DE2009743A1 - Substituted biguanides with antihyperglycemic effects - Google Patents

Description

It is known that a number of substituted biguanides have a blood sugar lowering effect. For example, phenethyl biguanide, n-butyl biguanide and N, N-dimethyl biguanide are commercially available for the treatment of diabetes. However, all these compounds have the disadvantage that their blood-sugar-lowering effect only occurs in high doses and that there is therefore a risk of intolerance in the case of long-term treatment. [see. H. Mehnert and H.S. Sadow in "Oral Hypoglycaemic Agents", p. 281, Academic Press, London, 1969].

The invention relates to biguanides of the general formula

(I)

and their salts with non-toxic acids, wherein

R and R [deep] 1 can be identical or different and represent fluorine, a straight-chain or branched alkyl or alkenyl radical (1 to 6 C atoms), which can optionally contain 1 to 3 fluorine atoms, a cycloalkyl, cycloalkylalkyl or cycloalkenyl radical ( 5 to 8 carbon atoms), an alkoxy or alkyl mercapto radical

Atoms) or a nitrile group,

R [deep] 1 can also mean hydrogen, chlorine or bromine,

R [deep] 2 represents an alkyl, alkenyl, cycloalkyl or alkoxyalkyl group with 1 to 12, preferably 2 to 8 carbon atoms, which, if it contains more than 3 carbon atoms, can also be branched, and

together do not contain more than 9 carbon atoms.

Compared to the known buguanides, the compounds according to the invention have an antihyperglycemic effect which is greatly superior; they can therefore be dosed at a lower level and are therefore far safer to handle than commercially available products.

The production of the new biguanides takes place according to methods known in principle, [cf. F. Kurzer and ED Pitchfork, in: Advances in Chemical Research, Volume 10, p. 375 (1968)]; so you can, for example, amines of the general formula in the

R and R [deep] 1 have the meaning given above,

as such or in the form of their salts on nitrile groups of

Dicyandiamides of the general formula in the

R [deep] 2 and R [deep] 3 have the meaning given above,

add, or amines of the general formula as such or in the form of their salts on nitrile groups of dicyandiamides of the general formula attach.

The N [deep] 1-aryl-N [deep] 5-alkyl biguanides according to the invention can also be prepared in such a way that the mercapto or S-alkyl mercapto group is obtained in thio- or dithiobiuret derivatives or their S-alkyl derivatives for an amino, alkylamino or arylamino group, as indicated by the following general formulas, in which R, R [deep] 1, R [deep] 2 and R [deep] 3 have the meanings given and R [deep] 4 stands for hydrogen or an alkyl group (1 to 4 carbon atoms), is shown:

+ <formula> arrow I

+ <formula> arrow I

+ NH [deep] 3 arrow I

+ NH [deep] 3 arrow I

The antihyperglycemic effect can be demonstrated in the following experiment:

After repeated oral administration of the active ingredient, fasting rats are administered per os glucose dissolved in physiological saline solution. The blood glucose level of the animals treated with an effective biguanide increases less strongly than in untreated animals as a function of the dose. The measurement is carried out 30 and / or 60 minutes after the administration of glucose. The dose indicated is the single dose administered in each case, which is a significant (P <0.05) reduction compared to an untreated control group causes hyperglycaemia after administration of glucose.

example 1

18.8 g of p-ethylphenyldicyandiamide and 8.2 g (0.1 mol each) of ethylamine hydrochloride are mixed and heated to 160 ° for 1 hour. The resulting oil is dissolved in 100 ml of isopropanol while hot. On cooling, 15.6 g (58%) of N [deep] 1-p-ethylphenyl-N [deep] 5-ethyl biguanide are obtained as the hydrochloride; 165-167 °.

Example 2 17.4 g of p-tolyldicyandiamide and 16.6 g (0.1 mol each) of n-octylamine hydrochloride are reacted as in Example 1. 16.2 g (48%) of N [deep] 1-p-tolyl-N [deep] 5-n-octyl biguanide are obtained as the hydrochloride; Mp 183-185 °.

Example 3 16 g of p-anisidine hydrochloride and 14 g (0.1 mol each) of n-butyldicyandiamide are stirred at 160 ° for 2 hours. 11.3 g (34%) of the hydrochloride of N [deep] 1-p-anisyl-N [deep] 5-n-butyl biguanide are obtained from isopropanol; Mp. 186 °.

Example 4

13.9 g of N-p-tolyl-N [deep] 1-n-pentylguanylthiourea, 12 g of mercury oxide and 100 ml of 17 percent strength. Ammonia in methanol are stirred in a pressure vessel at 50 ° for 6 hours. Insolubles are filtered off with suction, concentrated, 25 ml of 2N hydrochloric acid are added and, after renewed concentration, the residue is recrystallized from isopropanol. Yield: 6 g (38%) N [deep] 1-p-tolyl-N [deep] 5-n-pnetylbiguanide as the hydrochloride; Mp. 215 °.

The following table lists a number of the biguanides according to the invention. The antihyperglycemic effect of some substances is compared with that of n-butyl biguanide (buformin) as a comparison substance.

Claims (8)

1) Biguanides of the general formula (I) and their salts with non-toxic acids, wherein Group (1 to 4 carbon atoms) or a nitrile group, R [deep] 1 can also mean hydrogen, chlorine or bromine, R [deep] 2 represents an alkyl, alkenyl, cycloalkyl or alkoxyalkyl group with 1 to 12, preferably 2 to 8 carbon atoms, which, if it contains more than 3 carbon atoms, can also be branched, and together do not contain more than 9 carbon atoms. 2) Medicines, characterized by a content of a compound according to claim 1. 3) Process for the preparation of medicaments, characterized in that compounds according to claim 1 are used as active ingredients. 4) means with antihyperglycemic effect, characterized by a content of a compound according to claim 1. 5) Process for the preparation of agents with antihyperglycemic action, characterized in that compounds according to claim 1 are used as active ingredient. 6) Orally applicable agents with antihyperglycemic effect, characterized by a content of a compound according to claim 1. 7) Process for the preparation of orally administrable agents with antihyperglycemic action, characterized in that compounds according to claim 1 are used as active ingredients. 8) Process for the preparation of compounds of the general formula given in claim 1, characterized in that either a) amines of the general formula as such or in the form of their salts with compounds of the general formula converts, or by b) amines of the general formula as such or in the form of their salts with compounds of the general formula implements, or by c) in corresponding thio- or dithiobiuret derivatives or in their S-alkyl derivatives, the mercapto or S-alkyl mercapto groups are exchanged in a manner known per se for amino, alkylamino or arylamino groups, have genes.