FR2528429A1 - Amino-benzamide histamine H2 receptor blockers used for ulcers - are 3-sulphonamido or carboxamido N-2,5-di:methylamino:methyl-2-furyl-methyl-thio:ethyl benzamide derivs. - 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 present invention relates to novel amidobenzamides having H2 receptor blocking activity of histemine, their salts, a process for their preparation and pharmaceutical compositions containing them as active ingredients.

After subdividing the nistamine receptors into H1 receptors (Ash and Schild Brit J. Pharmac., Cremother 1966, 27, 427) and H2 receptors (Black et al., Nature 1972, 236, 385) and finding that the Selective blocking of H2 receptors causes inhibition of gastric secretion, many products have been proposed as histamine H2 receptor antagonists, hereinafter referred to as "H2-blockers". Thus, the compounds having received the
International commons Burimamide, metiamide, cimetidine, ranitidine, tiotidine, etintidine, oxmetidine have been the subject of a large number of scientific publications and one of them, cimetidine, is already a tool in the hands medecine for the treatment of ulcerative disease.

 It is also known that h2 histemine receptors are located not only in the gastric mucosa1 but also in the sinus node, ventricular myocardium and coronary vessels and that known H2-blockers are active at the same time. on the cardiac and gastric receptors. Thus, blockade of cardiac H2 receptors may be the cause of bradycardia and asistolia observed as side effects in the treatment of ulcerative disease by cimetidine (Clinica Terapeutica, 1991, 91, in particular page 84).

 It is therefore desirable to have compounds having a dissociation between the gastric and cardiac H2-blocking activity, in favor of the former, which are likely to cause fewer cardiac side effects.

It has now been found that certain amidobenzamides have a good histamine-receptor antagonist action and that this action preferably occurs at the level of the receptors.
H2 gastric.

où R est le groupe diméthylamino ou 1-pyrrclidinyle ; R et R représentent chacun l'hydrogène ou un groupe alkyle en C1-C2;R est l'hydrogène, un groupe alkyle en C1-C3 (substitué de manière faculta tive par un membre choisi dans le groupe se. composant de groupes cya- no, alcoxy en C1-C2 phényle, et d'un groupe hétérocyclique penta9o- nal GU hexagonal), un groupe cycloalkyle en C3-C@, un groupe aikényle en C2-C5 (substitué de manière facultative par un membre choisi dans le groupe se composant de groupes alcoxy en C2-C3, phényle et pnénoxy), un groupe aryle en C8-C10 (substitue de manière facultative par un ou deux membres choisis dans le groupe se composant de groupes hydroxy, halogène, nitro, sulfamoyle, alkyle en C1-C3, alcoxy en C1-C3, alccnoyle en C1-C3, alcoxycarbonyle en C2-C4, dialkylamino en C2-C4 et aicanesulfo nyle en C1-C3), ou un groupe hétérocyclique pentagonal ou hexagonal (éventuellement substitué par un membre choisi dans le groupe se compo sant de groupes oxo, halogène, alkyle en Ct-C; et alcoxy en C1-C@) et
X est l'oxygène ou le soufre, ainsi qu'à leurs sels d'addition avec les acides, pharmaceutiquement acceptables.The demand. French Patent Publication No. 2 471 376 describes and reyendic benzamides having the farmule;

where R is dimethylamino or 1-pyrrolidinyl; R 1 and R 2 are each hydrogen or C 1 -C 2 alkyl, R is hydrogen, C 1 -C 3 alkyl (optionally substituted with a member selected from the group consisting of no, C 1 -C 2 alkoxy phenyl, and a hexagonal hexagonal heterocyclic group GU), a C 3 -C cycloalkyl group, a C 2 -C 5 alkenyl group (optionally substituted with a member selected from the group consisting of C2-C3 alkoxy, phenyl and pnenoxy), C8-C10 aryl (optionally substituted with one or two members selected from the group consisting of hydroxy, halogen, nitro, sulfamoyl, alkyl, C1-C3, C1-C3 alkoxy, C1-C3alkenoyl, C2-C4alkoxycarbonyl, C2-C4-dialkylamino and C1-C3-alkanesulfonyl), or a 5- or 6-membered heterocyclic group (optionally substituted with a selected member) in the group consisting of oxo, halogen, C 1 -C 6 alkyl and C 1 -C 4 alkoxy; C @) and
X is oxygen or sulfur, as well as their pharmaceutically acceptable acid addition salts.

 Among the products described in the patent application above, the compound of formula I or R = dimethylamino, R = R = H and R = 4-sulphamoylphenyl, namely N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ) -ethyl] -4-sulfamoylbenzamide, in the form of oxalate, shows an ED 50 value of 2.54 mg / kc in the inhibitory activity of the acid sequestration of the stomach in the rat.

 However, the above-mentioned French patent application does not describe any amidobenzamide, that is to say no benzamide substituted in the benzene ring by an acylamido or sulphonylamido group.

dans laquelle
R1 représente un groupe NH-A-B, où A est un groupe CO ou
SO2 et B représente un groupe phényle,
R2 et R3, identiques représentent un radical alkyle
inférieur,
X représente un atome de soufre m représente 2, n représente I,
Alk représente un groupe alkylène ayant 1 atome de
carbone ainsi que leurs sels pharmaceutiquement
acceptables.Thus, the subject of the present invention is, according to one of its aspects, new amidobenzamides characterized by the following formula

in which
R 1 is NH-AB, where A is CO or
SO2 and B represents a phenyl group,
R2 and R3, identical represent an alkyl radical
inferior,
X represents a sulfur atom m represents 2, n represents I,
Alk represents an alkylene group having 1 atom of
carbon and their pharmaceutically acceptable salts
acceptable.

 The term "lower alkyl" as used herein refers to groups containing the residue of a saturated or unsaturated aliphatic hydrocarbon having up to 4 carbon atoms such as methyl, ethyl.

 The pharmaceutically acceptable salts include non-toxic salts derived from mineral or organic acids salifying the basic function present in the molecule of compounds of formula II, such as hydrochloride, hydrobromide, sulfate, oxalate, succinate, tartrate citrate, fumarate, maletatt, 4,4'-methylenebis- (3-hydroxy-2-naphthoate), hereinafter referred to as "pamoate", 2 naphthalenesulphonate, hereinafter referred to as "napsylate", methanesulphonate, ci -after designated "mesylate", p-toluenesulfonate, hereinafter referred to as tosate, and the like.

dans laquelle R, R , X, m, n et Alk ont la signification donnée ci-dessus, avec un dérivé fonctionnel d'un acide benzoque de formule

dans laquelle Ria la signification donnée ci-dessus, dans un solvant organique à une température comprise entre la température de 00C et la température d'ébullition du solvant employé et l'on transforme éventuellement le produit ainsi obtenu dans ses sels pnarmaceutiquement acceptables. According to another of its aspects, the subject of the present invention is a process for the preparation of novel compounds of formula II-1 above, said process being characterized in that a compound of formula

in which R, R, X, m, n and Alk have the meaning given above, with a functional derivative of a benzoic acid of formula

wherein Ria has the meaning given above, in an organic solvent at a temperature between the temperature of 00C and the boiling temperature of the solvent employed and optionally converting the product thus obtained into its pharmaceutically acceptable salts.

 As appropriate functional drift anhydride, a mixed anhydride, chloride or an activated ester can be used.

dans laquelle R@ a la signification donne ci-dessus et R représente un groupe nitrophênyle, méthoxyphenyle, trityle, benzhydryle.A preferred functional drift of the formula acid
IV above is represented by the following formula:

wherein R 1 has the meaning given above and R is nitrophenyl, methoxyphenyl, trityl, benzhydryl.

The reaction temperature can vary between 0 ° C. and the boiling point of the solvent employed, but in general the reaction is carried out at room temperature or at 30-50 ° C. It may be best to drive the reaction to cold when it is
exothermic, as in the case where chloride is used as a functional derivative of benzoic acid of formula
IV.

 As reaction solvent, an alcohol, such as methanol or ethanol, or a halogenated solvent, such as methylene chloride, dichloroethane, chloroform and the like, but other organic solvents compatible with the reactants, are preferably used. employas, for example dioxane, tetrahydrofuran or a hydrocarbon such as hexane may also be employed.

 The reaction can be carried out in the presence of a proton acceptor, for example an alkaline carbon or a tertiary amine, in the case where hydrochloric acid, or another acid, is released during the reaction, but this Proton acceptor is not essential for obtaining the final product.

The reaction is fast asser; in general, after 2-4 hours at room temperature or at 30-50 ° C the reaction is complete and the benzamide of formula 11 obtained is isolated according to conventional techniques in free base form or a salt thereof
The free base can be converted in one of its pharmaceutically acceptable salts by treatment with a soludion of the appropriate acid in an organic solvent and the salt thus obtained is isolated according to the usual techniques, generally by simple filtration of the precipitate.

 The novel compounds of formula II of the present invention, as well as their pharmaceutically acceptable salts, act as selective histamine H2 receptor antagonists by selectively inhibiting gastric secretion at gastric H2 receptors with low activity on cardiac H2 receptors. and are therefore useful for the treatment of ulcerative disease.

 The selectivity of the activity of the products of the present invention to H2-type receptors is confirmed by the absence of H1-type activity in the histamine-induced contraction test on the guinea pig isolated island.

The amidobenzemide antagonist activity of the present invention to gastric H 2 -receptors of histamine was conrmed in the anti-secretory activity assay based on antagonism for histamine-induced hypersecretion in the rat according to the method of the invention. Ghosh and Schiid (Brit, 1. Pharmac., 1958, 13, 54). According to this test, gastric acid hypersecretion is induced by intravenous infusion of a sub-maximal dose equivalent to 15 mcmol / kg / hour, and gastric secretion is measured by infusion of a physiological solution at a rate corresponding to
stant in the stomach of the animal.

The antagonistic activity of the compounds in the present invention
The invention at the cardiac H2 receptors of the hstarrne was evaluated in the test of inhibition of increase of
the frequency induced by histamine on the right atrium of
guinea pig (D. Reinhardt and C. Agents and Actions 1974, 4, 217-221).

Table I shows, for a representative compound of the present invention, 3-benzenesulfamido-N- [2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethyl] benzamide, designated by its code number CM 57888, for 3-methanesulfonamido
N- [2- (5-dimethylaminomethylfuran-2-ylmethyl) thio) -ethyl] benzamide, described in the French patent application 81.13 420 of the applicant and designated by its code number CM 57822 and for three reference products, the 2-cyano-1-methyl-3- [2 [(5-methylimidazol-4-yl) methylthio] ethyl] guanidine, hereinafter referred to by its International Denomina tion "cimetidine", N- [2 - [ 5 - [(dimethylamino) methyl] furfuryl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine, hereinafter referred to by its International Common Denomination "ranitidine" and N- [2 - (5-dimethylaminomethylfuran-2-ylmethylthio) -ethyl-4-sulfamoylbenzamide, hereinafter referred to as "Compound A": - the dose (in mcmol / kg per single dose venous route) which inhibits
50% gastric hypersecretion caused by histamine (Dl50)
which represents the index of the H2-gastric-gastric activity - the concentration of product under examination which inhibits by 50
histamine-induced frequency induction on the atrium
guinea pig isolated right (IC50) which represents the index of the activity
R2-blocking heart.

TABLE I

<tb> Compound <SEP> Dl50 <SEP> Cl50
<tb><SEP> (mcmol / kg) <SEP> (t) <SEP>
<tb> Cimetidine <SEP> I <SEP> 0.91 <SEP> 3.99.10-7 <SEP>
<tb> Ranitidine <SEP> 0.21 <SEP> 8.60.10-8
<tb> Compound <SEP> A <SEP> 2,23 <SEP> @@@@@@@@ SEP
<tb> CM <SEP> 57888 <SEP> 0.63 <SEP> 5.90.10-7 <SEP>
<tb> CM <SEP> 57822 <SEP> 0.99 <SEP> 2.07.10-6
<Tb>
From this table it appears that the representative compound of the present invention, the CM 57888, is about 1.5 times more active than cimetidine and 3 times less active than ranitidine as H2 blocking gastric, but compared to the two products of reference it is about 1.5 times and, respectively, about 7 times less active as H2-cardiac blocker.

 Similarly, the CM 57822 compound is almost as active as cimetidine and about five-fold less active than ranitidine as gastric X2-blcbut, in terms of H2-blockade activity there are more than five more than 24 times less active than cimetidine and ranitidine.

 Compound A is, relative to CM 57888 and CM 57822, less active as a gastric H2-blocker and more active as a H2-cardiac blocker.

 The compound of the present invention thus has, compared to the products of the prior art, a good dissociation between the H2-blocking cardiac and gastric activities in favor of the latter.

 With respect to their degree of activity, the compounds of the present invention are low in toxicity and represent a good therapeutic index.

 The present invention, according to another of its aspects, thus refers to pharmaceutical compositions containing, as active ingredients, the benzamides of formula II above as well as their pharmaceutically acceptable addition salts.

 The pharmaceutical compositions: H2-blocking action of the present invention may be formulated for oral administration; sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal, by mixing active ingradients with conventional pharmaceutical carriers.

They can be administered to animals and humans in the treatment of gastric hypersecretion and ulcer
peptic under unitary forms of administration.

In order to obtain the desired H2-blocking effect, the dose of
active ingredient can vary between 1 and 100 mg per kg of weight and
per day, preferably 10 to 50 mg per kg of weight per day.

 Each unit dose may contain from 10 to 1000 mg of active ingredient in combination with a pharmaceutical carrier. This unit dose can be administered at 4 times a day.

 Unit dosage forms include tablets, capsules, powders, granules and oral solutions or suspensions and tablets for subluxal administration, suppositories, and ampoules useful for parenteral administration.

 When preparing a tablet-solid composition, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. .

The tablets may be coated with sucrose or other suitable materials or they may be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

 A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

 A syrup or elixir preparation may contain the active ingredient together with an acaloric sweetener, methulparaben and propylparaben as antiseptics, as well as a flavoring agent and a suitable colorant.

Water-dispersible powders or granulates may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone and the like, as well as with sweeteners or correctors of taste.

 For rectal application, supernatants are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

 For oral administration in drops or for parenteral administration, sn uses aqueous suspensons; isotonic saline solutions or sterile and untreatable salts which support pharmacologically compatible dispersing agents and or gels, for example propylene glycol or butylene glycol.

 The active ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives.

 The following examples illustrate the invention without limiting it.

EXAMPLE 1
To a suspension of 0> 05 mol of 3-benzenesulphonamidobenzoic acid and 0.05 mol of 4-nitrophenol in 250 ml of anhydrous methylene chloride is added 0.05 mol of dicyclohexylcarbodiimide. The mixture is refluxed for 4 hours and then evaporated under reduced pressure. The residue is taken up in 300 ml of methanol and 0.05 mol of 2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethylamine are added to the solution thus obtained.

The reaction mixture is heated under reflux for 2 hours and then evaporated under reduced pressure to dryness.

The residue is thoroughly taken up in 150 ml of N hydrochloric acid and 100 ml of ethyl acetate and filtered.

The organic layer is separated, the pH of the aqueous layer is adjusted to 7.8 and the latter is thoroughly extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is taken up with 40 ml of isopropanol and 9.1 g of 3-benzenesulphonamido are obtained.
N - [2- (5-dimethylaminomethylfuran-2-ylmethylthioethyl) benzamide which is crystallized from isopropanol;
Mp 119-1210C.

EXAMPLE 2
By operating as described in Example 1, by reaction of 0.02 mol of 2- (5-dimethylaminomethylfuran-2-ylmethylthio) ethylamine with 0.02 mol of 3-benzamidobenzoic acid in the presence of dicyclohexylcarbodiimide, the 3- benzamido-N- [2- (5-diméthylaminométhylfuran-2ylméthylthio) ethyl] benzamide.

EXAMPLE 3
Tablets having the following composition
CM 57888 100 mg
lactose 70 mg
potato starch 40 mg
polyvinylpyrrolidone 8 mg
magnesium stearate 2 mg
The mixture of the active substance with lactose and potato starch is moistened with a 15% polyvinylpyrrolidone alcoholic solution, the granulate formed is passed through a 1 mm sieve, mixed with the stearate of magnesium and tablets are formed by compression. Weight of one tablet: 220 mg.

EXAMPLE 4
The tablets manufactured as described in Example 3 are covered in a known manner with a coating for dragees consisting essentially of sugar and talc and the finished dragees are polished with beeswax. Weight of a dragee: 300 mg.

EXAMPLE 5
Capsules having the following composition
CM 57888 200 mg
corn starch 90 mg
talcum 10 mg
The active ingredient and the excipients are intimately mixed and the mixture thus obtained is introduced into gelatin capsules of dimenstion 1. Contents of a capsule: 300 mg.

EXAMPLE 6
Suppositories having the following composition
CM 57888 300 mg
mass for suppositories
(Witospol W45) 1.450 mg
The finely powdered active ingredient is suspended in the suppository waste at 370 ° C. and the mixture is poured into slightly pre-cooled molds. Weight of a suppository: 1.750 mg.

Claims (5)

Alk represents an alkylene group having 1 carbon atom and its pharmaceutically acceptable salts. X represents a sulfur atom m represents 2, n represents 1 R2 and R3, identical, represent a lower alkyl radical,  S02 and B represents a phenyl group R is NH-A-B, where A is CO or  in which

 1. A compound of formula 2,3-Benzenesulfonamido-N-9- (dimethylaminomethylfuran-2-ylmethylthio) ethylbenzamide and its pharmaceutically acceptable salts. 3. Process for the preparation of compounds of formula

 wherein R has the meaning given above, in an organic solvent at a temperature between 0 ° C and the boiling point of the solvent employed and optionally converting the product thus obtained into its pharmaceutically acceptable salts.

 in which R, R, X, m. and Alk have the meaning denned above, with a functional derivative of a denzoic acid of formula

 in that a compound of formula  as well as its pharmaceutically acceptable salts, Alk represents an alkylene group having 1 carbon atom  n represents 1,  m represents 2,  X represents a sulfur atom  laughing,  50 and B represents a phenyl group, R2 and R3, identical represent an alkyl radical lower than  R 1 is NH-A-B, where A is CO or  in which  wherein R has the meaning given in claim 3 and R6 is nitrophenyl, methoxyphenyl, trityl, benzhydryl.

 4. Process according to claim 3, characterized in that the functional derivative of benzoic acid uses a compound of this formula  5. Pharmaceutical composition containing at least one compound according to claims 1 and 2.