FR2485526A1 - N-di:ethylamino-ethyl-3-substd.-6-alkoxy-benzamide derivs. - useful as gastric emptying agents and antiemetics - Google Patents

Abstract

N-(Diethylamino ethyl)-3-substd.-6- alkoxybenzamide derivs. of formula (I) and their acid-addn. salts are new. In (I), R is alkyl; R1 is H, halo, alkyl or alkoxy; R2 is NH2, alkanoyl or R4N(SO2-R3); R3 is alkyl or dialkylamino; and R4 is H or alkyl. Proviso is that when R2 is NH2 or alkanoyl, then R1 is alkyl. Cpds. (I) are gastric emptying agents and antiemetics, with lower toxicity than cpds. of this type such as metoclopramide, and are esp. useful for treating gastric disorders. They have typical LD50 values of 1000 mg/kg perorally in mice. Dose is 10-400 mg daily in adults.

Description

(où R est un groupe alkyle en C1-C5, R1 est l'hydrogène, un halogène, un groupe alkyle en C1-C5 ou un groupe alcoxy en C1-C5, R2 est le groupe amino, un groupe alcanoyle en C1-C5 ou R4 -N1 -SO2R3;; R3 est un groupe alkyle en C1-C5 ou un grou 4 pe dialkylamino en C2-C1O et R4 est l'hydrogène ou. un groupe
2 alkyle en C1-C5, en prévoyant que, lorsque R2 est le groupe amino ou un groupe alcanoyle en C1-C5, R1 est un groupe alkyle en C1-C5) et ses sels d'addition avec les acides, pharmaceutiquement acceptables.The present invention relates to N- (diethylaminoethyl) -2-alkoxybenzamide derivatives, which are useful as pharmaceuticals for curing gastric disorders or as antiemetic products. More particularly, the present invention relates to a compound having the formula

(where R is C 1 -C 5 alkyl, R 1 is hydrogen, halogen, C 1 -C 5 alkyl or C 1 -C 5 alkoxy, R 2 is amino, C 1 -C 5 alkanoyl) or R 4 -N 1 -SO 2 R 3; R 3 is C 1 -C 5 alkyl or C 4 -C 10 dialkylamino group and R 4 is hydrogen or a group
C 1 -C 5 alkyl, with the proviso that when R 2 is amino or C 1 -C 5 alkanoyl, R 1 is C 1 -C 5 alkyl and its pharmaceutically acceptable acid addition salts.

 Such compounds are described in US Pat. No. 3,177,252 and, in particular, the so-called metoclopramide product available commercially has the disadvantage of having rather high toxicity.

 As a result of various studies, in order to overcome the problem of the toxicity of metoclopramide, the Applicant has found that the compound (I) exhibits excellent pharmacological activities, such as stomach emptying activity and antiemetic activity, with a rather lower toxicity.

In formula (I) above, the definition of the terms used herein is explained by way of illustration as follows: the term "alkyl" means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl t-butyl, pentyl, isopentyl, etc .;
the term "alkoxy" means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, etc .;
the term "alkanoyl" means formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, etc .;
the term "dialkylamino" means dimethylamino, diethylamino, dipropylamino, dibutylamino, methylethylamino, methylpropylamino, etc .; and the term "halogen" means chlorine, bromine, iodine, fluorine, etc.

(où A est le groupe hydroxy, alcoxy, alcoxycarbonyle ou un halogène et R,R et R sont tels que définis précédemment).The compound (I) of the present invention can be prepared according to the following scheme
Path I

(where A is hydroxy, alkoxy, alkoxycarbonyl or halogen and R, R and R are as previously defined).

 The reaction is carried out in an inert solvent (for example acetones, dimethylformamide, methanol, benzene, dimethylsulfoxide, methylene chloride) at room temperature or by heating to the boiling point of the solvent used, if this is necessary in the presence of a condensing agent (for example DDC) and a base (for example triethylamine, pyridine).

(où R et R1 sont tels que définis précédemment).Way II

(where R and R1 are as defined above).

The reduction is carried out with a reduction means chosen from hydrogenation over a catalyst (for example palladium-carbon, platinum oxide, Raney nickel) and hydrogenation with tin dust or iron dust-hydrochloric acid in an inert solvent (eg methanol, ethanol, tetrahydrofuran, methylene chloride) at room temperature or by heating to the boiling point of the solvent used. The starting compound (III) is prepared by reacting the corresponding benzoyl chloride with N, N-diethylethylenediamine in the presence of a base (for example triethylamine)

(où R30 est un groupe alkyle et R,R et R sont tels que dé- finis précédemment).Way III

(where R 30 is alkyl and R, R and R are as previously defined).

 The hydrolysis is carried out by treating with an alkaline hydroxide (for example sodium hydroxide, potassium hydroxide) in a suitable solvent (for example methanol, ethanol, acetone or dimethylsulfoxide) at room temperature or heating to the boiling point of the solvent used.

 Alternatively, the compound (Ic) is prepared directly by reacting the compound (Ib) with a sulfonating agent having the formula A-SO 2 R (V) (where A is a halogen and R is as defined above), in which presence of a base (e.g. pyridine) in an inert solvent (e.g., methylene chloride, benzene, toluene, dioxane, tetrahydrofuran, dimethylsulfoxide, dimethylformamide) at room temperature or heating up at the boiling point of the solvent used.

 The starting compound (IV) is prepared by reacting the compound (Ib) with 2 moles of the sulfonating agent (V) in the presence of triethylamine or with two different kinds of sulfonating agents, in stages.

(où R, Rl-et R3 sont chacun tels que définis précédemment et R4 est un groupe alkyle en C1-C5).Way IV
The compound Id (R4 = alkyl group for I) is, if desired, prepared by reacting the compound (Ic) with an alkylating agent (for example an alkyl halide, a dialkyl sulphate), in the presence of a base (for example potassium carbonate, triethylamine, pyridine) in an inert solvent (for example dimethylformamide, tetrahydrofuran, dioxane, benzene, toluene) at room temperature or by heating up at the boiling point of the solvent used, according to the equation

(where R, R 1 and R 3 are each as previously defined and R 4 is C 1 -C 5 alkyl).

 The compound thus obtained (I) can be converted into its addition salts with acids for the purpose of formulation, crystallization and stabilization. Acids for forming these salts include inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) and organic acids (e.g., succinic acid, citric acid, maleic acid, methanesulfonic acid, acetic acid).

 The compound (I) and its pharmaceutically acceptable acid addition salts are useful as pharmaceuticals for curing gastric disorders or as antiemetic products, having excellent gastrointestinal motility stimulation, excellent For example, N- (diethylaminoethyl) -5-amino-2-methoxy-3-methylbenzamide exhibited nearly equal gastric emptying activity (49.2%). metoclopramide, and N- (diethylaminoethyl) -2-methoxy-4-chloro-5-methanesulfonamidobenzamide showed antiemetic activity (ED50 = about 0.5 mg / kg) in dogs comparable to that of metoclopramide, with acute toxicity in mice (LD50 = 1,000 g / kg) (orally) more than four times lower than that of metoclopramide. Other compounds of the present invention exhibited similar pharmacological activities.

Note: a) Draining activity of the stomach in mice
The stomach emptying report was evaluated by a modified procedure of Jacoby and Brodie (GI Jacoby, DA

Brodie; Gastroenterology, 52, 676, 1967) using each group of ten male mice, so-called SLC-ddY strain, which were starved for 24 hours prior to the experiments, water being supplied to them at will. 20 minutes after oral administration of an experimental compound, 0.15 ml of silver powder suspension (60% silver powder, 40% gum arabic) was administered into the stomach of the mice. Three minutes later, the silver powder remaining in the stomach of the killed mice was collected on filter paper and weighed after drying. The results are present as a percentage of the weight obtained in the control in which the mice were treated with saline.

b) Anti emetic activity in dogs
This test was performed by orally administering an experimental compound to 10-20 month old bigloin dogs, subcutaneously vomiting in 30 minutes. The result was presented by the ED50 (mg / kg) LJanssen, PAJ and collaborators,
Arzneim.-Forsch. 18 (3) 261-279 (1968)].

c) Acute toxicity in mice
Experimental compounds were orally administered to male mice of the so-called SLL-ddY strain with four toxic doses. For each dose, 10 mice were used, their body weight ranging from 20 to 23 grams. Experimental mice were observed for 72 hours after administration. Mortality was calculated by the method of Bliss [Bliss: Ann. Appl. Biol., 22, 134-307 (1935); As. J. Pharmacol., 11, 192 (1938)].

 The compound (I) and its pharmaceutically acceptable acid addition salts can be applied individually or in combination with pharmaceutical diluents, pharmaceutical carriers and / or pharmaceutical adjuvants (eg water, lactose, wheat starch, corn starch, gelatin, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycol, etc.). These products can be distributed in a suitable formulation, such as a solid form (for example tablets, capsules, dragees, granules, suppositories) or a liquid form (for example solutions, suspensions, emulsions) for enteral or parenteral application. The daily dose of compound (I) or salts thereof for oral application to a human adult is about 10 to 400 mg.

 The present invention will now be illustrated by the following examples which are given by way of illustration and not limitation.

EXAMPLE 1
To a solution of N- (diethylaminoethyl) -5-amino-4-chloro-2-methoxybenzamide (1.1 g) and triethylamine (815 mg) in dry methylene chloride (11 ml) was added dropwise. A solution of methanesulfonyl chloride (882 mg) in dry methylene chloride (5 ml) was cooled, cooled with ice and stirred, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture is mixed with an aqueous solution of sodium bicarbonate and the methylene chloride layer is separated. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated.N- (Diethylaminoethyl) -5-bis (methanesulfonyl) amino-4-chloro-2-methoxybenzamide, obtained as an intermediate in the form of The residue is mixed with 10% aqueous sodium hydroxide solution (18 ml) and methanol (2 ml) and heated at 500 ° C. for 30 minutes.The reaction mixture is acidified with concentrated hydrochloric acid, neutralized with an aqueous solution. of sodium bicarbonate, salted out with brine and stirred with methylene chloride The organic layer is dried over anhydrous sodium sulfate and concentrated The residue is chromatographed on a column of alumina, which is eluted with sodium chloride The eluate is concentrated and the residue is washed with a mixture of ethyl acetate-isopropyl ether to give N- (diethylaminoethyl) -4-chloro-5-methanesulfonamido-2-methoxybenzamide (993 mg). ) under crystalline form melting between 123 and 123.50C.

EXAMPLE 2
A solution of N- (diethylaminoethyl) -4-chloro-5-methanesulfonamido-2-methoxybenzamide (570 mg), triethylamine (914 mg) and N, N-dimethylsulfamoyl chloride (1.3 g) in methylene (30 ml) is refluxed for 40 hours. The reaction mixture is mixed with an aqueous solution of sodium bicarbonate.

The organic layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated. N- (diethylaminoethyl) -4-chloro-5- [N- (dimethylaminosulfonyl) methanesulfonamido] -2-methoxybenzamide, obtained as the intermediate product in the form of a residue, is mixed with a 10% aqueous solution of sodium hydroxide (10 ml) and methanol (10 ml) and refluxed for 10 minutes. The reaction mixture is concentrated to remove methanol and the residue is acidified once with 6N hydrochloric acid, neutralized with aqueous sodium bicarbonate solution, warmed up with brine and stirred with methylene chloride. The organic layer is dried over anhydrous sodium sulfate and the methylene chloride is evaporated.

The residue is chromatographed on a column of alumina, which is eluted with methylene chloride to 1% methylene chloride / methylene chloride. The eluate is concentrated and the residue is washed with a mixture of ethyl acetate-isopropyl ether to give N- (diethylaminoethyl) -4-chloro-5- (N-dimethylaminosulfonyl) amino-2-methoxybenzamide (410 mg ) in the form of crystals melting between 110 and 110.50C.

EXAMPLES 3-6
Using the starting material indicated later (Ib), the reaction is carried out as in Example 1, and, as a result, the corresponding product (Ic) is obtained.

<tb> Example
<tb> n <SEP> Ib <SEP> Ic
<tb> n <SEP> R <SEP> R <SEP> pf <SEP> (C)
<tb><SEP> 3 <SEP> 4-CH3 <SEP> CH3 <SEP> 122 <SEP> - <SEP> 122.5
<tb><SEP> 6 <SEP> 6 <SEP><SEP> 3-CH30 <SEP> CH3 <SEP> 94 <SEP> - <SEP> 95
<Tb>

EXAMPLE 7
A mixture of N- (diethylaminoethyl) -2-methoxy-3-methyl-5-nitrobenzamide (4.25 g), platinum oxide (425 mg) and methanol (85 ml) is stirred in a stream of hydrogen. After the hydrogen uptake has stopped, the reaction mixture is filtered to remove the catalyst.

The filtrate is concentrated in vacuo and the residue is chromatographed on a column of alumina, which is eluted with methylene chloride to methylene chloride-2% methanol. The eluate is concentrated in vacuo and the residue is washed with isopropyl ether to give N- (diethylaminoethyl) -5-amino-2-methoxy-3-methylbenzamide (2.38 g) as crystals. between 56 and 570C.

Analysis calculated for C15H20O2N3: C, 64.48; H, 9.02;
N, 15.04 (%).

Found: C, 64.57; H, 9.13; N, 15.11.

EXAMPLE 8
A mixture of 5-acetyl-2-methoxy-3-methylbenoic acid (1.0 g), thionyl chloride (1.14 g) and dry benzene (1.14 ml) is heated at reflux for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is dissolved in acetone (1 ml). N, N-diethylethylenediamine (558 mg) is added under ice-cooling. The reaction mixture is stirred at room temperature for 15 minutes and concentrated in vacuo.

The residue is mixed with water and ice, made alkaline with 10% aqueous sodium hydroxide solution and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on a column of alumina, which is eluted with a mixture of methylene benzenechloride (1: 1), methylene chloride and a mixture of 1% methanol-methylene chloride, in that order. The eluate is concentrated in vacuo to give N- (diethylaminoethyl) -5-acetyl-2-methoxy-3-methylbenzamide (928 mg) as an oil.

Analysis calculated for C17H20O3N2.1 / 5H2O: C, 65.86; H, 8.58;
N, 9.04. Found: C, 65.47; H, 8.73; N, 8.90.

IR: film 3350 (NH), 1683, 1658 (CO) cm
EXAMPLES 9-20
Using the starting material (II), the reaction is carried out as in Example 8, and, therefore, the corresponding product (Ia) is prepared.

<Tb>

<SEP> R <SEP> R1 <SEP> R2 <SEP> pf <SEP> (C) <SEP> or <SEP> IR <SEP> (cm <SEP> 1)
<tb> 9 <SEP> C2H5 <SEP> 3-CH <SEP> = <SEP> C0- <SEP> -3360, <SEQ> 1683, <SEQ> 1655 <SEP> (film)
<tb> 10 <SEP> C <SEP> 3 <SEP><SEP> C2HS <SEP> C ~ <SEP> 3350, <SEQ> 1683, <SEQ> 1658 <SEP> (film)
<tb> lo <SEP> CH3 <SEP>, <SEP> 4
<tb><SEP> I <SEP> CH3SO2NH- <SEP> II <SEP> L48 <SEP> 11 <SEP>"<SEP>C" -CH <SEP> -SO, NH-- <SEP> 111-112
<tb> 12 <SEP>"<SEP>"<SEP> L5 <SEP> L <SEP> ~ <SEP> 120.5-122 <SEP>
<tb> 13 <SEP> Pr-S02NII
<tb><SEP> II <SEP> I- <SEP>"<SEP> 1C2H, -SO, NH
<tb> 15 <SEP>"<SEP> H <SEP> CH <SEP> 48-50 <SEP> - <SEP> - <SEP>
<tb><SEP> 1 <SEP> 3
<tb><SEP> JCH3S02N
<tb> 17 <SEP>"<SEP> .. <SEP> C2H5-S02NH- <SEP> 168-170
<tb> 18 <SEP> .. <SEP> 4-C1 <SEP> .. <SEP> ~ <SEP> 116-117
<tb> 19 <SEP>"<SEP> 4-CH3 <SEP> CH, <SEP> 142.5-143.5
<tb><SEP> 1
<tb><SEP> rNSO, NH
<tb> H <SEP> 80 <SEP> NH- <SEP> 111.5-113
<Tb>
Note: The symbol Pr indicated above means propyl.

EXAMPLE 21
In a solution of N- (diethylaminoethyl) -5-methanesulfonamido-2-methoxybenzamide in acetone, dimethyl sulfate and potassium carbonate are added. The resulting mixture is refluxed for 2 hours. After evaporation of the solvent, the residue is mixed with water and stirred with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is washed with isopropyl ether to give N- (diethylaminoethyl) -2-methoxy-5- (N-methylmethanesulfonamido) benzamide as crystals melting at 48-500C.

EXAMPLE 22
Formulation for tablets N- (diethylaminoethyl) -5-acetyl-2-methoxy-3-methylbenzamide 60 mg
Lactose 250 mg
Wheat starch 80 mg
Magnesium stearate 10 mg
400 mg
The present invention is not limited to the embodiments which have just been described, it is instead capable of variations and modifications that will occur to those skilled in the art.

Claims (7)

 1 - Compound, characterized in that it is selected from the group consisting of a compound having formula

 (where R is a C 1 -C 5 alkyl group, R is hydrogen, a halogen, a C 1 -C 5 alkyl group or a C 1 -C 5 alkoxy group; C1-C5, R is amino, C1-C5 alkanoyl, or R-N-SO2R; R is a C 1 -C 5 alkyl group or a C 2 -C 10 dialkylamino group, and R 4 is hydrogen or C 1 -C 5 alkyl, providing that when R 2 is amino group or a C 1 -C 4 alkanoyl group; C5, R is a C1-C5 alkyl group and its pharmaceutically acceptable acid addition salts.  2 - Compound according to claim 1, characterized in that it is selected from the group consisting of N- (diethylaminoethyl) -5-amino-2-methoxy-3-methylbenzamide, N (diethylaminoethyl) -5- ethanesulfonamido-2-methoxy-3-methylbenzamide, N- (diethylaminoethyl) -5-methanesulfonamido-2-methoxy-3-methylbenzamide, N- (diethylaminoethyl) -5-acetyl-2-methoxy-3-methylbenzamide and N- (diethylaminoethyl) -5-acetyl-2-ethoxy-3-methylbenzamide.  3 - A pharmaceutical composition for treating patients suffering from gastric disorders or used as an antiemetic product, characterized in that it comprises an effective amount of the compound of claim 1 and pharmaceutical carriers, pharmaceutical diluents and / or pharmaceutical adjuvants.  4 - Process for preparing a compound having the formula

 (where R is a C1-C5 alkyl group; R1 is hydrogen, halogen, C1-C5 alkyl or alkoxy group; C1-C5, R2 is amino, C1-C5 alkanoyl, or R4 - # - SO2R, R is C1-C5 alkyl or C2-C10 dialkylamino, and R is hydrogen or C 1 -C 5 alkyl, with the proviso that when R is amino or C 1 -C 5 alkanoyl, R 1 is C 1 -C 5 alkyl) and its addition salts with them; acids, pharmaceutically acceptable, characterized in that it consists in reacting a compound having the formula

 (where A is hydroxy, an alkoxy group, an alkoxycarbonyl group or a halogen, and R, R 1 and R 2 are as defined above) and N, N-diethylethylenediamine in an inert solvent, at room temperature or by heating to the boiling point of the solvent used, if necessary, in the presence of a condensing agent and a base.  5 - Process for preparing a compound having the formula as indicated in the preamble of claim 4, and its pharmaceutically acceptable acid addition salts, characterized in that it consists in reducing a compound having the formula

 (where R and R 1 are as defined in claim 4), with a reduction means selected from hydrogenation over a catalyst and hydrogenation with tin dust or iron-hydrochloric acid dust, in an inert solvent, at room temperature or by heating to the boiling point of the solvent used, to give a compound having the formula

 (whereR and R1 are as defined in claim 4).  6. Process for preparing a compound having the formula as indicated in the preamble of claim 4, and its pharmaceutically acceptable acid addition salts, characterized in that it consists in hydrolyzing a compound having the formula

 (where R 30 is a C 1 -C 5 alkyl group, and R, R 1 and R 3 are as defined in claim 4), with an alkali hydroxide, in a suitable solvent, at room temperature or by heating to the point where boiling solvent used, to give a compound having the formula

 (where R, R1 and R3 are as defined in claim 4).  7 - Process for preparing a compound having the formula as indicated in the preamble of claim 4, or its pharmaceutically acceptable acid addition salts, characterized in that it consists in reacting a compound having the formula

 (where R, R and R are as defined in claim 4) with an alkylating agent introducing the group R4 (C1-C5 alkyl group), in an inert solvent, at room temperature or heating up to boiling point of the solvent used, in the presence of a base, to give a compound having the formula

 (where R, R 1 and R 3 are as defined in claim 4, and R 4 is a C 1 -C 5 alkyl group).