DE1670282C3 - Hydrindensulfonylamino-pyrimidines with antidiabetic activity and processes for their preparation - Google Patents

Description

3. Medicaments consisting of compounds according to claim 1 and customary excipients.

From the DT-PS 1147 948, the GB-PS 9 13 716 carry amino residue, see through a particularly slarke and 9 39 608 and BE-PS 6 09 270.6 22 085.6 22 086, 15 and long-lasting antidiabetic effect 6 37 083 and 6 64 178 are substituted 2-benzenesulfonylaminopyrimidines became known with blood sugar lowering effect. It has now been found that hydrindensulfonylamino-pyrimidines, the one acyl

to draw.

The present invention therefore relates to hydrindensulfonylamino-pyrimidines of the general Formula I.

A — CO — NH

SO. — NH

in the A optionally in the 5-position by a b) a hydrindene-sulfonyl-guanidine of the general

Methyl group, a chlorine or bromine atom substituted 2-methoxyphenyl radical, a 2-ethoxy-5-chlorophenyl radical or a / i-phenylethyl radical, R _{2 is} an alkyl radical with 3-4 Carbon atoms or an alkoxy radical with 2 to 3 carbon atoms, and R _{3 is} a hydrogen atom or a methyl group, their physiologically acceptable salts, a process for the preparation of the substances and medicaments according to the invention, which are derived from the Compounds according to the invention and customary carriers exist.

The inventive method for preparing the compounds of general formula I is thereby characterized in that one either in a known manner

a) a compound of the general formula 11 SO ₁ -NH-C

(IV)

in which A has the meaning given above, with a compound of the general formula V

Z — C — CH-C —Z '

O R,

45 or

ZC-CH-CR ₃

A — CO — NH

S (O) _n Cl OR,

(H)

in which A has the meaning given above and> i the number is 0 to 2, with a 2-amino-pyrimidine of the general formula III

H ₂ N- <

(III) in which R ₂ and R _{3 have} the meaning given above and Z and Z 'represent hydrogen atoms or alkoxy groups, or their functional derivatives are converted, whereupon they are then optionally hydroxylated in the 4- and / or 6-position

Pyrimidines converted into the desired pyrimidines by conversion into the halogen compounds and subsequent reductive dehalogenation, or
c) a compound of the general formula VI

in which R ₂ and R _{3 have} the meaning given above, is reacted, optionally being subsequently oxidized to the sulfonamide, or SO ₂ -NH- ^ '"\ -R,

N = Il (V!)

H ₇ N-

in which R ₂ and R _{3 have} the meaning given above

have reacted with a reactive derivative of an acid of the general formula A - COOH, where A has the meaning given above, or

d) a sulfonamide of the general formula VI

A-CO- -NH

SO ₂ -NH ₂

(VIl)

in which A has the meaning given above, with a pyrimidine derivative of the general formula VIII

(VIII)

in which R ₂ and R _{3 have} the meaning given above and T is a reactive ester group or a low molecular weight trialkylammonium group and, if desired, the compounds obtained are converted into physiologically acceptable salts.

The reaction of the compounds II and III is expediently carried out in the presence of an inert solvent carried out a base, preferably pyridine or trimethylamine. But you can also do it with one molar excess of the aminopyrimidine work around the hydrogen chloride formed in the reaction intercept. The subsequent oxidation of the sulfonamides or sulfonamides takes place in the usual way Way, e.g. B. by treatment with hydrogen peroxide, potassium permanganate or nitric acid.

The hydrindene sulfonyl guanidines used as starting compounds IV can e.g. B. can be obtained by melting together the hydrindene sulfonamides with guanidine carbonate. The condensation with the // - dicarbonyl compounds V can, for. B. be carried out by means of Alkalialkoholai in alcohol. The / i-dicarbonyl compounds are used here in free form or as functional derivatives, e.g. B. acetals, but they can also be used in the "one-pot process." according to V i 1 s m e i e r from aldehyde acetals or ketals or corresponding enamines, inorganic Acid chlorides and dialkylformamide are produced. Used in place of the dicarbonyl compounds Correspondingly substituted malonic acid diesters, malonic ester aldehydes, / i-keto esters or their functional derivatives, then those in 4- and / or δ-ste '.' ung of the pyrimidine ring The hydroxyl groups are replaced by chlorine with the aid of an inorganic acid chloride be, which is then reductive z. B. can easily be removed with zinc dust.

The acylation of the compounds VI is carried out in a customary manner, e.g. B. by implementing with the corresponding acids (or with their reactive derivatives, e.g. with acid halides), preferably in the presence of an acid acceptor.

Particularly suitable starting compounds of the formula VIII are 2-halopyrimidines; she can e.g. B. obtained by reacting 2-hydroxy-pyrimidines with phosphorus oxychloride.

The condensation according to the invention with the hydrindene sulfonamides VII takes place preferably in the presence of a base such as potassium carbonate. On Instead of the 2-halopyrimidines, the corresponding trialkylammonium-pyrimidine can also be used with the Sulfonamide reacted with the escape of trialkylamine to the hydrindene sulfonylamino-pyrimidines wcr-

In particular, alkali, alkaline earth and ammonium salts are suitable as physiologically harmless salts Question that are produced in a manner known per se, for example by reacting with sodium hydroxide solution, Alk'alilaugc, aqueous ammonia or the corresponding Carbonates.

Comparative experiments

The following abbreviations are used in the descriptions of the experiments:

MH 48 = 2- (5-chloro-2-melhoxybenzamido) -N- [5-propoxypyrimidinyl- (2)] -
hydrindene-5-sulfonamide.
MH 50 = 2- (5-chloro-2-melhoxybenzamido) -N- [5-propylpyrimidinyl- (2)] -

hydrindane-5-sulfonamide.
Hc 577 = 2- (5-chloro-2-methoxybenzamido) -N- [5-isobutylpyrimidinyl- (2)] -
hydrindcn-5-sulfonamide.
MH 55 = 2- (5-chloro-2-ethoxybenzamido) -

N- [4-methyl-5-isobutyl-pyrimidinyl- (2)] - hydrindene-5-sulfonamide.
MH 49 = 2- (5-bromo-2-methoxybenzamido) -

N- [5-propoxypyrimidinyl- (2)] - hydrindene-5-sulfonamide.

MH 91 = 2- (2-methoxy-5-methyl-benz-

amido) -N- [5-ethoxypyrimidinyl- (2)] - hydrindene-5-sulfonamide.
He 607 = 2- (o-methoxybenzamido) -N- [5-isobutylpyrimidinyl- (2)] - hydrindene-

; 5-sulfonamide.

He 625 = 2- (hydrocinnamoylamido) -N- [5-isobutylpyrimidinyl- (2)] - hydrindene-5-sulfonamide.
SH 717 = 2-benzenesulfonamido-5-methoxyethoxy-

pyrimidine.
He 430 = 4 - (/? - 2-methoxy-benzamido-ethyl) -

N- [5-isobutylpyrimidinyl- (2)] - benzene-

sulfonamide

(known from BE-PS 664 178).

1. The blood sugar-lowering effect was i. v. tested, and was in each case the so-called threshold dose is determined, which is the smallest dose of a substance with which currently a significant decrease in blood sugar (15%) is produced. The animals were pre-injected Held sober for 16 hours. At least four animals were used for each dose. the Blood sugar determinations were made every hour after substance administration and were also against a Control collective, which was treated with common salt in the same way, related.

substance

MH 48
MH 50
He 577
MH 55
MH 49

Void Dose (mg / kg IV)

0.05

0.025

0.025

0.05

0.025

continuation Smolder substance 0.025 MH 91 0.025 Hc 607 0.05 He 625 20th SH 717 0.1 He 430

As can be seen from the table, the hydrindensulfonylamino-pyrimidines according to the invention have a stronger blood sugar lowering effect than the constitutionally related commercial product as well as the structurally related comparative compound from BE-PS 6 64 178 on ".

2. The toxicity of the new hydrindeisulfonylamino-pyrimidine derivatives is very low. The LD ₅₀ values of compounds of this substance class are very high compared to the respective threshold dose. To determine the acute oral toxicity, the substance MH 50 was selected as the characteristic compound of the present application. No deaths occurred after oral or intraperitoneal administration of 1000 mg / kg of this substance to rats and after oral administration of 4.0 g / kg of this substance to mice, so LD ₅₉ > 4.0 g / kg applies.

The acute toxicity for the comparison compound He 430 was also determined in the mouse after oral administration to be LD ₅₀ > 4.0 g / kg.

3. The subchronic toxicity of the compound MH 50 was also determined in 14-day experiments determined both intravenously on dogs and intraperitoneally on rats.

Subchronic intravenous toxicity
(14-day trial on dogs)

MH 50 was administered to males and females in alcoholic solution at a dose of 0.5 mg / kg / day Purebred Beagle once a day and 7 times a week Administered for 14 days.

The examinations carried out during the duration of the experiment and after the animals were killed showed the following:

At this dose there were no signs of toxic damage, either clinically or pathologically-anatomically be detected. At the end of the experiment, it was 24 hours after the last substance was given male animals showed a blood sugar drop of 20%. The female dogs behaved like the control ticrc. In both sexes, there was moderate to severe granulation of the B cells Langerhans islands present. The granulation was somewhat stronger in the males than in the females.

Subchronic intrupcritoncal toxicity test
(14-day study on rats)

MH 50, micronized to a particle size of 1-6 µm; was growing female and male rats of the Spraguc Dawley strain in the dosage of 0.5 mg / kg / day administered intraperitoneally. An equal size Control group was injected with the solvent.

The tests carried out during the duration of the experiment and after the animals were killed showed: MH 50 is given intraperitoneally at a dose of 0.5 mg / kg / day for a period of 14 days tolerated by the growing white rat without toxic damage. After a term of 2 weeks, 24 hours after the injection ίο, a decrease in blood sugar was found in the female and male animals by about 20%. The pancreatic islet B cells show up in both female and male Animals had moderate degranulation.

The subchronic toxicity of the comparison compound He 430 was tested in rats with 5 mg / kg and 20 mg / kg, in dogs with 1 mg / kg and 5 mg / kg, these doses being administered orally daily for 4 weeks.

At these doses, neither during the duration of the experiment (clinical-chemical) nor after killing of the animals (pathological-anatomical) any signs of toxic damage were observed.

The process according to the invention is explained in more detail using the examples below.

example 1

2- (5-Chloro-2-methoxybenzamido) -N- [5-propoxypyrimidinyl- (2)] - hydrindene-5-sulfonamide

3.2 g of 2- (5-chloro-2-methoxy) are added in portions to a solution of 1.23 g of 2-amino-5-propoxypyrimidine (melting point 73-74 ° C.) in 5 ml of anhydrous pyridine, while stirring and cooling -benzamido) -hydrinden-5-sulfochloride (melting point 133-135 ° C.) ₁ the mixture is left to stand overnight and then heated on the steam bath for 2 hours. After cooling, it is poured into 50 ml of water and the crude product precipitated as a result is filtered off with suction. To clean it, it is dissolved in dilute sodium hydroxide solution, treated with activated charcoal and precipitated again with dilute hydrochloric acid. It is then recrystallized from methanol. Yield: 3.1 g (75% of theory) 2- (5-chloro-2-methoxybenzamido) -N - [5 - propoxypyrimidinyl - (2)] - hydrindene - 5 - sulfonamide with a melting point of 122-124 ° C. The 2- (5-chloro-2-methoxy-benzamido) -hydrindene-5-sulfochloride (melting point 133 ° C.) which is converted is obtained by sulfochlorination of 2- (5-chloro-2-methoxybenzamido) -hydrindene ; Mp. 124 ° C.

The following compounds are obtained in an analogous manner:

2- (5-Chloro-2-methoxybenzamido) -N- [5-propylpyrimidinyl- (2)] - hydrindane-5-sulfonamide

For cleaning, it is dissolved in dilute sodium hydroxide solution, treated with activated charcoal and with dilute hydrochloric acid precipitated and recrystallized from methanol; Mp. 138 ° C.

2- (5-Chloro-2-methoxybenzamido) -N- [5-isobutylpyrimidinyl- (2)] "hydrindane-5-sulfonamide

The product is dissolved in dilute sodium hydroxide solution, precipitated with hydrochloric acid and then with hot ethanol extracted; M.p. 122-124 "C.

2- (5-chloro-2-ethoxybenzamido) -N- [4-methyl- ' ⁵ 5-isobutyl-pyrimidinyl- (2)] -hydrindane-5-sulfonamide

For cleaning, the product is dissolved in dilute sodium hydroxide solution, treated with activated charcoal and

709 B42 / 43

ίο

precipitated with dilute hydrochloric acid. After a further drop of the melting point is 105 -108 ⁰ C.

The 2- (5-chloro-2-ethoxybenzamido) -hydrindene-5-sulfochloride was used (Mp. 60-65 ° C) is obtained by sulfochlorination of 2- (5-chloro-2-ethoxybenzamido) -hydrindene (M.p. 128 ° C) obtained.

2- (5-Bromo-2-methoxybenzamido) -N- [5-propoxypyrimidinyl- (2)] - hydrindene-5-sulfonamide

For cleaning, the crude product is dissolved in dilute sodium hydroxide solution, treated with activated charcoal, with dilute hydrochloric acid precipitated again and recrystallized from methanol. It will then be repeated dissolved in dilute sodium hydroxide solution and precipitated with dilute hydrochloric acid; Mp. 133-134 ° C.,

The 2- (5-bromo-2 - methoxy - benzamido) - hydrindene - 5 - sulfochloride used as the starting substance (M.p. 128-129 ° C.) is obtained by sulfochlorination of 2 - (5 - bromo - 2 - methoxybenzamidone) - hydrindene (mp. 121-123 ° C).

Example 2

2- (2-methoxy-5-methyl-beiizamido) -N- [5-ethoxy-

pyrimidinyl- (2)] - hydrindene-5-sulfonamide

1.9 g of 2-amino-N- [5-ethoxy-pyrimidinyl- (2)] - hydrindene-5-sulfonamide are dissolved in 3.0 ml of 2N sodium hydroxide solution and 5 ml of water and added dropwise with a solution of 1.3 g of 2-methoxy-5-methylbenzoyl chloride in 10 ml of methylene chloride was added. To brief stirring, the methylene chloride is evaporated, acidified with acetic acid and the precipitated substance sucked off. For cleaning, it is dissolved in dilute sodium hydroxide solution, filtered, by introducing Carbon dioxide precipitated, suctioned off, dissolved again in dilute sodium hydroxide solution and diluted with dilute hydrochloric acid again precipitated, filtered off with suction and recrystallized from ethanol / ethylene chloride.

Yield: 2.0 g (73% of theory), melting point 214-216 ° C.

Used as a starting product 2-Amino N - [5 - ethoxy - pyrimidinyl 1 - (2)] - hydrindene - 5 - sulfone amide (mp. 232 ⁰ C) is obtained by alkaline Hy drolyse of 2- (Äthoxycarbonylamino) -N- [5-ethoxy pyrimidinyl- (2)] hydrindene-5-sulfonamide, m.p. 165 ° C

Example 3

2- (o-Methoxybenzamido) -N- [5-isobutylpyrimidinyl- (2)] - hydrindene-5-sulfonamide

To 1.7 g of 2-amino-N- [5-isobutylpyrimidinyl- (2)] - hy drinden-5-sulfonamide, dissolved in 10 ml of anhydrous] Pyridine, 0.9 g of o-methoxy-benzoyl chloride are obtained give. The mixture stays at room temperature stand overnight, then heat it up on the steam bath for one hour and then put it in water after it has cooled down. poured. The precipitated substance is dissolved in dilute soda solution and filtered through activated charcoal and precipitated again by adding dilute hydrochloric acid. Used for recrystallization ma Propanol / water. The compound contains 1 MoI crystal water.

Yield: 0.8 g (34% of theory), melting point 107 ° C.

The 2-amino N - [5 -! Sobuty 1 - pyrimidinyl - (2)] - hydrindene - 5 - sulfon amide (melting point 235-240 ° C) used as the starting product is hydrolyzed by alkaline hydrolysis of 2- (ethoxycarbonylamino) -N- [5-isobuty pynmidinyl- (2)] - faydrinden-5-sulfonamide (mp. 160-161 ° C). ^F.

Example 4

2- (Hydrocinnamoylamido) -N- [5-isobutylpyrimidinyl- (2)] - hydrindene-5-sulfonamide

2.3 g of 2-hydrodynnamoylamido-hydrindene-5-sulfone amide, 1.15 g of 2-chloro-5-isobutylpyrimidine and 0.9 ι Potassium carbonate are fused at 190 ° C. After falling from dilute soda solution with ver dilute hydrochloric acid and recrystallization from ethyl acetate the melting point is 202-204 ° C

Claims (2)

Claims: 1. Hydrindensulfonylamino-pyrimidine of the general formula I. A — CO — NH in A, a 2-methoxyphenyl radical optionally substituted in the 5-position by a methyl group, a chlorine or bromine atom, a .l-ethoxy-S-chlorophenyl radical or an i-phenylethyl radical, R _{2 is} a Alkyl radical with 3-4 carbon atoms or an alkoxy radical with 2-3 carbon atoms, and R _{3 is} a hydrogen atom or A-CO-NH SO, —NH- < N = denotes a methyl group, as well as their physiologically harmless salts. 2. Process for the preparation of hydrindensulfonylamino-pyrimidines according to claim 1, characterized in that either in a known manner a) a compound of the general formula 11 S (O) _n Cl (Π) in which A has the meaning given in claim 1 and η is the number O to 2, with a 2-aminopyrimidine of the general formula III ^Ν Ί R ₃ in which R ₂ and R _{3 have} the meaning given in claim 1, is reacted, optionally being subsequently oxidized to the sulfonamide, or A-CO-NH in which A has the meaning given above, with a compound of the general formula V Z — C — CH-C —Z ' I! I I! OR ₂ O (v; (HI) Il I Il OR ₂ O in which R ₂ and R _{3 have} the meaning given above and Z and Z 'represent hydrogen or alkoxy groups, or their functional derivatives are reacted, whereupon the pyrimidines, which may be hydroxylated in the 4- and / or 6-position, are then converted by conversion converted into the halogen compounds and subsequent reductive enthalogenation into the desired pyrimidines, or b) a hydrindensulfonyl-guanidine of the "general Formula IV SO, -NH-C NH NH ₂ (IV) c) a compound of the general formula VI in which R ₂ and R _{3 have} the meaning given above, with a reactive derivative of an acid of the general formula A — COOH, where A has the meaning given above, or d) a sulfonamide of the general formula VII A-- CO - NH- SO ₂ -NHj (VII) in which A has the meaning given above, with a pyrimidine derivative of the general form! VIII ^R J '"V /"" ² (viii) in which R ₂ and R _{3 have} the meaning given above and T is a reactive ester group or a low molecular weight trialkylammonium group, and the compounds obtained are, if desired, converted into physiologically acceptable salts.