through a bacteria-retaining filter and filled into
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 inven-tion are those compounds of the general formula:
~ CONH ~ N-CH-R4 R ~
[wherein R represents a lower alkoxy or lower alkenyloxy group;
Rl and R2, which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkyl-10 amino) di~lower)alkylamino, lower alkylsulphonyl or lower alkyl-sulphamoyl group, or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, including halogen substituted carboxylic acids such as trifluoroacetic acid (pre-ferably a lower alkanoylamino group), the halogen atom or group represented by the symbol Rl being in the 3- or 4-position of the phenyl ring (preferably in the 4-position), with the proviso that R and R2 do not both represent hydrogen atoms; R3 repre-sents a hydrogen atom or a lower alkyl group, and R4 represents a cycloalkyl group having from 3 to 7 carbon atoms in the ring optionally substituted by an alkyl group containing 1 to 3 car-bon atoms, or R4 represents an adamantyl group;] and pharmaceut-ically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides thereof.
The qualification "lower" as applied in this specification to alkoxy, alkenyloxy, alkyl, acyl and alkanoyl groups means that the group in question contains at most 6 carbon atoms.
10~40S9 Preferred compounds of general formula I are those of the more specific formula:
R ~ CONH ~ N-13'R4' 11 R
[wherein R' represents a lower alkoxy ~preferably methoxy or ethoxy) or allyloxy group, Rl represents a hydrogen atom, or an amino, lower alkylamino (preferably methylamino), di(lower)-alkylamino (preferably dimethylamino) or a lower acylamino (preferably lower alkanoylamino, e.g. acetamido or trifluoro-acetamido) group, R2 represents a halogen (preferably chlorine or bromine) atom, or an amino, sulphamoyl or lower alkylsulphonyl (preferably methylsulphonyl) group, R3 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms (prefer-ably methyl) group, and R4 represents a cycloalkyl group option-ally substituted by a lower alkyl (preferably methyl) group] and pharmaceutically acceptable acid addition salts thereof.
Of outstanding importance are N-(l-cyclohexylmethyl-piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, N{l-cyclo-hexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide, N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, N-~l-cyclohexylmethylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide and N-(l-cyclohexylmethylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide, and their pharmaceutic-ally-acceptable acid addition salts.
According to a feature of the present invention, the piperidine derivatives of general formula I are prepared by the process which comprises reacting a reactive derivative r~
109~59 of a benzoic acid of the general formula:
Rl ~ COOH III
R
~wherein R, Rl and R2 are as hereinbefore defined) with a piperidine derivative of the general formula:
~ 1 4 2N ~ N-CH-R IV
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~, anhydride or a mixed anhydride, the N-imidazolamide or acid azide.
The reaction is preferably carried out in the presence of an inert organic solvent, for example benzene, toluene, chloroform, tetrahydrofuran or dioxan, at a temperature between -5 and 120C.
The piperidine derivatives of general formula IV can be prepared by reduction of corresponding piperid-4-one oximes with lit~ium aluminium hydride in the presence of diethyl ether or *etrahydrofuran, or by reductive amination of corresponding piperid-4-ones dissolved in an organic solvent~ e.g. an alcohol containing up to 6 carbon atoms, in the presence of Raney nickel or platinum as catalyst.
Halides of the benzoic acids of genera~ 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 sol-vent, e.g. tetrahydrofuran or methylene chloride, and at a temperature between -20 and +25C. Esters and anhydrides of the benzoic acids of formula III, which may be employed as starting materials in the aforementioned process, can be pre-pared from the benzoic acids by methods known per se, as can also the N-imidazolamides or acid azides of the acids.
The piperidine derivatives of general formula I are also prepared, according to a further fea~ure of the invention, by the direct reaction of a benzoic acid of general formula III with a piperidine derivative of general formula IV in the presence of an appropriate dehydrating agent. Such agents are silicon tetrachloride, a mono-, di- or trialkyl-silyl chloride, titanium tetrachloride, N,N'-dicyclohexyl-carbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene-~-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 llo&.
In the preparation of those compounds of general formula I wherein the symbol(s) R and/or R represent(s) an amino group by the aforementioned processes, it is sometimes advisable to protect the amino group(s) of the A ~
lr~ ~ acid of general formula ~ or derivative thereof before reacting the compound with the piperidine derivative of general formula ~Y~ In this case an N-J~
acyl derivative of the amino-substituted benzoic acid of general formula is initially prepared, the acyl protecting group preferably being acetyl, chloroacetyl, trifluoroacetyl or phthalimido. After the reaction between the lLL
N-acylated compound of general formula ~ or reactive derivative thereof, with the piperidine derivative of general formula ~Y~ the corresponding N-acyl derivative of the compound of general formula I is obtained and that compound is then subjected to acid or alkaline hydrolysis to give the corresponding compound of general formula I in which R and/or R represent(s) 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 room temperature with sodium or potassium hydroxide in an aqueous-alcoholic solu-tion.
The piperidine derivatives of general formula I have as one of their principal pharmacological properties the ability to antagonize the effects of dopamine or dopaminergic agents of endogenous or exogenous origin. They have exhibited activities which may be considered beneficial in the treatment of gastrointestinal and cerebral malfunction in mammals, including man. They have also been shown to be capable of exerting anorectic properties. Their characteristic properties are an antagonism of the effects of the dopaminergic agent, apomorphine, in animals, local anaesthetic activity and the ability to induce catatonia in rats and mice. Consequently, they may be useful in the treatment of nausea and vomiting of diverse origin and as neuroleptic or tranquilizing agents. They may be useful for the treatment of nausea and vomiting resulting from gastrointestinal disorders, congestive heart failure, postoperative conditions, etc., other gastrointestinal disorders such as dyspepsia, flatulance, bile regurgitations, hiatus hernia, peptic ulcer, reflux aerophagitis, gastritis, duodenitis and cholethiasis, and a variety of conditions affecting the central nervous system such as acute and chronic psychosis, manical psychosis, schizophrenias, serious disturbances of behaviour and non-melancholic depressive states and migraine. They may also be useful in the treatment of obesity and allied conditions where the administration of an appetite supressant is warranted.
For therapeutic purposes the piperidine derivatives of general formula I may be employed in the form of non-toxic pharmaceutically-acceptable inorganic or organic acid addition salts such as sulphates, hydrohalides, phosphates, lower alkanesulphonates, arylsulphonates, salts of aliphatic mono-di- or tri-basic acids of from 1 to 20 carbon atoms which may contain one or more double bonds, an aryl nucleus or other functional group such as hydroxy, amino or keto; salts of aromatic acids in which the aromatic nucleus may optionally be substituted by groups such as hydroxy, lower alkoxy, amino, mono-S~,t lp~ah~
or di-(lower)aIkylamino and ~ -groups. They may also be employed in the form of pharmaceutically-acceptable quaternary ammonium salts such as those salts formed by reaction of the piperidine derivatives of general formula I with lower aIkyl halides or sulphates, or in the form of oxygenated derivatives in which oxygen is attached to the nitrogen atom of the piperidine n~cleus, viz. the N-oxides.
The pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides of the piperidine derivatives of general formula I may be prepared by methods known ~ se.
10~4059 Also included within the scope of the present invention are pharma-ceutical compositions which comprise, as active ingredient, at least one piperidine derivative of general formula I, or a non-toxic pharmaceutically-acceptable acid addition salt or quaternary ammonium derivative or N-oxide 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 ad-mixed with the active compound, or compounds, to form the compositions of this invention are well known ~ se and the actual excipients used depend inter a _ on the method of administering the compositions. Compositions of this invention are preferably adapted for administration ~ 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 composi-tions include those liquid and solid diluents which are compatible with the active ingredient, together with, if desired, colouring or flavouring agents.
Tablets or capsules may conveniently contain between 0.1 and ~0 mg of active ingredient or the equivalent amount of an acid addition salt or quaternary ammonium or N-oxide derivative 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 a water-insoluble active compound of the invention or an acid addition salt or quater-nary ammonium or N-oxide derivative thereof in association with water, 10940.~9 together with a suspending agent and flavouring agent.
Compositions for parenteral injection may be prepared from water-soluble salts, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injection fluid.
In another aspect of the invention, the compounds may be mixed ~ith other active anti-acid and anti-ulcer agents (excluding anticholinergic agents) for oral, or in appropriate cases, for parenteral use.
The following Reference ~xample and Examples illustrate the prepara-tion of piperidine derivatives of general formula I.
(a) A solution of l-cyclohexylmethylpiperid ~-one oxime (37.8 g; 0.18 moles) dissolved in anhydrous diethyl ether (250 ml) was added little by little to a suspension of lithium aluminium hydride (14.04 g; 0.36 moles) in anhydrous diethyl ether (200 ml.). On completion of the addition, the resultant mixture was heated to the boiling point and maintained there under reflux for 12 hours and then thoroughly cooled whilst water (14 ml), 15~ (w/v) aqueous sodium hydroxide solution (14 ml) and water (42 ml) wer~ added successively. The mixture was filtered and the ethereal solution was dried (Na2S04) and the solvent removed in vacuo. The product l-cyclohexylmethyl 1-aminopiperidine (31 g) was isolated as a viscous liquid, b.p. 105 -110 & /0,3 mm Hg.
In a similar r.lanner, using appropriate oximes as starting materials, there were also prepared:
l-cyclopentylmethyl-4-aminopiperidine, b.p. 90 -92 & /0.45 mm Hg;
l_cyclobutylmethyl ~-aminopiperidine, b.p. 70 -71 C/0.05 mm Hg;
l-(l-adamantylmethyl)-4-aminopiperidine, m~p. 76 -79 C, and 1-(4-methylcyclohexylmethyl) ~-aminopiperidine, b.p. 127 -130 C/4 mm Hg.
(b) A solution of 1 cyclohexylmethylpiperid ~-one (65 g; 0.33 moles)in a saturated ethanolic solution of ammonia (350 ml) was hydrogenated in the presence of Raney nickel catalyst (6.5 g) at 75 C and 13 atmospheres for 3.5 10~40~9 hours. The mixture was cooled, the catalyst filtered off and the solvent removed by distillation in vacuo. The residue was treated with a saturated ethanolic solution of hydrogen chloride, and the insoluble dihydrochloride was filtered off, treated with an aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was dried (Na2S04) and the solvent removed in vacuo giving l-cyclohexylmethyl-4 aminopiperidine (45.5 g) as a viscous liquid, b.p. 105 - 110 & /0.3 mm Hg.
Also prepared in a similar manner were:
l_cycloheptylmethyl_4_aminopiperidine, b.p. 101- 102 C/0.15 mm Hg, and 1-cyclobutylmethyl-4-aminopiperidine, b.p. 70 - 71 & /0.05 mm Hg.
E~AMPLE 1 Triethylamine (5.6 ml; 0.04 moles) and ethyl chloroformate (3.84 ml;
0.04 moles~ were added successively to a stirred suspension of 2-methoxy-4-amino-5-chlorobenzoic acid (8 g; 0.04 moles) in anhydrous tetrahydrofuran (300 ml) whilst maintaining the temperature between -5 and -lo&. After stirring at this temperature for 0.5 hours, a solution of l-cyclohexylmethyl-4-aminopiperidine (7.85 g; 0.04 moles) in anhydrous tetrahydrofuran (50 ml) was added, the temperature was maintained at -5 to -10 C for 1 hour and then allowed overnight to reach room temperature. The solvent of the mixture was removed in vacuo~ the residue poured into water, extracted with chloroform and the organic layers washed with water. The chloroformic solution was dried (Na2S04) and the solvent removed in vacuo to give a solid which as triturated with a mixture of methanol and diethyl ether. N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-amino-5-chlorobenzamide (8 g) was thus obtained.
The hydrochloride was prepared by addition of a saturated ethanolic solution of hydrogen chloride to a solution of the base in ethanol. Recrystal-lization from ethanol gave a white solid, melting point 225 - 227 C (dec).
Also prepared in a similar ma~mer were:
N-(l-cyclopentylmethylpiperid 1-yl)-2-methoxy-4-amino-5-chlorobenzamide 10940~9 hydrochloride, m.p. 226 - 227 C;
N-(l-cyclobutylmethylpiperid-4-yl)-2_methoxy_4_amino-5-chlorobenzamide hydrochloride, m.p. 240 - 242 C;
N-[l-(l-adamantyl)methylpiperid-4-yl]-2-methoxy_4-amino-5-chlorobenzamide hydrochloride, m.p. 259 - 260 C;
N-(l-cycloheptylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 218- 220C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide hydrochloride, m.p. 229 - 230 C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy 1-acetamido-5-chlorobenzamide hydrochloride monohydrate, m.p. 219 - 221C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-5-chlorobenzamide hydrochloride, ^ ~ sc~lpha,.~
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-5-oulphon~miaobenzamide hydro-chloride, m.p. 237 - 238 C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-trifluoroacetamido-5-chloro-benzamide hydrochloride, m.p. 218 - 220 C (dec);
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-5-methylsulphonylbenzamide hydro-chloride, m.pO 216 - 218 & (dec);
N-[1-(4-methylcyclohexyl)methylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenz-amide hydrochloride, m.p. 229 - 230 C;
N-[l-(l-cyclohexyl)ethylpiperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 225 - 227 C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-ethoxy ~-acetamido-5-chlorobenzamide, the fumarate of which melts at 189 - 191 C;
N-(l-cyclohexylmethy]piperid-4-yl)-2-ethoxy 1-amino-5-chlorobenzamide hydro-chloride, m.p. 242 - 243 C;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4,5-diaminobenzamide dihydro-chloride, m.p. 270 - 272 C (dec);
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy_4_dimethylamino-5-chlorobenz~mide, ~? ~c - ~ ~Vc A the fumarate of which melts at ~ a;
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, the fumarate of which melts at 216 - 218 C, and N-(l-cyclohexy~ethylpiperid-4-yl)_2_allyloxy_4-amino_5-chlorobenzamide hydro-chloride, m.p. 212 - 214&.
The fumarates of certain piperidine derivatives indicated above were prepared by the procedure described in subsequent Example 9 illustrating the preparation of the fumarate of N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide.
To a solution of l-cyclohexylmethyl-4-aminopiperidine (9.8 g; 0O05 moles) in methyl ethyl ketone (100 ml), a solution of 2-methoxy-4-acetamido-5-chlorobenzoyl chloride (14.4 g, 0.055 moles) in methyl ethyl ketone (100 ml) was slowly added at a temperature between 0 and 5&. The mixture was stirred at the same temperature for 1 hour followed by 4 hours at room temperature.
The precipitated solid was filtered off, washed with methyl ethyl ketone and recrystallized from a mixture of ethanol-water to give N-(l-cyclohexylmethyl-piperid 1-yl)-2-methoxy-4-acetamido-S-chlorobenzamide hydrochloride monohydrate (21 g), m.p. 219_ 221C.
Also prepared in a similar manner was N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy 1-trifluoroacetamido-5-chlorobenzamide hydrochloride, m.p.
218- 220C (dec.).
A mixture of N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-acetan~ido-S-chlorobenzamide hydrochloride monohydrate (10 g; 0.02 moles)~ concentrated hydrochloric acid (6 ml) and water (20 ml) was boiled under reflux for 1.5 hours. The solution was then made a~aline with sodium hydroxide solution and extracted with chloroform. The organic solution was dried (Na2S04) and the solvent removed in vacuo to give N-(l-cyclohexylmethylpiperid 1-yl)-2-methoxy-4-amino-5-chlorobenzamide (7.1 g), m.p. 213- 215 & after recrystallization from methanol.
The base was converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride. The solid obtained melted at 225 - 227& (dec).
A mixture of N-(l-cyclohexylmethylpiperid 1-yl)-2-methoxy ~-tri-fluoroacetamido-5-chlorobenzamide (8.1 g; 0.017 moles), ethanol (25 ml), water (15 ml) and 8N sodium hydroxide aqueous solution (25 ml) was stirred for 12 hours at room temperature. After dilution with water, the mixture was extracted with chloroform and the chloroformic solution dried (Na2S04) and evaporated in vacuo. N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (5 g) was obtained. It was converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride; the hydrochloride melted at 225 - 227 & (dec).
E~AMPLE 5 A mixture of methyl 2-methoxy-4-acetamido-5-chlorobenzoate (25.? g;
0.1 moles~, xylene (80 ml), l-cyclohexylmethyl ~-aminopiperidine (21.6 g;
0.11 moles) and aluminium isopropoxide (5 g) was heated to the boiling point whilst methanol was distilled off as it was formed. When the theoretical quantity of methanol was removed, the xylene was distilled off and the residue was dissolved in 2N hydrochloric acid (200 ml). The aqueous solution was made aIkaline with sodium hydroxide solution, extracted with chloroform and the chloroformic layer evaporated to dryness to give N-(l-cyclohex~lmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (27 g). Its hydrochloride mono-hydrate was prepared by the procedure described in Example 1, m.p. 219 - 221C~
N,N'-dicyclohexylcarbodiimide (10.3 g; 0.05 moles) and l-cyclohex~l-methyl-4-aminopiperidine (9.8 g; 0.05 moles) were added successively to a solution of 2-methoxy-4-acetamido-5_chlorobenzoic acid (12.1 g; 0.05 moles) in methylene chloride (250 ml). After stirring overnight at room temperature, the insoluble N,N'-dicyclohex~lurea was filtered off, the solution was washed with water, dried (Na2S04) and the solvent removed in vacuo. The residue was recrystallized and the product converted into its hydrochloride to give 14.2 g of N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy ~-acetamido-5-chlorobenzamide hydrochloride monohydrate, m.p. 219 - 221C.
To a warm solution of N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (10 g; 0.023 moles) in diethyl ether (300 ml) a solution of methyl iodide (1.8 ml; 0.033 moles) in diethyl ether (25 ml) was added. The mixture was stirred at room temperature for 1 hour and then heated under reflux for 2 hours. An additional amount of methyl iodide (1 g; 0.0023 moles) was added and the reflux of the mixture was kept up for 3 more hours.
The mixture was then evaporated in vacuo and the residue recrystallized from a mixture of diethyl ether-ethanol. N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-acetamido-5-chlorobenzamide methyl iodide (10.5 g), m.p. 209- 211C
was thus obtained.
To a solution of N-(l-cyclohexylmethylpiperid l-yl)-2-methoxy 1-acetamido-5-chlorobenzamide (10 g; 0.023 moles) in glacial acetic acid (50 ml) a 30% hydrogen peroxide solution (6 ml) was added. The mixture was heated for 8 hours at a temperature between 70 and 80 C. Afterwards the solvent was evaporated in vacuo, and N-(l-cyc]ohexylmethylpiperid-4-yl)-2-methoxy ~-acetamido-5-chlorobenzamide N-oxide was obtained as a viscous liquid. After recrystallization from a mixture of aceton and diethyl ether, there was obtained 7.3 g of the N-oxide, melting at 206 - 208 C.
10!~4(~59 E~AMPLE 9 To a hot solution of N~ cyclohexylmethylpiperid ~-yl)-2-methoxy-4-amino-5-chlorobenzamide (5 g; 0.013 moles) in ethanol (30 ml) there was added fumaric acid (1.7 g; 0.014 moles). The hot mixture was stirred until complete dissolution. After cooling N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-amino-5-chlorobenzamide fumarate crystallized: yield 6.3 g, m.p.
229 - 231 C.
The following Examples illustrate pharmaceutical compositions according to the present invention and procedures for their preparation.
E~AMPIE 10 100,000 Tablets each containing 2 mg of N-(l-cyclohexylmethylpiperid -4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride were prepared from the following formulation:
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy ~-amino-5-chlorobenzamide hydrochloride 200 g microcrystalline cellulose 1870 g lactose spray dried 9880 g carboxymethyl starch 430 g sodium stearyl fumarate 60 g colloidal silicon dioxide 60 g Procedur-e:
All the powders were passed through a screen with an opening of 0.6 mm. They were then all mixed in a suitable mixer for 20 minutes and compressed into 125 mg tablets using 6 mm. discs and flat bevelled punches. The disin-tegration time of the tablets was about 60 seconds.
100,000 Capsules each containing 1 mg of N-(l-cyclohexylmethylpiperid -4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride were prepared from the following formulation:
N-(l-cyclohexylmethylpiperid ~-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 100 g lactose 9000 g sodium lauryl sulphate 370 g corn starch 8000 g alpine talc 530 g Procedure:
The above ingredients were sieved through a 40 mesh sieve, then mix-ed in a suitable mixer and distributed into 100,000 gelatine capsules (180 mg).
10,000 Suppositories each containing 5 mg of N-(l-cyclohexylmethyl-piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride were prepared as follows:
N-~l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 50 g theobroma oil 19950 g Procedure:
. . .
The theobroma oil was melted and the N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-~-amino-5-chlorobenzamide hydrochloride suspended in it. The mixture was then poured into appropriate suppository moulds to make 2.0 g suppositories.
50,000 Ampoules each containing 2 mg of N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-~-amino-5-chlorobenzamide hydrochloride were prepared from the following formulation:
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy ~-amino-5-chlorobenzamide hydrochloride 100 g sodium chloride 500 g water injectable grade q.s. 100 litres _ 15 -10~40~;9 Procedure:
The N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chloro-benzamide hydrochloride and the sodium chloride were dissolved in approximat-ely 80 litres of water with slight heating. The solution was diluted with water to 100 litres, passed through a bacteria-retaining 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.
1,000 Bottles of 150 ml each containing 75 mg of N-(l-cyclohexyl-methylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride were prepared as follows:
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 75 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-(l-cyclohexylmethylpiperid-4-yl~-2-methoxy-4-amino-5,chloroben-zamide hydrochloride and the sorbic acid were dissolved in 100 litres of water and then the sorbitol, citric acid and flavouring agent were added with stir-ring until dissolution. The mixture was diluted to 150 litres and d~vided 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-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, for example other products conforming to that formula men-- 16 _ tioned in EXamples 1, 2 and 5 to 8.
The piperidine derivatives of general formula VI are new compounds and as such constitute another feature of the present invention.
1,000 Bottles of 150 ml each containing 75 mg of N-(l-cyclohexyl-methylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride were prepared as follows:
N-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 75 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-(l-cyclohexylmethylpiperid-4-yl~-2-methoxy-4-amino-5,chloroben-zamide hydrochloride and the sorbic acid were dissolved in 100 litres of water and then the sorbitol, citric acid and flavouring agent were added with stir-ring until dissolution. The mixture was diluted to 150 litres and d~vided 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-(l-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, for example other products conforming to that formula men-- 16 _ tioned in EXamples 1, 2 and 5 to 8.
The piperidine derivatives of general formula VI are new compounds and as such constitute another feature of the present invention.
Claims (15)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of piperidine derivatives of the general formula:
I
wherein R represents a lower alkoxy or lower alkenyloxy group;
R1 and R2, which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkylamino, di(lower)alkylamino, lower alkylsulphonyl or lower alkylsulphamoyl group, or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, the halogen atom or group represented by the symbol R1 being in the 3- or 4-position of the phenyl ring, with the proviso that R1 and R2 do not both represent hydrogen atoms; R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a cycloalkyl group having from 3 to 7 carbon atoms in the ring optionally substituted by an alkyl group containing 1 to 3 carbon atoms, or R4 represents an adamantyl group, and pharmaceutically-acceptable acid addition salts and quaternary ammonium deriva-tives and N-oxides thereof, which process comprises reacting a reactive derivative of a benzoic acid of the general formula:
III
(wherein R, R1 and R2 are as defined above) with a piperidine derivative of the general formula:
IV
wherein the various symbols are as defined above, and, if desired, converting the thus obtained compound into its N-oxide or into a pharmaceutically acceptable acid addition salt thereof.
I
wherein R represents a lower alkoxy or lower alkenyloxy group;
R1 and R2, which may be the same or different, each represent a hydrogen or halogen atom, or a sulphamoyl, amino, lower alkylamino, di(lower)alkylamino, lower alkylsulphonyl or lower alkylsulphamoyl group, or a lower acylamino group in which the acyl moiety is derived from a carboxylic acid, the halogen atom or group represented by the symbol R1 being in the 3- or 4-position of the phenyl ring, with the proviso that R1 and R2 do not both represent hydrogen atoms; R3 represents a hydrogen atom or a lower alkyl group, and R4 represents a cycloalkyl group having from 3 to 7 carbon atoms in the ring optionally substituted by an alkyl group containing 1 to 3 carbon atoms, or R4 represents an adamantyl group, and pharmaceutically-acceptable acid addition salts and quaternary ammonium deriva-tives and N-oxides thereof, which process comprises reacting a reactive derivative of a benzoic acid of the general formula:
III
(wherein R, R1 and R2 are as defined above) with a piperidine derivative of the general formula:
IV
wherein the various symbols are as defined above, and, if desired, converting the thus obtained compound into its N-oxide or into a pharmaceutically acceptable acid addition salt thereof.
2. A process according to claim 1 in which the reactive derivative of the benzoic acid is a halide, an alkyl ester, anhydride, a mixed anhydride, the N-imidazolamide or acid azide.
3. A process according to claim 1 in which the reaction is carried out in an inert organic solvent at a temperature between -5° and 120°C.
4. A process according to claim 1 in which the benzoic acid of general formula III is reacted with the piperidine de-rivative of general formula IV in the presence of a dehydrating agent.
5. A process according to claim 4 in which the dehydrat-ing agent is silicone tetrachloride, a mono-, di- or trialkyl-silyl chloride, titanium tetrachloride, N,N'-dicyclohexyl-carbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene-p-sulphonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent.
6. A process according to claim 4 or 5 in which the reaction is carried out in an inert organic solvent at a temper-ature between 20° and 110°C.
7. Piperidine derivatives of general formula I as de-fined in claim 1, and pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
8. Process for the preparation of piperidine derivatives of general formula:
II
wherein R' represents a lower alkoxy or allyloxy group, R1' represents a hydrogen atom or an amino, lower alkylamino, di(lower)alkylamino or a lower acylamino group, R2' represents a halogen atom, or an amino, sulphamoyl or lower alkylsulphonyl group, R3' represents a hydrogen atom or a lower alkyl group, and R4' represents a cycloalkyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms, and pharma-ceutically-acceptable acid addition salts thereof, which pro-cess comprises reacting a reactive derivative of a benzoic acid of formula:
III' wherein R', R1', and R2' are as defined above, with a piper-idine derivative of general formula:
IV' wherein R3' and R4' are as defined above, and, if desired, converting the thus obtained compound into a pharmaceutically-acceptable acid addition salt thereof.
II
wherein R' represents a lower alkoxy or allyloxy group, R1' represents a hydrogen atom or an amino, lower alkylamino, di(lower)alkylamino or a lower acylamino group, R2' represents a halogen atom, or an amino, sulphamoyl or lower alkylsulphonyl group, R3' represents a hydrogen atom or a lower alkyl group, and R4' represents a cycloalkyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms, and pharma-ceutically-acceptable acid addition salts thereof, which pro-cess comprises reacting a reactive derivative of a benzoic acid of formula:
III' wherein R', R1', and R2' are as defined above, with a piper-idine derivative of general formula:
IV' wherein R3' and R4' are as defined above, and, if desired, converting the thus obtained compound into a pharmaceutically-acceptable acid addition salt thereof.
9. Piperidine derivatives of formula II as defined in claim 8, and pharmaceutically-acceptable acid addition salts thereof, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
10. Process according to claim 8 wherein starting com-pounds of formula III' and IV' are employed in which R' repre-sents methoxy or ethoxy' R1' represents a methylamino, di-methylamino, or lower alkanoylamino group; R2' represents chlorine, bromine, or methylsulphonyl; R3' represents methyl, and R4' represents a cycloalkyl group optionally substituted by a methyl group.
11. Piperidine derivatives according to claim 9, and pharmaceutically-acceptable acid addition salts, wherein R' represents a methoxy or ethoxy; R1' represents methylamino, dimethylamino, or lower alkanoylamino; R2' represents chlorine, bromine or methylsulphonyl; R3' represents methyl, and R4' represents a cycloalkyl group optionally substituted by a methyl group; whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
12. Process according to claim 8 wherein a starting com-pound of formula III' is employed in which R1' represents an acetamido or trifluoroacetamido group.
13. Piperidine derivatives according to claim 9, wherein R1' is an acetamido or trifluoroacetamido group, and pharma-ceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
14. Process according to claim 1 wherein a compound of formula IV is employed in which R4 represents a cyclobutyl, cyclopentyl, cycloheptyl or adamantyl group, or a cyclohexyl group optionally substituted in the 4-position by an alkyl group containing 1 to 3 carbon atoms.
15. Piperidine derivatives, and their pharmaceutically acceptable acid addition salts, as defined in claim 7, wherein R4 represents a cyclobutyl, cyclopentyl, cycloheptyl or adamantyl group, or a cyclohexyl group optionally substituted in the 4-position by an alkyl group containing 1 to 3 carbon atoms, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB6207/76 | 1976-02-17 | ||
GB6207/76A GB1513631A (en) | 1976-02-17 | 1976-02-17 | Piperidine derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1094059A true CA1094059A (en) | 1981-01-20 |
Family
ID=9810379
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA271,918A Expired CA1094059A (en) | 1976-02-17 | 1977-02-16 | Piperidine derivatives |
CA271,917A Expired CA1094075A (en) | 1976-02-17 | 1977-02-16 | Piperidine derivatives |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA271,917A Expired CA1094075A (en) | 1976-02-17 | 1977-02-16 | Piperidine derivatives |
Country Status (13)
Country | Link |
---|---|
JP (2) | JPS596851B2 (en) |
AT (2) | AT356105B (en) |
AU (1) | AU509216B2 (en) |
BE (2) | BE851509A (en) |
CA (2) | CA1094059A (en) |
CH (2) | CH605751A5 (en) |
DE (2) | DE2705949C2 (en) |
ES (5) | ES455832A1 (en) |
FR (2) | FR2342963A1 (en) |
GB (1) | GB1513631A (en) |
IE (2) | IE44610B1 (en) |
NL (2) | NL7701631A (en) |
ZA (2) | ZA77562B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1574418A (en) * | 1976-11-16 | 1980-09-03 | Anphar Sa | Piperidine derivatives |
JPS59145558A (en) * | 1983-02-09 | 1984-08-21 | Hitachi Ltd | Laminated stack for semiconductor rectifying device |
FR2584401B1 (en) * | 1985-07-04 | 1987-11-20 | Ile De France | NOVEL BENZAMIDE, METHOD FOR PREPARING THE SAME, AND APPLICATION THEREOF IN THE THERAPEUTIC FIELD |
TW213460B (en) * | 1991-02-15 | 1993-09-21 | Hokuriku Pharmaceutical | |
US5395832A (en) * | 1991-02-15 | 1995-03-07 | Hokuriku Seiyaku Co., Ltd. | Benzamide derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU167379B (en) * | 1972-06-01 | 1975-09-27 | ||
AR216043A1 (en) * | 1974-03-21 | 1979-11-30 | Anphar Sa | PROCEDURE FOR THE PREPARATION OF 1-BENZOYLAMINE-4-PIPERIDINE DERIVATIVES AND ITS PHYSIOLOGICALLY ACCEPTABLE SALTS |
-
1976
- 1976-02-17 GB GB6207/76A patent/GB1513631A/en not_active Expired
-
1977
- 1977-02-01 ZA ZA770562A patent/ZA77562B/en unknown
- 1977-02-01 ZA ZA00770563A patent/ZA77563B/en unknown
- 1977-02-03 AU AU21925/77A patent/AU509216B2/en not_active Expired
- 1977-02-11 ES ES455832A patent/ES455832A1/en not_active Expired
- 1977-02-11 ES ES455831A patent/ES455831A1/en not_active Expired
- 1977-02-11 ES ES455834A patent/ES455834A1/en not_active Expired
- 1977-02-11 ES ES455835A patent/ES455835A1/en not_active Expired
- 1977-02-11 ES ES455833A patent/ES455833A1/en not_active Expired
- 1977-02-12 DE DE2705949A patent/DE2705949C2/en not_active Expired
- 1977-02-12 DE DE19772706038 patent/DE2706038A1/en not_active Ceased
- 1977-02-14 CH CH179977A patent/CH605751A5/xx not_active IP Right Cessation
- 1977-02-14 AT AT97877A patent/AT356105B/en not_active IP Right Cessation
- 1977-02-14 CH CH179877A patent/CH620678A5/en not_active IP Right Cessation
- 1977-02-14 AT AT98577A patent/AT356106B/en not_active IP Right Cessation
- 1977-02-15 FR FR7704988A patent/FR2342963A1/en active Granted
- 1977-02-16 IE IE327/77A patent/IE44610B1/en unknown
- 1977-02-16 CA CA271,918A patent/CA1094059A/en not_active Expired
- 1977-02-16 NL NL7701631A patent/NL7701631A/en not_active Application Discontinuation
- 1977-02-16 IE IE328/77A patent/IE44611B1/en unknown
- 1977-02-16 CA CA271,917A patent/CA1094075A/en not_active Expired
- 1977-02-16 BE BE175001A patent/BE851509A/en not_active IP Right Cessation
- 1977-02-16 BE BE175000A patent/BE851508A/xx not_active IP Right Cessation
- 1977-02-16 NL NL7701630A patent/NL7701630A/en not_active Application Discontinuation
- 1977-02-16 FR FR7705169A patent/FR2341570A1/en active Granted
- 1977-02-17 JP JP52016656A patent/JPS596851B2/en not_active Expired
- 1977-02-17 JP JP1665577A patent/JPS52122378A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
ZA77562B (en) | 1977-12-28 |
JPS596851B2 (en) | 1984-02-15 |
ES455835A1 (en) | 1978-01-01 |
NL7701631A (en) | 1977-08-19 |
IE44610B1 (en) | 1982-01-27 |
DE2705949A1 (en) | 1977-08-25 |
FR2342963B1 (en) | 1980-10-03 |
ES455834A1 (en) | 1978-01-01 |
ES455832A1 (en) | 1978-01-01 |
IE44611L (en) | 1977-08-17 |
GB1513631A (en) | 1978-06-07 |
JPS52122379A (en) | 1977-10-14 |
NL7701630A (en) | 1977-08-19 |
AT356105B (en) | 1980-04-10 |
CA1094075A (en) | 1981-01-20 |
DE2706038A1 (en) | 1977-08-18 |
BE851509A (en) | 1977-06-16 |
IE44610L (en) | 1977-08-17 |
CH605751A5 (en) | 1978-10-13 |
DE2705949C2 (en) | 1983-04-21 |
IE44611B1 (en) | 1982-01-27 |
AU509216B2 (en) | 1980-05-01 |
ATA98577A (en) | 1979-09-15 |
ES455833A1 (en) | 1978-01-01 |
FR2341570A1 (en) | 1977-09-16 |
AU2192577A (en) | 1978-08-10 |
FR2341570B1 (en) | 1981-10-30 |
ZA77563B (en) | 1978-04-26 |
AT356106B (en) | 1980-04-10 |
CH620678A5 (en) | 1980-12-15 |
JPS52122378A (en) | 1977-10-14 |
ATA97877A (en) | 1979-09-15 |
ES455831A1 (en) | 1978-01-16 |
BE851508A (en) | 1977-06-16 |
FR2342963A1 (en) | 1977-09-30 |
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