GB2207673A - 2, 4, 5-tri-substituted benzamide derivatives - Google Patents
2, 4, 5-tri-substituted benzamide derivatives Download PDFInfo
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- GB2207673A GB2207673A GB08818350A GB8818350A GB2207673A GB 2207673 A GB2207673 A GB 2207673A GB 08818350 A GB08818350 A GB 08818350A GB 8818350 A GB8818350 A GB 8818350A GB 2207673 A GB2207673 A GB 2207673A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
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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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Compounds of the general formula: <IMAGE> [wherein R<1> represents hydrogen or an acetyl group; R<2> represents halogen; R<3> represents a group selected from: <IMAGE> (wherein R<5> represents C1-C6 alkyl group; R<6> represents hydrogen or a methyl or methoxy group; R<7> represents a cyclohexenyl, phenyl, 4-fluorophenoxy, tetrahydrofuryl or 1, 3-dioxolanyl group; and n is a number from 1 to 3); R4 represents a C3-C6 cycloalkyl, tetrahydrofuryl, cyclohexenyl or phenoxy group; and m 0, 1, 2, 3 or 4 (with the proviso that when m is 0, R<4> is either a C3-C6 cycloalkyl or tetrahydrofuryl group)] and a pharmaceutically acceptable acid addition salts thereof have pharmacological properties rendering them useful as antiemetic agents in the treatment of a wide range of gastrointestinal disorders of somatic, psychosomatic and @in comparison with prior art.
Description
NEW BENZAMIDE DERIVATIVES
THIS INVENTION relates to new substituted benzamides, methods for their preparation, intermediates involved in these methods, compositions containing them and their use in medical treatment.
Substituted benzamides have been shown to possess a number of pharmacological properties most of which are related to their ability to antagonise the central and peripheral effects of dopamine and/or facilitate the release of acetyicholine onto muscarinic receptors in the gastrointestinal smooth muscle. This has led to their successful clinical use as antiemetic and in the treatment of a wide range of gastrointestinal disorders of somatic, psychosomatic and iatrogenic origin.
Nevertheless, blockade of dopamine receptors in the striatum and hypophysis has been associated with the occurrence of extrapyramidal symptoms and hyperprolactinemia related side effects in some patients treated with benzamide drugs such as metoclopramide and clebopride, which limits their overall usefulness.
We have now found that the introduction of new groups in 2 position of the benzamide ring, provides new compounds, which while maintaining the desired gastrokinetic activity, have a significantly reduced antidopaminergic activity.
Accordingly, the present invention provides a compound of the formula:
wherein R1 represents a hydrogen atom or acetyl group,
R2 represents a halogen atom (preferably chlorine),
R3 represents a group selected from:
(wherein R5 represents a C1-C6 alkyl group, R6 represents a hydrogen atom or a methyl or methoxy group, R7 represents a cyclohexenyl, phenyl, 4-fluorphenoxy, tetrahydrofuryl or 1,3-dioxolanyl group and n represents an integer from 1 to 3),
R4 represents a C3-C6 cycloalkyl, tetrahydrofuryl, cyclohexenyl, or a phenoxy group.
m represents an integer from 0 to 4, with the proviso that when m is 0, R4 is only a
C3-C6 cycloalkyl or tetrahydrofuryl group, and pharmacologically-acceptable acid addition salts thereof.
Presently preferred compounds are N-[2-diethylamino)ethyl]-2-cyclopropyl methoxy- 4-amino-5-chlorobenzamide, N-(1-ethylpiperid-3-yl)-2-cyclopropylmethoxy-4-amino5-chlorobenzamide and N-! 1-[2-(1 ,3 -dioxolanyl) methyl] piperid-4-yl] -2-cyclopropyl methox y-4-amino-5-chiorobenzamide.
According to a feature of the present invention, the compounds of the invention are prepared by the process which comprises reacting a reactive derivative of a benzoic acid of the general formula:
(wherein the various symbols are as hereinbefore defined) with an amine of the general formula:
H2N-R3 Vl wherein R3 is as hereinbefore defined. The reactive derivative of the said benzoic acid may be a halide (preferably chloride), an alkyl ester (preferably methyl ester), an anhydride or a mixed anhydride. The benzoic acid of general formula V in which R4 represents a C3-C6 cycloalkyl group is novel and represents a further aspect of this invention. It is prepared by condensation of a lower alkyl ester of the corresponding 2-hydroxy acid with the appropriate halogen derivative, and further alkaline hydrolysis.
The reaction is preferably carried out in the presence of an inert organic solvent, for example benzene, toluene, chloroform, tetrahydrofuran, N,N-dimethylformamide or dioxan, at a temperature between -5-0 and 1200C.
Halides of the benzoic acids of general formula V 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 V can be prepared by the reaction of the acid with, for example, an alkyl chloroformate in the presence of an organic nitrogencontaining base, e.g. triethylamine, in an inert organic solvent, e.g. tetrahydrofuran,
N,N-dimethylformamide or methylene chloride and at a temperature between -209 and +259C. Esters and anhydrides of the benzoic acids of formula V, which may be employed as starting materials in the aforementioned process, can be prepared from the benzoic acids by methods known Per se.
In the preparation of those compounds of general formula I wherein the symbol R1 is a hydrogen atom it is sometimes advisable to use as starting material corresponding compounds in which the amino group is protected by an acyl group, the acyl protecting group preferably being acetyl, chloroacetyl, trifluoracetyl or phthaloyl.
After the reaction the N-acylated intermediate products are subjected to alkaline hydrolysis to give the corresponding compounds of general formula I in which R1 represents a hydrogen atom. In some cases, the N-acylated intermediate products can also be subjected to acid hydrolysis. Alkaline hydrolysis of the N-acylated compound is preferably carried out at a temperature between 202 and 900C with sodium or potassium hydroxide in an aqueous-alcoholic solution, while acid hydrolysis is preferably carried out by heating with dilute hydrochloric acid at the boiling point of the reaction mixture.
The compounds of the invention, in which R3 is other than a group of formula II as defined above, can also be prepared from an N-unsubstituted compound of formula:
wherein R1, R2, R4 and m are as hereinbefore defined and Y represents one of the following groups:
wherein R6 is an hereinbefore defined.
The compound VII is prepared by subjecting the corresponding N-benzyl compound to catalytic hydrogenolysis in a solvent such as a C1-C6 alcohol in the presence of a noble metal-catalyst, e.g. palladium or platinum, which may be absorbed on an inert support such as carbon or barium sulphate, in the presence of hydrogen at normal or elevated pressure and at temperatures between room temperature and 1002C. The compound VII can also be prepared from an ethoxycarbonyl compound of formula X:
(wherein the various symbols are as hereinbefore defined) by hydrolysis with sodium or potassium hydroxide in an organic solvent, for example ethanol or isopropanol, at the boiling point of the solvent.The compound VII may then be reacted with an appropriate halide or sulphonate of structure:
W- R8 xl where W is a halogen atom or a methanesulphonate, p-toluenesulphonate or benzenesulphonate group and R8 represents one of the following groups:
- R5 XII (CH2)n- R7 xm wherein R5,R7 and n are as hereinbefore defined. The reaction is carried out in the presence of a base such as sodium or potassium carbonate or sodium or potassium bicarbonate, in an organic solvent such as toluene, dioxane or methyl isobutyl ketone at a temperature between 40 and 140 C.
The compounds of general formula I can also be prepared, according to a further feature of the invention,by the direct reaction of a benzoic acid of general formula V with an amine of general formula VI in the presence of an appropriate dehydrating agent. Such agents include silicon tetrachloride, a mono-, di- or trialkyl-silyl chloride, titanium tetrachloride, N,N'-dicyclohexylcarbodiimide, carbonyl diimidazole, thionyl chloride, sulphur trioxide in dimethyl sulphoxide, toluene-psulphonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent. The reaction can be carried out in an inert organic solvent, e.g. methylene chloride, acetone, pyridine, ethyl acetate or dioxan, at a temperature between 20 and 1100 C.
The compounds of the invention of formula I can also be prepared from the hydroxy derivative of formula XIV:
(wherein the various symbols are as hereinbefore defined) by reaction with a halogen derivative of formula XV:
Z-(CH2)m-R4 XV wherein Z is chloro, bromo or iodo and R4 and m are as hereinbefore defined. The reaction can be carried out in an organic solvent such as methyl isobutyl ketone, N,Ndimethylformamide, dioxane, or toluene at a temperature between 40 and 140nC and in the presence of an organic or inorganic base such as sodium or potassium carbonate.
The intermediate amines of formula VI wherein R3 is IV and R6 is other than hydrogen can give cis and trans isomers according to the amino and R6 groups positions. Both isomers can be prepared by the methods disclosed in Europ. Pat. App.
076530.
The benzoic acids starting materials V used in the preparation of the compounds of the invention, are prepared according to the general methods described, for example, in GB 1,507,462, GB 1,088,581 and GB 1,019,781.
The new compounds of general formula I can be converted by methods known Der se into acid addition salts, for example by reaction of the basic compounds with acids in appropriate solvents, for example alcohols, dialkyl ketones or ethers. Suitable acid addition salts are those derived from inorganic acids, for example the hydrochlorides and sulphates, and organic acids, for example, the fumarates, acetates, succinates and citrates.
The new compounds of general formula I have potent gastrokinetic in the absence of dopamine antagonist effects.
The pharmacological screening of compounds to optimise these effects was carried out using the following tests 1) Apomorphine-induced emesis in the dog administering compounds by subcuta
neous or intravenous route. (Prala, J.J., High, J.P., Hasses, G.L., Burke, J.C.
and Craven, B.N. J. Pharmac. Exp. Therap. 127. 55-65, 1959).
2) Stomach emptying in the rat, administering compounds by oral route. (Jacoby,
H.I., and Brodie, D.A. Gastroenterol. 52, 676-684, 1967).
The new compounds of general formula I were compared with Metoclopramide (N-[2 (diethylamino) ethyl] -2-methoxy-4-am ino-5-chlorobenzamide) and Clebopride (N-(1- benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide) and were shown to have advantageous profile due to the presence of the new substituents in position 2 of the benzamide group.
As shown Table I, compounds of general formula I, produce a potent prokinetic activity in the gastric emptying of glass beads in the rat. The compounds are claimed to be gastrointestinal kinetics more active than metoclopramide with no antidopaminergic activity in the apomorphine induced vomiting in the dog, and therefore without the potential for associated extrapyramidal side effects.
TABLE I
GASTRIC EMPTYING IN THE RAT APOMORPHINE - INDUCED @@@@@@@@@ @@@ @@@@ Compound MAX.EMPT-DRUGEMPT x 100 %Protected animais No (Tables II MAX EMPT. - VEHICLE EMPT.
and III) 1 mg/Kg p.o. 1 mg/Kg i.v.
Metoclopramide 42 100 Clebopride 82 100 1 59 0 3 54 0 10 44 0 13 45 21 27 . 0 29 66 0 The present invention also provides pharmaceutical compositions which comprise, as active ingredient, at least one compound of general formula I, or a pharmacologi cally acceptable salt in association with a pharmaceutically acceptable carrier or diluent. Preferably the compositions are made up in a form suitable for oral, topical, percutaneous or parenteral administration.
The pharmaceutically acceptable carriers or diluents which are admixed with the active compound, or compounds or salts of such compounds, to form the compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Compositions of this invention are preferably adapted for administration per os. In this case, the composition for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing one or more compounds of the invention; such preparations may be made by methods well known in the art.
The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or capsules may conveniently contain between 0.1 and 20 mg of active ingredient or the equivalent amount of an acid addition salt thereof.
The liquid compositions adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.
Compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injection fluid.
A further aspect of the present invention provides a method of treating various gastro-intestinal disorders including vomiting in mammals and in man by administering an effective amount of a compound or salt of formula I, suitably using compositions and administration routes described above. Effective doses are normally in the range of 0.1-100 mg of active ingredient per day.
In another aspect of the invention, the compounds may be mixed with active antiacid and anti-ulcer agents (excluding anti-cholinergic agents) for oral or, in appropriate cases, for parenteral use.
The following Examples illustrate the preparation of compounds of the present invention.
EXAMPLE 1
To a solution of 2-cyclopropylmethoxy-4-amino-5-chlorobenzoic acid (3.2 g, 0.0134 moles) in pyridine (30 ml), a solution of N,N diethylethylenediamine dihydrochloride (2.4 g; 0.0125 moles) and sodium hydroxide (0.5 g; 0.0125 moles) in water (15 ml) was added. To the resulting solution N,N'-dicyclohexyl-carbodiimide (3.1 g; 0.0146 moles) was added and the mixture stirred at room temperature for 20 hours. A new amount of N,N'-dicyclohexyl-carbodiimide (3.1 g; 0.0146 moles) was added, stirred for 8 hours and again N,N'-dicyclohexyl-carbodiimide (3.1 g; 0.0146 moles) was added.After stirring at room temperature for 24 hours, the insoluble solid was filtered off, washed with water and the solvent removed in vacuo at a temperature between 30 and 450C.
The solid residue was taken up in water, made alkaline with sodium hydroxide and extracted with methylene chloride. Then the solution was dried (Na2SO4), decolourised and the solvent removed in vacuo to give a solid which was treated with diethyl ether and filtered, yielding N-[2-(diethylamino)ethyl]-2-cyclopropilmethoxy- 4-amino-5-chlorobenzamide (2.3 g) as the free base, m.p. 119-121oC (recrystallized from ethanol).
EXAMPLE 2
Triethylamine (1.6 ml; 0.0113 moles) and ethyl chloroformate (1.15 ml; 0.0113 moles) were added succesively to a stirred solution of 2-cyclopropylmethoxy-4-amino-5- chlorobenzoic acid (2.7 g; 0.0113 moles) in methylene chloride (125 ml) whilst maintaining the temperature between -5 and -lOQC. After stirring at this temperature for 2 hours, a solution of 4-amino-1-benzylpiperidine (2.2 g; 0.0113 moles) in methylene chloride (10 ml) was added, the temperature was maintained at -5 to -10 C for 1 hour and then allowed overnight to reach room temperature The reaction mixture was washed with water, sodium hydroxide aqueous solution, and then with water.After drying (Na2SO4) the solvent was removed in vacuo to give an impurified oil which was dissolved in ethanol and reacted with the stoichiometric amount of fumaric acid. By cooling N-(l-benzylpiperid-4-yl)-2-cyclopropylmethoxy-4amino-5-chlorobenzamide acid fumarate (3.2 g) crystallized, m.p. 198-200 C (d).
EXAMPLE 3
A mixture of cis-N-(3-methoxypiperid-4-yl)-2-cyclopropylm ethoxy-4-amino-5chlorobenzamide (3 g; 0.009 moles), 3-(4-fluorphenoxy) propyl chloride (1.9; 0.010 moles), potassium carbonate (1.3 g; 0.009 moles) and acetonitrile (125 ml) was boiled under reflux for 48 hours after which, a new amount of 3-(4-fluorphenoxy)propyl chloride (0.19 g; 0.0010 moles) was added and refluxed again for other 24 hours. The solvent was removed in vacuo the residue treated with water and extracted with methylene chloride. The organic solution was dried (Na2SO4), decolorized with charcoal and the solvent removed in vacuo to give an oil (4.2 g).This product was purified by column chromatography with silica gel and methanol: ammonium hydroxide (100:1.5) as solvent, when pure cis-N-[ 1-[3-(4-fluorphenoxy)propyl] -3- methoxypiperid-4-y1]-2-cyclopropylm ethoxy-4- amino-S -chlorobenza m ide was obtained (3.4 g) as an oiL Then it was salified with the stoichiometric amount of fumaric acid in ethanol-acetone to give the hydrogen fumarate salt; m.p, 157-160 C (d) after recrystallisation from ethanoL
The compounds of general formula I included in the following Tables II and III were prepared according to the processes disclosed in Examples 1, 2 and 3 as indicated. TABLE II
No R R R3 R4 m Method Base/Salt m.p.oC Example form 1 H Cl # Cyclopropyl 1 1,2 Base 119.121 2 " " " Cyclopentyl 0 1,2 " 86-87 3 " " # Cyclopropyl 1 2 C4H4O4* 208-210 (d) 4 " " " Cyclopentyl 0 2 Base 160-162 5 " " " Cyclohexyl 1 2 1/2C4H4O4 205-207 6 " " " " 2 2 C4H4O4 155-157 7 " " " 3-Cyclohexenyl 1 2 Base 200-202 (d) 8 " " " 2-Tetrahydrofuryl 1 2 " 181-183 (d) 9 " " " " 2 2 1/2C4H4O4 164-166 10 " " " " 3 2 " 111-113 11 " " " 3-Tetrahydrofuryl 0 2 Base 183-185 (d) 12 " " " " 1 2 C4H4O4 206-208 (d) 13 " " " Phenoxy 2 2 177-179 14 OC-CH3 " " Cyclopropyl 1 2 162-164 (d) (*) Fumaric acid TABLE III
Method Base/Salt No R R R4 R6 R7 m n Example form m.p.oC 15 H Cl Cyclopropyl H Phenyl 1 1 2 C4H4O4* 198-200 16 " " Cyclopentyl " " 0 " 2 Base 150-161 17 " " Cyclohexyl " " 1 " 2 1/2C4H4O4 227-229 18 " " " " " 2 " 2 Base 170-172 19 " " 3-Cyclohexenyl " " 1 " 2 " 133-136 20 " " 2-Tetrahydrofuryl " " 1 " 2 " 170-172 21 " " " " " 2 " 2 " 149-151 22 " " " " " 3 " 2 C4H4O4 154-157 23 " " 3-Tetrahydrofuryl " " 0 " 2 1/2C4H4O4 240-242 (d) 24 " " " " " 1 " 2 Base 142-144 25 " " Phenoxy " " 2 " 2 " 151-153 26 " " Cyclopropyl " 3-Cyclohexenyl 1 " 2 " 131-133 27 " " Cyclopentyl " " 0 " 2 C4H4O4 207-209 (d) 28 " " Cyclohexyl " " 1 " 2 1/2C4H4O4 229-231 29 " " Cyclopropyl " 1,3-Dioxolan-2-yl 1 " 2 C4H4O4 181-183 (d) 30 " " Cyclopentyl " " 0 " 2 Base 204-207 31 " " Cyclohenxyl " " 2 " 2 C4H4O4 196-198 (d) 32 " " Cyclopropyl " 2-Tetrahydrofuryl 1 " 2 " 197-9 (d) .../...
Method Base/Salt m.p.oC No R R R4 R6 R7 m n Example form .../...
33 H Cl Cyclopentyl H 2-Tetrahydrofuryl 0 1 2 C4H4O4 186-188 (d) 34 " " Cyclopropyl " " 1 3 2 " 191-198 (d) 35 " " " OCH3 " " " 2,3 "** 162-169 (d) 36 " " " " " " " 2,3 "** 200-202 37 " " " CH3 " " " 2,3 "** 140-142 38 " " " H 4-Fluorphenoxy " " 2,3 " 171-173 (d) 39 " " " OCH3 " " " 2,3 "** 157-160 (d) 40 " " " CH3 " " " 2,3 ClH.H2O** 102-146 (*) Fumaic acid (**) Cis-isomer The following Examples illustrate pharmaceutical compositions according to the present invention and procedures for their preparation.
EXAMPLE 4 50,000 Tablets each containing 1 mg of N-(l-benzylpiperid-4-yl)-2-cyclopropyl methoxy-4-amino-5-chlorobenzamide were prepared from the following formulation:
N-(1-benzylpiperid-4-yl)-2-cyclopropylmethoxy-4amino-5-chlorobenzamide 50 g microcrystalline cellulose 950 g lactose spray dried 4950 g carboxymethyl starch 200 g sodium stearyl fumarate 50 g colloidal silicon dioxide 50 g
Procedure
All the powders were passed through a screen with aperture of 0.6 mm, then mixed in a suitable mixer for 20 minutes and compressed into 125 mg tablets using 6 mm circular and flat bevelled punches. The disintegration time of the tablets was about 60 seconds.
EXAMPLE 5 2,000 Bottles (125 ml volume) each containing a solution of 25 mg of N-(1benzylpiperid-4-yl)-2-cyclopropylmethoxy-4-am ino-5-chlorobenzam ide were prepared as follows:
N-(1-benzylpiperid-4-yl)-2-cyclopropylm ethoxy-4amino-5-chlorobenzamide 50 g sorbitol 120000 g sorbic acid 250 g citric acid 250 g distilled water q.s. 250 litres flavouring agent q.s.
Procedure
The N-(1-benzylpiperid-4-yl)-2-cyclopropylmethoxy-4-a;n ino-5-chlorobenzam ide and the sorbic acid were dissolved in 150 litres of water and then the sorbitol, citric acid and flavouring agent were added with stirring until dissolution. The mixture was diluted to 250 litres and filled into 125 ml bottles using an appropriate filling machine.
EXAMPLE 6 10,000 Ampoules each containing 0.5 mg of N-(1-benzylpiperid-4-yl)-2-cyclopropyl methoxy-4-amino-5-chlorobenzamide were prepared from the following formulation: N-(1-benzylpiperid-4-yl)-2-cyclopropyl m ethoxy-4- amino5-chlorobenzamide 5g sodium chloride 250 g lactic acid 5g 1N Sodium hydroxide aqueous solution q.s. to pH= 3 water injectable grade q.s. 50 litres
Procedure
The N-(1-benzylpiperid-4-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide, the lactic acid and the sodium chloride were dissolved in 40 litres of water. The resulting solution was neutralised to pH=3 with the sodium hydroxide solution, diluted to 50 litres, then passed through a bacteria-retaining filter and filled under sterile conditions into 5 ml glass ampoules in known manner.
EXAMPLE 7 5,000 Suppositories each containing 1 mg of N-(1-benzylpiperid-4-yl)-2-cyclopropyl methoxy-4-amino-5-chlorobenzamide, were prepared as follows: N-(1-benzylpiperid-4-yl)-2-cyclopropyl methoxy-4- amino-5-chlorobenzamide 5g theobroma oil 9995 g
Procedure
The theobroma oil was melted and the active compound suspended in it. The mixture was then poured into appropriate suppository moulds to make 2.0 g suppositories.
EXAMPLE 8 100,000 Capsules each containing 1 mg of N-(1-benzylpiperid-4-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide were prepared as follows:
N-(1-benzylpiperid-4-yl)-2-cyclopropylmethoxy-4amino-5-chlorobenzamide 100 g lactose 10500 g corn starch 9000 g colloidal silicon dioxide 200 g magnesium stearate 200 g
Procedure
All the powders, previously passed through a screen with an opening of 0.6 mm, were mixed for 20 minutes and distributed into 100,000 capsules of appropriate size using a filling machine.
Claims (22)
1. A compounds of the general formula:
wherein R represents hydrogen or an acetyl group ;
R represents halogen ;
R represents a group selected from :
wherein R5 represents a C1-C6 alkyl group; R6 represents hydrogen or a methyl or methoxy group;
R7 represents a cyclohexenyl, phenyl, 4-fluorophenoxy, tetrahydrofuryl or 1,3-dioxolanyl group and n is a number
from 1 to 3;
R4 represents a C3-C6 cycloalkyl, tetrahydrofuryl, cyclohexenyl or phenoxy group; m is 0, 1, 2, 3 or 4 with the proviso that when m is 0, R4 is either a C3-C6 cycloalkyl or tetrahydrofuryl group; and pharmaceutically acceptable acid addition salts thereof.
2. A compound according to claim 1 wherein R2 is chlorine.
3. A compound according to claim 1 or 2 wherein
R represents hydrogen.
4. A compound according to any one of the preceding claims wherein R3 is a group of formula III.
5. A compound according to claim 4 wherein R5 represents an ethyl group.
6. A compound according to any one of claims 1 to 3 wherein R3 is a group of formula IV wherein n is 1.
6
7. A compound according to claim 6 wherein R6 represents hydrogen.
8. A compound according to any one of the preceding claims wherein R4 represents a C3-C6 cycloalkyl group.
9. A compound according to claim 1 hereinbefore specifically mentioned.
10. N-[2-(diethylamino)ethyl]-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide.
11. N-(l-ethylpiperid-3-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide.
12. N-Il-[2-(1,3-dioxolanyl)methyl]piperid-4 yl]-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide.
13. A process for preparing a compound of formula I as defined in any one of the preceding claims which comprises reacting a benzoic acid of the general formula:
or a reactive derivative thereof with an amine of general formula: H2N-R VI wherein R1, R2, R3 and R4 are as defined in any one of the preceding claims.
14. A process according to claim 13 wherein the reactive derivative of the benzoic acid of formula V is a halide, an alkyl ester, an anhydride or a mixed anhydride.
15. A process according to claim 14 wherein the halide is a chloride.
16. A process according to claim 14 wherein the alkyl ester is methyl ester.
17. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 9, 11 and 12 which comprises reacting a compound of the general formula:
with a compound of general formula:
W-R8 XI wherein Y represents a group of the formula:
W is a halogen or sulphonate group;
R8 is a group of the formula: XII or
(CH2)n-R7 XIII and R1, R2, R4, R5, R6, R7, m and n are as defined in any one of claims 1 to 9, 11 or 12.
18. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 12 which comprises reacting a compound of the general formula:
with a compound of general 'formula:
z- (CH2) m-R4 XV wherein R1, R2, R3, R4 and m are as defined in any one of claims 1 to 12 and Z is a halogen group.
19. A process according to any one of claims 13 to 18 substantially as hereinbefore described with reference to any one of Examples 1 to 3.
20. A pharmaceutical composition comprising, as active ingredient, a compound according to any one of claims 1 to 12 together with a pharmaceutically acceptable diluent or carrier.
21. A pharmaceutical composition according to claim 20 substantially as hereinbefore described with reference to any one of Examples 4 to 8.
22. A compound according to any one of claims 1 to 12 or a composition according to claim 20 or 21 for use in a method of treatment of the human or animal body by surgery or therapy or in a method of diagnosis practised on the human or animal body.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878718346A GB8718346D0 (en) | 1987-08-03 | 1987-08-03 | Substituted benzamides |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8818350D0 GB8818350D0 (en) | 1988-09-07 |
| GB2207673A true GB2207673A (en) | 1989-02-08 |
| GB2207673B GB2207673B (en) | 1991-09-11 |
Family
ID=10621741
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB878718346A Pending GB8718346D0 (en) | 1987-08-03 | 1987-08-03 | Substituted benzamides |
| GB8818350A Expired - Lifetime GB2207673B (en) | 1987-08-03 | 1988-08-02 | New benzamide derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB878718346A Pending GB8718346D0 (en) | 1987-08-03 | 1987-08-03 | Substituted benzamides |
Country Status (2)
| Country | Link |
|---|---|
| ES (1) | ES2007281A6 (en) |
| GB (2) | GB8718346D0 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0481756A2 (en) * | 1990-10-16 | 1992-04-22 | Teikoku Chemical Industry Co., Ltd. | Benzamide derivatives |
| EP0445862A3 (en) * | 1990-03-06 | 1992-05-20 | Janssen Pharmaceutica Nv | N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2h-benzopyran)carboxamide derivatives |
| WO1994002462A1 (en) * | 1992-07-17 | 1994-02-03 | Janssen Pharmaceutica N.V. | 4-amino-n^_-(4-methyl-4-piperidinyl)-2-methoxybenzamides |
| WO2001064641A1 (en) * | 2000-03-02 | 2001-09-07 | Kissei Pharmaceutical Co., Ltd. | Hydroxyethoxybenzamide derivatives and drugs containing the same |
| WO2008114971A1 (en) * | 2007-03-16 | 2008-09-25 | Dong-A Pharm. Co., Ltd. | Novel benzamide derivatives and process for the preparation thereof |
| CN110950843A (en) * | 2019-11-28 | 2020-04-03 | 广东东阳光药业有限公司 | Substituted benzamide derivatives and uses thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2160871A (en) * | 1984-06-28 | 1986-01-02 | Bristol Myers Co | Pharmacologically active substituted benzamides |
-
1987
- 1987-08-03 GB GB878718346A patent/GB8718346D0/en active Pending
-
1988
- 1988-08-02 ES ES8802412A patent/ES2007281A6/en not_active Expired
- 1988-08-02 GB GB8818350A patent/GB2207673B/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2160871A (en) * | 1984-06-28 | 1986-01-02 | Bristol Myers Co | Pharmacologically active substituted benzamides |
Non-Patent Citations (1)
| Title |
|---|
| J. MED. CHEM., VOL. 31, NO 8, AUGUST 1988, PAGES 1548 TO 1558, * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0445862A3 (en) * | 1990-03-06 | 1992-05-20 | Janssen Pharmaceutica Nv | N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2h-benzopyran)carboxamide derivatives |
| US5185335A (en) * | 1990-03-06 | 1993-02-09 | Janssen Pharmaceutica N.V. | N-(4-piperodinyl)(dihydrobenzofuran or dihydro-2h-benzopyran) carboxamide derivatives |
| US5262418A (en) * | 1990-03-06 | 1993-11-16 | Tanssen Pharmaceutica N.V. | N-(4-piperidinyl) (dihydroxybenzofuran or dihydro-2H-benzopyran)carboxamide derivatives |
| EP0481756A2 (en) * | 1990-10-16 | 1992-04-22 | Teikoku Chemical Industry Co., Ltd. | Benzamide derivatives |
| EP0481756A3 (en) * | 1990-10-16 | 1992-08-26 | Teikoku Chemical Industry Co., Ltd. | Benzamide derivatives |
| WO1994002462A1 (en) * | 1992-07-17 | 1994-02-03 | Janssen Pharmaceutica N.V. | 4-amino-n^_-(4-methyl-4-piperidinyl)-2-methoxybenzamides |
| US5498618A (en) * | 1992-07-17 | 1996-03-12 | Janssen Pharmaceutica N.V. | 4-amino-N-(4-methyl-4-piperidinyl)-2-methoxybenzamides for treating smooth muscle contraction disorders |
| AU668208B2 (en) * | 1992-07-17 | 1996-04-26 | Janssen Pharmaceutica N.V. | 4-amino-N-(4-methyl-4-piperidinyl)-2-methoxybenzamides |
| WO2001064641A1 (en) * | 2000-03-02 | 2001-09-07 | Kissei Pharmaceutical Co., Ltd. | Hydroxyethoxybenzamide derivatives and drugs containing the same |
| WO2008114971A1 (en) * | 2007-03-16 | 2008-09-25 | Dong-A Pharm. Co., Ltd. | Novel benzamide derivatives and process for the preparation thereof |
| CN110950843A (en) * | 2019-11-28 | 2020-04-03 | 广东东阳光药业有限公司 | Substituted benzamide derivatives and uses thereof |
| CN110950843B (en) * | 2019-11-28 | 2022-12-27 | 广东东阳光药业有限公司 | Substituted benzamide derivatives and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8818350D0 (en) | 1988-09-07 |
| GB2207673B (en) | 1991-09-11 |
| ES2007281A6 (en) | 1989-06-01 |
| GB8718346D0 (en) | 1987-09-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930802 |