CS229935B2 - Production method of 3-amido-n-(2(5dimethylaminomethylfura-2-ylemthylthyltio)benzamide - Google Patents

Abstract

3-B-A-NH-N- (2-(5-dimethylaminomethyl- furan-2-yl-methylthio) ethyl)- benzamide derivs. of formula (III) and their salts are new (where A is CO or SO2 and B is 1-6C alkyl, phenyl, pyridyl, pyridyl-1-oxide, pyrazinyl or thienyl). Histamine H2 receptor antagonists, which inhibit gastric secretion and are used to treat ulcers. Activity tests show that many of the cpds. have better gastric H2 blocking activity than does cimetidine or rasitidine, whereas their cardiac H2 blocking activity is much weaker. (III) may be administered enterally or parenterally in doses of 1-100, pref. 10-50, mg/Kg/ day. Adult doses comprise 10-100, pref. 100-500, mg. (III) where B-A is methanesulphonyl, ethanesulphonyl, butanesulphonyl, benzenesulphonyl or 2-thiophenecarbonyl and their salts.

Description

The invention relates to a process for the production of amidobenzamides which are particularly effective for blocking histamine H2 receptors.

After the histamine receptors have been divided into the Hi receptors (Ash and Schild, Brit. J. Pharmac. Chemother. 1966, 27, p. 427) and H2 receptors (Black et al., Nature 1972, 236, p. 385) and after discovery, that selective blocking of H2 receptors causes inhibition of gastric fluid secretion, numerous products have been proposed as histamine H2 receptor antagonists, hereinafter referred to as " H2 blockers ". A large number of scientific papers have been published on these compounds, which have received the international designation burimamide, methiamide, cimetidine, ranitidine, thiotidine, etintidine, oxmetidine. one of them, cimetidine, is already an effective means in the hands of doctors for the treatment of stomach ulcer.

All of the above compounds have a group of formula I-NH-C-NH-

II y (i) where

Y represents an oxygen or sulfur atom or a residue of N-CN or CH-NO2, which is either linear or ring-forming, as in the case of oxmetidine.

Thus, the above products are all characterized by two nitrogen atoms linked through a carbon atom.

French Patent Application, Publication No. 2,471,376, describes benzamides of formula II

where

R is a dimethylamino or 1-pyrrolidinyl radical, each of R ¹ and R ² being hydrogen or an alkyl radical of 1 to 3 carbon atoms,

R ³ is hydrogen, C 1 -C 3 alkyl optionally substituted by cyano, C 1 -C 3 alkoxy, phenyl or 5- or 6-membered heterocyclic group, C 3 -C 6 cycloalkyl radical 229935 k, C 2 -C 6 alkenyl radical C 5 -C 5 optionally substituted by C 1 -C 3 alkoxy, phenyl or phenoxy, C 6 -C 10 aryl, optionally substituted by one or two hydroxyl groups, halogens, nitro groups, sulfamoyl groups, C 1 -C 3 alkyl groups C 1 -C 3 alkoxy, C 1 -C 3 alkanoyl, C 2 -C 4 alkoxycarbonyl, C 2 -C 4 dialkylamino or C 1 -C 3 alkanesulfonyl, or a 5- or 6-membered heterocyclic group optionally substituted oxo,. halo, C 1 -C 3 alkyl or C 1 -C 3 alkoxy, and

X is oxygen or sulfur, as well as pharmaceutically acceptable acid addition salts.

Among the compounds described in the above published application, the compound of formula II wherein R is dimethylamino, R1 and R2 are both hydrogen and R3 is 4-sulfamoylphenyl, i.e. N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) Ethyl] -4-sulfamoylbenzamide in the form of oxalate, characterized by an inhibitory activity, expressed as DE 50 = 2.54 mg / kg, against gastric acid secretion in the rat.

The aforementioned French application relating to compounds having no groupings of the formula I does not include in its general formula any amidobenzamide, i.e. no benzamide substituted on the benzene ring by an acylamide or sulfonylamido group.

It is also known that histamine H2 receptors occur not only in the gastric mucosa, but also in the sinus node, in the myocardium of the ventricle and in the coronary arteries, and that known H2 blockers act simultaneously on the heart and gastric receptors. Thus, blockade of cardiac H2 receptors may also be the cause of bradycardia and asystole observed as side effects in the treatment of ulcer by the administration of cimetidine (Clinice Therapeutica, 1981, 9S, pp. 81-91, especially p. 84).

It would therefore be desirable to have compounds in which the efficacy of blocking gastric H2 receptors would be separated from the blocking activity of the heart receptors in favor of blocking gastric receptors, and which would have fewer side effects with respect to heart receptors. The above groupings of the formula I, which have a good histamine H2 receptor antagonistic effect, which is advantageous for gastric receptors.

Surprisingly, it has also been found that the blocking effect on H2 receptors is sufficiently pronounced only when the amido group of these new amidobenzamides is bonded in the meta position on the phenyl core of these benzamides.

Furthermore, it has been found that these novel amidobenzamides do not have the secondary effects of H2 blocking products, in particular cimetidine, such as an antiandromyogenic effect.

The invention therefore relates to a process for the preparation of amidobenzamides of the general formula III

CH3

CH ₃ where

A is CO or SO2. and

B represents a C 1-6 alkyl radical, a phenyl radical, a pyridyl radical, a pyridyl-1-oxide radical, a pyrazinyl radical or a thienyl radical, as well as their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts include non-toxic salts derived from mineral or organic acids bound to one or both of the basic groups occurring in the molecule of compounds of Formula III, such as hydrochloride, hydrobromide, sulfate, succinate, tartrate, citrate, fumarate, maleate, 4,4'-methylenebis- (3-hydroxy-2-naphthoate), hereinafter referred to as pamoate, 2-naphthalenesulfonate, hereinafter referred to as napsylate, methane sulfonate, hereinafter referred to as mesylate, p-toluenesulfonate, hereinafter. called tosylate, and the like.

The process according to the invention for the preparation of the compounds of the general formula (III) is characterized in that the 2- (5-dimethylaminomethylfuran-2-ylmethylthio) -ethylamine of the formula (IV) is: N-CH CH-S- spews CH.N ^{J-2 20 2 2} ^ сн ₅ (IV) is treated with a functional derivative of benzoic acid of formula V

HH-A-B. (V) where

A and B are as defined above, in an organic solvent at a temperature of from 0 ° C to the boiling point of the solvent used, whereupon the product thus obtained is optionally converted into a pharmaceutically acceptable salt.

An appropriate functional derivative is anhydride, mixed anhydride, chloride or activated ester.

A preferred functional acid derivative of formula (V) above may be represented by formula (VI)

COOR ⁰

NHA-B

WD where

A and B are as defined above and

R 0 represents a nitrophenyl, methoxyphenyl, trityl, or benzhydryl radical.

The reaction temperature may vary from 0 ° C to the boiling point of the solvent used, but is generally carried out at room temperature or in the range of 30 to 50 ° C. It may be advantageous to carry out the cold reaction if it is exothermic, such as when chloride is used as the functional benzoic acid derivative of formula (V).

The reaction is preferably carried out with an alcohol such as methanol or a halogenated solvent such as methylene chloride, dichloroethane, chloroform and the like, but other organic solvents compatible with the reagents used such as dioxane, tetrahydrofuran may also be used. or a hydrocarbon such as hexane.

The reaction may be carried out in the presence of a proton acceptor, for example an alkali metal carbonate or a tertiary amine, when hydrochloric acid or some other acid is released during the reaction, but the use of a proton acceptor is not necessary to obtain the desired product.

The reaction proceeds quite rapidly; as a rule, it is terminated after 2 to 4 hours at room temperature or at a temperature between 30 ° C and 50 ° C and the amidobenzamide (III) formed is isolated by a known procedure in the form of the free base or one of its salts.

The resulting free base can be converted into one of its pharmaceutically acceptable salts by treatment with a solution of the appropriate acid in an organic solvent. When the amidobenzamide of formula III is isolated in the form of a salt, the corresponding free base can be liberated by treatment with an alkali metal hydroxide or carbonate.

The compounds of formula III produced by the process of the invention, and their pharmaceutically acceptable salts, act as selective histamine H2 receptor antagonists by selectively inhibiting gastric juice secretion by acting on gastric H2 receptors at low cardiac II2 receptor activity and are therefore useful in the treatment stomach ulcer diseases.

The selectivity of the activity of the compounds produced by the method according to the invention towards H2-type receptors is confirmed by the lack of activity against the H1-type receptor in histamine-induced contraction in the isolated guinea pig hip.

The antagonist activity of the amidobenzamides produced by the method of the invention against gastric histamine I-12 receptors was confirmed in an antagonist-based anti-secretory activity assay. against histamine-induced hypersecretion in the rat, according to the method of Ghose and Schild (Brit. J. Pharmacol., 1958, 13, p. 54). In this test, gastric acid hypersecretion is induced by intravenous infusion of a submaximal dose of histamine of 15 mcmoles / kg / h and gastric secretion is determined by perfusion of saline to the stomach of the test animal.

Table I shows the compounds produced by the process of the invention and designated by the code number, as well as the three compounds compared, i.e. 2-cyano-1-methyl-3- / 2 - ((5-methylimidazol-4-yl) methylthio ] ethyl / guanidine, hereinafter referred to by its international generic designation 'cimetidine', for N- (2 - ((5 - ((dimethylamino) methyl) furfuryl] thio) ethyl) -N'-methyl-2-methyl-11-yl. -ethendlamine, hereinafter referred to by its international generic designation "ranitidine" and the N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) -ethyl] -4-isulfamoylbenzamide described in French Patent Application No. 2,471 cited above. 376 and hereinafter referred to as "Compound A", a dose (in mmol / kg intravenously in a single dose) that 50% inhibits histamine-induced gastric hypersecretion (DI50) and which represents the efficacy index blocking gastric H2 receptors.

Table I Compound

DI50 (mcmoly / kg) relative efficiency (cimetidine = l)

cimetidine 0.95 1.00 raditidine 0.25 3.80 Compound A 2.26 0.42 CM 57822 0.98 0.97 CM 57888 0.63 1.50 SR 57912 0.33 2.88 SR 57922 1.15 0.82 SR 57927 1.15 0.82 SR 57933 1.82 0.52 SR 57975 0.93 1,02 SR 57981 0.49 1.94

From this table it is apparent that the compounds produced by the process of the invention are all more potent than Compound A and that most of them have an activity comparable to or greater than that of clmétidine. In particular, the two compounds, ie SR 57981 and SR 57912 are very potent and the potency of SR 57912 is very close to that of ranitidine.

The antagonist activity of the compounds of the invention against histamine 112 receptor receptors was evaluated by inhibition of the histamine-induced increase in heart rate in guinea pig right atrium (D. Reinhardt et al., Agent and Actlons 1974, 4, 217-221). ~

Table II shows the concentration of the test product which inhibits the increase in heart rate by 50% in the four compounds produced by the process of the invention and designated by their code numbers CM 57822, CM 57888, SR 57912 and SR 57922 as well as clmethidine, ranitidine and Compound A. induced by histamine in the isolated right atrium of the guinea pig, and which is an index of activity blocking cardiac receptors

I-I2. .

Table II

compound CI50 relative efficiency (mcmol / kg) (cimetidine = 1) cimetidine ranitidine compound A CM 57822 CM 57888 SR 57912 SR 57922 4.10- ⁷ 1 8.10- 8 5 3.1.1Ο ⁷ 1.3 2. ΙΟ® 0.2 5.9. 0,6 ⁷ 0.67 5.10- 8 0.08 6.10- 8 0.06

It can be seen from Table II that the compounds produced by the method of the invention are all much less potent as heart blockers of H2 receptors than cimetidine, while compound A is more potent than cimetidine.

Thus, the compounds produced by the process of the present invention are distinguished by a good separation of blocking activity into the heart over the compounds known in the art. H2 receptors and H2 gastric receptors for efficacy on H2 gastric receptors.

The antiandromyogenic effect of the compound produced by the method of the invention, ie CM 57888, was tested in comparison to the effect of cimetidine and ranitidine on sexually immature rats (in groups of 9 experimental animals) of Sprague Dawley strain CD (SD) BR (Charles River, France) 22 to 23 days of age, whose sexual adnexa as well as anus was stimulated by daily testosterone injection. Testosterone. · Was administered subcutaneously as a suspension in a steroid carrier, either at 0.2 mg / animal / day or at 0.4 mg / animal / day. At each testosterone dose, cimetidine, ranitidine and CM 57888 were injected intraperitoneally as saline solutions for ranitidine and steroid carrier suspensions for the other two compounds; the doses used were 400 mg / kg / day for cimetidine, 100 mg / kg / day for ranitidine and 200 mg / kg / day for CM 57888. A group of animals treated with carriers only served as controls. The test was run for 8 days. 24 hours after the last injections, the animals were sacrificed and immediately removed and weighed the abdominal prostate, seminal vesicle and anus lift.

The three compounds have been found to have antiandrogenic and anti-anabolic activity. However, at the doses used, the efficacy is CM

57888 was significantly less than that of the compounds to be compared, since, unlike the compounds to be compared, no effect was observed with the test compound CM 57888 at a testosterone dose of 0.4 mg / animal / day.

This experiment shows that the compound produced by the method of the invention is less able to induce characteristic side effects associated with the antiandromyogenic effect of known H2 receptor blockers.

In relation to their potency, the compounds produced by the process of the invention are of low toxicity and have a good therapeutic index.

The amidobenzamides of the above formula (III) and their pharmaceutically acceptable addition salts are active ingredients of pharmaceutical compositions characterized by blocking activity at H2 receptors. These compositions may take a form suitable for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration and are prepared by admixing the active ingredients with appropriate suitable pharmaceutical carriers. They can be administered to animals and humans for the treatment of gastric hypersecretion and gastric ulcer in unit dosage forms.

In order to achieve the desired blocking effect on H2 receptors, the dose of active ingredient may vary from 1 to 100 mg per kg body weight per day, and is preferably 10 to 50 mg / kg body weight per day.

Each unit dose may contain 10 to 1000 mg, preferably 100 to 500 mg, of the active ingredient in combination with a pharmaceutically acceptable carrier. This unit dose may be administered one to four times daily.

Unit dosage forms include tablets, pills, powders, granules, and solutions or suspensions for oral administration, tablets for sublingual administration, suppositories, as well as ampoules for parenteral administration.

For the preparation of a solid mixture in the form of a tablet, the active ingredient is admixed with a pharmaceutically acceptable carrier such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. The tablets may be coated with sucrose or other suitable substances, or may be adjusted to have a protracted or delayed effect and to continuously release a predetermined amount of the active ingredient.

A capsule formulation is obtained by mixing the active ingredient with a diluent and filling the resulting mixture with soft or hard capsules.

A composition in the form of a syrup or elixir may contain the active ingredient together with a low-calorie sweetener, methylpanaben and propylparaben as antiseptic, as well as a flavoring and a suitable colorant.

Water-dispersible powders or granules may contain the active ingredient in admixture with dispersing or wetting agents, or suspending agents, such as polyvinylpyrrolidone and the like, as well as sweetening and flavoring agents.

For rectal administration, suppositories are used which contain carriers melting at body temperature, such as cocoa butter or polyethylene glycols.

For oral administration in the form of drops or for parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersing agents and / or wetting agents, such as propylene glycol or butylene glycol, are used.

The active ingredient may also be formulated as microcapsules, optionally with at least one carrier or excipient.

The invention is illustrated in more detail by the following non-limiting examples.

Example 1

A solution of 4.3 g (0.02 mol) of 2- ^{(5-Dimethylamino!} Nomethylf furan-2-yl-methylthio) ethylamine and 6 g (0.02 mol) of 4-nitrophenyl 3-acetamidobenzoic acid in 150 ml of methanol were The mixture is stirred at 40 DEG C. for 2.5 hours, the solvent is evaporated off under reduced pressure and the residue is dissolved in 100 ml of 1 N hydrochloric acid. The solution was washed twice with 40 mL of ethyl acetate and adjusted to pH 7.8 with sodium hydroxide. The residue is then extracted thoroughly with ethyl acetate, the organic phase is dried over anhydrous sodium sulphate and the solvent is evaporated off under reduced pressure. The residue is taken up in 20 ml of isopropanol and the solution obtained is poured into a solution of 1.7 g of anhydrous oxalic acid in 20 ml of isopropanol. The precipitated product is filtered off and recrystallized from ethanol. 6 g of 3-acetam ⁵ -N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethyl] benzamide oxalate (code number CM 57320), m.p. 123 DEG-126 DEG C., are thus obtained.

In a similar manner, 0.02 moles were reacted

2- [5-dimethylaminomethylfuran-2-ylmethylthio) ethylamine with 0.02 mole of 4-nitrophenyl ester of 3-propionamino-benzoic acid or 0.02 mole of 4-nitrophenyl 3-butyramidobenzoate or with 0.02 mole of 4-nitrophenyl ester 3-trimethylacetamidobenzoic compounds yield the following compounds:

3-Propionamido-N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethyl] benzamide oxalate, m.p. 133-135 ° C, 3-butyramido-N- [2- (5-dimethylaminomethylfuran) oxalate -2-ylmethylthio) ethyl] benzamide, m.p.

S-trimethylacetamido-N- [2- (5-dimethylammomethylfuran-2-ylmethylthio) ethyl] benzamide oxalate, m.p. 153-155 ° C.

Example 2

Stirring is continued for 2 hours at room temperature. a solution of 0.02 mol of 2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethylamine and 0.02 mol of 4-nitrophenyl ester was heated at 45 ° C. of 3-methanesulfonamidobenzoic acid in 150 ml of methanol, the solvent is evaporated off under reduced pressure and the residue is dissolved in 100 ml of 1 N hydrochloric acid. The acidic solution was washed with ethyl acetate and adjusted to pH 7.5 by addition of sodium hydroxide. The solution is extracted thoroughly with ethyl acetate, the organic phase is dried over anhydrous sodium sulphate, the solvent is evaporated off under reduced pressure and the residue is dissolved in 20 ml of isopropanol. There was thus obtained 3-methanesulfonamido-N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethyl] benzamide (code number CM 57822) which, after recrystallization from isopropanol, melted at 109-111 ° C.

In a similar manner, 0.02 moles were reacted

2- (d-dimethalaminomethylturan-2lyl-methylthiojethylamine) with 0.02 mol of 3-ethanesulfonamidobenzoic acid 4-nitrophenyl ester or with 3-butanesulfonamidobenzoic acid 4-nitrophenyl ester of 0.02 mol:

3-ethanesulfaoamido-N- [2- (5-dimethyylaminomethylfuran-2-yl-1-thienyl) ethyl] benzamide, isolated as oxalate, m.p. 144-146 ° C and b-batansulfonamido-N- [2- (5-Dimethylaminomethyl-furan-2-ylmethyl-ethyl) -ethyl] -benzamide, isolated as oxalate according to Example 1, code number SR 57981 A, m.p. 103-110 ° C.

Example 1 a d 3

To a suspension of 0.05 mole of 3-benzenesulfonamidobenzoic acid and 0.05 mole of 4-nitrophenol in 250 ml of anhydrous methylene chloride was added 0.05 mole of dicyclohexylcarbodiimide. The resulting mixture was refluxed for 4 hours and then evaporated under reduced pressure. The entire residue was dissolved in 300 ml of methanol and 0.05 mol of methylfuranosyl-4-ethylamine was added.

The reaction mixture was then heated at reflux for 2 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in 150 ml of 1 N hydrochloric acid and 100 ml. ml of ethyl acetate - and the resulting solution is filtered. The resulting organic layer was separated, the pH of the aqueous layer was adjusted to 7.8, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in 40 ml of isopropanol and then separated from the solution

9.1 g of 3-benzenesulfonaolido-N ([2- (5-dimethyluminomethylfurun-2-ylmethyl) thio) ethyl] benzamide (code number CM)

57888), which is recrystallized from isopropanol. Melting point: 119-121 ° C.

In a similar manner, the reaction of 0.05 mole of 3- (3-pyridine-sulfonamido) benzoic acid and 3- [2-thiophenesulfonumido) benzoic acid with 0.05 mole of 4-nitrophenol in 250 ml of anhydrous methyl tetrocoride in the presence of 0.05 mole of dicyclohexylcarbodiimide activated ester, which is then reacted with 0.05 mol of 2- (5-chloro-2-aminomethylfuran-2-ylmethylthio) ethylamine. The team. the following compounds are obtained:

3- [3-Pyridolidone-4-anido-N- [2- (5-dimethyl-molol-2-yugan-2-yl-meteylthio) -ethyl] -benzamide (SR code 57933) as a glassy solid after isolation from diethyl ester, m.p. 80-83 ° C ( decomposition), respectively

3- (- thiophenesulfonamido-N- [2- (5-dimethyluminomethylfurun (2 (ylmethylthio) thiyl) thiyl) benzumide (SR code 57975)), melting after recrystallization from ethyl acetate at 113-115 ° C .

Example 4

Following the procedure described in Examples 1-3 by reacting 0.02 mole of 2- (5-ďimeteyluminomethylfuluan-2 (olethylthio yl) tthyl m · ^s nu activated ester obtained from 0.02 mole of 3-benzarnidobenzoové and 0.02 mole

Of 4-fluoro-phenol in the presence of dicyclohexylcarbodiimide, prepared 3-benzumido-N- [2- (5-dimethylaminomethyl-furun-2-yl-meteylthio) -ethyl] -benzamide (SR code 57916), which after recrystallization from ethyl acetate has a melting point of 112 to 115 degrees Celsius.

In the same manner, the reaction of 2- (5-dimethyl-aminomethylfuran (2 (yl (meteylthio) ethylamine) with activated 3- [2 (thienylkurboxamido) benzoic acid ester or 3- (3-pyridinecarboxamido) benzoic acid or 3- (4 (Pyridocarbonyl (amido) benzoic acid or 3- (2-pyridinecurboxumido) benzoic acid or 3- (2-pyrazinocarbonyl) - benzoic acid yields the following compounds:

3- (- Thienylcarboxamido) -N- [2- (5-dimethyl-2-fluoromethyl-2H-furan-2-ylmethyl-thio) -ethyl] -benzamide (code number SR)

57922), m.p. 116 DEG-118 DEG C., 3- (3-pyridinylcarbamoyl) di-oxalate -N- [2- (- dimethylamino) monoethylfuran-2 (oxoethyl) thioethyl] -benzamide (code number SR)

57927 A), melting point after recrystallization from 95% ethanol in the range of 137 to 140 ° C, 3- (4-pyridinecarboxamido) -N- [2- (5-dimethylaminomethyl-furan-2-yl) -phenyl (thio) dioxalate dioxalate Benzamide (code SR 57944 A), m.p. after recrystallization from 95% ethanol in the range of 176-178 degrees Celsius, 3- (2-pyridinecarboxamido) -N- [2- (5-dimethylammomethylfuran-2-ylmethylthio) ethyl oxalate of benzamide (code number SR 57953 A), having a melting point after recrystallization from ethanol in the range of 143-145 ° C, respectively.

3- [pyrazinecarboxamido] -N- [2- (5-dimethylammomethylfuran-2-ylmethylthio) ethyl] benzamide (code number SR 57939), m.p. 80-82 ° C.

Example 5

To a suspension of 9.5 g (0.037 mol) of 3 - [(3-pyridine-1-oxide) carboxamido] benzoic acid and □ g (0.037 mol) of α-nitrophenol in 400 ml of anhydrous methylene chloride were added 7.7 g (0.037 mol) ) dicyclohexylcarbodiimide. The resulting mixture was refluxed for 4 hours and then evaporated under reduced pressure. All the residue was dissolved in 300 ml of methanol and 7.9 g (0.037 mol) of 2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethylamine was added to the solution thus obtained. The reaction mixture was then heated at 40 ° C for 2.5 hours, after which time the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in 70 ml and an amount of hydrochloric acid until the reaction was clearly acidic, and the solution was washed with ethyl acetate containing 10% ethanol. The combined organic phases were dried over anhydrous sodium sulphate and then evaporated to dryness under reduced pressure. The residue is taken up in 10 ml of acetone and 0.3 g of 3- [(3-pyridine-1-oxide) carboxamido] -N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethyl] is obtained from the resulting solution. benzamide (product code SR 57912), m.p. 160-162 ° C.

In a manner similar reaction of 0,0-37 mol of 2- (5-dimethylaminomethylfuran-2-yl-methylthio) ethylamine activated ester obtained from 0.037 mol of 3- [(4-pyridin-oxide ^r nl) carboxamido] benzoic acid and 0.037 mole of 4-nitrophenol in the presence of dicyclohexylcarbodiimide, prepared 3 - [(3-pyridine-1-oxide) carboxamido] -N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethyl] benzamide (codename SR) 57 937), m.p. after recrystallization from isopropanol in the range 145-147 ° C.

Example 6

To a solution of 1 g of 3-benzenesulfonamido-N- [2- (5-dimethylaminomothylfuran-2-ylmethylthio) ethyl] benzamide in 15 ml of ethanol is added a solution of 0.3 g of oxalic acid in 10 ml of ethanol. The precipitated salt is filtered off, dried and recrystallized from 10 ml of 95% ethanol. 1 g of 3-benzenesulfonamido-N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethyl) benzamide oxalate is obtained as a glassy solid.

Example 7

To a solution of 2 g of 3-butanesulfonamido-N- [2- (5-dimethylaminomethyl-furan-2-ylmethyl-thio) -ethyl] -benzamide oxalate in 10 ml of water was added sodium hydroxide until the reaction of the solution was clearly basic. The solution was extracted with ethyl acetate containing 10% ethanol, the resulting organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. There was thus obtained 3-butanesulfonamido-N- [2- (5-dimethylaminomethylthiran-2-yl-methylthio) ethyl] benzamide (1.5 g) as a yellowish oil.

IR spectra: 3560, 3000, 164.0 and 1148 cm? NMR spectrum R1 (solvent: dimethylsulfoxyl)? _TMS (ppm):

0.83 (3H, m > t),

1.1-1.8 (4H, m),

2.11 (6H, s),

2.63 (2 H, m-t),

2.9-3.6 (4H, mj,

3.34 (2 H, s),

3.75 (2 H, s),

6.15 (2 H, m),

6.2- 6.8 (4H, m);

8.5 (1H, tb, disappear by addition of D2O).

Example 8

Tablets are prepared containing as active ingredient one of the compounds described in Examples 1 to 7 having the following composition:

active substance 100mg

Lactose 70mg potato starch 40mg polyvinylpyrrolidone 8mg magnesium stearate 2mg

The mixture of the active compound with lactose and bromoborch starch is moistened with a 15% alcoholic solution of polyvinylpyrrolidone, the resulting granulate is passed through a 1 mm sieve, mixed with magnesium stearate and compressed into tablets. The tablet weight is 220 mg.

Example 9

The tablets obtained in the manner described in Example 8 are coated according to the known method. for crepe, which consists essentially of sugar and talc; finished dragees are polished with beeswax. The weight of 1 dragee is 300 mg.

Example 1 0

Pills containing as active are made

Example 1 a d 14

Tablets are prepared containing as active ingredient one of the compounds described in Examples 1 to 7, having the following composition:

component one of the compounds described in Examples 1 to 7, having the following composition:

active substance 200mg corn starch 90mg talc 10mg

First, the active ingredient is mixed with the other ingredients and the resulting mixture is filled with size 1 gelatin capsules.

Example 11

Suppositories are prepared containing as active ingredient one of the compounds described in Examples 1 to 7 having the following composition:

active substance 300 mg suppository (Witespol W45) 1450 mg

The finely divided active ingredient is suspended in a suppository mass at 37 ° C and the resulting mixture is poured into pre-cooled forms. Weight of one suppository: 1750 mg.

Example 12

active substance 150 mg microcrystalline cellulose 75 mg talc 15 Dec mg polyvinylpyrrolidone 30 mg precipitated silica 25 mg magnesium stearate 5 mg In a mixing and kneading machine, the during 15 Dec minutes thoroughly mix all above i ive- copper components except lubricant, whereupon se

knead the mass by gradually adding water. The mixed mixture is passed through a 1.25 mm sieve. The resulting granulate is dried in a forced-air oven until a relatively low residual moisture content of approximately 2% is reached. The granulate is homogenized, lubricant is added and tablets are compressed. Weight of one tablet: 300 mg.

Tablets containing 250 mg of active ingredient are prepared in the same manner.

Example 15

Tablets are prepared containing as active ingredient one of the compounds described in Examples 1 to 7 having the following composition:

Active Substance 150mg Microcrystalline Cellulose 75mg Lactose 100mg Magnesium Stearate 7mg Talc 18mg

The powders are sieved through a 0.3 mm sieve and mixed together until a homogeneous mixture is obtained which is compressed and granulated. Tablets are compressed from the granules so formed. Weight of one tablet: 350 milligrams.

Example 13

Following the procedure of Example 12, tablets were prepared containing as active ingredient one of the compounds described in Examples 1 to 7 having the following composition:

The coated tablets were prepared according to the procedure of Example 14, containing as active ingredient one of the compounds described in Examples 1 to 7 having the following composition:

active substance 150 mg carboxymethylstarch 10 mg microcrystalline cellulose 85 mg lactose 135 mg hydrogenated castor oil 10 mg magnesium stearate 5 mg The tablets are coated, consisting of a mixture comprising: butyl phthalate 0.300 mg polybutyl methacrylate and poles (dimethylaminoethyl) - methacrylate 1,850 mg polyethylene glycol 1500 0.080 mg precipitated silica 0.020 mg talc 0.900 mg titanium dioxide 1,850 mg

Active Substance 350mg Microcrystalline Cellulose 100mg Lactose 125mg Magnesium Stearate 10mg Talc 15mg

Weight of one tablet: 600 mg.

This mixture is dissolved in a solvent, which is then evaporated after application of the solution in a forced-air oven. Weight of one tablet: 400 mg.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of 3-amido-N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethyl] benzamide derivatives of the general formula III nh-a-b (III) wherein: A is CO or 802; V represents a (C1-C6) alkyl, phenyl, pyridyl, pyridyl-1-oxide, pyrazlnyl or thienyl radical, as well as their pharmacologically acceptable salts, characterized in that they are 2- (5-dimethylaminomethylfuran) -2-ylmethylthio) ethylamine of formula IV wherein They are as previously described in an organic solvent at a temperature ranging from 0 ° C to the boiling point of the solvent used, whereupon the compound of formula III thus obtained is optionally converted into a pharmaceutically acceptable salt. 2. A process according to claim 1, wherein the functional benzoic acid derivative is a compound of formula NH-A-B acts as a functional benzoic acid derivative of formula V wherein A and V are as defined in 1, and R 0 represents a nitrophenyl, methoxyphenyl, trityl or benzhydryl radical.