NO168356B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE N-PIPERAZINYLALKANOYLANILIDES - Google Patents

Description

The present invention relates to an analogue method for the production of therapeutically active N-piperazinylalkanoylanilides with the general formula (I)

wherein n is 0, 1 or 2, R represents a hydrogen atom or a C1_4-alkyl group, one of R2 and R3 represents a hydrogen atom and the other of R2 and R3 represents a hydroxy-C1_4~alkyl-,<C>i_4-alkylthio-, Ci_4-alkylsulfonyl-, C]__4-alkylsulfinyl-, Ci_4-alkanoyl-, carbamoyl or guanidino-sulfonyl group, or a group of formula SO2NR5R6in which each of R5 and R5 independently represents a hydrogen atom or a Ci_4-alkyl-, phenyl or Ci_4- alkanoyl group, respectively one of R2 and R3 stands for a halogen atom and the other of R2 and R3 stands for a sulfamoyl group, optionally in the form of a free base or acid addition salt thereof. The invention is characterized in that a compound of the general formula (II) in which R, R2, R3 and n have the above-mentioned meaning and X represents a halogen atom, is reacted with 1-(2-methoxyphenyl)-piperazine in the presence of a solvent, or to prepare of a compound of formula (I) in which R2 and R3 have the above meaning and n is 1, a compound of the general formula (III) is reacted

wherein R 2 and R 3 have the above meaning with 1-(2-methoxyphenyl)-piperazine in the presence of a solvent such as e.g. dimethyl sulfoxide

and, if desired, the C 1-4 -alkanoyl group R 2 or R 3 in an obtained compound I is reduced to a hydroxy-C 1-4 -alkyl group

and, if desired, an optionally obtained free base is converted into its acid addition salt or vice versa.

These features of the invention appear in the patent claim.

The reactions are carried out in the presence of a solvent such as e.g. a ketone, hydrocarbon, dimethylsulfoxide or a mixture thereof. When using dimethylsulfoxide, a reaction temperature of from 40 to 60°C is sufficient. In other cases, the reflux temperature of the solvent is preferred. The compounds thus obtained can be purified using methods known per se and crystallized or recrystallized from suitable solvents in purified form. The pharmaceutically acceptable salts according to the invention can be prepared from the bases in a conventional manner. Preferred pharmaceutically acceptable acid addition salts are the salts of hydrochloric acid, sulfuric acid, maleic acid, succinic acid, citric acid, methanesulfonic acid and toluenesulfonic acid.

The N-piperazinalkanoylanilides and their salts which can be prepared by the invention have a valuable anti-hypertensive effect and a very low toxicity. The compounds of formula (I) are advantageously used in admixture with pharmaceutically acceptable diluents or carriers.

The LD50 of the compounds prepared in accordance with the invention was determined in mice pro os using the method described in C.S. Weil (Biometrics, 8, 249, 1952). The results obtained are set out below.

The following table lists the compounds from the specified examples. The anti-hypertensive activity was assessed in spontaneously hypertensive male rats (SHR, Wister-Kyoto strain, 15-25 weeks old). Determination of the blood pressure was carried out using the indirect method (M. Gerald et al, Arzneim.-Forsch. , 18, 1825, 1968).. The animals were pre-warmed in a heating chamber at a temperature of from 35 to 37° C for a period of 15 min before adding the compounds. The compounds were tested by oral administration dissolved or suspended in a 0.5% methylcellulose solution. Control animals were given vehicle only. Systolic blood pressure and heart rate were measured 1, 3, 5 and 7 hours after the administration of the compounds using a tail-wrap and pulse recording method using a recorder.

In the table, the anti-hypertensive activity is expressed as ED25, which is the drug dose that produces a 25% reduction in systolic blood pressure in conscious SHR. ED25 was calculated from linear development of the dose-response curve. The compounds tested did not show any significant variation in heart rate.

Corresponding values for these sizes are listed for the comparison compound "URADIPIL".

OAK SAMPLE X

4-sulfamoyl-[4-(2-methoxyphenyl)-1-piperazinyl]-butyrylanilide

(In: R=R2=H, R3=NH2SO2, n=2)

2.61 g of sodium carbonate and 4.8 g of 1-(2-methoxyphenyl)-piperazine dissolved in 25 ml of acetone were added to 6.9 g of 4-sulfamoyl-7-chloro-butyrylanilide in 25 ml of acetone. The entire mixture was refluxed for 32 hours. At the end of the reaction, the solid formed was removed by filtration and discarded. The solvent was evaporated under vacuum and the oily

residue treated with diethyl ether until a solid was obtained. This solid was collected, dried and suspended in ethanol. Hydrogen chloride in ethanol was added until acidic pH. The product thus obtained was collected and crystallized first from 90% ethanol and then from methanol to give the title compound as its hydrochloride.

Yield: 3.82 g (32%), m.p. 235 - 237°C.

EXAMPLE 2

4-methylsulfonyl-p-[4-(2-methoxyphenyl)-1-piperazinyl]-propionylanilide

(In: R=R2=H, R3=CH3SO2, n=1)

2.02 g of 4-methylsulfonyl-acryloylanilide and 1.92 g of 1-(2-methoxyphenyl)-piperazine in 20 ml of toluene were refluxed for 4 hours. At the end of the reaction after cooling, the thus formed solid was collected, dried and crystallized from 95% ethanol. After a long drying under vacuum at 100°C, 2.92 g (78%) of the compound mentioned in the title was obtained which melted at 142 - 143°C.

EXAMPLE 3

4-sulfamoyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide

(In: R=R2=H, R3=NH2SO2, n=1).

A mixture comprising 2.26 g of 4-sulfamoyl-acryloylanilide and 2.01 g of 1-(2-methoxyphenyl)-piperazine in 60 ml of toluene was refluxed with stirring. After 8 hours thin layer chromatography showed no starting materials. The crude product was collected, dried and crystallized from dioxane:water. 2.08 g (46%) of the title compound was obtained as its dihydrate melting at 180-181°C. The product was suspended in hot ethanol and hydrogen chloride in ethanol was added until acidic pH. After cooling, the solid was collected and crystallized from water to give the hydrochloride hydrate of m.p. 237 - 239°C.

EXAMPLE 4

4-carbamoyl-p-[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide

(In: R=R2=H, R3=NH2CO, n=1).

A mixture comprising 1.9 g of 4-carbamoyl-acryloylanilide and 2.01 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of dimethylsulfoxide was stirred for 8 hours at 50-60°C. The mixture was then poured into 150 ml of water and the thus precipitated solid was collected and crystallized from methanol:diethyl ether.

The compound mentioned in the title was obtained with

m.p. 235 - 237°C with yield 2.88 g (75%).

The corresponding hydrochloride was obtained as described in example 3, with m.p. 246 - 249°C.

EXAMPLE 5

4-ethoxycarbonyl-p-[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide

(In: R=R2=H, R3=COOC2H5, n=1).

By proceeding as described in example 3, but by using 2.2 g of 4-ethoxycarbonyl-acryloylanilide instead of 4-sulfamoyl-acryloylanilide, the compound mentioned in the title was obtained. The product was crystallized from diethyl ether:petroleum ether. Yield 3.3 g (80%) with m.p. 82 - 83°C, with the hydrochloride m.p. 211°C.

Using the corresponding acryloylanilide derivatives and by working as described in Example 3, the following compounds were obtained:

a) 4-acetyl-B-[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide, m.p. 138 - 140°C, crystallized from ethyl acetate, yield 77%. The corresponding hydrochloride melted at 232°C. b) 4-methylthio-p-[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide, yield 75%, m.p. 165 - 166°C, crystallized from ethyl acetate. The corresponding hydrochloride hemihydrate melted at 210 - 211°c.

EXAMPLE 6

4-(1-hydroxyethyl)-p-[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide

(In: R=R2=H, R3=CH3CHOH, n=1)

1.14 g of sodium borohydride was slowly added to 11.44 g of the compound from Example 5a in 200 ml of ethanol. The whole mixture was stirred at room temperature for 8 hours. The solution thus formed was then acidified with dilute hydrochloric acid and then neutralized with aqueous sodium carbonate. Ethanol was evaporated under vacuum and the aqueous phase made alkaline with aqueous sodium carbonate and then extracted with chloroform. The organic layers were dried over calcium chloride and the solvent was evaporated under vacuum. The oily residue was purified on a silica gel column using a mixture of chloroform:methanol (volume ratio 97:3) as eluent. The solvent was evaporated and the residue was crystallized from toluene to give 5.61 g (48%) of the title compound, m.p. 137 - 138°C.

EX EMP EL 7

4-sulfamoyl-p-[4-(2-methoxyphenyl)-1-piperazinyl]-butyryl-anilide

(In: R=CH3, R2=H, R3=NH2SO2, n=1)

7.2 g of 4-sulfamoylcrotonylanilide and 6.33 g

1-(2-Methoxyphenyl)-piperazine was stirred for 6 hours at 50°C.

At the end of the reaction, the solution was cooled and poured into 100 ml of water. The precipitate thus formed was collected and dried. The crude product was dissolved in ethanol and hydrogen chloride in ethanol was added until acidic pH. The title compound was collected as its hydrochloride, dried and crystallized first from water and then from 95% ethanol. 6.16 g of the compound mentioned in the title with m.p. 183 - 184°C.

EXAMPLE 8

4-acetylsulfamoyl-p-[4-(2-methoxyphenyl)-1-piperazinyl]-propionylanilide

(In: R=R2=H, R3<=>CH3CONHS02, n=1)

10.73 g of crude 4-acetylsulfamoyl-acryloylanilide and 8.80 g of 1-(2-methoxyphenyl)-piperazine were stirred for 3 days at room temperature with 40 ml of dimethyl sulfoxide. The reaction was then carried out as described in example 7 and 9.24 g of the compound mentioned in the title with m.p. 193 - 195°C (crystallization from ethanol).

EXAMPLE 9

3-sulfamoyl-p-[4-(2-methoxyphenyl)-1-piperazinyl]-proprionyl-anilide hydrate

(In: R=R2=H, R2=NH2SO2, n=1)

6.78 g of 3-sulfamoyl-acryloylanilide and 6.60 g of 1-(2-methoxyphenyl)-piperazine in 120 ml of toluene were refluxed with stirring for 12 hours. At the end of the reaction, after cooling, the solid thus formed was collected, dried and crystallized twice from 70% ethanol. Yield 9.5 g of the compound mentioned in the title with m.p. 118 - 124°C.

EXAMPLE 10

4-methylsulfamoyl-B-[4-(2-methoxyphenyl)-1-piperazinyl]-propionylanilide

(In: R=R2=H, R3=CH3NHS02, n=1)

To 13.8 g of 4-methylsulfamoyl-B-chloro-propionylanilide in 100 ml of acetone, 5.3 g of sodium carbonate and 10.57 g of 1-(2-methoxyphenyl)-piperazine in 100 ml of acetone are added while stirring. The mixture was refluxed for 9 hours and the solid thus formed collected by filtration. Solvents were then evaporated to give 13.74 g (from ethanol) of the title compound with m.p. 168 - 169°C.

EXAMPLE 11

4-phenylsulfamoyl-B-[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide

(In: R=R2<=>H, R3=PhNHSO2, n=1)

By working as described in Example 10, but using 16.9 g of 4-phenylsulfamoyl-B-chloro-propionyl anilide, refluxing for 20 hours and crystallization from methanol, 14.88 g of the desired compound was obtained with m.p.

197 - 201°C.

EKS EMPEL 1 2

4-guanidinosulfonyl-B-[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide

(I: R=R2=H, R3=guanidinosulfonyl, n=1)

The reaction was carried out as described in example 10, but by using 9.14 g of 4-guanidinosulfonyl-B-chloro-propionyl-aniline, 6.35 g of the piperazine derivative, 3.15 g of sodium carbonate and 75 ml of acetone. Refluxing was carried out for 13 hours and then excess piperazine derivative (0.58 g) was added and the mixture was refluxed for another 13 hours. Yield 6.84 g (from ethanol).

EXAMPLE 13

4-chloro-3-sulfamoyl-B-[4-(2-methoxyphenyl)-1-piperazinyl]-

propionylanilide

(In: R=R1=R4=H, R2=C1, R3<=>SO2NH2, n=1)

The reaction was carried out using 5.94 g of 4,B-dichloro-3-sulfamoyl-propionyl anilide, 30 ml of acetone, 2.10 g of sodium carbonate and 4.21 g of the piperazine derivative in 30 ml of acetone. Reflux was carried out for 18 hours without excess of the piperazine derivative. The residue obtained from the mother liquors was treated with ethyl acetate until a precipitate was obtained and this was added to the first precipitate. The solid mixture was crystallized from dioxane to give 6.71 g of the title compound with m.p. 191 - 193°C.

EXAMPLE 14

4-(Dimethylsulfamoyl)[4-(2-methoxyphenyl)-1-piperazinyl]-propionyl anilide

(In: R=R2=H, R3=SO2N(CH3)2, n=1)

By working as described in example 10, but below

using 7.28 g of 4-(dimethylsulfamoyl)-B-chloro-propionyl-

anilide, 2.64 g of sodium carbonate, 5.26 g of piperazine

derivative and 70 ml of acetone (reflux 10 hours), 8.35 g of the compound mentioned in the title was obtained (from dioxane)

with m.p. 178 - 179°C.

Claims (1)

Analogous process for the preparation of therapeutically active N-piperazinylalkanoylanilides of the general formula (I) wherein n is 0, 1 or 2, R represents a hydrogen atom or a C1_4-alkyl group, one of R2 and R3 represents a hydrogen atom and the other of R2 and R3 represents a hydroxy-C1_4-alkyl-, C1_4-alkylthio-,<C> i_4-alkylsulfonyl-, <C>i_4-alkylsulfinyl-, C1_4-alkanoyl-, carbamoyl or guanidino-sulfonyl group, or a group of formula SO2NR5R5in which each of R5 and R5 independently represents a hydrogen atom or a C1_4-alkyl-, phenyl- or C]__4-alkanoyl group, respectively one of R2 and R3 represents a halogen atom and the other of R2 and R3 represents a sulfamoyl group, possibly in the form of a free base or acid addition salt thereof, characterized in that a compound of the general formula (II) in which R, R2, R 3 and n have the above meaning and X represents a halogen atom, is reacted with 1-(2-methoxyphenyl)-piperazine in the presence of a solvent, or to prepare a compound of formula (I) in which R 2 and R 3 have the above meaning and n is 1, a compound of the general formula (III) is reacted in which R2 and R3 have the above meaning with 1-(2-methoxyphenyl)-piperazine in the presence of a solvent such as e.g. dimethylsulfoxide and, if desired, the C1_4~alkanoyl group R2 or R3 in an obtained compound I is reduced to a hydroxy-C1_4 alkyl group and, if desired, an optionally obtained free base is converted into its acid addition salt or vice versa.