IL30493A - 2-alkoxy-4,5-azimidobenzamides and the process for the preparation thereof - Google Patents

Description

2-Alkoxy- » 5-azimidoben2amIdes and the process for the preparation thereof SGCIETE D 'ETUDES SCIENTIFIQUES ET INDUSTRIELLES DE L ' ILE-DE-FRANCE C. L8^ifJ - 2 - 30493/2 The present invention concerns new 2-alkoxy-4,5-azimido benzamides, their pharmacologically acceptable salts and the process for their preparation.

The benzamides of the present invention correspond to the following gen ____ _ in which in which R^ and Rg are independently hydrogen or alkyl radioals with from 1 to 5 carbon atoms, or R^ and R2 form together with the nitrogen atom to whioh they are attached a heterooyclio ring optionally containing a further nitrogen, oxygen or sulphur heteroatom (and when this ring contains a nitrogen atom, this latter may be substituted by an alkyl group with from 1 to 5 carbon atoms), e.g.apyrrolidinyl, piperidinyl, piperazino, N-me hyl-pyrrolidinyl, N-ethyl- ' "rin piperidinyl. jor A is a heterooyolio radioal in whioh R is an alkyl radical with from 1 to 5 carbon atoms and fii is an integer of less than 4", B is an alkyl radical with from 1 to 5 carbon atoms and ί The pharmacologically acceptable salts of the above described bases can be : - salts of addition with a mineral acid, for example: hydrochloric acid, hydrobromic acid, phosphoric acid or organic acid for example : citric acid, tartaric acid, lactic acid, acetic acid. - quaternary ammonium salts produced b reacting the above described bases with an aliphatic or aromatic alkylating agent such as methyl chloride, methyl bromide, dimethyl υΐρΐ^ΐε, methyl p-toluene sulphonate...

The compounds of the invention have interesting pharmacological e. properties and in particular can be used as anti-emetics, spasmogenics, analgesics ... j It is obvious that when the compounds of the invention have in their chemical formula one or more assymetric carbons, the dextrorotatory and levorotatory forms are part of the invention.

According to the invention, the process for the preparation of these compounds essentially comprises treating' a substituted 2-alkoxy-4,5-aminobenzamide with a metallic nitrite in acid medium. The ί ' · metallic nitrites used can be for example alkaline nitrites such as sodium nitrite, potassium nitrite ... The metallic nitrites can be replaced by another nitrification agent such as amyl nitrite.

The preparation of the following compounds is given by way of example, without in any way limiting the invention.

E X A M P L E I N-(diethylaminoethyl)-2-meth6xy-i ,5-azircidobenzamide Stage A - methyl 2-methoxy-^-acetoamino-5-nitrobenz6ate 223 g ( 1 mole) of methyl 2-methoxy- -acetoaminobenzoate, I82 g (Ο.68 mole) of methyl 2-methoxy-if-acetoamino-5-nitrobenzoate and 600 ml of glycol are introduced into a 2 litre balloon flask provided with an agitator and a thermometer, and 236 g (Ο.68 mole x 3) of diethylahiinoethylamine is added. The reactionis slightly exothermic (T° = 31°C). A suspension is obtained, which is heated to 55°c» After three-quarters of an hour, dissolution is complete and half an hour afterwards the formation of a large amount of precipitate is observed.

The reaction mixture is maintained at 55°C for 95 hours.

Everything is then soluble in dilute acetic acid. 60O ml of water is then added at from to ^°C with agitation. Cooling is then effected, the product obtained is dried without heating, washed with 1.3 litres of water and dried at 60°C. .152 g (yield : 63.5$) of -(diethylaminoethyl)-2-methoxy- -amino-5-nitrobenzamide is obtained (melting point : 206 to 208°C) .

Stage C - N-(diethylaminoethyl)-2-methoxy- ,5-diaminobenzamide I g (0 9 mole) of N-(diethylaminoethyl)-2-methoxy-if-amino-5-nitrobenzamide, 230 ml of water and k9 ml of concentrated hydrochloric acid are introduced into a 2 litre balloon flask provided with an agitator, a thermometer and a dropping funnel. A thick mass is obtained to which is added 9^ g of. tin.. The mass is then heated to 50°C and highly exothermic. The temperature reaches from 80 to 100°C. Cooling is effected if necessary.

When the operation of introduction is concluded, heating is effected on a water bath until all the tin has dissolved. ml of soda lye is introduced into a 3 litre balloon flask provided with an agitator, a thermometer and a dropping funnel, and then the above solution is gradually added below 0°C. The base separates in the form of a brown oil. After cooling, it is decanted, the aqueous solution is extracted with methylene /chloride The organic solution ρΓθάμοεά is washed once with water and dried on potassium carbonate. .

The methylene /chloride, is then distilled, concluding under vacuum until a constant weight is attained. 137 g (yield : 10C#) of N-(diethylaminoethyl) -2-methoxy- ,5-diaminobenzamide is obtained. jStage D - N-(diethylaminoethyl) -2-methoxy- , -azimidobenza.mide II6 g (0.284 moles) of N-(diethylaminoethyl) -2-methoxy- , 5-diaminobenzamide dihydrochloride, 568 ml of water and 28 ml of concentrated hydrochloric acid are placed in a 2 litre balloon flask provided with an agitator, a thermometer and a dropping funnel. The mixture is heated to from O to 5°C to dissolve it. Cooling is then effected to 0°C and g (0.284 moles) of sodium nitrite is poured in dropwise by means of the dropping funnel. When this operation is concluded, agitation is continued for one hour and the temperature is allowed to rise to 20°C.

The solution produced is treated with black, filtered and evaporated to dryness. The^ solid residue is dissolved with 400 ml of boiling ethanol. The remaining sodium . chloride is hot. filtered. By cooling and concentrating the alcohol solution, N-(diethylamnoethyl) -2-methoxy- ,5-azimidobenzamide hydrochloride crystallises, is dried without heating and washed with alcohol. It is a white solid (melting point: I89 to 191°C) (yield: 77.5#) .

E X A M P L E II N-(l-ethyl-2-Tiyrrolidylmethyl) -2-methoxy-415-azimidobenzamide Stage C - N-(l-ethyl-2-pyrrolidylmethyl)-2-methoxy- ,5-diaminobenzamide 120 g (Ο.372 moles) of -(l-ethyl-2-pyrrolidylmethyl)-2-methoxy- i-amino-5-nitrobenzamide, 170 ml of water and 37 ml of concentrated hydrochloric acid are introduced into a 2 litre balloon flask provided ■ with an agitator, a thermometer and a dropping funnel, and the mixture is heated to 50°C. The hydrochloride formed is completely soluble. 71 g of tin and then 290 ml of concentrated hydrochloric acid are then added. The reaction is slightly exothermic. The temperature reaches 65°C At the end of the operation of addition, there is formed a thick precipitate. The vessel is then heated on a water bath until all the tin has dissolved. 680 ml of soda lye is introduced into a 2 litre balloon flask provided with an agitator and a thermometer, and then the above slurry is gradually added without the temperature . exceeding WC. The base separates in the form of a brown oil and some tin salts precipitate. 200 ml. of methylene/chloride is added to dissolve the base and the mineral salts are filtered.

. The organic solution is decanted and the aqueous solution is extracted once with 200 ml of methylene/chloride and once with 100 ml.

The' organic solution is washed once with 100 ml of water and dried on potassium carbonate. The methylene/chloride is then distilled, concluding under vacuum until a constant weight is attained. 100 g. (yields-935 of N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy-i , 5-diaminobenzamide is obtained.

Stage D - N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy-i ,5-azimidobenzamide 112 g (Ο.278 moles) of N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy- , 5-diaminobenzamide dihydrochloride, 58Ο ml of water and 28 ml of concentrated hydrochloric acid are introduced into a 2 litre balloon flask provided with an agitator, a thermometer and a dropping funnel. The mixture is heated to from .0 to 5°C to dissolve- all the reagents 'and then cooled to 0°C. 19 g (Ο.278 moles) of sodium nitrite dissolved in 28 ml of water is then added dropwise. Agitation is continued for one hour at 0°C and the temperature is allowed to rise to 20°C. The mixture is evaporated to dryness and the solid residue is dissolved in hOO ml of absolute alcohol and the sodium chloride formed is hot filtered. The alcohol solution is concentrated, the N-(l-ethyl-2-pyrrolidylmethyl)- 2-methoxy-if,5-azimidobenzamide hydrochloride formed crystallises, is dried without heating, washed with alcohol and then with ether. 55 g (yield : 85 of product is obtained in the form of white crystals (melting point : 197 to 200°C) .

E X .A: M P: L:;E HI ,Dextrorotatory, N- (l-ethyl-2-pyrrolidylmethyl) -2-methoxy- , 5-azimidobenzaaide Stage A is similar to that described in Example I.

Stage B - Dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy- -amino- 3-nitrobenaard.de 80 g (0.3 moles) of methyl 2-methoxy- -acetoamino-5~nitrobenzoate, 285 ml of glycol and 8 g (2.2 x 0.3 moles) of dextrorotatory l-ethyl-2-aminomethylpyrrolidine are introduced into a 2 litre balloon flask provided with an agitator and a thermometer. maintained at this temperature for 216 hours.

It is then cooled to O°C and 500 ml of water is added with agitation. Cooling is concluded at 20°C, the produce obtained is dried without heating, washed with 1 litre of water and dried at 50°C. ^5 g (yield : 58?a) of dextrorotatory H-(l-ethyl-2~pyrrolidylmethyl)-2-methoxy-½-amino-5-nitrobenzamide (melting point : 185 to' l87°C) is obtained.

Stage C - Dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy-f ,5-diaminobenzamide . ' The reduction of 150 g (0.4 moles) of dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-nitrobenzamide hydrochloride is effected in an autoclave in 95° alcohol and in the presence of Raney nickel as a catalyst. The reaction lasts- for one hour. The pressure of the hydrogen at the beginning is 6k kg at 5°C.

At the end of the reaction, the temperature has attained 83°C.

The nickel is hot filtered and the dihydrochloride is prepared by means of O ml of concentrated hydrochloric acid. After recrystallisation from alcohol, 110 g of dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy-J ,5-diaminobenzamide dihydrochloride is obtained (yield 70i¾) (melting point : 215°C) .

Stage D - Dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy-*f,5-azimidobenzamide. 3 g (O.IO7 moles) of dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl)-2-methoxy-i ,5-azimidobenzamide dihydrochloride, 215 ml of water and 11 ml of concentrated hydrochloric acid are introduced into a 1 litre balloon flask provided with an agitator, a thermometer and a dropping funnel.

The mixture is heated to 55°0 to dissolve all the reagents and is then cooled to 0°C.. 7·5 g (0.107 moles) of sodium nitrite dissolved in ml of water is then added dropwise by means of the dropping funnel.

Agitation is continued for 1 hour at 0°C and then the mixture is allowed to return to ambient temperature.

• The alcohol solution is concentrated. The benzaraide hydrochloride formed crystallises, is dried without heating, and washed with alcohol and then with ether. 23 g (yield : 635o) of dextrorotatory N-(l-ethyl-2-pyrrolidylraethyl) -2-methoxy-i ,5-azimidobenzamide hydrochloride is obtained (melting point: 170 to 172°C) - aqueous solution), E XAM PL E IV Levorotatory N-(l-ethyl-2-pyrrolidylmethyl) ^-methoxy-^g-azimidobenzamide Operating in the same way as in Example III but replacing the dextrorotatory amine by the levorotatory amine, levorotatory N-(l-ethyl-2-pyrrolidylmethyl) -2-methoxy-i ,5-azimidobenzamide dihydrochloride is obtained, the characteristics of which are as follows: ( Melting point : 170 to 172°C) Ja D = - 5° * (550 aqueous solution) , EXA M PLE V N-^thyl-^ropylaminoethyl) -2-methoxy- ,5-azimidobenzamide I88 g (0.7 moles) of methyl 2-methoxy-i-acetoamino-5-nitrobenzoate and 7OO ml of glycol are placed in a 2 litre balloon flask provided with an agitator and a thermometer, and then 273 g (3 x 0.7 moles) of ethyl-propylethylene diamine is added.

The suspension produced is heated to 55°C and maintained at this temperature for 72 hours.

The ester partially dissolves at the beginning of the reaction and then the benzamide formed begins to precipitate.. At the end of the. reaction all is soluble in dilute acetic acid. 7OO ml of water is then added at 50°C and then after cooling, the solution is dried without heating, and the product obtained is 30493/2 _ Stage C - -(N'-eth.yl-N?-prop.ylaminoet .yl)-2-methoxy-4.¾-diaminobenzamide ' 4-amino- __l65:g': (9·5 moles) of N-(N,-ethyl-N'-propylaminoethyl)-2-methoxy-/ -nitrobenzamide, 230 ml of water and 50 m of concentrated hydrochloric acid are' placed in a 2 litre balloon flask provided with an agitator, a thermometer and a dropping funnel. The hydrochloride' formed dissolves. 9k g of tin is then added. The mixture is heated to 55°C and 30 ml of concentrated hydrochloric acid is added in small fractions. The reaction is highly exothermic. Whe the operation of introduction is concluded, the vessel is heated on a water bath until the tin is completely dissolved. . · · ·· ' · • 5 ral of soda lye is placed in a 3 litre balloon flask provided. with an agitator, a thermometer and a dropping- funnel and then the above solution is gradually added without the temperature exceeding O°C The base separates in the form of a paste which is redissolved in 150 ml of ' methylene chloride. The aqueous solution is extracted' with methylene . chloride. The organic solution obtained is washed with water and dried " . di ··. < o potassium carbonate.. The methylene/ chloride is then distilled, concluding under vacuum until a constant weight is attained. 131 g (yield: 90 ) of N-(K,-ethyl- ,-propylaminoethyl)-2-methoxy-4,5- diaminobenzamide is obtained.

Stage D - N-(N'-ethyl-N'-propylaminoethyl)-2-methoxy-4.5- azimidobenzamide J ·. methoxy-4> 106 g (0.258 raoles> of N-(N' -ethyl- · -propylaminoe.thyl)-2-/ ■ -diaminobenzarade dihydrochloride, 516 nil of water and 26 ml of concentrated hydrochloric, acid are placed in a 2 litre balloon flask provided with an agitator, a thermometer and a dropping funnel. The mixture is dissolved by heating. It is then cooled to 0°C and l8 g (0.258 moles) of sodium nitrite dissolved in 20 ml of water is then poured in dropwise by means of the dropping funnel. When this operation is complete, the mixture.- is maintained under' agitation and at 0°C for 1 hour and then is allowed to return* to ambient temperature.

• The solution is then treated with black, filtered and«- evaporated - ί·2 - - 30493/1 Π A I P L E VII -(Piperldinoethy1) -2~meth.9x.y~41 iji-aziinldobenzamide hydrochloride 53 g of N-(piperidinoeth l)-2-methoxy-4,5-diamlno-benzamide dihydrochlOride , 288 ml of water and 14 ml of hydrochloric acid (density « 1.18) are placed in a 1 litre balloon flask provided with a stirrer, a thermometer, and a dropping funnel; The mixture is heated to 45°C in order to dissolve it, and is then cooled to 0°C. At that temperature a solution of 10 g of sodium nitrate in 15 ml of water is introduced. Stirring of the reaction mixture is continued for one hour at 0°C and the temperature of the mixture is then allowed to rise to 18°C. The water is distilled off ih vacuo and the residue is taken up in 200 ml of boiling anhydrous ethanol. The sodium chloride residue is removed by filtetion and the alcohol is evaporated from the filtrate, whereupon the N-(piperidinoethyl)-2-methoxy-4,5-azimido-benzamide hydrochloride crystallizes. The crystals are collected, washed with ethanol and dried. Yield: 34 g« M.P. 208°C.

E X A M P L E VIII M~(Piperazinoethyl)"2~methoxy-4.5-azimidobenzamide hydrochloride 40 g of methyl 2-methoxy-4-acetylamino-5-nitro-benzoate (prepared as in Example I Stage A) are treated according to the procedure described in Example I Stage B with 258 g of piperazinoethylamine dissolved in toluene. 4.8 g of N-(piperazinoethyl)-2~methoxy-4-amiho-5-nitro-benzamide, m.p. 184°C are obtained. This compound is reduced by the procedure described in Example I Stage C to - 13 - 30493/1 yield 4.3 g of N-(plpera2inoethyl)-2-methoxy-4 t 5-diamino-benzamide, melting at 250°C (with decomposition). 3·0 g of the last mentioned product is reacted with sodium nitrate in the presence of hydrophloric acid at 0°C according to the procedure described in Example I Stage D. 0.8 g of -(piperazinoethyl)-2-methoxy-4,5razimidobenzamide hydrochloride is obtained, m.p. after recrystallization from ethanol 204 °C (with decomposition). ΕΛΧοΑ B ,P 1 B IX N-(E'*-methylplperazinylethyl )-2-methox.y- « 5-azimldo-benzamide According to the procedure described in Example I Stage B, 12.5 g of methyl 2-methoxy-4-acetylamino-5-nitro-benzoate (prepared as in Example I Stage A) in 60 ml of glycol is reacted with 20 g of (if-methylpiperazinylj-ethyl-amlne to yield 13 g of N—(153 methylplperazinylethyl)-2-methoxy-4-amino-5-nitro~benzamide, m.p. 207°0. 8 g of this compound are reduced, according to the procedure described in Example I Stage C, to form 7 g of N-iW'-methylpiperazinyl-ethyl)-2~methoxy-4 , 5-diamino-benzamide, m.p. 154°C . 1.5 g of the last mentioned compound are treated with sodium nitrite, by the procedure described in Example I Stage D, to yield 0.9 g (64 .2$ of theory) of N-(H'-methyl-piperazinylethyl)-2-methoxy-4 » 5-azimido-benzamide, m.p. 243 0. - 14 - 30493/2.

·-''' The compounds of the invention have been the subject of pharmacological and clinical studies in order to determine on the one hand their non-toxicity and on the other hand their anti-emetic activity.

The acute degrees of toxicity which have been studied on mice' have shown that the compounds subject of the present invention are of a toxicity which is completely compatible with therapeutic use. They have been summed up by. way of example in the following .table : . .

DL 50 in rag/kg compound Compounds in base form oral intra- .. intra- · subveinous peritoneal cutaneous N-(diethylaminoethyl) -2-methoxy 1500 3&7-ΙΛΟ ' 600-576 ,5-azimidobenzaraide . (305* mortality) -(l-ethyl-2-pyrroli'dylmethyl)- 1517 69 21A-216 35O-32I 2-methoxy-if,5-aziraidobenzamide Dextrorotatory ' ' 8i . - §5 2½ 339 N-(l-ethyl-2-pyrrolidylmethyl)- 2-methoxy-^,5-azimidobenzainide Levorotatory 83 - 8'i 207 2^3 N-( 1-ethyl-2-pyrrolidylraethyl) -2-methoxy-it,5-azimidobenzamide The anti-emetic action of these compounds on the vomiting centres was studied on dogs by means of apomorphxne using the technique of CHEN and EN30R taken up by DUCROT and P.DECOURT. Tests were carried out on groups of four ■dogs.

The apomorphine was- administered sub-cutaneously in doses of 0.10 rag/kg. The compounds under study are administered 30 minutes previously, also sub-cutaneously. The number of vomitings in the minutes follov/ing the injection of apomorphine was counted.

The following figures were extracted from the experimental results for several of the compounds of the present invention : The compounds of the present invention have the interesting . pharmacological property that they are not cataleptic. Thus in the case of two compounds of the invention, the cataleptic activity of the product gave the following results : (results measured at maximum effect, i.e. after from 300 to 3&0 mins.) Compounds Manner Effective dose 0 in mg/kg -(diethylaminoethyl) -2-methoxy-k ,5~aziraidobenzamide sub-cutaneously ¾¾ effect with X ' The experimental results were confirmed in clinics where tne products have been administered in the form of compressed tablets or phials of a pharmacologically acceptable salt.

ICS In clinical conditions corresponding to pharmacodynamy, the treatments have not give rise to any manifestation of medicament intolerence. The vomiting has rapidly stopped and has not reappeared after stopping the treatment. Thus, in the case of a seventy year old man suffering from serious recto-colitis with repeated attacks of 'vomiting when given nourishment, two phials per day containing 10 mg of N-(diethylaminoe.thyl)-2-methoxy-i ,5-a.zimidobe zamide hydrochloride were administered. Tolerance was excellent and in two days there was observed a very marked reduction in the .vomiting attacks, permitting the patient to be put back on nourishment. The vomiting attacks stopped completely after four days of treatment.

In the case of a fifty-five year old woman suffering from cancer of the breast and being treated with nitrogen mustards, the vomiting attacks due to the treatment stopped two days after the administration of three phials per day containing 10 mg of N-(l-ethyl-2-pyrrolidylmethyl) -2- methoxy-^^-aziraidobenzamide hydrochloride.

The anti-emetic compounds according to the present invention can be administered in the form of a pharmacologically acceptable salt in the form of sugar-coated pills, injectable phials or phials for aerosols, suppositories, a granulated preparation made with sugar, or a sweetened syrup. . - 17 - 30493/2

Claims (11)

1. 2-Alkoxy-4,5-azimidobenzamides of the general formula In which A is either a mono- or dialkylamino radical -H in which R.^ and R2 are independently hydrogen or ^R2 alkyl radicals with from 1 to 5 carbon atoms, or R^^ and R≥ form together with the nitrogen atom to which they are attached a heterocyclic ring optionally containing a further nitrogen, oxygen or sulphur heteroatom (and when this ring contains a nitrogen atom, this latter may be substituted by an alkyl group with from 1 to 5 carbon atoms), e.g.apyrrolidinyl, piperidinyl, piperazlno, N-methyl-pyrrolldinyl, N-ethyl- xing piperidinyl ;or A is a heterocyclic radical . R in which R is an alkyl radical with from 1 to 5 carbon atoms and m is an integer of less than 4; B is an alkyl radical with from 1 to 5 carbon atoms and n is 1 or 2; and optical isomers of those compounds of formula I which contain at least one asymmetric centre. - 18 - 30493/2

2. Addition salts with mineral or organic acids and pharmacologically acceptable quaternary ammonium salts of the. b'enzamides according to Claim 1.

3. N-(diethylaminoethyl)-2-methoxy-4,5-a2imidobenzaaide.

4. . H-( l-ethyl-2-pyrrolidy;lmethyl)-2-methoxy-4» 5-azimidobenzamide.

5. Dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl)-2-methoxy-4 , 5-azimidobenzamide .

6. Levorotatory N-(l-ethyl-2-pyyolidylmeth l)-2-methoxy-4 > 5-azimidobenzamide .

7. » N-CU'-ethyl-lT'-propylaminoethylJ^-methoxy^.S-azimidobenzamide .

8. N-(diethylaniinoethyl)-2-methoxy-4i 5-azimidobenzamide iodomethylate.

9. A process for the preparation of the 2-alkoxy- , 5-azimidobenzamides according to Claim 1, which comprises treating a substituted 2-alkoxy-4 » 5-aminobenzamide with a metal nitrite in an acid medium.

10. * A process for the preparation of the addition salts with a mineral or organic acid and of quaternary ammonium salts of the .compounds according to Claim 1, which comprises treating a compound of formula I in Claim 1 with a mineral or organic acid or with an aliphatic or aromatic alkylating agent. - 19 - 30493/2

11. Pharmaceutical compositions comprising as an active ingredient a compound of formula I in Claim 1 or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof. PC/rb