CA1094075A - Piperidine derivatives - Google Patents
Piperidine derivativesInfo
- Publication number
- CA1094075A CA1094075A CA271,917A CA271917A CA1094075A CA 1094075 A CA1094075 A CA 1094075A CA 271917 A CA271917 A CA 271917A CA 1094075 A CA1094075 A CA 1094075A
- Authority
- CA
- Canada
- Prior art keywords
- amino
- cyclohexa
- methoxy
- chlorobenzamide
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Abstract of the Disclosure Compounds and process for their preparation, of formula I
[wherein R represents a lower alkoxy or allyloxy goup; R1 represents ahydrogen atom R' and R2, which may be the same or different, each represent a 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; R3 represents a hydrogen atom or a lower alkyl group, R4 represents a cyclohexenyl or cyclohexadienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides thereof.
These compounds find pharmaceutical use as agents to antagonize tho effects of dopamino and dopaminoergic agents.
[wherein R represents a lower alkoxy or allyloxy goup; R1 represents ahydrogen atom R' and R2, which may be the same or different, each represent a 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; R3 represents a hydrogen atom or a lower alkyl group, R4 represents a cyclohexenyl or cyclohexadienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides thereof.
These compounds find pharmaceutical use as agents to antagonize tho effects of dopamino and dopaminoergic agents.
Description
10!~075 This invention relates to new therapeuticslly useful N-(piperid-4-yl)benzamide derivatives, to processes for their preparation and pharm-aceutical compositions containing them.
The new N-tpiperid-4-yl)benzanide derivatives of the present invention are those compounds of the general for~ula:
~ CONH- (C~2) X --~ N~ R
R R
twherein R represents a lower alkoxy or allyloxy group; Rl represents a hydrogen atom or Rl and R2, which may be the same or different, each represent a 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 càrboxylic acid, including halogen substituted carboxylic acids such as trifluoroacetic acid (preferably 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); R3 represents a hydrogen atom or a lower alkyl group; R4 represents a cyclohexenyl or cyclohexadienyl group optioDally substituted by an alkyl group containing 1 to 3 carbon atoLs3and pharmaceuti-cally-acceptable acid addition salts and quaternary anmonium derivatives and N-oxides thereof.
The qualification "lower" as applied in this specification to alkoxy, alkyl, acyl and alkanoyl groups means that the group in question contains at most 4 carbon atoms.
iO94075 Preferred compounds of general formula I are those of the more specific formula:
Rl' ~ CONH ~ 3' II
\=~.
[wherein R' represents a lower alkoxy (preferably methoxy or ethoxy) or allyloxy group, R 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, R represents a halogen (preferably chlorine or bromine) atom, or an amino, sulphamoyl or lower alkylsulphonyl (preferably methyl-sulphonyl group, R3 represents a hydrogen atom or a lower alkyl (preferably methyl) group and R represents a cyclohexenyl or cyclohexadienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms (preferably methyl)] and pharmaceutically-acceptable acid addition salts thereof.
Of outstanding importance are those compounds of general formula II
wherein R represents the cyclohexa 1,4-dienyl group optionally substituted by a methyl group and, in particular, N [l-cyclohexa-1',4'-dienylmethylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l cyclohexa-1',4'-dienylmethyl-piperid-4-yl]-2-methoxy-4-methylamino-5-chlorobenzamide, N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide and N-[1-(4-methylcyclohexa-1,4-dienyl)methylpiperid-4-yl~-2-methoxy-4-amino-5-chlorobenz-amide, and their pharmaceutically-acceptable acid addition salts.
10~3 ~07S
According ~o a feature of the present invention, the N-(piperid-4-yl) benzamide derivatives of general formula I are prepared by the process which comprises reacting a reactive derivative of a benzoic acid of the general formula:
~2 ,~
~ r COOH III
/~
~: Rl R
. 10 (wherein R, Rl and R2 are as hereinbefore defined) with a piperidine derivative of the general formula:
~ ,R
2N ~ N - ~ R IV
wherein the various symbols are as hereinbefore defined. The reactive deriva-tive of the said benzoic acid may be a halide (preferably chloride), an alkyl ester (preferably methyl ester), anhydride or a mixed anhydride, the N-imida-zolamide or acid azide.
The reaction is preferably carried out in the presence of an inertorganic solvent, for example benzene, toluene, chloroform, tetrahydrofuran or dioxan, at a temperature between -5 and 120~C.
The piperidine derivatives of general formula IV can be prepared by reduction of corresponding piperid-4-one oximes with lithium aluminium hydride in the presence of diethyl ether or tetrahydrofuran, 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. The piperidine derivatives of general formula IV whereill R4 represents a cyclohexadienyl group can be prepared from a corresponding phenyl derivative of the fol~ula R4 represents a phenyl group by reduction with lithium in the presence of liquid ammonia or a lower alkylamine.
~094~75 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 chloro-formate in the presence of an organic nitrogen-containing base, e.g. triethyl-amine, in an inert organic solvent, e.g. tetrahydrofuran or methylene chloride, and at a temperature between -20C 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 prepared from the benzoic acids by methods known per se, as can also the N-imidazolamides or acid azides of the acids.
The N-(piperid-4-yl)benzamide 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 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 110C.
In the preparation of those compounds of general formula I wherein the sym'ool(s) Rl and/or R2 represent(s) an amino group by the aforementioned processes, it is sometimes advisable to protect the amino group(s) of the acid of general formula III or derivative thereof before reacting the compound with the piperidine derivative of general formula IV. In this case an N-acyl deri-vative of the amino-substituted benzoic acid of general formula III is initially prepared, the acyl protecting group preferably being acetyl, chloroacetyl, trifluoroacetyl or phthalimido. After the reaction between the N-acylated compound of general formula III, or reactive derivative thereof, with the ~ 4 _ . ~
`` 1094075 piperidine derivative of general formula IV, 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 Rl and/or R2 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 solution.
The N-(piperid-4-yl)benzamide derivatives of general formula I
have as one of their principal ~harmacological properties the ability to antogonize 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.
~onsequently, they may be useful in the treatment of nausea and vomiting of diverse origin and as neuroleptic or tranquillizing agents. They may be useful for the treatment of nausea and vomiting resulting from gastrointestinal disorders, congestive heart failure, post-operative 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 N-~piperid-4-yl)benzamide derivatives of general formula I may be employed in the form of non-toxic pharmaceutically-~ ~ - 5 -... ...
10~407S
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 or aromatic acids in which the aromatic nucleus may optionally be substituted by groups such as hydroxy, lower alkoxy, amino, mono- or di-(lower)alkylamino and sulphonamido groups.
They may also be employed in the form of pharmaceutically-acceptable quaternary ammonium salts such as those salts formed by reaction of the N-(piperid-4-yl)benzamide derivatives of general formula I with lower alkyl halides or sulphates, or in the form of oxygenated derivatives in which oxygen is attached to the nitrogen atom of the piperidine nucleus, viz. the N-oxides.
The pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides of the N-(piperid-4-yl)benzamide derivatives of general formula I may be prepared by methods known per se.
Also included within the scope of the present invention are pharma-ceutical compositions which comprise, as active ingredient, at least one N-~piperid-4-yl)benzamide derivative of general formula I, or a non-toxic pharmaceutically-acceptable acid addition salt or quaternary ammonium deriva-tive 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 admixed with the active compound, or compounds, to form the compositions of this invention are well known per se and the actual excipients used depend inter alia on the 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, - 105~4075 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 li~uid and solid diluents which are compatible with the active ingredient, together with, if desired, colouring or flavouring agents. Tab-lets or capsules may conveniently contain between 0.1 and 20 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 ex-ample, sucrose to for~ a syrup. The suspension may comprise a water insoluble active compound of the invention or an acid addition salt or quaternary ammoni-um or N-oxide derivative thereof in association with water, together with 3 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 with 20 other active anti-acid and anti-ulcer agents (excluding anticholinergic agents) for oral or, in appropriate cases, for parenteral use.
The following Reference Example and Examples illustrate the prepara-tion of piperidine compounds of the present invention.
~ERENCE EXAMPLE
A solution of lithium (5 g.; 0.7 mol) in liquid ammonia (250 ml.) was added little by little to another solution of l-benzyl-4-aminopiperidine (S0 g.;
0.264 moles) in anhydrous diethyl ether (100 ml.~. After stirring for half an hour, absolute ethanol (180 ml.) was added little by little, the solvent re_ moved _ vacuo and the residue taken up with water. The aqueous solution was extracted with diethyl ether and the organic layers dried and distilled in vacuo `` 1094075 to give l-cyclohexa-l'J4'-dienylmethyl-4-aminopiperidine (48 g.), b.p. 117 -118C,/0.5 mm.Hg.
Also prepared in similar manner were:
1-(4-methylcyclohexa_1,4-dienyl)methyl-4-aminopiperidine, b.p.
104 - 106C/0.07 mm.Hg.;
l-(l-cyclohexa-1',4'-dienyl-ethyl)-4-aminopiperidine, b.p. 103 -105C./0.08 mm.Hg. and l-cyclohexen_3'_ylmethyl_4_aminopiperidine, b.p. 101 - 103C./0.05 mm.Hg.
Triethylamine (7.0 ml.; 0.05 moles) and ethyl chloroformate (4.8 ml.;
0.05 moles) were added successively to a stirred suspension of 2-methoxr-4-amino-5-chlorobenzoic acid (10.1 g.; 0.05 moles) in anhydrous tetrahydrofuran (300 ml.) whilst maintaining the temperature between -5 and -10C. After stirring at this temperature for 0.5 hours, a solution of 1-cyclohexa-1',4'-dienylmethyl-4-aminopiperidine (9.6 g.; 0.05 moles) in anhydrous tetrahydro-furan (50 ml.) was added; the temperature was maintained at -5 to -10C. for 1 hour and then the reaction mixture was allowed to stand overnight at room temperature. The solvent was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layers washed with water. The chlo-roform solution was dried (Na2S04) and the solvent removed in vacuo to give a solid which was triturated with a mixture of methanol and diethyl ether. N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenz-amide (12.2 g.) was obtained.
The hydrochloride monohydrate was prepared by addition of a saturated ethanolic solution of hydrogen chloride to a solution of the base in ethanol.
Recrystallization of the precipitate from ethanol gave a white solid, m.p.
226 - 227C. (dec.).
Also prepared in a similar manner were:
N-(l-cyclohexa-1',4'-dienrlmethylpiperid-4-yl)-2-methoxy-5-methyl-sulphonylbenzamide hydrochloride, m.p. 209 - 211~C. (dec.);
109~075 N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-chloro-benzamide hydrochloride, m.p. 231 - 233C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide hydrochloride, m.p. 215C. ~dec.);
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-sulpha~oyl-benzamide hydrochloride, m.p. 230 - 231C. ~dec.);
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide hydrochloride monohydrate, m.p. 193 - 195C~
N-[1-~4-methylcyclohexa-1,4-dienyl)methylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 246 - 248C. ~dec.);
N-[l-~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 241 - 242C. ~dec.);
N-~l~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-acet-amido-5-chlorobenzamide, the fumarate of which melts at 171 - 173C.;
N-[l-~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 264 - 266C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4,5-di-aminobenzamide dihydrochloride monohydrate, m.p. 240 - 242C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-dimethyl-amino-5-chlorobenzamide, the fumarate of which melts at 182 - 184C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-methyl-amino-5-chlorobenzamide, the fumarate of which melts at 203 - 205~C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 180 - 182C.;
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 247 - 249C.;
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-acetamido-5-chlorobenzamide, the fumarate of which melts at 173 - 175C., and N-( cyclohexen-3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chloro-benzamide, m.p. 189 - 191C.
_ g ~, ~ ",, , The fumarates of th0 piperidine derivatives mentioned aboYe were obtained by adding fumaric acid to a hot ethanolic solution of the piperidine base, the amount of added acid being substantially equimolecular to that of the piperidine base present, stirring the hot mixture until dissolution, and then cooling the resulting solution to crystallize the fumarate.
To a warm solution of N-(l-cyclohexene-3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino_5-chlorobenzamide (3.5 g; 0.0093 moles) in acetone (75 ml.) a solution of methyl iodide (2.63 g.; 0.0185 moles) in acetone (25 ml.) was slow-ly added. The mixture was stirred at room temperature for 12 hours and thenheated under reflux for 4 more hours. The mixture was then concentrated in vacuo to a small volume and the residue filtered off to give N-~l-cyclohexen-3'_ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide methyl iodide (4 g.), m.p. 231 - 233C (dec.) after recrystallization from a mixture of ethanol-water.
The following Examples illustrate pharmaceutical compositions accord-ing to the present invention and procedures for their preparation.
100,~00 Tablets each containing 2 mg. of N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino_5-chlorohenzamide hydrochloride monohydrate were prepared from the following formulation:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydr~te 200 g.
microcrystalline cellulose 1870 ~.
lactose spray dried 9880 g.
car~oxyme~hyl starch 430 g.
sodium stearyl fumarate 60 g.
colloidal silicon dioxide 60 g.
" 1094075 Procedure-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-cyclohexa-1',4'-di-enylmethylpiperid-4-yl)-2-methoxy-4_amino_5_chlorobenzamide hydrochloride mono-hydrate were prepared from the following formulation:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride nohydrate 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 sieYe, then mixed in a suitable mixer and distributed into 100,000 gelatine capsules (180 mg.).
10,000 Suppositories each containing 5 mg. o~ N-(l-cyclohexa-1',4'-dienylmethylpiperid_4_yl)_2_methoxy-4_amino_5-chlorobenzamide hydrochloride monohydrate were prepared as follows:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate 50 g.
~heobroma oil 19950 g.
Proc _ ure:
The theobroma oil was melted and the N~ cyclohexa-1',4'-dienyl-109~075 methylpiperid-4-yl)_2_methoxy-4-amino-5-chlorobenzamide hydrochloride monohyd-rate 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-cyclohexa-1',4'-dienyl-methylpiperid-4_yl)_2_methoxy_4_amino-5_chlorobenzamide hydrochloride monohyd-rate were prepared from the following formulation:
N-(l-cyclohexa-1'-4'-dienylmethylpiperid-4-yl)_2_methoxy_4_amino-5-chlorobenzamide hydrochloride monohydrate monohydrate 100 g.
sodium chloride 500 g.
water injectable grade q.s. 100 litres Procedure:
The N-(l -~yclohexa .1',4'_dienylmethylpiperid-4_yl)-2-methoxy-4-amino-5_chlorobenzamide hydrochloride monohydrate and the sodium chloride were dissolved in approximately 80 litres of water with slight heating. The solu-tion was diluted with water to 100 litres passed through a bacteria-retaining filter and filled into 2 ml. glass ampoules in known msnner. 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-cyclohexa-1',4'-dienylmethylpiperid-4_yl)-2_methoxy_4_amino-S_chlorobenzamide hydrochlo-ride monohydrate were prepared as follows:
N~ cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate 75 g, sorbitol 70000 g.
sorbic acid 125 g.
-~ 10~407S
citric acid 125 g.
distilled water q.s. 150 litres flavouring agent q.s.
Procedure:
-The N-(l-cyclohexa-1',4'-dienylmethylpeperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate 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 *o 150 litres and divided amongst the bottles.
Similar compositions to those described in Examples 3 to 7 can be prepared having as the active ingredient piperidine derivatives of general formula I other than N-(l-cyclohexa-$',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, for example other products conforming to that for-mula mentioned in Example 1.
The piperidine derivatives of general formula IV are new compounds and as such constitute another feature of the present invention.
The new N-tpiperid-4-yl)benzanide derivatives of the present invention are those compounds of the general for~ula:
~ CONH- (C~2) X --~ N~ R
R R
twherein R represents a lower alkoxy or allyloxy group; Rl represents a hydrogen atom or Rl and R2, which may be the same or different, each represent a 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 càrboxylic acid, including halogen substituted carboxylic acids such as trifluoroacetic acid (preferably 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); R3 represents a hydrogen atom or a lower alkyl group; R4 represents a cyclohexenyl or cyclohexadienyl group optioDally substituted by an alkyl group containing 1 to 3 carbon atoLs3and pharmaceuti-cally-acceptable acid addition salts and quaternary anmonium derivatives and N-oxides thereof.
The qualification "lower" as applied in this specification to alkoxy, alkyl, acyl and alkanoyl groups means that the group in question contains at most 4 carbon atoms.
iO94075 Preferred compounds of general formula I are those of the more specific formula:
Rl' ~ CONH ~ 3' II
\=~.
[wherein R' represents a lower alkoxy (preferably methoxy or ethoxy) or allyloxy group, R 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, R represents a halogen (preferably chlorine or bromine) atom, or an amino, sulphamoyl or lower alkylsulphonyl (preferably methyl-sulphonyl group, R3 represents a hydrogen atom or a lower alkyl (preferably methyl) group and R represents a cyclohexenyl or cyclohexadienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms (preferably methyl)] and pharmaceutically-acceptable acid addition salts thereof.
Of outstanding importance are those compounds of general formula II
wherein R represents the cyclohexa 1,4-dienyl group optionally substituted by a methyl group and, in particular, N [l-cyclohexa-1',4'-dienylmethylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l cyclohexa-1',4'-dienylmethyl-piperid-4-yl]-2-methoxy-4-methylamino-5-chlorobenzamide, N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide and N-[1-(4-methylcyclohexa-1,4-dienyl)methylpiperid-4-yl~-2-methoxy-4-amino-5-chlorobenz-amide, and their pharmaceutically-acceptable acid addition salts.
10~3 ~07S
According ~o a feature of the present invention, the N-(piperid-4-yl) benzamide derivatives of general formula I are prepared by the process which comprises reacting a reactive derivative of a benzoic acid of the general formula:
~2 ,~
~ r COOH III
/~
~: Rl R
. 10 (wherein R, Rl and R2 are as hereinbefore defined) with a piperidine derivative of the general formula:
~ ,R
2N ~ N - ~ R IV
wherein the various symbols are as hereinbefore defined. The reactive deriva-tive of the said benzoic acid may be a halide (preferably chloride), an alkyl ester (preferably methyl ester), anhydride or a mixed anhydride, the N-imida-zolamide or acid azide.
The reaction is preferably carried out in the presence of an inertorganic solvent, for example benzene, toluene, chloroform, tetrahydrofuran or dioxan, at a temperature between -5 and 120~C.
The piperidine derivatives of general formula IV can be prepared by reduction of corresponding piperid-4-one oximes with lithium aluminium hydride in the presence of diethyl ether or tetrahydrofuran, 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. The piperidine derivatives of general formula IV whereill R4 represents a cyclohexadienyl group can be prepared from a corresponding phenyl derivative of the fol~ula R4 represents a phenyl group by reduction with lithium in the presence of liquid ammonia or a lower alkylamine.
~094~75 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 chloro-formate in the presence of an organic nitrogen-containing base, e.g. triethyl-amine, in an inert organic solvent, e.g. tetrahydrofuran or methylene chloride, and at a temperature between -20C 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 prepared from the benzoic acids by methods known per se, as can also the N-imidazolamides or acid azides of the acids.
The N-(piperid-4-yl)benzamide 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 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 110C.
In the preparation of those compounds of general formula I wherein the sym'ool(s) Rl and/or R2 represent(s) an amino group by the aforementioned processes, it is sometimes advisable to protect the amino group(s) of the acid of general formula III or derivative thereof before reacting the compound with the piperidine derivative of general formula IV. In this case an N-acyl deri-vative of the amino-substituted benzoic acid of general formula III is initially prepared, the acyl protecting group preferably being acetyl, chloroacetyl, trifluoroacetyl or phthalimido. After the reaction between the N-acylated compound of general formula III, or reactive derivative thereof, with the ~ 4 _ . ~
`` 1094075 piperidine derivative of general formula IV, 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 Rl and/or R2 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 solution.
The N-(piperid-4-yl)benzamide derivatives of general formula I
have as one of their principal ~harmacological properties the ability to antogonize 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.
~onsequently, they may be useful in the treatment of nausea and vomiting of diverse origin and as neuroleptic or tranquillizing agents. They may be useful for the treatment of nausea and vomiting resulting from gastrointestinal disorders, congestive heart failure, post-operative 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 N-~piperid-4-yl)benzamide derivatives of general formula I may be employed in the form of non-toxic pharmaceutically-~ ~ - 5 -... ...
10~407S
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 or aromatic acids in which the aromatic nucleus may optionally be substituted by groups such as hydroxy, lower alkoxy, amino, mono- or di-(lower)alkylamino and sulphonamido groups.
They may also be employed in the form of pharmaceutically-acceptable quaternary ammonium salts such as those salts formed by reaction of the N-(piperid-4-yl)benzamide derivatives of general formula I with lower alkyl halides or sulphates, or in the form of oxygenated derivatives in which oxygen is attached to the nitrogen atom of the piperidine nucleus, viz. the N-oxides.
The pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives and N-oxides of the N-(piperid-4-yl)benzamide derivatives of general formula I may be prepared by methods known per se.
Also included within the scope of the present invention are pharma-ceutical compositions which comprise, as active ingredient, at least one N-~piperid-4-yl)benzamide derivative of general formula I, or a non-toxic pharmaceutically-acceptable acid addition salt or quaternary ammonium deriva-tive 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 admixed with the active compound, or compounds, to form the compositions of this invention are well known per se and the actual excipients used depend inter alia on the 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, - 105~4075 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 li~uid and solid diluents which are compatible with the active ingredient, together with, if desired, colouring or flavouring agents. Tab-lets or capsules may conveniently contain between 0.1 and 20 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 ex-ample, sucrose to for~ a syrup. The suspension may comprise a water insoluble active compound of the invention or an acid addition salt or quaternary ammoni-um or N-oxide derivative thereof in association with water, together with 3 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 with 20 other active anti-acid and anti-ulcer agents (excluding anticholinergic agents) for oral or, in appropriate cases, for parenteral use.
The following Reference Example and Examples illustrate the prepara-tion of piperidine compounds of the present invention.
~ERENCE EXAMPLE
A solution of lithium (5 g.; 0.7 mol) in liquid ammonia (250 ml.) was added little by little to another solution of l-benzyl-4-aminopiperidine (S0 g.;
0.264 moles) in anhydrous diethyl ether (100 ml.~. After stirring for half an hour, absolute ethanol (180 ml.) was added little by little, the solvent re_ moved _ vacuo and the residue taken up with water. The aqueous solution was extracted with diethyl ether and the organic layers dried and distilled in vacuo `` 1094075 to give l-cyclohexa-l'J4'-dienylmethyl-4-aminopiperidine (48 g.), b.p. 117 -118C,/0.5 mm.Hg.
Also prepared in similar manner were:
1-(4-methylcyclohexa_1,4-dienyl)methyl-4-aminopiperidine, b.p.
104 - 106C/0.07 mm.Hg.;
l-(l-cyclohexa-1',4'-dienyl-ethyl)-4-aminopiperidine, b.p. 103 -105C./0.08 mm.Hg. and l-cyclohexen_3'_ylmethyl_4_aminopiperidine, b.p. 101 - 103C./0.05 mm.Hg.
Triethylamine (7.0 ml.; 0.05 moles) and ethyl chloroformate (4.8 ml.;
0.05 moles) were added successively to a stirred suspension of 2-methoxr-4-amino-5-chlorobenzoic acid (10.1 g.; 0.05 moles) in anhydrous tetrahydrofuran (300 ml.) whilst maintaining the temperature between -5 and -10C. After stirring at this temperature for 0.5 hours, a solution of 1-cyclohexa-1',4'-dienylmethyl-4-aminopiperidine (9.6 g.; 0.05 moles) in anhydrous tetrahydro-furan (50 ml.) was added; the temperature was maintained at -5 to -10C. for 1 hour and then the reaction mixture was allowed to stand overnight at room temperature. The solvent was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layers washed with water. The chlo-roform solution was dried (Na2S04) and the solvent removed in vacuo to give a solid which was triturated with a mixture of methanol and diethyl ether. N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenz-amide (12.2 g.) was obtained.
The hydrochloride monohydrate was prepared by addition of a saturated ethanolic solution of hydrogen chloride to a solution of the base in ethanol.
Recrystallization of the precipitate from ethanol gave a white solid, m.p.
226 - 227C. (dec.).
Also prepared in a similar manner were:
N-(l-cyclohexa-1',4'-dienrlmethylpiperid-4-yl)-2-methoxy-5-methyl-sulphonylbenzamide hydrochloride, m.p. 209 - 211~C. (dec.);
109~075 N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-chloro-benzamide hydrochloride, m.p. 231 - 233C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide hydrochloride, m.p. 215C. ~dec.);
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-sulpha~oyl-benzamide hydrochloride, m.p. 230 - 231C. ~dec.);
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide hydrochloride monohydrate, m.p. 193 - 195C~
N-[1-~4-methylcyclohexa-1,4-dienyl)methylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 246 - 248C. ~dec.);
N-[l-~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 241 - 242C. ~dec.);
N-~l~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-acet-amido-5-chlorobenzamide, the fumarate of which melts at 171 - 173C.;
N-[l-~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 264 - 266C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4,5-di-aminobenzamide dihydrochloride monohydrate, m.p. 240 - 242C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-dimethyl-amino-5-chlorobenzamide, the fumarate of which melts at 182 - 184C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-methyl-amino-5-chlorobenzamide, the fumarate of which melts at 203 - 205~C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 180 - 182C.;
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 247 - 249C.;
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-acetamido-5-chlorobenzamide, the fumarate of which melts at 173 - 175C., and N-( cyclohexen-3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chloro-benzamide, m.p. 189 - 191C.
_ g ~, ~ ",, , The fumarates of th0 piperidine derivatives mentioned aboYe were obtained by adding fumaric acid to a hot ethanolic solution of the piperidine base, the amount of added acid being substantially equimolecular to that of the piperidine base present, stirring the hot mixture until dissolution, and then cooling the resulting solution to crystallize the fumarate.
To a warm solution of N-(l-cyclohexene-3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino_5-chlorobenzamide (3.5 g; 0.0093 moles) in acetone (75 ml.) a solution of methyl iodide (2.63 g.; 0.0185 moles) in acetone (25 ml.) was slow-ly added. The mixture was stirred at room temperature for 12 hours and thenheated under reflux for 4 more hours. The mixture was then concentrated in vacuo to a small volume and the residue filtered off to give N-~l-cyclohexen-3'_ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide methyl iodide (4 g.), m.p. 231 - 233C (dec.) after recrystallization from a mixture of ethanol-water.
The following Examples illustrate pharmaceutical compositions accord-ing to the present invention and procedures for their preparation.
100,~00 Tablets each containing 2 mg. of N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino_5-chlorohenzamide hydrochloride monohydrate were prepared from the following formulation:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydr~te 200 g.
microcrystalline cellulose 1870 ~.
lactose spray dried 9880 g.
car~oxyme~hyl starch 430 g.
sodium stearyl fumarate 60 g.
colloidal silicon dioxide 60 g.
" 1094075 Procedure-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-cyclohexa-1',4'-di-enylmethylpiperid-4-yl)-2-methoxy-4_amino_5_chlorobenzamide hydrochloride mono-hydrate were prepared from the following formulation:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride nohydrate 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 sieYe, then mixed in a suitable mixer and distributed into 100,000 gelatine capsules (180 mg.).
10,000 Suppositories each containing 5 mg. o~ N-(l-cyclohexa-1',4'-dienylmethylpiperid_4_yl)_2_methoxy-4_amino_5-chlorobenzamide hydrochloride monohydrate were prepared as follows:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate 50 g.
~heobroma oil 19950 g.
Proc _ ure:
The theobroma oil was melted and the N~ cyclohexa-1',4'-dienyl-109~075 methylpiperid-4-yl)_2_methoxy-4-amino-5-chlorobenzamide hydrochloride monohyd-rate 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-cyclohexa-1',4'-dienyl-methylpiperid-4_yl)_2_methoxy_4_amino-5_chlorobenzamide hydrochloride monohyd-rate were prepared from the following formulation:
N-(l-cyclohexa-1'-4'-dienylmethylpiperid-4-yl)_2_methoxy_4_amino-5-chlorobenzamide hydrochloride monohydrate monohydrate 100 g.
sodium chloride 500 g.
water injectable grade q.s. 100 litres Procedure:
The N-(l -~yclohexa .1',4'_dienylmethylpiperid-4_yl)-2-methoxy-4-amino-5_chlorobenzamide hydrochloride monohydrate and the sodium chloride were dissolved in approximately 80 litres of water with slight heating. The solu-tion was diluted with water to 100 litres passed through a bacteria-retaining filter and filled into 2 ml. glass ampoules in known msnner. 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-cyclohexa-1',4'-dienylmethylpiperid-4_yl)-2_methoxy_4_amino-S_chlorobenzamide hydrochlo-ride monohydrate were prepared as follows:
N~ cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate 75 g, sorbitol 70000 g.
sorbic acid 125 g.
-~ 10~407S
citric acid 125 g.
distilled water q.s. 150 litres flavouring agent q.s.
Procedure:
-The N-(l-cyclohexa-1',4'-dienylmethylpeperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate 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 *o 150 litres and divided amongst the bottles.
Similar compositions to those described in Examples 3 to 7 can be prepared having as the active ingredient piperidine derivatives of general formula I other than N-(l-cyclohexa-$',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, for example other products conforming to that for-mula mentioned in Example 1.
The piperidine derivatives of general formula IV are new compounds and as such constitute another feature of the present invention.
Claims (31)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a N-(piperid-4-yl)benzamide derivative or a pharmaceutically-acceptable acid addition salt thereof, of the general formula:
(I) [wherein R represents a lower alkoxy or allyloxy group; R1 represents a hydrogen atom or R1 and R2, which may be the same or different, each represent a 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; R3 represents a hydrogen atom or a lower alkyl group; R4 represents a cyclohexenyl or cyclohexadienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives 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 a pharmaceutically acceptable acid addition salt.
(I) [wherein R represents a lower alkoxy or allyloxy group; R1 represents a hydrogen atom or R1 and R2, which may be the same or different, each represent a 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; R3 represents a hydrogen atom or a lower alkyl group; R4 represents a cyclohexenyl or cyclohexadienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable acid addition salts and quaternary ammonium derivatives 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 a pharmaceutically acceptable acid addition salt.
2. N-(piperid-4-yl)benzamide derivatives of general formula I, as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
3. 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.
4. A process according to claim 1 or 3 in which the reaction is carried out in an inert organic solvent at a temperature between -5° and 120°C.
5. A modification of the process claimed in claim 1 in which the benzoic acid of general formula III is reacted with the piperidine derivative of general formula IV in the presence of a dehydrating agent.
6. A process according to claim 5 in which the dehydrating agent is silicon tetrachloride, a mono-, di- or trialkyl-silyl chloride, titanium tetra-chloride, N,N'-dicyclohexyl-carbodiimide, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene-p-sulphonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent.
7. A process according to claim 5 or 6 in which the reaction is carried out in an inert organic solvent at a temperature between 20° and 110°C.
8. Process according to claim 1 for the preparation of piperidine deri-vatives of the general formula II:
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 cyclohexenyl or cyclohexadienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable acid addition salts thereof, which process comprises reacting a reactive derivative of a benzoic acid of formula (III') (III') with a piperidine derivative of general formula (IV') (IV') wherein the various symbols R are as defined above, and if desired, convert-ing the thus obtained compound into a pharmaceutically acceptable salt there-of.
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 cyclohexenyl or cyclohexadienyl group optionally substituted by an alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable acid addition salts thereof, which process comprises reacting a reactive derivative of a benzoic acid of formula (III') (III') with a piperidine derivative of general formula (IV') (IV') wherein the various symbols R are as defined above, and if desired, convert-ing the thus obtained compound into a pharmaceutically acceptable salt there-of.
9. N-(piperid-4-yl)benzamide derivatives of general formula II, as defined in claim 8, and pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 8, or by an obvious chemical equivalent thereof.
10. A process for the preparation of N-(1-cyclohexa-1',4'-dienylmethyl-piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide which process comprises reacting 2-methoxy-4-amino-5-chlorobenzoic acid with 1-cyclohexa-1',4'-dienylmethyl-4-aminopiperidine.
11. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
12. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-methylpiperid-4-yl)-2-methoxy-5-methylsulphonylbenzamide which process comprises reacting 2-methoxy-5-methylsulphonylbenzoic acid with 1-cyclohexa-1',4'-dienylmethyl-4-aminopiperidine.
13. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-methylsulphonylbenzamide whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
14. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-methylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide which process comprises reacting 2-methoxy-4-amino-5-bromobenzoic acid with 1-cyclohexa-1',4'-dienyl-methyl-4-aminopiperidine.
15. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
16. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-methylpiperid-4-yl)-2-methoxy-5-sulphamoylbenzamide which process comprises reacting 2-methoxy-5-sulphamoylbenzoic acid with 1-cyclohexa-1',4'-dienylmethyl-4-aminopiperidine.
17. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-sulphamoylbenzamide whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.
18. A process for the preparation of N-[1-(4-methylcyclohexa-1,4-dienyl) methylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which process comprises reacting 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(4-methylcyclohexa-1, 4-dienyl)methyl-4-aminopiperidine.
19. N-[1-(4-methylcyclohexa-1,4-dienyl)methylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.
A process for the preparation of N-[1-(1-cyclohexa-1',4'-dienylethyl) piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which process comprises reacting 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(1-cyclohexa-1',4'-dienyl-ethyl)4-aminopiperidine.
21. N-[1-(1-cyclohexa-1',4'dienylethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.
22. A process for the preparation of N-[1-(1-cyclohexa-1',4'-dienylethyl) piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide which process comprises reacting 2-ethoxy-4-amino-5-chlorobenzoic acid with 1-(1-cyclohexa-1',4'-dienyl-ethyl)-4-aminopiperidine.
23. N-[1-(1-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.
24. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-methylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide which process comprises reacting 2-methoxy-4-methylamino-5-chlorobenzoic acid with 1-cyclo-hexa-1',4'-dienylmethyl-4-aminopiperidine.
25. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-methyl-amino-5-chlorobenzamide whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.
26. A process for the preparation of N-(1-cyclohexa-1'.4'-dienyl-methylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide which process comprises reacting 2-allyloxy-4-amino-5-chlorobenzoic acid with 1-cyclohexa-1', 4'-dienylmethyl-4-aminopiperidine.
27. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide whenever prepared by the process of claim 26 or by an obvious chemical equivalent thereof.
28. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-methylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide which process comprises reacting 2-ethoxy-4-amino-5-chlorobenzoic acid with 1-cyclohexa-1',4'-dienylmethyl-4-aminopiperidine.
29. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide whenever prepared by the process of claim 28 or by an obvious chemical equivalent thereof.
30. A process for the preparation of N-(cyclohexen-3'-ylmethyl-piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide which process comprises reacting 2-methoxy-4-amino-5-chlorobenzoic acid with 1-cyclohexen-3'-ylmethyl-4-aminopiperidine.
31. N-(cyclhexen-3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide whenever prepared by the process of claim 30 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 |
|---|---|
| CA1094075A true CA1094075A (en) | 1981-01-20 |
Family
ID=9810379
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA271,917A Expired CA1094075A (en) | 1976-02-17 | 1977-02-16 | Piperidine derivatives |
| CA271,918A Expired CA1094059A (en) | 1976-02-17 | 1977-02-16 | Piperidine derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA271,918A Expired CA1094059A (en) | 1976-02-17 | 1977-02-16 | Piperidine derivatives |
Country Status (13)
| Country | Link |
|---|---|
| JP (2) | JPS596851B2 (en) |
| AT (2) | AT356106B (en) |
| AU (1) | AU509216B2 (en) |
| BE (2) | BE851508A (en) |
| CA (2) | CA1094075A (en) |
| CH (2) | CH605751A5 (en) |
| DE (2) | DE2705949C2 (en) |
| ES (5) | ES455833A1 (en) |
| FR (2) | FR2342963A1 (en) |
| GB (1) | GB1513631A (en) |
| IE (2) | IE44610B1 (en) |
| NL (2) | NL7701630A (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 |
| US5395832A (en) * | 1991-02-15 | 1995-03-07 | Hokuriku Seiyaku Co., Ltd. | Benzamide derivatives |
| TW243449B (en) * | 1991-02-15 | 1995-03-21 | Hokuriku Pharmaceutical |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MC965A1 (en) * | 1972-06-01 | 1974-02-01 | Soc Et Scient Et Ind De L Ile | New method of preparing 2-alkoxy-4,5-substituted benzamides |
| 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 ES455833A patent/ES455833A1/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 ES455835A patent/ES455835A1/en not_active Expired
- 1977-02-11 ES ES455834A patent/ES455834A1/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 AT AT98577A patent/AT356106B/en not_active IP Right Cessation
- 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
- 1977-02-15 FR FR7704988A patent/FR2342963A1/en active Granted
- 1977-02-16 FR FR7705169A patent/FR2341570A1/en active Granted
- 1977-02-16 NL NL7701630A patent/NL7701630A/en not_active Application Discontinuation
- 1977-02-16 BE BE175000A patent/BE851508A/xx not_active IP Right Cessation
- 1977-02-16 CA CA271,917A patent/CA1094075A/en not_active Expired
- 1977-02-16 IE IE327/77A patent/IE44610B1/en unknown
- 1977-02-16 IE IE328/77A patent/IE44611B1/en unknown
- 1977-02-16 NL NL7701631A patent/NL7701631A/en not_active Application Discontinuation
- 1977-02-16 CA CA271,918A patent/CA1094059A/en not_active Expired
- 1977-02-16 BE BE175001A patent/BE851509A/en not_active IP Right Cessation
- 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 |
|---|---|
| IE44611L (en) | 1977-08-17 |
| ATA98577A (en) | 1979-09-15 |
| AT356105B (en) | 1980-04-10 |
| ZA77562B (en) | 1977-12-28 |
| JPS596851B2 (en) | 1984-02-15 |
| CA1094059A (en) | 1981-01-20 |
| IE44611B1 (en) | 1982-01-27 |
| FR2342963A1 (en) | 1977-09-30 |
| AU509216B2 (en) | 1980-05-01 |
| DE2706038A1 (en) | 1977-08-18 |
| ES455831A1 (en) | 1978-01-16 |
| IE44610L (en) | 1977-08-17 |
| ES455834A1 (en) | 1978-01-01 |
| BE851509A (en) | 1977-06-16 |
| ATA97877A (en) | 1979-09-15 |
| CH605751A5 (en) | 1978-10-13 |
| ZA77563B (en) | 1978-04-26 |
| AT356106B (en) | 1980-04-10 |
| CH620678A5 (en) | 1980-12-15 |
| FR2341570A1 (en) | 1977-09-16 |
| JPS52122379A (en) | 1977-10-14 |
| DE2705949C2 (en) | 1983-04-21 |
| JPS52122378A (en) | 1977-10-14 |
| ES455832A1 (en) | 1978-01-01 |
| IE44610B1 (en) | 1982-01-27 |
| AU2192577A (en) | 1978-08-10 |
| NL7701630A (en) | 1977-08-19 |
| BE851508A (en) | 1977-06-16 |
| NL7701631A (en) | 1977-08-19 |
| ES455835A1 (en) | 1978-01-01 |
| ES455833A1 (en) | 1978-01-01 |
| GB1513631A (en) | 1978-06-07 |
| FR2341570B1 (en) | 1981-10-30 |
| FR2342963B1 (en) | 1980-10-03 |
| DE2705949A1 (en) | 1977-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1095044A (en) | N-piperid-4-yl benzamide compounds | |
| CA1095046A (en) | N-piperid-4-yl-benzamide compounds | |
| GB1575310A (en) | Piperidine derivatives | |
| IE45833B1 (en) | Octahydro-quinolizinyl benzamide derivatives | |
| US3813400A (en) | Derivatives of 3-amino-1,2,4-triazoles | |
| US4207327A (en) | N-(4-Pyrazolidinyl)benzamides and their amino precursors | |
| US3875165A (en) | (4-Quinolylamino)-(N-piperidyl)benzamides and N-{8 (quinolylamino)-benzoyl{9 piperidines | |
| US4087428A (en) | N-(1-substituted-3-pyrrolidinyl)-4-quinoline carboxamides | |
| CA1094075A (en) | Piperidine derivatives | |
| EP0116347B1 (en) | Substituted 1-azaspiro(4.5)decanes and 1-azaspiro(5.5)-undecanes, intermediates and a process for their preparation, and their use as medicaments | |
| US3479346A (en) | N-acyl-n- (and n,n-bis-) ((1-piperidyl)-lower-alkyl)amines | |
| US4163789A (en) | Anti-psychotic (cycloalkenylalkylpiperidino) benzamides | |
| US3515725A (en) | 2,3a-diazahydrindanone and 3h-pyrido-(1,2-c)pyrimidin-3-one derivatives | |
| US3970661A (en) | 2-Amino, 5-carbamoyl pyridine compounds | |
| US3936459A (en) | 1',4'-Dihydro-1-methyl-spiro [piperidine and pyrrolidine-2,3'(2'H)quinoline]-2'-one compounds | |
| US3225037A (en) | 10-[(amino- and acylamino-1-piperidyl) lower-alkyl]-phenothiazines | |
| US4039678A (en) | N-(substituted-3-pyrrolidinyl)-1-naphthalene carboxamides | |
| CA1105037A (en) | N-(4-pyrazolidinyl) benzamides | |
| US3031455A (en) | 1-phenethyl-4-piperidyl carbamates | |
| GB1574419A (en) | Piperidine compounds | |
| US4959375A (en) | Piperidine derivatives useful as 5-HT3 antagonists | |
| US3907811A (en) | Stereoisomeric forms of 4-anilido-3-methyl-piperidine-1-carboxylates | |
| US3221019A (en) | N-alkinyl and n-alkinyloxy-amides of 4-phenyl - 1,2,5,6 - tetrahydropyridino alkanoic acids and intermediates thereof | |
| US4279822A (en) | N-(1-Substituted-3-pyrrolidinyl)benzamides | |
| US2701797A (en) | - indolylmethyl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |