NO118917B - - Google Patents

Description

Analogy method for the production of new antidiabetic active benzenesulfonylamidopyrimidines.

Substituted 2-benzenesulfonamido-pyrimidines with good sugar-lowering action are known from German patent specification 1.14-7.94-8, British patent specification 913,716 and 939,608' and Belgian patent specification 609,270, 622,085 and 622,086.

It has now been found that benzenesulfonylamidopyrimidines of the general formula I:

where A denotes a thiophene or furan group, which may optionally be substituted with lower alkyl or lower alkoxy, or a 3,4—

tetramethylene-thiophene group, R^ denotes hydrogen or lower alkyl, and Rp denotes lower alkyl or lower alkyl mercapto, is distinguished by a particularly strong and long-lasting antidiabetic effect.

The new benzenesulfonylamidopyrimidines listed below (compounds He) were compared with regard to blood sugar-lowering effect and toxicity with three known antidiabetic drugs (D 860, SH-717 and BZ 55).

He 4-62 = 2-[4--(p-3-methoxythiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine

He<4>-76 - 2-[4-(p-thiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine

He 4-77 - 2-[4-(p-3-ethoxythiophene-2-carbonamido-ethyl)-benzenesulfon-araido]-5-isobutyl-pyrimidine

He 4-80 = 2-[4-(p-3-methylthiophene-2-carbonamido-ethyl)-benzenesulfone-• amido]-5-isobutyl-pyrimidine

He<4>-85 = 2-[4-(p-3,4-tetramethylenethiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine

He<4>-86 = 2-[4--(p-furfuroyl-aminoethyl)-benzenesulfonamide]-5-iso-butyl-pyrimidine'

He<4>-88 = 2-[4-(p-3-ethoxythiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5-propyl-pyrimidine

He 501 2-[4-(p-3'-ethoxythiophene-2-carbonyl-N-methyl-aminoethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine

He 565 = 2-{4-[p-(N-methyl-3»-methoxy-thiophene-2-carbamido)-ethyl]-benzenesulfonamido}-5-ethylmercapto-pyrimidine

He 571 = 2-(4~[p-(3'-methoxy-thiophene-2-carbamido)-ethyl]-benzenesulfonamido]-5-methyl-pyrimidine

He 570 2- [ 4-[p-(3-methoxy-thiophene-2-carbamido)-ethyl]-benzenesulfonamido j -5-methylmercapto-pyrimidine

D 860 = N-(4-methylbenzenesulfonyl)-N'-(n-butyl)-urea

SH 717 = 2-benzenesulfonamido-5-methoxyethoxy-pyrimidine

BZ 55 = N-sulfanylyl-N'-(n-butyl)-urea

The hypoglycemic effect was investigated intravenously in rabbits by determining the swelling dose, i.e. the smallest dose that produces a significant blood sugar lowering (15%). The animals were not given fbde in the 16 hours preceding the injection.

For each dosage, at least h animals were used. Determination of the blood sugar was carried out every hour after the administration of the test compound, and the measurement results were compared with the values for a control group which had been treated in a similar way with sodium bicarbonate.

The toxicity was determined in the usual way by subcutaneous administration to mice.

In the table below, the results are listed together with the relative value of the blood sugar-lowering effect when the effect of the known compound BZ 55 is set equal to 1.

As can be seen from the table, the new compounds are far more effective than the known antidiabetics. The toxicity of the new and of the known compounds is approximately of the same order of magnitude, so that the new benzenesulfonylamidopyrimidines overall have a higher therapeutic index than the known antidiabetics.

The new benzenesulfonylamidopyrimidines are produced according to conventional methods in themselves, as they can be produced by either:

a) reacts a compound of the general formula II:

where A and R have the meanings given above, and m is an integer

numbers from 0 to 2, with a 2-aminopyrimidine of the general formula III:

where Rp has the meaning stated above, and then optionally oxidizes the compound obtained to the sulfonamide, or b) reacts a benzenesulfonylguanidine of the general formula IV:

where A and R1 have the meanings given above, with a compound

of the general formula V:

where Rp has the meaning given above, and Y and Y' denote hydrogen or alkoxy, or a functional derivative thereof, after which the pyrimidine is optionally hydroxylated in the h- and/or 6-position by conversion to a corresponding halogen compound and reductive dehalogenation of this is transferred to the pyrimidine unsubstituted in the 4 and 6 positions, or

c) acylates a compound of the general formula VI:

where and B.^ have the meanings given above, with a reactive derivative of an acid of the formula A-CG-OH, where A has the meaning given above, or d) reacts a sulfonamide of the general formula VII:

where A and R have the meanings given above, with a pyrimidine derivative of the general formula VIII:

where R 2 has the above meaning, and Z denotes a reactive ester group or a lower trialkylamino group.

The reaction of compounds II and III is conveniently carried out in an inert solvent in the presence of a base, preferably pyridine or trimethylamine. However, one can also work with a $100 excess of the aminopyrimidine to bind the hydrogen chloride that is formed during the reaction. The ultimately carried out oxidation of the sulfenamide or sulfinamide is carried out in the usual way, e.g. by treatment with hydrogen peroxide, potassium permanganate or nitric acid.

The benzenesulfonylguanidines IV used as starting materials can be obtained, e.g. by condensation of the benzenesulfonamide with guanidine carbonate. The condensation with the p-dicarbonyl compounds (V) can for example be carried out using alkali alcoholate in alcohol, the p-dicarbonyl compounds are used here in free form or as functional derivatives, e.g. such as acetals. However, they can also be prepared by the method according to Vilsmeier from aldehyde acetals, acid chloride and dialkylformamide. If, instead of the dialdehydes, correspondingly substituted malonesters or malonaldehydes are used, or their functional derivatives, the hydroxy group in the h- and/or 6-position of the pyrimidine ring must finally be replaced with chlorine using an inorganic acid chloride, which chlorine can easily be removed reductively , e.g. with zinc rod.

The acylation of the compounds VI is carried out in the usual way, e.g. by reaction with the corresponding acid halides or anhydrides, preferably in the presence of an acid acceptor, or by treatment with reactive acid esters.

As starting materials of formula VIII, 2-halo-pyrimidines are particularly relevant. They can be produced e.g. by reaction of 2-hydroxypyrimidines with an excess of phosphorus oxychloride. The condensation with the benzenesulfonamides VII is preferably carried out in the presence of a base such as potassium carbonate. Instead of the 2-halogen pyrimidines, one can also react the corresponding trialkylaminopyrimidine with the sulfonamide, giving trialkylamine to the benzenesulfonamidopyrimidine.

The following examples illustrate the preparation of the new benzenesulfonylamidopyrimidines.

Example 1

2- [*+ - (8-3-methoxythiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5- i sobutyl- pyrimidine

2 g of 2-[h-(p-aminoethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine are dissolved in 6 ml of pyridine, and 1.1 g of 3-methoxythiophene carboxylic acid chloride is added. After a 12-hour standstill, the mixture is heated for 1 and a half hours in a water bath, after which it is cooled, poured over

ice and acidify with hydrochloric acid. The material that precipitates is filtered off and dissolved in an aqueous soda solution. The solution is filtered over charcoal, and the product is precipitated with hydrochloric acid and finally recrystallized from alcohol.

Melting point: l80 - l8l°C.

Prepared in a similar way: 2 - [*+ - (B-thiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine with melting point 208 - 210°C; 2-['+-(8-3-ethoxythiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine with melting point 170°C; 2-['+ - (p -3-methylthiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine with melting point 150°C; 2-['+-(p-3,4-tetramethylenethiophene-2-carbonamido-ethyl)-benzenesulfonamido J-5-isobutyl-pyrimidine with melting point 193 - 191+0C; 2-[ h-(6-furfuro<y>l-aminoeth<y>l )-<b>enesulfonamido]-5-isobutyl-pyrimidine with melting point 201 - 202°C; 2-[*+-Cp-3-ethoxy thiophene-2-carbonamido-ethyl)-benzenesulfonamido]-5-propyl-pyrimidine with melting point 158 - 159°C. Example 2 2^[1+-(p-3'-ethoxy-thiophene-2-carbonyl-N-methyl-aminoethyl)-benzenesulfonamido]-5-isobutyl-pyrimidine 2.5 g 2-[4--(p-N -methylamino-ethyl)-benzenesulfonamido]-5-iso-butyl-pyrimidine is dissolved in a mixture of 3.5 ml of 2n-sodium hydroxide solution, 5 ml of water and 3.7 ml of 2n-soda solution. A solution of 1.5 g of 3-ethoxy-thiophene-2-carboxylic acid chloride in 5 ml of methyl chloride is then added while stirring, and the mixture is stirred for two hours at room temperature. The methylene chloride is then separated, and the aqueous phase is acidified. This precipitates 2-Cps-3'-ethoxythiophene-2-carbonyl-N-methyl-aminoethyl)-benzenesulfonamido]-5-isobutylpyrimidine, which after recrystallization from propanol melts at 1<1>+2°C.

Example

2-{h-[p-(N-methyl-3'-methoxy-thiophene-2-carbamido)-ethyl]-benzenesulfonamido}-5-ethylmercapto-pyrimidine

1.7 g ^-[p-CN-methyl-31-methoxy-thiophene-2-carbamido)-ethyl-benzenesulfochloride (oily; prepared by sulfochlorination of p-(N-methyl-3<1->methoxy-thiophene- 2-carbamido)-ethylbenzene) is dissolved in 7 ml of absolute pyridine, and 0.7 g of 2-amino-5-ethylmercapto-pyrimidine (melting point llh - 116°C) is added at 0°C. After a standstill of 18 hours, the mixture is heated for 1 hour at 100°C, after which it is cooled and poured over ice. The precipitated material is filtered off and dissolved in dilute soda solution. After adding charcoal, the mixture is filtered, and the filtrate is acidified with dilute hydrochloric acid. The residue is then recrystallized from dioxane. Melting point 170°C. Example h

2- { h-[p-C3V-methoxy-thiophene-2-carbamido)-ethyl]-benzenesulfonamido } - 5- methyl- pyrimidine

When proceeding in the same way as described in example 3, reaction of 0.8 g<*>+-[p-(3-methoxy-thiophen-2-carbamido)-ethyl]-benzenesulfochloride (melting point 85 - 87 °C) with 0.25 g of 5~raethyl-2-aminopyrimidine {melting point 192°C) the compound 2-{_4-[B-(3'-methoxy-thiophene-2-carbamido)-ethyl]-benzenesulfonamido} - 5~ methyl-pyrimidine in good yield. Melting point 236 - 239 C. The compound is purified by recrystallization from dilute soda solution/ dilute hydrochloric acid.

Example 5

2-[6-(furan-2-carbonamido)-ethyl]-benzenesulfonaminoj-5-isobutyl-pyrimidine

From 4-[8-(furan-2-carbonamido)-ethyl]-benzenesulfonamide (melting point 224 - 225°C) the sodium salt is first prepared by adding an equivalent amount of sodium methylate solution in ethanol. 3.16 g of the dried sodium salt and 2.30 g of 2-trimethylammonio-5-isobutyl-pyrrinidine hydrochloride (melting point 165°C during decomposition; - prepared from 2-chloro-5-1-isobutyl-pyrimidine and trimethylamine in benzene) stirred for 4-0 hours at room temperature in 15 ml of N,N-dimethyl-acetamide. The solution is then diluted with water to 100 ml. 4--(_B-(furan-2-carbonamido)-ethyl]-benzenesulfonamide is precipitated and recovered by filtration. The filtrate is acidified with dilute hydrochloric acid, whereby 2-;4-- [ 6 - (furan-2-carbonamido) - ethyl ] -benzenesulfonamino \ - 5-isobutyl-pyrimidine is precipitated.After recrystallization from ethanol, the compound melts at 200 - 201°C.

Example 6

2-(4- - [B-(furan-2-carbcnamido)-ethyl benzenesulfonamino}-5-isobutyl-pyrimidine

Into a solution of 9 g of dimethylformamide in 4-0 ml of dry toluene, 12 g of phosgene are introduced with stirring at 0-5°C, after which 11 g of isobutyl acetaldehyde-diethyl acetal (bp.-^<:>74-°C) is added dropwise. The mixture is then heated at 60°C for 3 hours with stirring, after which the toluene is distilled off in a vacuum, and the mixture, after the addition of 10 ml of absolute methanol, is adjusted to pH 8 with 20 30% sodium methylate solution. The mixture is poured with stirring into a boiling mixture of 3 g of sodium in 60 ml of absolute methanol and 20 g of 4-(B-furan-2-carbonamido-ethyl)-benzenesulfonyl-guanidine (melting point 238°C; prepared from 4 --(B-furan-2-carbonamido-ethyl)-benzenesulfonamide by condensation with sodium carbonate and guanidine nitrate), and the mixture is boiled with stirring for 8 hours. The precipitated salts are filtered off, the filtrate is evaporated and the residue is dissolved in dilute sodium carbonate solution,

Claims (1)

filtered and precipitated with dilute hydrochloric acid. The 2-{h-[p-(furan-2-carbonamido)-ethyl]-benzenesulfonamido \-5-isobutyl-pyrimidine recrystallized from ethanol melts at 200 - 201 C. Analogous method for the production of new antidiabetic active sulfonamides of the general formula in: where A denotes a thiophene or furan group which may optionally be substituted with lower alkyl or lower alkoxy, or a 3,^-tetramethylene-thiophene group, R^ denotes hydrogen or lower alkyl, Rp denotes lower' alkyl or lower alkyl mercapto, characterized by either) reacting one compound of the general formula II: where A and R-^ have the meanings given above, and m is an integer from 0 to 2, with a 2-aminopyrimidine of the general formula III: where Rp has the meaning stated above, and then optionally oxidizes the compound obtained to the sulfonamide, b) reacts a benzenesulfonylguanidine of the general formula IV: where A and R^ have the meanings given above, with a connection of the general formula V: where R^ has the meaning given above, cg Y and Y' denote hydrogen or alkoxy, or a functional derivative thereof, after which the optionally hydroxylated pyrimidine in the 4- and/or 6-position by conversion to a corresponding halogen compound and reductive dehalogenation of this is transferred to the pyrimidine unsubstituted in the k- and 6-positions, c) acylates a compound of the general formula VI: where R^ and R^ have the meanings indicated above, with a reactive derivative of an acid of the formula A-CO-OR, where A has the meaning indicated above, or d) reacts a sulfonamide of the general formula VII: where A and R have the meanings given above, with a pyrimidine derivative of the general formula VIII: where Rp has the meaning given above, and Z denotes a reactive ester group or a lower trialkylamino group.