CH636084A5 - Process for preparing guanidine derivatives - Google Patents

Abstract

Compounds of the formula I, which can be used as medicaments in the form of the bases, the acid addition salts and the quaternary ammonium salts, are obtained by reacting corresponding pyrrolidonimines with a chloroformimidamide of the formula Cl(NR)NR4R5 in the molar ratio 2:1, since one mol of the imine serves as an acid-capturing agent. The resulting bases can be converted into acid addition salts or quaternised. The meanings of the formula symbols are explained in Patent Claim 1. <IMAGE>

Description

The invention relates to a process for the preparation of new heterocyclic guanidine derivatives. These compounds can inhibit gastric juice secretion and lower blood sugar.

GB-PS No. 1409768 describes various heterocyclic derivatives of guanidine in which the heterocyclic radical is a 5-membered or saturated, 1,3-diazacarbocyclic 2-ylidene radical. These derivatives are unsubstituted on the amino nitrogen atom of the guanidine residue.

Other similar compounds are described in DT-OS Nos. 2321330 and 2502397.

The invention relates to a process for the preparation of guanidine derivatives of the general formula I:

(XIV)

(XVIII)

in a molar ratio of 2: 1, and optionally converting the compound obtained into a salt with an acid.

2. The method according to claim 1, characterized in that one carries out the reaction in an aprotic solvent in which the compound of formula (I) is soluble and the salt of compound (XIV) is insoluble and precipitates.

and their salts with acids and their quaternary ammonium salts, in which n has the value 1, 2 or 3, Ri is a hydrogen atom, a C [_8-alkyl radical, a C3.6-cycloalkyl radical, preferably a Cyc-40 lopentyl or cyclohexyl group, a C3.5-alken-2-yl radical, a lower hydroxyalkyl radical, preferably a hydroxyethyl group, an aralkyl radical, preferably a benzyl group, or an aryl radical, preferably a phenyl group, R2 a hydrogen atom, a Cj-alkyl radical or an aryl radical, preferably a phenyl group, 45 R3 is a hydrogen atom, a Q-alkyl radical or an aryl radical, preferably a phenyl group, R4 is a hydrogen atom, a methyl * or ethyl group and Rs is a Q-alkyl radical, a C3-cycloalkyl radical, preferably a cyclopentyl or cyclohexyl group, an aralkyl radical, preferably a benzyl group, or an aryl group, preferably a phenyl group or a phenyl group mono-, di- or tri-substituted by halogen atoms, lower alkyl or alkoxy groups means, or R4 and Rs together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, where a membered ring a) 55 is also an oxygen or sulfur ring atom or, optionally by a lower alkyl radical, a phenyl or contains a benzyl group-substituted nitrogen ring atom or b) the ring is substituted by a lower alkyl radical on a carbon atom which is not directly adjacent to the nitrogen atom which is bonded to the carboximidamide function, in particular an aziridynyl, azetidinyl, pyrrolidinyl or piperidino -, 2,3,4,5,6,7-hexahydro-azepinyl, morpholino, thiamorpholino, thiamorpholino-l-oxide, thiamorpholino-l, l-dioxide or 2,6-diniederalkylmorphlino group, preferably one 2,6-dimethylmorpholino group, a 4-65 lower alkylpiperazinyl group, preferably a 4-

Methylpiperazinyl group, a 4-phenylpiperazinyl, 4-benzylpiperazinyl or 2,6-di-lower alkylpiperazinyl group, preferably a 2,6-dimethylpiperazinyl group, and R denotes a C4_10-Al-

3rd

636 084

alkyl radical, preferably a branched alkyl radical, such as a tert-butyl, neopentyl or 1,1,3,3-tetramethylbutyl group, a C5.8 cycloalkyl radical, preferably a cyclopentyl or cyclohexyl group, a C7-10 bicycloalkyl radical, for example an exo or endo-2-norbornyl, 2-bicyclo [2.2.2] octyl or endo-2-bicyclo [3.2.1] octyl group, a C7.10 bicycloalkenyl group, such as an anti -7-norbornenyl group, a Cg.jo-tricycloalkyl group such as nor-adamantyl, 1- or 2-adamantyl, 1- or 2- (2,3,3a, 4,5,6,7,7a-octa -hydro-4,7-methanoindanyl) group, a 1-adamantylmethyl group, a Cg.jQ-tricycloalkenyl group, such as a 3- (2,3,6,6a-tetrahydro-, 3a-ethanopentalenyl) - or 5- (3a, 4,5,6,7,7a-hexahydro-4,7-methanoindenyl) group, a phenyl-C 1-4 alkyl or naphthyl-cralkyl radical, such as a benzyl, d- or 1-a-phenethyl, a, a-dimethylbenzyl, a, a-dimethyl-β-phenethyl, d- or l- (a-naphthyl) -ethyl group, an a, a-tetramethylenephenethyl group, a diphenyl-C | .2-alkyl group how a dip henylmethyl or 2,2-diphenyl-ethyl group, an a- or β-naphthyl group, a condensed diarylcycloalkenyl group, such as a 9-fluorenyl or 5-azenaphthyl group, a condensed arylcycloalkyl group, such as a 4- (2,3-di -hydro- [lH] -indenyl) -, lp (l, 2,3,4-tetrahydronaphthyl) - or 7- (Bi-cyclo- [4.2.0] -octa-l, 3,5-trienyl) group, a phenyl-C5.7-cycloalkyl radical, such as a cis or trans-2-phenylcyclopentyl, cis or trans-2-phenylcyclohexyl or cis or trans-2-phenylcyclo-heptyl group, a C5_7-cycloalkyl-C5_7 cycloalkyl radical, such as a cis or trans-2-cyclohexylcyclopentyl or cis or trans-2-cyclopentylcyclopentyl group, a phenyl or methylenedioxyphenyl group, a phenyl group mono-, di- or tri-substituted by halogen atoms, lower alkyl or alkoxy radicals, one by an amino, dimethylamino, methylethylamino, diethylamino, lower alkanoylamino, thione lower alkyl, sulfinyl lower alkyl, sulfonyl lower alkyl, trifluoromethyl, hydroxyl, benzyloxy, never deralkanoyloxy, lower alkanoyl or nitro group substituted phenyl group, a 3-pyridyl or a 3-pyridyl group mono- or disubstituted by halogen atoms, lower alkyl or alkoxy radicals, such as a 6-methoxy-3-pyridyl, 6-chloro-3 -pyridyl, 2,6-dimethyl-3-pyridyl, 2,6-dichloro-3-pyridyl or 2,6-dimethoxy-3-pyridyl group, or a 5-membered heterocyclic radical such as a 2- Furyl or 2-thienyl group.

The term lower means that the corresponding group contains 1 to 4 carbon atoms. Halogen atoms are fluorine, chlorine, bromine and iodine atoms. If one of the radicals R2 or R3 denotes an alkyl or aryl radical, the other radical is preferably a hydrogen atom. If n has one of the two values 2 or 3, the radical is R2 and R3, preferably a hydrogen atom.

The compounds of general formula I can form salts with acids and quaternary ammonium salts due to the presence of a tertiary nitrogen atom. Examples of the acids which can be used for salt formation are inorganic acids, such as hydrohalic acids, for example hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids, such as acetic, propionic, glycolic, pamoinic, pyruvic, malonic, Amber, maleic, fumaric, apple, wine, ci-tronene, benzoic, cinnamon, almond, methane sulfone, ethane sulfone, benzenesulfone, p-toluenesulfone, cyclohexansuliamine, salicyl and p - amino salicylic acid. The free bases can be obtained from the salts by treatment with a base.

Examples of the compounds which can be used for quaternization are alkylating agents, such as alkyl, alkenyl and aralkyl halides, sulfates and sulfonates, such as methyl iodide, ethyl bromide, propyl bromide, allyl chloride, benzyl chloride, dimethyl sulfate, diethyl sulfate, p-toluenesulfonic acid sulfonate and fluorine sulfonate -methyl ester. The quaternization can be carried out in the presence or absence of a solvent at room temperature or with cooling, at atmospheric pressure or overpressure. Examples of usable inert organic solvents are ethers, such as diethyl ether and tetrahydrofuran, hydrocarbons, such as benzene and heptane, ketones, such as acetone and butanone, lower aliphatic alcohols, such as ethanol, propanol and butanol, and acid amides, such as formamide and dimethylformamide. The anion of the quaternary ammonium salt can easily be exchanged for another anion by ion exchange.

5 Due to their very high blood sugar-lowering effects, compounds of the general formula II are:

H

11 R10

- (CH2) n * 2 * 9

■ N-C-N '

-R-

NRc

II

R £

and their salts with acids and the quaternary ammonium salts are preferred. In this formula, n has the value 1 or 2, R6 denotes a lower alkyl or hydroxyalkyl radical, an allyl or benzyl group, R, a methyl or ethyl group, Rs denotes a lower Al-20 alkyl radical, a cyclopentyl or cyclohexyl group or R, and Rs together with the nitrogen atom to which they are attached, a pyrrolidino, piperidino, morpholino or thiamorpholino group, R9 a phenyl group or a phenyl group substituted by the substituents defined above, with the exception of a 25-sulfonyl-lower alkylphenyl group, a 1- Adamantyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, diphenylmethyl, naphthyl or 9-fluorenyl group, R10 is a hydrogen atom or a C 1-8 alkyl radical and R,! is a hydrogen atom or a C] .3-alkyl radical, where at least one of the radicals R10 and R! t represents a hydrogen atom-30.

The compounds of general formula I are prepared by using a compound of general formula XIV:

(CH9)

XIV

with a compound of general formula XVIII:

NO

45 II

C1-C-NR4R5 XVIII

in a molar ratio of 2: 1, and optionally converting the compound obtained into a salt with an acid.

The process for the preparation of the compounds of the general formula I from the 2-imino compounds of the general formula XIV consists, as mentioned, in the reaction of 2 mol equivalents of the free base XIV with a compound of the general formula XVIII, in which R4, R5 and R have the meaning given above. During the reaction, an equivalent of the 2-imino compound is formed in the salt form XIX. The reaction is therefore preferably carried out in an aprotic solvent in which the compound of the general formula I is soluble, while the chlorohydrate formed of the compound XIV 60 fails. In this way, the two compounds can be easily separated from one another by filtration. The acid addition salt can be converted into the free base with alkali and this can be recovered. Examples of preferred usable solvents are ethers such as diethyl ether and tetrahydrofuren, lower aliphatic ketones and esters such as acetone, methyl ethyl ketone and ethyl acetate, aromatic hydrocarbons such as benzene, toluene and xylene, and acetonitrile. Diethyl ether is generally preferred. This process is illustrated by the following reaction scheme:

636 084

4th

R-

(ch2)

il

NO

l!

N

I.

R1

XIV

+ Cl-C-NR R, -

Et20

XVIII

R3- (CH-j) "NO

R? (CH.)

I '"v'nil Ì

I J = N-C-NR H + R2 \ NK

5 * XIX

R,

N

I.

? ..

1

HCl

Et = C2H5

^ 20

The 2-imino compounds of the formula XIV which serve as starting substances, in which n, R !, R2 and R3 have the meaning given above, are largely known or can be prepared by the process described in CA-PS No. 950464, for example according to Example 14 of this patent.

The starting compounds of the formula XVIII in which R is, for example, an alkyl, cycloalkyl, aralkyl or diphenylalkyl radical, a phenyl group or a phenyl group substituted by a lower alkyl or alkoxy radical, a halogen atom or a nitro group after that of -E. Cool, "Appl. Chemie ", Internat. Ed., Vol. 8 (1968), pp. 24 and 26, can be obtained. In this process, the chlorine atoms of the corresponding isocyanide dihalide of the general formula XXIII are successively substituted. 35 The preparation of the isocyanide dihalide is described in" Angew. Chemie ", Internat. Ed., Vol. 6 (1967), p. 649. The isocyanide dihalide is reacted with an amine of the general formula HNR4R5, in which R4 and R5 have the above meaning, but R5 is not a phenyl or substituted phenyl group, in the presence of a trialkylamine, such as triethylamine, in an inert aprotic anhydrous solvent, such as Diethyl ether, a halogenated hydrocarbon or an aromatic hydrocarbon, converted to the corresponding monohalide of the general formula XVIII. This implementation is illustrated by the following 45 reaction scheme:

Cl NR4R5

I I

RN = C-Cl + HNR4R5 + Et3N - RN = C-C1 + Et3N • HCl

XXIII

XVIII

Another process for the preparation of the chlorine compounds of formula XVIII, in which R has the above meaning, follows that of H.G. Viehe & Z. Janousek, "Angew. Chemie ", Internat. Ed., Vol. 12 (1973), p. 806, in which a 55 dichloromethylene ammonium salt of the general formula XXVIII, in which R4 and R5 have the above meaning, but the group NR4Rs no thiamorpholino-1 oxide group is reacted with an amine of the general formula XXV to give the monohalide of the general formula XVIII, This reaction is illustrated by the following reaction scheme:

Cl NR4R5 I _ _ I NH3 Alkali RNH2 + C1-C = NR4Rs © Cl 0 -► RN = C — Cl ► ►

XXV XXVIII XVIII IV 65

The compounds of general formula I and their salts with acids and quaternary ammonium salts are valuable medicinal substances,

that inhibit gastric juice secretion and lower blood sugar.

The inhibition of gastric juice secretion was demonstrated in rats in the gastric fistula test. For the experiments, female rats of the Sprague-Dawley strain were used, to whom the compound to be examined was injected intraduodenally in a dose of 2.5 to 40 mg / kg body weight. The rats are no longer fed 24 hours before the experiment, but water is offered to them. The rats are kept individually. On the test day, the rats are weighed and selected so that the body weight for each test group is in the range of ± 20 g.

The operation is carried out under mild ether anesthesia. As soon as the rat is anesthetized, the teeth are removed using small pliers. An approximately 1.5 cm long median laparatomy is performed and the stomach and duodenum are shown. If at this point the stomach is filled with food or faeces, the rat is discarded. A 4-0 suture is used to create a tobacco pouch suture in the fundus area, taking care not to pierce any blood vessels in this area. In the center of the tobacco pouch seam, a small incision is made in the stomach wall and a cannula made of a small vinyl tube with a flange at one end is inserted into the stomach. The tobacco pouch seam is then pulled tight around the flange.

Immediately afterwards, the compound to be examined is administered intraduodenally in an amount of 0.5 ml / 100 g of rat. Three rats are generally used for each test dose. Control rats receive the vehicle used in the test, generally 0.5% aqueous methyl cellulose solution.

After the test fluid has been added, the abdominal wall and skin are closed simultaneously with three to four 18 mm wound clips. A collecting tube is connected to the cannula. Each rat is then placed in a cage into which a longitudinal slot has been cut to allow the cannula to hang freely and to allow the rat to move freely. After the rat has been able to stabilize and recover for 30 minutes, the collecting tube is discarded from the cannula and replaced by a clean tube for taking up the gastric juice. The secreted amount is collected every hour. At the end of this examination, the cannula is removed and the rat is killed.

The sample of the stomach contents is emptied into a centrifuge tube and centrifuged to deposit the sediment. The volume is read and 1 ml of the supernatant is placed in a beaker containing 10 ml of distilled water and titrated to pH 7 with 0.01N sodium hydroxide solution. The volume, the titratable acidity and the total acidity are determined. The volume is calculated from the total volume of gastric juice, minus the sediment. The titratable acid in milliequivalents / 1 is the amount of 0.01N sodium hydroxide solution that is required to titrate the acid up to pH 7. The total acidity is the product of titrable acid times volume. The results are given in% inhibition against the value of control animals. A minimum of 5% inhibition is an indication of significant inhibition of gastric juice secretion.

The compounds of general formula I and their salts also lower blood sugar, i.e. they have hypoglycemic properties. This is demonstrated by the glucose tolerance test on rats. The compounds of general formula II have particularly pronounced hypoglycemic properties.

The glucose tolerance test in rats is an extremely sensitive standard test for the diagnosis of diabetes and hypoglycemic clinical pictures.

Male rats of the Sprague-Dawley strain with a body weight of 184 to 250 g are used for the experiment. The rats are no longer fed 24 hours before the experiment, but they are offered water. After oral administration of 1 g glucose / kg body weight in 1 ml water, 0.1 ml blood from the tail vein without anesthesia is given to them after 0, 30, 60, 90, 120, 150 and 180 min.

hesie taken. The blood samples are immediately deproteinized with aqueous solutions of barium hydroxide and zinc sulfate, and the glucose levels are determined by the L.P. Caw-ley and co-workers, "Ultra Micro Chemical Analysis of Blood Glucose with Glucose Oxidase", in "Amer. J. Clin. Path.", Vol. 32 (1959), p. 195. 2 to 5 rats and a control group are used for each experiment. The compounds to be examined are administered in a dose of 1 to 200 mg / kg either subcutaneously or intraperitoneally in 0.5 or 1 ml of a 0.5 to 1% strength methylcelulose solution. The control groups are given the same volume of carrier subcutaneously. Blood glucose values are expressed at all times in milligram percent (mg glucose / 100 ml blood). The mean glucose values of the control groups are compared statistically according to Student's t-test with the mean values of the test group at each corresponding point in time. If the compound to be tested significantly reduces blood glucose at any point in time with a confidence limit of 95%, the compound has hypoglycemic activity.

Preparation A:

The following salts of the 2-imino compounds of the general formula XIV are prepared by the process described in CA-PS No. 950464:

a) 2-imino-l-methyl-5-phenylpyrrolidine fluoroborate, mp 128 to 131 ° C;

b) 2-imino-l-methylpyrrolidine fluoroborate, mp 109 to 111 ° C;

c) 2-imino-l-ethylpyrrolidine hydrochloride, melting point 181 to 185 ° C;

d) 2-imino-l-n-butylpyrrolidinecyclohexanesulfamate, mp 110 to 114.5 ° C;

e) 2-imino-l-benzylpyrrolidine fluoroborate, mp 112 to 114 ° C;

f) 2-imino-l, 5-dimethylpyrrolidine fluoroborate, mp 100 to 102 ° C;

g) 2-imino-1-methylpiperidine hydrochloride;

h) hexahydro-2-imino-1-methyl- [1 H] -azepinecyclohexane sulfamate, mp 143 to 145 ° C;

i) l-Hydroxyethyl-2-iminopyrrolidincyclohexanesulfamat, mp 105 to 108 ° C.

These salts are converted into the free bases by treatment with 50% sodium hydroxide solution.

Example 1:

N- (l-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide-L - (+) - tartrate

A mixture of 1.74 g (0.01 mol) of phenyl isocyanide dichloride in anhydrous diethyl ether is dissolved under nitrogen as a protective gas and with cooling with 0.71 g (0.01 mol) of pyrrolidine and then with 1.01 g (0.01 mol) Triethylamine added. The mixture is stirred for 90 minutes and then triethylamine crystallized out.

636 084

filtered hydrochloride. 1.96 g (0.02 mol) of l-methyl-2-iminopyrrolidine are added to the filtrate while cooling with ice, the mixture is stirred under nitrogen as a protective gas for 16 h and then the crystallized N-methyl-2-iminopyrrolidine hydrochloride (mp 182 to 188 ° C) filtered off. The filtrate is evaporated to dryness under reduced pressure. An oil remains, which is dissolved in 10 ml of methanol and treated with an equimolar amount of L - (+) - tartaric acid. The resulting solution is evaporated and at the same time isopropanol is added. The crystals formed are filtered off and recrystallized from a mixture of isopropanol and acetonitrile. The title compound of F. 153 to 156 ° C is obtained.

Example 2:

N- (l-methyl-2-pyrrolidinylidene) -N'-phenyl-l-pyrrolidinecarboximidamide is converted into the salts listed below:

Fumarate, mp 156-157 ° C;

Phosphate, mp 200-201 ° C (dec.);

Hydrobromide, F. (206) 207-209 ° C;

Oxalate, mp 129-131 ° C;

Pamoat, mp 253-256 ° C (dec.);

Nitrate, mp 170-171 ° C (weak dec.);

Maleate, mp 115-117 ° C, and p-hydroxybenzoate, mp 179-180 ° C.

Example 3:

This example illustrates processes for the preparation of quaternary ammonium salts of the compounds of general formula I.

A) N- (2,6-dichlorophenyl) -N '- (l-methyl-2-pyrrolidinylidene) -l-pyrrolidinecarboximidamidinium methofluorosulfonate

A mixture of 6.83 g (0.02 mol) of N- (2,6-dichlorophenyl) -N '- (l-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide in anhydrous methylene chloride is added under nitrogen as a protective gas and with stirring mixed with 2.70 g (0.023 mol) of methyl fluorosulfonate. The mixture is stirred for about 16 hours and then evaporated to dryness under reduced pressure. The oily residue is digested with diethyl ether. The crystals formed are first recrystallized from acetone and then from ethyl acetate. The title compound of F. 148 to 150 ° C is obtained.

B) N- (l-Methyl-2-pyrrolidinylidene) -N'-phenyl-l-pyrrolidine-carboximidamidinium methoiodide

A solution of 0.05 mol of N- (l-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide in 30 ml of acetone is mixed with 0.05 mol of methyl iodide. After 48 hours of reaction, the crystals formed are filtered off and recrystallized from acetone. The title compound of F. (156) 162 to 164 ° C. is obtained.

5

5

10th

15

20th

25th

30th

35

40

45

R

Claims (4)

636 084 1. Process for the preparation of guanidine derivatives of the general formula (I): <ayn NO (I) N — C — N ' Rr and their acid addition salts, in which n has the value 1, 2 or 3, R [is a hydrogen atom, a Cj.g-alkyl-, C3.6-cycloalkyl-, C3.5 -alken-2-yl, lower hydroxyalkyl- , Aralkyl or aryl radical, R2 is a hydrogen atom, a C 1-4 alkyl radical or an aryl radical, R3 is a hydrogen atom, a C [.8-alkyl radical or an aryl radical, R4 is a hydrogen atom, a methyl or ethyl group and R5 is a Ci_4-alkyl radical, represents a C3.7-cycloalkyl radical, an aralkyl radical or an aryl radical, or R4 and Rs together with the nitrogen atom to which they are bonded form a 3- to 7-membered saturated heterocyclic ring, a 6-membered ring a) Contains oxygen or sulfur ring atom or a nitrogen ring atom optionally substituted by a lower alkyl radical, a phenyl or benzyl group, or b) the ring is substituted by a lower alkyl radical on a carbon atom which is not directly adjacent to the nitrogen atom attached to the carbox imidamide function, and R is a C4_10 alkyl group, a C5.8 cycloalkyl group, a C7_10 bicycloalkyl group, a C7.10 bicycloalkenyl group, a C9.10 tricycloalkyl group, a 1-adamantylmethyl group, a C9.10 tricycloalkenyl group, one Phenyl-CM-alkyl or naphthyl-C [.4-alkyl radical, an a, a-tetramethylenephenethyl group, a diphenyl-C ^ -alkyl radical, an a- or β-naphthyl group, a condensed diarylcyclo-alkenyl radical, a condensed arylcycloalkyl radical, one Phenyl-C5-cycloalkyl radical, a C5.7-cycloalkyl-C5.7-cycloalkyl radical, a phenyl or methylenedioxyphenyl group, a phenyl group mono-, di- or tri-substituted by halogen atoms, lower alkyl or alkoxy radicals, one by an amino, dimethylamino -, Methyl-ethylamino, diethylamino, lower alkanoylamino, thione lower alkyl, sulfinyl lower alkyl, sulfonyl lower alkyl, trifluoromethyl, hydroxyl, benzyloxy, lower alkanoyloxy, lower alkanoyl or nitro group substituted phenyl group, a 3-pyridy l- or a 3-pyridyl group mono- or disubstituted by halogen atoms, lower alkyl or alkoxy radicals, or a 5-membered heterocyclic radical, characterized in that a compound of the general formula (XIV): with a compound of the general formula (XVIII) NO II C1-C-NR4R5 2nd PATENT CLAIMS 3. The method according to claim 2, characterized in that the by-product obtained in the reaction, namely the chlorohydrate of the half of the imino compound (XIV) used, is recovered as a base by adding alkali. 4. Use of the heterocyclic guanidine derivatives of the formula I prepared by the process according to claim 1 for the preparation of quaternary ammonium salts, characterized in that the compound of the formula I is quaternized with an alkylating agent.