DE2022746A1 - Blood sugar lowering sulfonylaminopyrimidines and processes for their preparation - Google Patents

Description

BOEHRXNG! H MANNHEIM GMBH, 169.4 '

Blood sugar lowering sulfonylaminopyrimidines and methods for their Manufacturing

From the German patent specification 1 147 948 * the British patents 913 716 and 939 608 and the Belgian patents 609 270, 622 085, 622 086 and 637 083 are substituted 2-benzenesulfonylamino-pyrimidine with blood sugar-lowering effect known. It has now been found that tetrahydronaphthalenesulfonylamino-pyrimidines, that carry an acylamino residue, through a particularly strong and long-lasting antidiabetic Distinguish effect.

The present invention relates to these new compounds of the general formula I.

A-CO-Ii-f T! -1 . .. _ // W- ·, -, (l)

in the

A öinen optionally by halogen, alkyl, alkoxy or Alkoxyalkoxy groups with 1 bjLS 3 carbon atoms substituted aryl, aralkyl, furyl, thionyl, isoxazolyl, Isothiazolyl or pyrazolyl Rcst :,

R or a hydrogen atom or a lower alkyl radical,

R oinon goradkottigen or branched alkyl, cycloalkyl, CycXoalkylalkyl, alkoxy, cycloalkoxy, alkoxyalkyl, Alkoxy, alkoxy- or alkylinorcnpi o-Rcah odor an optionally substituted by Htilfitjen-, Alkoxy- utlnr-alkyl radical Aryl or aralyl radical,

109849/1940

R, hydrogen or a lower alkyl group, where R ₁ and R ₂ together can also form a ring of 3 to 5 methylene groups,

as well as their physiologically harmless salts ""

The present invention also relates to processes for production of the compounds of general formula I “pharmaceutical Preparations containing compounds of the general formula I. and / or their physiologically harmless salts, as well as the use of compounds of the general formula I together with their physiologically acceptable salts for the production of blood sugar lowering agents Drug.

^ The method according to the invention for the preparation of compounds of general formula I and their physiologically tolerable salts is characterized in that either in a known manner

a) Substances of the general formula II

in which A and R have the meaning given above and η dia Numbers O to 2 represents »

ι -

with 2-amino-pyrimidinone of the general formula III

in the R, and U ₂ dl η indicated above mo l »a <kHU.uiiq hnbon,

implemented 'and gocjobunon.1 alls anaohlt «0« uir | mim sulphontunide oxidized, oiio-r

'"■ 109849/1940

b) substances of the general formula IV

Ii ;,

in which R, R. and R "have the meaning given above,

with a dom rGaktional-'tligen derivative of an acid of the formula A-COOH converts, where A has the meaning given above, or

c) sulfonamides of the general formula V.

A-CO-li-j - υ ^ J-SO ₂ NiI ₂ (V),

in which A and R have the meaning given above, with a pyrimidine derivative of the general formula VI

• in which R ₁ and R _{0 have} the meaning given above and T is a reactive ester group or a low molecular weight trialkylammonio group,

implements or

d) sulfonylguanidines of the general formula VlI

(VII),

in which A and R have the meaning given above ^

1098A9 / 194G

ZC -. CH - C Il ι It O «Ι O

with substances of the general formula VIII

-C - CU - C ■ - Ζ «or ZG-. CH - c - R ₂ ■ (VIIl), -

Il I ti - ' A. -V Λ »

ο Ji ₁ ο

in which R. and R _{2 have} the meaning given above and Z or Z ^{1 represent} hydrogen or an alkoxy group,

or their functional derivatives implemented, which is then followed the ones obtained, optionally hydroxlated in 4- and / or 6-struc- tures Pyrimidines by converting them into the halogen compounds and subsequent reductive dehalogenation into the desired pyrimidines transferred, and possibly with physiologically harmless bases Converts salts.

The implementation of the compounds II and III is expedient in one inert solvent in the presence of a base, preferably pyridine or trimethylamine. But you can also do it with one work molar excess of the aminopyrimidine to trap the hydrogen chloride formed in the reaction. The subsequent Oxidation of the sulfenamides (n ».-O) or sulphinamides (n = 1) takes place in the usual way, e.g. B. by treatment with hydrogen peroxide, potassium permanganate or nitric acid. ,

The 'acylation of the compounds IV is carried out in a customary manner Reaction with the corresponding acids or with their reactive ones Derivatives carried out, preferably in the presence of one Acid acceptors. 5 ^.

The condensation of the sulfonamides V with the pyrimidine derivatives VI takes place preferably in the presence of a base such as potassium carbonate instead of. As starting compounds of the general formula VI come in particular 2-halopyrimidines in question? you can z. B. by; · Implementation of 2-hydroxy-pyrimidines with excess phosphorus? - oxychloride are obtained *,

109849/1940

Instead of 2-halopyrimidines of the general formula VI the corresponding trialkylammonio-pyrimidines can also be reacted with the sulfonamide V with the escape of trialkylamine will.

The condensation of the sulfonylguanidines VII with the ß-dicarbony1 compounds VIII can e.g. B. be carried out by means of alkali alcoholate in alcohol. The β-dicarbony compounds are used here in free form or as functional derivatives, ζ. Β. Acetals, inserted; But you can also use the "one-pot process". ViIsmeier from aldehyde acetals or ketals or corresponding. , Ehamines, an inorganic acid chloride, and dialkylformamide getting produced. Used instead of the dicarbonyl compounds appropriately substituted malonic acid diesters, malonic ester aldehydes, β-ketoesters or their functional derivatives must then be those in the 4- and / or 6-position of the pyrimidine ring Hydroxyl groups are replaced by chlorine with the help of an inorganic acid chloride, which is then reductive ζ. B. can easily be exchanged for hydrogen with zinc dust.

The sulfonylguanidines VII used as starting compounds can, for. B. by melting together the corresponding sulfonamides can be obtained with guanidine carbonate.

Suitable physiologically harmless salts are in particular alkali, alkaline earth and ammonium salts / as well as salts with blood sugar lowering effective basic compounds, mainly biguanides. These salts are produced in a manner known per se, for example by reaction with alkali or alkaline earth solutions, aqueous ammonia or corresponding carbonates.

The substances I and their physiologically harmless salts can be administered enterally and parenterally in liquid or solid form, water is preferably used as the injection medium, which contains the usual additives for injection solutions such as stabilizers, solubilizers and / or buffers. Such Additions are z. B. tartrate or borate buffer, ethanol,

109849 / 19AO

Complexing agents (such as ethylenediamine tetraacetic acid and their non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) to regulate viscosity. Fixed straps are z. B. starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silica, higher molecular weight fatty acids (such as. Stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearafc, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols). For oral application If desired, suitable preparations can contain flavorings and sweeteners.

The new substances and the method according to the invention are explained using the following examples.

IQS 849/194: 0

example 1

2- (2-Methoxy-5-methy1-benzamido) -N-15-isopropoxy-pyrimldinyi- (2) 3 - 1,2,3, 4-tetrahydronaphthalene-7-sulfonamide

6.4 g of 2- (2-methoxy-5-methyl-benzamido) -1 , 2, 3 , 4-tetrahydronaphthalene-7-sulfochloride are converted to 2.5 g of 2-amino-5-isopoxypyrimidine (melting point 73-75) with ice-cooling ° C) entered in IO ml of absolute pyridine. The mixture initially remains at room temperature for 2 hours, is then heated on the steam bath for 2 hours and, after cooling, poured into dilute hydrochloric acid (from 100 ml of water and 15 ml of conc. Hydrochloric acid). The precipitated crude product is filtered off with suction , dissolved in dilute sodium hydroxide solution for purification, the solution is treated with activated charcoal and the substance is precipitated again with dilute hydrochloric acid. It is then recrystallized from ethanol. Yield 4.5 g (= 54.4% of theory); Mp 185-187 ° C.

The 2- (2-methoxy-5-methyl-benzamido) - used as starting material

1,2,3,4-tetrahydronaphthalene-7-sulfochloride, melting point 142-143 ° C (from Benzene) is obtained in the usual way from 2- (2-methoxy-5-methylibenzamido) -l, 2,3,4-tetrahydronaphthalene (M.p. 79-81 ° C) and chlorosulfonic acid.

The following compounds are obtained in an analogous manner:

2- (2-Methoxy-5-methyl-'benzamido) -N- [5-propyl-pyrimidinyl- (2)] -1,2,3 / 4-tetrahydronaphthalene-7-sulfonamide

Mp. 167-170 ° C (from ethanol) \

2- (2-Methoxy-5-methyl-benzamido) -N-t5- (methoxymethyl) -pyrimidinyl- (2) 3-1,2,3,4-tetrahydronaphthalene-7-sulfonamide

Mp. 108-110 ° C (after repeated falling over and removal of an impurity by adsorption on silica gel).

2- (^ -Methoxy-S-methyl-benzamido) -N- [5- (isopropylmercapto) -pyrimi " (2) -} - l, 2i3, A- te trahydronaph thalin-7-sulfonamide

I * p, lo6-109 ° C (after chromatographic purification and repeated reprecipitation) ^

- ö - - '. ■. ■■. ■ '■', '

2- (2-methoxy-5-methyl-benzamido) -N- [4-methyl-5-isobutylpyrimidinyl- (2) 3-1,2,3 » 4-tetrahydronaphthalene-7-sulfonamide

Mp. 112-114 ⁰ C (after chromatographic purification and repeated drop).

2- (5-chloro-2-methoxy-benzamido) -N- [5 ~ isobutyl ~ pyrimidinyl- (2) 3.- 1.2 / 31 4-tetrahydronaphthalene-7-sulfonamide

Mp. 221-223 ° C (from ethyl acetate)

The starting substance used is _-- 2- (5-chloro ~ 2-methöxybenzamido) -1,2,3,4-tetrahyronaphthalene-7-sulfochloride, Mp. 165-166 C (from benzene), which is obtained in the usual way. From 2- (5-chloro-2-methoxy-benzamido) -1, 2,3,4-tetrahydronaphthalene (Mp. 111-113 ° C) and chlorosulfonic acid.

2- (5-chloro-2-methoxy-'bengamido) "N- [5-benzyl-pyrimidinyl" (2)] - 1,2,3,4-tetrahydronaphthalene-7-sulfonamide .

Mp. 114-116 ° C (after removal of an impurity by adsorption on silica gel and subsequent falling over).

2- (5-chloro-2-ethoxy-benzamido) -N- [5- (2-metho3cy-ethoxy) -pyrimidinyl- (2) 3-1,2,3,4- ° tetrahydronaphthalene -7-sulfonamide

Mp. 130-135 ° C (from ethanol) ^v

The starting substance used is 2- (5-chloro-2-ethoxybenzamido) -1,2,3,4-tetrahydronaphthalene-7-suifocM ^: ör ^ ä (oily), which is obtained in the usual way from 2 "(5-chloro -2-ethoxy-benzamido) -1,2,3,4-tetrahydronaphthalene (melting point 104-105 ° C.) and chlorosulfonic acid. ^ V

2- (5-chloro-2-ethoxy-benzamido) ° N- [5,6 ■ ·, 7,8-tetrahydroquinazolinyl- (2) 3-1, 2 _y 3,4- tetrahydronaphthalene-7-sulphonamide

Mp. 159-161 ° C (from isopropanol)

1940

2- (5-Fluoro-2-methoxy-benzamido) -N- E 5-cyclohexyl-pyfimidinyl- (2) 3-1 , 2, 3 _r 4-tetrahydronaphthalene-7-sulfonamide

Wp. 125-127 ° C (from isopropanol)

As a starting material to which is obtained in the usual manner from 2 used 2- (5-fluoro-2-methoxybenzamido) -1,2, 3,4-tetrahydronaphthalen-7-sulphonyl chloride, Pp. 77-8O ° (from benzene) - (5-Fluoro-2-methoxy-benzamido) -1,2,3,4-tetrahydronaphthalene (m.p. 122-125 ^O C) and chlorosulphonic acid.

2- (5-Bromo-2-methoxy-benzamido) - K -. [5- (cyclohexy! Methyl) -pyrimidinyl- (2)] - 1 , 2, 3/4-tetrahydronaphthalene-7-sulfonamide

Mp. 133-136 ° C (from methanol / water).

As a starting material is used 2- (5-bromo-2-methoxybenZamidoy-!, 2, 3,4-tetrahydro-naphthalene-7-sulphonyl chloride _/ mp. 116-118 ⁰ C (from methylene chloride / ether), which won in the usual manner is made from 2- (5-bromo-2-methoxy-benzamido) ~ 1 , 2, 3 _/ 4-tetrahydronaphthalene (melting point 125-127 ° C.) and chlorosulfonic acid.

example

2- [Fluorenyl- (9) -acetamido] -N-E5-isobutyl-pyrimidinevl • - (2)] - 1 / 2,3 / 4-tetrahydronaphthalene-7-sulfonamide

2.4 g of fluorenyl (9) acetic acid and 3 ml of thionyl chloride are refluxed for 3 hours, the excess thionyl chloride is distilled off in vacuo and the remaining fluorenyl (9) 7 acetyl chloride is taken up in 10 ml of absolute methylene chloride. This solution is under ice-cooling to the solution of 3, 2 g of 2-amino-N-E5-isobutyl-pyrimidinyl- (2)] -1, 2, _f 3 _r 4 tetrahydronaphthalen-7-sul £ onamid EFp. 244-245 ° C? represented by alkaline hydrolysis of 2- (ethoxycarbonylamino) -N-

109849/1940

[5-iisobutyl-pyrimidinyl- (2)] -1,2,3,4-te ^ rahydronaphthalin - 7-sul.fonamid added dropwise mp 108-112 ⁰ C3 in 5 ml 2 / n sodium hydroxide solution and 30 ml water. . The pH value is increased by gradual addition because. «Tor caustic soda to about 12 fold. There will be another / ",. Stirred for hour, then acidified with Esäigsäu / e and the methylene chloride pre-evaporated by heating ψ. The precipitated crude product is dissolved in very dilute sodium hydroxide solution, the solution is treated with activated charcoal, the substance is precipitated by introducing carbon dioxide, dissolved again in sodium hydroxide solution and precipitated with hydrochloric acid. For further purification, the substance is taken out

Isopropanol is recrystallized. ■

Yield 1.8 g (* 36% d / th.); M.p. 132-134 ° C.

/ ■ ■ ■ ■■ '■

The following compounds are obtained in an analogous manner

2- (2-Methoxyberiζamiiio) -N-15-isobuty 1 -pyrImidiny 1- (2) .J-1 _f 2,3,4-tetrahydronaphthalene-T-sulfonamide

M.p. 112-114 ° C (as isopropanol).

2-1 i ~ Xhhox y-thdnpy 1- (2) -amino] -N- [5-I t; o bubyl-pyrimidinyl- (2) J- 1,2,3, ^ -tfetrahydronaphthalin-y-sulfonamide

Mp. 1 1.4-116 Qf (from isopropanol)

2-1 λ ( 2-Mot , lbxyäthoxv) -thonoyl · ^ (2) -amino]> N- (5-isobutyl-

Ullnylr (2)] -1,2,3,4-tetrahydronaphthalene-7-sulfonamide

Mp. Lo6-108 ° C (from ethanol)

9849/1 940 ORIGINAL INSPECTED

- ii - '■■ -.' ■ - ■■ -. 'Y-

At game 3 Λ

2- (5-chloro-2-ethaxy-benzamido) -N- [5-cyclohexyloxy-pyrimldinyl- (2) 3-1 12th , 3 ', 4-tetrahydronaphthalene sulfonamide

9.9 g of crude 2- (5-chloro-2-ethoxy-ben2amido) -1,2,3-, 4-tetrahydronaphthalene sulfochloride (oily), which consists of an isonate mixture (sul-fochloride group predominantly in the 7-position, partly in 5- or 8-digit length) are mixed with 15 ml of absolute pyridine and in addition 3.9 g of 2-amino-5-cyclohexyloxypyrimidine with ice-cooling

(Mp. 71-72 ° C) entered. The mixture initially remains for 2 hours stand at room temperature, is then heated for 2 hours on the steam bath and, after cooling, poured into dilute hydrochloric acid (from 150 ml of water and 25 ml of concentrated hydrochloric acid). The unusual one The crude product is filtered off with suction, dissolved in highly dilute sodium hydroxide solution with heating (22 ml of 2N sodium hydroxide solution and 350 ml Water), the solution treated with activated charcoal and the substance through Introducing carbon dioxide precipitated. This transformation is still going to happen repeated once, but acidifying with dilute hydrochloric acid.

Recrystallization from isopropanol gives the sparingly soluble 2- (5-chloro-2-ethoxy-benzamido) -N-E5-cyclohexyloxypyrimidinyl- (2)] - 1,2,3, ^ - tetrahydronaphthalene-7-sulfonamide, m.p. 203-2O6 ° C., while a substance is obtained from the mother liquor by chromatographic separation and then repeated reprecipitation which, upon spectroscopic examination, turns out to be a mixture of 2- (5-chloro-2-ethoxy-benzamido) -N- [S- cyclohexyloxypyrimidinyl (2) 3-1.2 _t 3,4-tetrahydronaphthalene-5-sulfonamide and 2- (5-chloro-2-ethox'y-benzamido) -N- [5-cyclohexyloxy-pyrimidinyl- (2) 3 -1,2,3,4-tetrahydronaphthalene-8-sulfonamide. This mixture melts at 118-12O ° C *

Example 4

2- (S-chloro-a-methoxy-benzamido) -N-15-isobutyl-1-pyriinidinyl- (2) J-1,2,3,4-tetrahydronaphthalene-7-sulfonamide

109849/1940

From 2- (5-chloro-2-methoxy-benzamido) -1,2,3,4-tetrahydronaphthalen-7-sulfonamide (mp 128-13O ₀ ° C) is first prepared the sodium salt forth. 4.2 g of this sodium salt and 2.3 g of 2-trimethylammonio-5-isobutyl-pyrimidine-chloride (melting point 165 ° C. with decomposition; prepared from 2-chloro-5-isobutyl-pyrimidine and trime thy land, η in Benzene ·) werdeii in 15 ml Ν, Ν-dimethylacetamide at room temperature for 16 hours. Then the solution is diluted to 100 ml with water? some 2- (5-chloro-2-methoxy-benzamido) -1,2,3,4-tetrahydronaphthalene-7-sulfonamide precipitates out and is recovered by suction. The filtrate is acidified with dilute hydrochloric acid and thus 2- (5-Chloro-2-methoxy-benzamido) -N- [5-isobutyl-pyrimidinyl- (2) 3-1 ^, S ^ -tetrahydronaphthalene-T-sulfonamide, which is recrystallized from ethyl acetate after drying. _{Mp 0} 220-221 ° C. The compound is identical to the substance prepared according to Example 1. .

example

1- (2-Phenyl-ethyl) biguanide salt of 2- (2-MethQxy-5- ^ methylbenzamido ) -N- [5- isopoxy ° pyrimidiny, 1- (2) ] -l., 2,3, 4-tetrahydronaphthalene-7-sulfonamide

The solution of 2.05 g prepared according to Example 1-2- (2-methoxy-5-methyl-benzamido) -N- [5-isopropoxy-pyrimidinyl- (2 |] -1, 2, 3,4-tetrahydronaphthalene- 7-sulfonamide and 0.75 ml of 30% sodium methylate solution in 8 ml of absolute ethanol is mixed with the solution of 1.0 g of l- (2-phenylethyl) biguanide hydrochloride in 40 ml of absolute ethanol and the mixture is mixed for 4 hours heated under reflux, after cooling, the precipitated sodium chloride is filtered off with suction and the filtrate is evaporated to dryness in vacuo, melting point 10-2-1O4 ° C.

1 0 98 h 97194

B e i a ρ i ο 1 6

1 "2, _t ^ 4-tetrahydronaphthalen-7 ~ 3ulfonamid

To the Loe3Un, cooled in an ice-table salt mixture; of 3 »5 ml of dimethylformamide in 2o ml of abs. Methylene chloride - 3 »2.ml 'of liquefied phosgene are pipetted. Then 3.7 ml of phenyl acetaldehyde dimethylacetal are added with further cooling, the mixture is slowly warmed up and refluxed for a further 4 hours, vK ^ at which the crystal paste dissolves. The methylene chloride is then distilled off, the residue is taken up in 6 ml of anhydrous methanol, the solution is neutralized with sodium methylate solution, a further 6.4 ml of a 10% sodium methylate solution and 9.6 g of 2- (5-chloro-2 -niethoxy-benzamido) -1,2,3 '' t-4 ^{e 'fc: ra} l ⁱ ydronaphthalin-7-sulfonylguanidin (Pp L67-L69 °} prepared from 2- (5 - (. hlor-2-methoxy -benzamido) -1, 2,3 »4-'t ^e! " t ^ra hyäronaphthalin-7-sulfochloride and guanidine carbonate in acetone] and heated under reflux for 12 hours. The methanol is then distilled off and the residue in the water digested with water with the addition of dilute sodium hydroxide solution. Unreacted sulfonylguanidine is recovered by suction and can be used for a new batch after drying. The alkaline solution is treated with activated charcoal and the 2- (5-chloro-2- methoxy-benzamido) -lf- [5-phenylpyrimidinyl- (2)] - 1,2,3i4-tetrahydronaphthalene-7-sulfonai iid precipitated, which is recrystallized from ethanol. Melting point i47 ° (Z.)

109849/1940

Claims (1)

ft claims 1. / Tetrahydronaphthalene-sulfonylamino-pyrimidines of the general ^ - formula I. in the A is an aryl, aralkyl, furyl, thienyl, isoxazolyl, optionally substituted by halogen, alkyl, alkoxy or alkoxyalkoxy groups with 1 to 3 carbon atoms,
Isothiazolyl or pyrazolyl radical, R is a hydrogen atom or a lower alkyl radical,. '. " R ^ a straight-chain or branched alkyl, cycloalkyl / cycloalkylalkyl, alkoxy, cycloalkoxy, alkoxyalkyl,
Alkoxyalkoxy or alkylmercapto radical or an optionally halogen, alkoxy ·. or alkylres.te substituted aryl or aralkyl radical, R, hydrogen or a lower alkyl group, where R ₁ and R ₀ together form a ring of 3 to 5 methylene groups 'Can educate
and their physiologically harmless salts. 2. Process for the preparation of compounds of the general.
Formula I, characterized in that either 109849/1940 fs a) Substances of the general formula II (II), in which A and R have the meaning given above and η the Represents numbers 0 to 2, with 2-amino-pyrimidines of the general formula III IL (IH), in which R ₁ and R have the meaning given above, converts and, if necessary, then oxidizes to sulfonamide, or b) substances of the general formula IV in which R, R and R "have the meaning given above, with the reactive derivative of an acid of the formula A-COOH converts, where A has the meaning given above, or 9 8 4 9/1940 BAD ORIQlNAl. c) sulfonamides of the general formula V. A-CO-ii in which A and R have the meaning given above / with a pyrimidine derivative of the general formula VI in which R ₁ and R _{3 have} the meaning given above and T is a reactive ester group or a low molecular weight trialkylammonio group,. implements or · ' d) sulfonylguanidines of the general formula VII in which A and R have the meaning given above / with substances of the general formula VIII ZC - CH -CZ 'or ZC - CH-- C - K ₂ (VIII), Il I Il r lit Il ^{0 l} \ ° ■ ■ 0 B ₁ 0 in which R. and R have the meaning given above and Z and Z ^{1 represent} hydrogen or alkoxy groups, 109849/1940 202274ß or their functional derivatives implemented, which is then followed those obtained, optionally hydroxlated in the 4- and / or 6-position Pyrimidines by converting them into the halogen compounds and ' subsequent reductive dehalogenation into the desired pyrimidines transferred, -and possibly with physiologically harmless bases to " Converts salts. ". - 3. Use of compounds of general formula I and / or their physiologically harmless salts for the production of Medicines with a blood sugar lowering effect '. , / 4. Pharmaceutical preparations, characterized in that they contain compounds of the general formula 1 and / or their physiologically acceptable salts. ' 1 09 8A9 / 1940