NO800697L - PROCEDURE FOR THE PREPARATION OF HETEROCYCLIC COMPOUNDS FOR USE IN THE TREATMENT OF DIABETES - Google Patents

Description

The invention relates to a process for the preparation of a class of new heterocyclic compounds which are useful in the treatment of diabetes.

The compound of formula (I):

has been described as useful in the treatment of diabetes in Belgian Patent No. 852,565 and in Diabetes, 2_7'856°9868 (1978).

We have now found a class of heterocyclic imine compounds that have hypoglycemic activity.

Accordingly, the invention provides a method by which a compound of formula (II) or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof is prepared:

where X represents oxygen or sulfur;

n represents zero or 1;

7

R represents hydrogen or C 1 -alkyl;

1 2

R and R are the same or different and represent hydrogen, C1-4 alkyl, phenyl, benzyl or C1-cycloalkyl;

R"^ represents hydrogen, C 1 -alkyl, phenyl or benzyl;

R represents hydrogen or C 1-6 alkyl;

R"* represents C 1-6 alkyl, phenyl, optionally substituted

with up to 3 groups selected from halogen, C-1-4-alkyl and C-1-6-alkyl, or benzyl optionally substituted with up to 3

groups selected from halogen, C 1 -C 6 -alkyl and C 1 -C 6 -Alkoxy,

4 5

or R and R^ together represent the remaining members of a 5- or 6-membered ring which optionally contains an oxygen, sulfur or additional nitrogen atom and which is optionally substituted by C-1-4-alkyl, carboxy or 1-4-alkyl -carbonyl; and

R represents phenyl, optionally substituted with up to

3 groups selected from halogen, C 1 -C 6 -alkyl, C 1 -C 6 -Alkoxy, C 1 -C 6 -alkanoyl, C 1 -C 6 -alkanoyloxy, nitro, hydroxyl, amino, substituted amino, carboxy and C 6 -Alkoxycarbonyl.

Suitable quaternary salts of compound (II) include γ-alkyl halides, di-C 1 -alkyl sulfates and benzyl halides.

Preferred quaternary salts are the C 1-4 alkyl halides; especially the methyl halide, e.g. the methyl iodide salt.

Suitable acid addition salts of compound (II) include inorganic salts, e.g. the sulphate, nitrate, phosphate and borate, hydrohalides, e.g. the hydrochloride, hydrobromide and hydroiodide, and organic acid addition salts, ■e.g. acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulfonate and p-toluenesulfonate.

Preferred salts are hydride salts.

The group X in the compounds of formula (II) preferably represents sulfur and n is preferably zero.

15 7 Examples of suitable C-^^-alkyl groups such as R -R and R

may represent, include methyl, ethyl, n- and iso-propyl and n-, sec-, iso- and tert-butyl.

o 12

Examples of cycloalkyl groups that R and R can represent include cyclopentyl and cyclohexyl.

Suitable substituents for the phenyl and benzyl groups for R 1

and the phenyl group for R includes ortho-, meta- and para-methyl, methoxy, chlorine and bromine.

Preferably, n is equal to zero.

12 7

suitably, R , R , and R represent hydrogen, methyl, ethyl, or n-propyl. Preferably, both R 1 and R 2 are hydrogen. When n is 1, then o is .R<7>preferably hydrogen.

Optionally, R 3 is methyl, ethyl, n-propyl or phenyl. Advantageously, R 1 represents hydrogen or C 1-6 alkyl, especially methyl or ethyl.

Suitably, R 4 is hydrogen, methyl, ethyl or n-propyl, and

R~* represents methyl, ethyl, n-propyl, phenyl or benzyl.

4 5

When R and R form a complete ring, such rings suitably include pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine and 4-(C-,^-alkyl)piperazine, e.g. 4-methylpiperazine rings.

Suitably, R is phenyl.

One subgroup of compounds falling within the scope of the invention includes compounds of formula (III) and pharmaceutically acceptable quaternary and acid addition salts thereof:

8 9

where R and R represent hydrogen or C 1-4 alkyl;

R"1"0 represents hydrogen or C1-6-alkyl;

R and R' together represent the remaining members of a 5- or 6-membered ring optionally containing an oxygen or further nitrogen atom and which is optionally substituted with C-, , -alkyl; and

14

R represents hydrogen, C 1-6 alkyl or halogen. Compounds of formula (II) include the following: N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-pyrrolidinecarboxamidine;

N-(3-methylthiazolidin-2-ylidene)-N<1->phenyl-1-piperidine-carboxamidine;

N-(3-methylthiazolidin-2-ylidene)-N<1->phenyl-1-(4-methylpiperazine)carboxamidine;

N-(3-methylthiazolidin-2-ylidene)-N<1->phenyl-4-morpholine-carboxamidine;

N'-(4-methylphenyl)-N-(3-methylthiazolidin-2-ylidene)-1-pyrrolidinecarboxamidine;

N1 -(4-chlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-1-pyrrolidinecarboxamidine;

N-(3-ethylthiazolidin-2-ylidene)-N<1->phenyl-1-pyrrolidinecarboxamidine;

N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-4-thiamorpholine-carboxamidine}

N1 -(4-chlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-1-morpholinecarboxamidine;

N1 -(4-bromophenyl)-N-(3-methylthiazolidin-2-ylidene)-4-morpholinecarboxamidine;

N'-(3,4-dichlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-1-pyrrolidinecarboxamidine;

N,N-diethyl-N'-(3-methylthiazolidin-2-ylidene)-N"-phenyl-guanidine;

N'-(2,6-dichlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-4-morpholinecarboxamidine;

N-(3-methyloxazolidin-2-ylidene)-N'-phenyl-1-pyrrolidinecarboxamidine.

Compounds of formula (II) can be prepared by reacting a compound of formula (IV) or a salt thereof:

1 2 3 6 7 where R , R , R , R , R , n and X are as defined with respect to formula (II) above, and R 5 represents C, , -alkyl, with a 4 5 4 5 •

amine of formula R R NH, where R and R are as defined with respect to formula (II) above, and then, if desired, converting a free base of formula (II) thus obtained into a pharmaceutically acceptable salt, or converting a salt of a compound of formula (II) thus obtained into the free base.

The reaction is conveniently carried out in a polar organic solvent, and the choice of this is not critical for the reaction to be successful, provided that it forms a homogeneous solution of the reagent and is essentially inert towards the reagent and the product. It has been shown that lower alkanols, e.g. isopropanol, is particularly suitable.

The reaction is generally carried out at moderate temperature, i.e. higher than room temperature, as the return temperature for the solution

ning medium is chosen for convenience.

The length of time in which the reaction is allowed to proceed depends on the particular starting materials used. The course of the reaction can be followed by conventional methods, e.g. thin layer chromatography, and ends when an optimal amount of product is present in the reaction mixture. However, we have generally found it convenient to reflux the reaction mixture overnight.

Intermediates of the general formula (IV) are new and represent a further aspect of the invention.

Examples of lower alkyl groups that R "<*> can represent include methyl, ethyl, n-propyl or n-butyl, but preferably R represents methyl.

The intermediates of formula (IV) can be prepared via the route shown in the following scheme:

Thus, intermediates (IV) are prepared by alkylation of a thiourea (VI) using an alkylating agent R^.Z or ( ^^SO^ where R1^ is as defined with respect to formula (IV) and Z is a leaving group, f .e.g. chloride, bromide or iodide.<p>suitably, the reaction is carried out in a polar organic solvent, and the choice of this is not critical, provided that the solvent is essentially inert towards the reagents and the product. Suitable solvents include lower alkanones and alkools.The reaction is conveniently carried out at the boiling point of the solvent.

Thiourea vi) is in turn produced by reacting an iso-thiocyanate R^.NCS with a corresponding imino compound (V),

1 2 3 61

where R , R , i , R , R , n and X are as defined with respect to formula (II). This reaction is carried out in a solvent such as e.g. toluene benzene, dioxane, tetrahydrofuran, methanol or ethanol. The reaction is carried out at non-extreme temperatures, i.e. up ten. and including the reflux temperature for the solvent.

• Compounds of formula (II) can also be prepared by reacting a compound of formula (VII): 4 5 6 where R , R o< R are as defined with respect to formula (II) 12 3 7 above; with ( n imino compound (V), where R , R , R , R , n X are as defined with respect to formula (II) above, and then, if desired, conversion of a free base of formula (II) as thus e: obtained, to a pharmaceutically acceptable salt, or converting, see of a salt of a compound of formula (II) as thus e. obtained, to the free base.

The reaction is conveniently carried out in a non-hydroxyl solvent system, e.g. an ether, a chlorinated hydrocarbon or a mixture thereof. Suitable solvent systems include mixtures of diethyl ether and chloroform. The reaction is conveniently carried out at ambient temperature. The length of time the reaction is allowed to proceed can be determined by methods described above. However, we have found it convenient to allow the reaction mixture to stand overnight.

The intermediates of formula (VII) can be prepared by reacting an isocyanide dichloride of formula: R 6 -N=CCl2 where R<6>

is as defined with respect to' formula (II) above; with an amine of formula R R NH where R and R are as defined with respect to formula (II) above. The reaction is usually carried out in an ether solvent, e.g. diethyl ether or tetrahydrofuran. The reaction is preferably carried out at ambient temperature. The time period 1 during which the reaction is allowed to proceed can be determined by methods as described above. However, we have found that a

A reaction time of 2 hours is sufficient.

The quaternary ammonium salts of compounds of formula

(II) can be prepared by reacting the compounds of formula (II) with the corresponding quaternizing agent, e.g. (C 1-6 )-alkyl, or benzyl halides, e.g. methyl iodide, ethyl bromide, propyl bromide or benzyl chloride, or sulfuric acid esters, e.g. di(C 1-6 -alkyl)sulfates, e.g. dimethyl sulfate or diethyl sulfate.

The quaternization can be carried out in the presence or absence of a solvent, depending on whether the quaternization agent is or is not itself capable of serving as a solvent, at ambient temperature or under cooling, and under atmospheric pressure or under pressure in a sealed container. Organic solvents which are inert as far as the reaction is concerned and which are suitable for this purpose are ethers, e.g. diethyl ether or tetrahydrofuran, hydrocarbons, e.g. benzene or heptane, ketones, e.g. acetone or butanone, and c^_^-alkanols, e.g. ethanol, propanol or butanol. The anionic function of the quaternary salt can be easily replaced with a traditional ion exchange technique.

If one wants to use the compounds (II) as medicinal agents for the treatment of diabetes, they are presented as pharmaceutical preparations in a selection of dosage forms. Thus, a pharmaceutical preparation may comprise a compound of formula (II) together with a pharmaceutically acceptable carrier or excipient.

The preparations can be prepared for administration ad which

by any route, although oral administration is preferred. the preparations can be in the form of tablets, capsules, powders, granules,

lozenges.or, liquid preparations, e.g. oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration can be

in unit dose form and may contain conventional excipients, e.g. binders, e.g. gum acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, e.g. calcium phosphate, sorbitol or glycine; tableting lubricants, e.g. magnesium stearate, talc, polyethylene glycol, or silicon dioxide; crumbling agents, e.g. potato starch; or acceptable wetting agents, e.g. sodium lauryl sulfate. The tablets can be coated according to methods that are well known in normal pharmaceutical practice. Oral liquid preparations can be in the form of e.g. water or oil suspensions, solutions, emulsions, syrups or elixirs, or they can be presented as a dry product for reconstitution with water or another suitable drug carrier, e.g. for use. Such liquid preparations can contain conventional additives, e.g. suspending agents, e.g. sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat, emulsifiers, e.g. lecithin, sorbitan mono-oleate, or gum acacia; non-aqueous drug carriers (which may include edible oils), e.g. almond oil, fractionated coconut oil, oily esters, e.g. glycerol, propylene glycol or ethyl alcohol; preservatives, e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavoring or coloring agents. The compounds can also, if desired, be incorporated into a food product, e.g. in the form of a biscuit.

Suppositories will contain conventional suppository bases, e.g. cocoa butter or other glyceride.

For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile drug carrier, water being preferred. The compound can, depending on the drug carrier and the concentration used, either be suspended or dissolved in the drug carrier. when preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling in a suitable glass container, otherwise: ampoule and seal. It is an advantage if such excipients are a local anesthetic preservative

and buffering agents can be dissolved in the drug carrier. For

to improve stability, the preparation can be frozen after filling

in the glass container and the water is removed under vacuum,<p>arenteral suspensions are prepared in practically the same way, with the exception that the compound is suspended in the drug carrier instead of being dissolved, and that the sterilization cannot take place by filtration. The compound may be sterilized by exposure to ethylene oxide prior to suspension in the sterile drug carrier. Advantageously, a surfactant or wetting agent is included in the preparation to make it easier to distribute the compound evenly.

the preparations can contain from b,l to 99% by weight, preferably 10-60% by weight, of the active material, depending on the method of administration. The dosage used for treating adults will naturally depend on the dose-response characteristics of the particular active ingredient, but will normally be in the range 0.5-150 mg/kg/day.

The following examples illustrate the method according to the invention in the preparation of a number of compounds.

Example 1

N- (3-methylthia:-';olidin-2-ylidene)-N'-phenyl-1-pyrrolidine-carboxamidine-hydroiodide

a) 1-(3-methylthiazolidin-2-ylidene)-3-phenyl1-2-thiourea

2.16 g of sodium methoxide was added to a mixture of

10.0 g of 2-imino-3-methylthiazolidine hydroiodide in 50 ml of ethanol and brought to reflux, with stirring. 5.4 g of phenyl isothiocyanate in 20 ml of ethanol was added to the mixture over 5 minutes, and the resulting mixture was heated under reflux, with stirring, for 1 hour and then cooled in ice. Filtration gave analytically pure product, m.p. 169-170°, which can be recrystallized from isopropanol.

b) 2- methyl- 3-( 3- methylthiazolidin-2- ylidene)- 1- phenyl- 2-thiopseudourea- hydroiodide

A mixture of 2.30 g of 1-(3-methylthiazolidin-2-ylidene)-3-phenyl-2-thiourea and 1.65 g of iodomethane in 75 ml of acetone was heated under reflux for 45 minutes and evaporated to dryness in vacuo. The evaporation residue was triturated with acetone, diluted with ether and filtered. Recrystallization of the resulting solid from isopropanol gave the product, m.p. 158-159°.

c) N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-pyrrolidine-carboxamidine-hydroiodide

A mixture of 4.0 g of 2-methyl-3-(3-methylthiazolidin-2-ylidene)-1-phenyl-2-thiopseudourea hydroiodide and 1.2 g of pyrrolidine in 40 ml of isopropanol was heated under reflux for 22 hours, cooled and diluted with diethyl ether. The precipitated solid was recrystallized from methanol/diethyl ether to give the product of analytical purity, m.p. 157.5-159°.

Example 2

N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-piperidinecarboxamidine

A mixture of 2.0 g of 2-methyl-3-(3-methylthiazolidin-2-ylidene)-1-phenyl-2-thiopseudourea hydroiodide and 1.0 g of piperidine in 20 ml of dry isopropanol was heated under reflux for 3 7 hours, cooled, evaporated to dryness, aqueous sodium hydroxide added to the residue, and extracted with diethyl ether (2x). The combined organic extracts were washed with water, dried over MgSO 4 , filtered and evaporated to dryness. Crystallization of the residual gum from petroleum ether, b.p. 60-80°, gave analytically pure product,

m.p. 122.5-123.5°.

Example 3

N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-(4- methylpiperazine)- carboxamidine

This product, m.p. 112.5-113.5° (from petroleum ether, b.p. 60-80°), was prepared using a method analogous to that described in example 2, with the exception that N-methylpiperazine was used instead piperidine.

Example 4

N-(3-methylthiazolidin-2-ylidene)-N1-phenyl-4-morpholine-carboxamidine

This product, m.p. 143-145° after recrystallization from ethyl acetate/petroleum ether, was obtained by a method analogous to that described in example 2, with the exception that morpholine was used instead of piperidine.

Example 5

N'-(4-methylphenyl)-N-(3-methylthiazolidin-2- ylidene\~ 1- pyrrolidine- carboxamidine- hydroiodide

This product, m.p. 168-169° (MeOH-ether), was prepared by a method analogous to that described in example 1 via 3-(4-methylphenyl)-1-(3-methylthiazolidin-2-ylidene)-2-thiourea, m.p. 161.5-163°, and 2-methyl-1-(4-methyl-phenyl)-3-(3-methylthiazolidin-2-ylidene)-2-thiopseudourea hydroiodide, m.p. 161-163°.

Example 6

N'-(4-chlorophenyl)-N-(3-methylthiazolidin-2-ylidene-1-pyrrolidine-carboxamidine

This product, m.p. 120-121.5° (petroleum ether, bp. 60-80°) was obtained by a procedure analogous to that described in example 2 (reaction time - 48 hours). The precursors for this synthesis, 3-(4-chlorophenyl)-1 -(3-methylthiazolidin-2-ylidene)-2-thiourea, m.p. 177.5-179°, and 2-methyl-1-(4-chlorophenyl)-3-(3-methylthiazolidin-2-ylidene)-2-thiopseudourea hydroiodide, m.p. 124-127° (CH^OH-ether), was prepared by methods analogous to those described in examples la) and lb), respectively.

Example 7

N-(3-ethylthiazolidin-2-ylidene)-N'-phenyl-1-pyrroidine-carboxamidine

a) 1-(3-ethylthiazolidin-2-ylidene)-3-phenyl-2-thiourea

Temp. 138-140°, was prepared by an analog procedure

the one described in "example la).

b) ; 2- methyl- 3-( 3- ethylthiazolidine-2- yidene)- 1- phenyl- 2-thiopseudourea- hydroiodide

A mixture of 4.0 g of 1-(3-ethylthiazolidin-2-ylidene)-3-phenyl-2-thiourea and 3.0 g of methyl iodide in 100 ml of acetone was heated under reflux for 45 minutes, cooled and evaporated to dryness. The residual gum was crystallized from CH^OH-ether and gave the analytically pure product, m.p. 112-114°.

c) N-(3-ethylthiazolidin-2-ylidene)-N'-phenyl-1-pyrrolidine carboxamidine

Temp. 92.5-93.5° (petroleum ether, b.p. 60-80°), was obtained by a method analogous to that described in example 2 (reaction time - 21 hours).

Example 8

N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-4-thiomorpholine-carboxamidine

The product, m.p. 158-160° after recrystallization from ethyl acetate/petroleum ether (bp. 60-80°) was obtained by a method analogous to that described in example 2, with the exception that thiomorpholine was used instead of piperidine.

Example 9

N'-(4-Chlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-4-morfolin-carboxamidine

This product, m.p. 179-181° after recrystallization from ethyl acetate/petroleum ether (b.p. 60-80°) was obtained by reaction of 2-methyl-1-(4-chlorophenyl)-3-(3-methylthiazolidin-2-ylidene)-2- thiopseudourea hydroiodide with morpholine by a method analogous to that described in example 2.

Example 10

N'-(4-bromophenyl)-N-(3-methylthiazolidin-2-ylidene)-4-morpholine- carboxamidine

• a) 3-(4-bromophenyl)-1-(3-methylthiazolidin-2-ylidene)-2-thiourea

Temp. 179-181°, was produced by a method analogous to that described in example la). b) 2-methyl-1-(4-bromophenyl)-3-(3-methylthiazolidin-2-ylidene)-2-thiopseudourea hydroiodide.

Temp. 158-159°, was produced by a method analogous to that described in example lb).

c) N'-(4-bromophenyl)-N-(3-methylthiazolidin-2-ylidene)-4-morpholine- carboxamidine

Temp. 179-182° after recrystallization from ethylene acetate/petroleum (bp. 40-60°) was obtained from 2-methyl-1-(4-bromophenyl)-3-(3-methylthiazolidin-2-ylidene)-2 -thiopseudo-urea hydroiodide and morpholine by a method analogous to that described in example 2.

Example 11

N'-(3,4-dichlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-1-pyrrolidine-carboxamidine

a) 3-( 3, 4- dichlorophenyl)- 1-( 3- methylthiazolidin- 2- ylidene-

2- thiourea

Temp. 14'5-149°, was produced by a method analogous to that described in example la).

b) 2- methyl- 1-( 3, 4- dichlorophenyl)- 3-( 3- methylthiazolidin- 2-ylidene)- 2- thiopseudourea- hydroiodide

Temp. 130-132, was produced by an analogous method

the one described in example lb).

c) N't-(3,4-dLchlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-

1- pyrroli' iin- carboxamidine

Temp. 89-92°, after recrystallization from petroleum ether

(bp. 40-60°) was obtained from 2-methyl-1-(3,4-dichlorophenyl)-3-(3-methylthiazolidin-2-ylidene)-2-thiopseudourea hydroiodide by a method analogous to that which is described in example 2.

Example 12

N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-pyrrolidine-carboxamidine hydrochloride

1.5 g of pyrrolidine in 10 ml of dry diethyl ether was added dropwise at 0°C, with stirring to a solution of 1.7 g of phenyl isocyanide dichloride in dry ether, the mixture stirred for 2 hours and filtered. 1:1 of the filtrate was added a solution of 2.3 g of 2-imino-3-methylthiazolidine in 50 ml of chloroform, and the mixture was allowed to stand overnight. Dilute sodium hydroxide solution was added and the mixture was extracted with chloroform. The extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated to dryness. The evaporation residue was dissolved in diethyl ether, and dry hydrogen chloride gas was passed through the solution. The resulting solid was recrystallized from methanol/diethyl ether to give the product,

m.p. 225-227°, with analytical purity.

Examples 13-15

By a method analogous to that described in Example 12, the following carboxamidines were prepared using the appropriate imine, amine and isocyanide dichloride.: Example 13

N,N-diethyl-N1-(3-methylthiazolidin-2-ylidene)-N"-phenyl-guanidine as an oil, purified by column chromatography on silica using 5% of (33% dimethylamine in IMS) in CH ^Cl.-, as eluent.

Example 14

N'-(2,6-dichlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-4-morpholinecarboxamidine, m.p. 145-147° (ethanol).

Example 15

N-(3-Methyloxazolidin-2-ylidene)-N<1->phenyl-1-pyrrolidinecarboxamidine as an oil, purified by chromatography using 1% of (33% dimethylamine in IMS) in Cr^C ^ as eluent< lei.

Example 16

N-(3-methylethylisolidin-2-ylidene)-N'-phenyl-1-pyrroidine-carboxamidi- methiodide

A mixture of N-(3-methylthiazolidin-2-ylidene)-N<1->phenyl-l-pyrrolidine-carboxamidine (developed from 0.7 g of its hydroiodide) and 0.5 g of iodomethane in 50 ml of toluene gave leave at room temperature for 2 days. Filtration gave the desired methiodide salt of analytical purity, m.p. 160-162°.

Example 17

N-(3-methylthiazolidin-2-ylide,ene)-N'-phenyl-1-pyrrolidine-carboxamidine hydrochloride

26 g of sodium hydroxide in 115 ml of water were added to a solution of 208.2 g of N-(3-methylthiazolidin-2-ylidene)-N<1->phenyl-1-pyrrolidine-carboxamidine hydroiodide in 550 ml of water, stirred and extracted with diethyl ether (3 times). The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate and filtered. Dry hydrogen chloride gas was bubbled through the filtrate, and the resulting solid was recrystallized from isopropanol to give the product, m.p. 227.5-228°.

Biological data

Activity on glucose tolerance in fasting mice

For this investigation, mice were allowed to fast for 24 hours before the experiment, and then they were randomized so that each treatment group contained 8 mice. The compounds were dosed orally in 1% aqueous carboxymethyl cellulose (lo ml/kg body weight), and 30 minutes later, glucose (lg/kg) was administered subcutaneously. Blood samples for glucose analysis were taken from the tail 60 minutes after glucose administration. The results are shown in the table below.

N. B. A standard system for indicating the significance of results with respect to the control samples (dose = zero mmol/kg) which received only the 1% aqueous carboxymethyl cellulose drug carrier is as follows:

Claims (2)

1. Process for the preparation of a compound of formula (II) or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof: where X represents oxygen or sulfur; n represents zero or 1; R 7 represents hydrogen or C -, , -alkyl; 12 '' h R and R are the same or different and represent hydrogen, C 1-6 alkyl, phenyl, benzyl or C 3-6 cycloalkyl; R 3 represents hydrogen, C 1 -6 alkyl, phenyl or benzyl; R 4 represents hydrogen or C 1 -C 4 -alkyl; R 5 represents C 1-6 -alkyl, phenyl, optionally substituted with up to 3 groups selected from halogen, C 1-6 alkyl and C 1-6 -alkyl, or benzyl optionally substituted with up to 3 groups selected from halogen, C 1-6 -alkyl and C-1-6-alkyloxy, or R 4 and R 5 together represent the remaining members of a 5- or 6-membered ring which optionally contains an oxygen, sulfur or additional nitrogen atom and which is optionally substituted with C 1-3 alkyl, carboxy or C 1-6 alkoxycarbonyl? and R<6> represents phenyl, optionally substituted with up to 3 groups selected from halogen, C16 -alkyl, C1 -g- alkoxy, C1 -g-alkanoyl, C-L -g-alkanoyloxy, nitro, hydroxyl, amino, substituted amino, carboxy and C-^g-alkyloxycarbonyl, characterize by reacting a compound of formula (IV ) or a salt thereof: 2 3 6 7 where R,R,R,R,R,n and X are as defined for formula (II) above, and R"^ represents C-, ,-alkyl, with an amine 4 5 4 5 of formula R R NH, where R and R are as defined with respect to formula (II) above, and then, if desired, converting a free base of formula (II) thus obtained into a pharmaceutically acceptable salt or converting a salt of a compound of formula (I I) thus obtained into the free base. 2. 'Procedure as stated in claim 1, characterized by reacting a compound of formula (VII) 4 5 6 where R , R , and R are as defined with respect to formula (I I ) above; with an imino compound (v) 12 3 7 where R , R , R , R , n and X are as defined with respect to formula (II) above, and then, if desired, converting a free base of formula (II) thus obtained into a pharmaceutically acceptable salt , or conversion of a salt of a compound of formula (II) thus obtained into the free base.