CH635073A5 - Process for the preparation of guanidine derivatives - Google Patents

Abstract

Heterocyclic guanidine derivatives of the general formula I <IMAGE> in which the substituents are defined in Claim 1, and the pharmaceutically acceptable acid addition salts thereof are obtained by reacting a lactam salt of the general formula III with a guanidine derivative of the general formula IV in a preferably anhydrous organic solvent and optionally converting the compounds obtained into the pharmaceutically acceptable acid addition salts thereof. The compounds which can be prepared according to the invention inhibit, for example, gastric secretion and lower the blood sugar level. <IMAGE>

Description

The present invention relates to a process for the preparation of guanidine derivatives. The compounds that can be produced according to the invention inhibit gastric juice secretion, for example, and lower the blood sugar level.

60 GB-PS-1 409 768 describes various heterocyclic derivatives of guanidine in which the heterocyclic radical is a 5- or 6-membered saturated 1,3-diazacarbocyclic 2-ylidene radical. These derivatives are unsubstituted on the amino nitrogen atom of the guanidine residue.

65 Further similar compounds are described in DT-OSen-2 321 330 and 2 502 397.

The process according to the invention for the preparation of heterocyclic guanidine derivatives of the general formula I

635 073

* 3 "

Rr ^

(CH2) n? R

U

-N-C-fî

/ R4

(I)

and the pharmaceutically acceptable acid addition salts thereof, in which n is 1, 2 or 3, Rj is a hydrogen atom, a Ci_8 alkyl group, a C3_6 cycloalkyl group, preferably a cyclopentyl or cyclohexyl group, a C3_5-AI-ken-2-yl group , a lower hydroxyalkyl group, preferably a hydroxyethyl group, an aralkyl group, preferably a benzyl group, or an aryl group, preferably a phenyl group, R2 is a hydrogen atom, a C 1-4 alkyl group or an aryl group, preferably a phenyl group, R3 is a hydrogen atom, a C 1 -C 8 -alkyl group or an aryl radical, preferably a phenyl group, R4 is a hydrogen atom, a methyl or ethyl group and R5 is a C 1-4 alkyl radical, a C3_7-cycloalkyl radical, preferably a cyclopentyl or cyclohexyl group, an aralkyl radical, preferably a benzyl group, or an aryl radical, preferably a phenyl group or a phenyl group mono-, di- or tri-substituted by halogen atoms, lower alkyl or alkoxy radicals , or R4 and R5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, a 6-membered ring (a) also having an oxygen or sulfur ring atom or an optionally by a contains a lower alkyl radical, a phenyl or 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 aziridinyl , Azetidinyl-, Pyrrolidinyl-, Piperidino-, 2,3,4,5,6,7-Hexahydroazepinyl-, Morpholino-, Thiamorpholino-, Thiamor-pholino-l-oxide-, Thiamorpholino-l, l-dioxide or 2, 6-di-nie-der-alkylmorpholino group, preferably a 2,6-dimethylmorpholino group, a 4-lower alkylpiperazinyl group, preferably a 4-methylpiperazinyl group, a 4-phenylpiperazinyl, 4-benzylpiperazinyl or 2,6- Di-lower alkylpiperazinyl group e, preferably a 2,6-dimethylpiperazinyl group, and R denotes a gno-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_io-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_i0-bicycloalkenyl radical, such as an an-ti-7-norbornenyl group, a C9_10-tricycloalkyl radical, such as a nor-adamantyl, 1- or 2-adamantyl, 1- or 2- (2,3,3a, 4,5 , 6,7,7a-octahydro-4,7-methanoindanyl) group, an l-adamantylmethyl group, a C9_10-tricycloalkenyl group, such as a 3- (2,3,6,6a-tetrahydro-lH-l, 3a -ethanopen-talenyl) - or 5- (3a, 4,5,6,7,7a-hexahydro-4,7-methanoinde-nyl) group, a phenyl-C ^ alkyl or naphthyl-C ^ -al -kylrest, such as a benzyl, d- or 1-a-phenethyl, a, a-dimethyl-benzyl, a, a-dimethyl-β-phenethyl, d- or l- (cx-naphthyl) ethyl group, an a, <x-tetramethylenephenethyl group, a diphenyl-C1_2-alkyl group, such as a diphenylmethyl or 2,2-diphenylethyl group, an a- or ß-naphthyl group, a condensed diarylcycloalkenyl group, such as a 9- Fluorenyl or 5-azenaphthyl group, a condensed arylcycloalkyl radical, such as a 4- (2,3-dihydro-lH-indenyl) -, l- (l, 2,3,4-tetrahydronaphthyl) - or 7- (bicyclo [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-phenylcycloheptyl 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, one by halogen atoms, lower alkyl or alk- soxy radicals mono-, di- or tri-substituted phenyl group, one by an amino, dimethylamino, methylethylamino, di-ethylamino, lower alkanoylamino, thio-lower alkyl, sulfonyl, lower alkyl, sulfonyl lower alkyl, trifluoromethyl, hydroxyl, benzyloxy, lower alkanoyloxy, lower alkanoylio or nitro group substituted phenyl group, a 3-pyridyl group or a mono- or disubstituted by halogen atoms, lower alkyl or alkoxy radicals 3-pyridyl group, 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-is grappe, or a 5-membered heterocyclic radical, such as a 2-furyl or 2-thienyl group, is characterized in that a compound ng of the general formula III

20th

25th

0

CCB2> *

.0

(III)

30 in which X is a methoxy or ethoxy group or Cl and Y® is a BF4®, Cl®, CH30S03® or OSO2F0 group, and Rj, R2, R3 and n have the above meanings, with the proviso that Y is only Cl ® means when X is chlorine, with a compound of general formula IV

35

NO

H2N-C-NR4R5

(IV)

40

wherein R, R4 and R5 have the above meanings, reacted in an organic solvent and the compounds of general formula V obtained

45

CCH2) n NO

W

L 11

-i = N-C-NR R 4 5

HY

(V)

wherein R, Rj, R2, R3, R4, R5 and n have the above meanings, 55 and Y 'is either Y or Yx, converted into the free base of the formula I and optionally into the pharmaceutically acceptable acid addition salts thereof.

The term “lower” means that the corresponding group preferably contains 1 to 4 carbon atoms. As Ha-60 logen atoms, fluorine, chlorine, bromine and iodine atoms are usually suitable. If one of the radicals R2 or R3 denotes an alkyl or aryl radical, the other radical is preferably a hydrogen atom. If n is 2 or 3, the radical R2 and R3 is 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

65

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ren, such as hydrohalic acids, for example hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoic acid. and organic acids, such as vinegar, propion, glycol, pamoin, pygmy, malon, amber, maleic, fumaric, apple, wine, lemon, benzoin, cinnamon, almond , Methanesulfone. Ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyciohexanesulfamic, salicylic and p-aminosalicylic acids. 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 and methyl ester Fluorosulfonic acid 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 excess pressure. 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 also acid amides, such as formamide and dimethylformamide. The anion of the quaternary ammonium salt can generally be easily exchanged for another anion by ion exchange.

Because of their very high blood sugar-lowering activity, compounds of the general formula II which can be prepared according to the invention are

preferably carried out anhydrous solvent. Examples of usable solvents are lower aliphatic alcohols, such as methanol, ethanol, isopropanol and tert-butanol, ethers, such as diethyl ether, tetrahydrofuran and dioxane, lower 5 halogenated hydrocarbons, such as chloroform, methylene chloride and 1,2-dichloroethane, and aromatic hydrocarbons, such as benzene, toluene and xylene. In general, the reaction is carried out at temperatures from 0 ° C. to room temperature. The reaction product of the general formula V given below in the form of the corresponding HY salt can be converted in a manner known per se into the corresponding free base of the general formula I, for example by treatment with an alkali metal or alkaline earth metal hydroxide or carbonate. The reaction can be explained by the following 15 reaction scheme:

20th

25th

R3-y- (CH2)

_ NO

ô 11

+ H ^ N-C-NR ^ g -

30th

(HI)

(IV)

R11 Rio

- <CH2) n ^ f9

^ N-C-N

%

(II)

35

cayn ^

j l 11

NR R 4 5

Hy

alkali

(I)

and their salts with acids and quaternary ammonium salts are preferred. In this formula, n is 1 or 2, R6 is a lower alkyl or hydroxyalkyl radical, an allyl or benzyl group, R7 is a methyl or ethyl group, R8 is a C 1-4 alkyl radical, a cyclopentyl or cyclohexyl group or R7 and Rg together with the nitrogen atom to which they are attached, a pyrrolidino, piperidino, morpholino or thiamorpholino group, R9 is a phenyl group or a phenyl group substituted by the substituents defined above, with the exception of a 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 Cj_3-alkyl radical and Rn is a hydrogen atom or a C] _3-alkyl radical, at least one of the radicals R10 and Rn represents a hydrogen atom.

The compounds of the general formula I are expediently prepared by reacting a lactam salt of the general formula III given below, in which n, R1; R2 and R3 have the meaning given above, X represents either a methoxy or ethoxy group and Y® represents either a BF4S or OSQ2F® group, with a guanidine derivative of the general formula IV given below, in which R, R4, R5 and NR4R5 have the meaning given above, in stoichiometric amounts. The reaction is carried out in an anhydrous organic,

(V)

The lactam fluoroborates of the general formula III used in the process, in which Y® represents the BF4® group, are generally known or can be prepared by customary processes; see. CA-PSen-850 116 and 950 464, US-PS-3 876 658, Chem. Ber., Vol. 89, (1956), p. 2063, and Org. Synth., Vol. 46 (1966), p. 113 and 120. The lactam fluorosulfonates of the general formula III, in which Ye represents the group OSQ2Fe, are generally prepared in a similar manner 55. In general, the lactams of the general formula VI are reacted with the corresponding trialkyloxonium fluoroborate of the general formula VII or a methyl fluorosulfonate of the formula VIII to give the corresponding lactam salts. The reaction is preferably carried out at temperatures from 60 ° C. to room temperature under a protective gas, such as nitrogen or argon, and in an inert, anhydrous, lower halogenated hydrocarbon, such as chloroform, 1,2-dichloroethane or, preferably, methylene dichloride. Examples of other organic solvents which can be used are 65 ethers, such as diethyl ether, dioxane, tetrahydrofuran and 1,2-dimethoxyethane, and aromatic hydrocarbons, such as benzene, toluene and xylene. These reactions can be illustrated by the following reaction scheme:

5

635 073

3 «2"

(CH2) n

-O

(VI)

R3-j-CCH2) n

*1

(VI)

(Et) 3OBF4

(VII)

+ - MeOSO F 2

(VIII)

Me = CH3; Et = C2H5.

25th

V

V

-r ©

(CH,),

BF

©

©

'(CH.)

Vn

'N

i

R

(Ill-b)

oso2F

0

The corresponding 2-lower alkylthiolactim ethers of the general formula III-c can be obtained by reacting the lactam of the general formula VI with P2Ss according to the method described by R. Gompper and W. Elser, Org. Syn., Coll., Vol. V, pages 780 to 783, described method can be produced. The thiolactams of the general formula VI-a are normally obtained first. The reaction of these compounds with an alkylating agent, such as methyl iodide, fluorosulfonic acid methyl ester,

Dimethyl sulfate, toluenesulfonic acid methyl ester or methanesulfonic acid methyl ester generally provides the corresponding 2-alkylthiolactim ether in the form of the corresponding salts. The reaction of these lactim ether salts with the corresponding 30 guanidine of the general formula IV gives the corresponding salts of the general formula I. This reaction can be illustrated by the following reaction scheme:

r2

(CH2) Ä

Alkylation

(VI)

(Via)

-lower alkyl) (I) (salt)

(III-c)

It was found that under the above-mentioned conditions of the reaction of the lactam fluorosulfonates of the general formula III-b with the guanidines of the general formula IV, a side reaction takes place which leads to the formation of the following compounds:

-ö

55

(CHJ NO

<n »

2Ï-C-NR4Rs • CH3

0S02F

©

which can be isolated in a manner known per se. These salts are quaternary ammonium salts of the compounds of the general formula I which, for example, inhibit gastric juice secretion and lower the blood sugar level.

60 The preferred process for the preparation of the compounds of the general formula I, in which Rx represents a hydrogen atom, consists in the reaction of the free bases of the general formula III with the guanidine derivatives of the general formula IV. The reaction of the salts of the general formula 65 III with alkali , preferably in a halogenated hydrocarbon as solvent, such as methylene dichloride or chloroform, provides the free bases of the general formula IX, which are then mixed with the guanidine derivative of the general formula IV,

635 073

6

preferably in an anhydrous lower aliphatic alcohol as solvent, such as methanol, isopropanol or tert-butanol, to give the corresponding compounds of the general formula I, which may be in a tautomeric form X. The free base of the general formula IX

is preferably used in stoichiometric excess. The reaction is preferably carried out during the last stage at the reflux temperature of the reaction mixture. The reaction usually proceeds according to the following reaction scheme:

1 ©

NaOH Y0

Y CH2C12

N

dew 2'ïi

(IV)

Alkanol

(III)

(IX)

- (CHJ NR 2 n "

N

H

I "II /fcN-C-NR.R

Tautomer

4 5

tcch) "m

Il I

S-C- «R (

N

H

4 5

(X)

An alternative process for the preparation of the compounds of the general formula I is based on lactams of the general formula VI, which can be reacted with dimethyl sulfate of the formula XI to give the corresponding methosulfates of the general formula III; see. H. Bredereck u. Mitarb., Chem. Ber., Vol. 96 (1963), p. 1350. The reaction is preferably carried out in an anhydrous, inert organic solvent, for example an aromatic hydrocarbon, such as benzene, toluene, or xylene, an ether, such as tetrahydrofuran or dioxane , or a halogenated hydrocarbon such as 1,2-dichloroethane or chloroform. The methosulfate of the general formula XII obtained is then normally reacted with the corresponding guanidine derivative of the general formula IV in the manner described above, preferably at temperatures from 25 to 100 ° C., to give the corresponding methyl sulfate salt of the compound of the general formula I, which by treatment with Alkali can be converted into the corresponding free base of the general formula I.

30 The free bases of the general formula I can also starting from the methosulfate salt of the general formula XII by reaction with a lower alkali alkoxide, preferably sodium methoxide or ethoxide, in the corresponding lower aliphatic alcohol as solvent, among those of 35 H. Bredereck u. Mitarb., Chem. Ber., Vol. 97 (1964), pp. 3081 to 3087, reaction conditions described, to the corresponding lactam acetals of the general formula Xll-a. The lactam acetals are then usually reacted with the corresponding guanidine of the general formula IV 40 to give the free bases of the general formula I. These reactions can be illustrated by the following reaction scheme:

<ay "

J = 0 we0.2s02

N

(vi)

(XI)

Ofrîe

(XII)

OSO

hosojme

Alkali metal alkoxide

■ I. umilili 2) Ti

_J l "0-ni n_s

(IV)

lower alkyl 0-lower alkyl

(I)

(free base)

Me = CH3

(Xlla)

635 073

Another process for the preparation of the compounds of the general formula I can consist in the reaction of the guanidine derivative of the general formula IV with a chloride salt of the general formula XIII in an anhydrous aprotic solvent, for example an ether such as diethyl ether, dioxane or tetrahydrofuran, a halogenated one Hydrocarbon such as chloroform, methylene dichloride or 1,2-dichloroethane, or preferably an aromatic hydrocarbon such as benzene, toluene or xylene.

The chloride salts of the general formula XIII can in turn by reacting the lactams of the general formula VI with phosgene or thionyl chloride according to the method described by W. Jentzsch and M. Seefelder, Chem. Ber., Vol. 98, (1965), p. 274 getting produced. The process can be illustrated by the following reaction scheme:

CO Î

1— (CH2> n + C1COC1 2 — ï

k JLq (or SOCl2) (S02 Î

N

I.

R1

(VI)

«HO

Cl

©

(IV)

(I)

NR4R5 NR4R5

I alkali

RN = C-NH2HX RN = C-NH2

5 (tautomer) (XXII)

(IV)

The process for the preparation of the guanidines of the general formula IV, in which R is a phenyl or substituted phenyl group, R4 is a hydrogen atom and R5 is a phenyl or substituted phenyl group, is usually based on the corresponding N, N'-diarylthioureas of the general

(XIII)

The preparation of a wide variety of guanidine derivatives is generally described in detail in the literature. The guanidines of the general formula IV can be prepared by various methods. For example, a thio-urea of the general formula XX, in which R has the above meaning, is converted into the corresponding alkylthiover compound of the general formula XXI by alkylation with the alkylating agent of the general formula R'X. The alkylthio compound is then normally reacted with the corresponding amine of the general formula HNR4R5, where R4 and R5 have the above meaning, but R5 represents a phenyl or substituted phenyl group. The guanidine derivatives of the general formula XXII are usually obtained as a salt of an acid (HX), which are converted with alkali into the corresponding free bases of the general formula IV. To accelerate the reaction rate, the reaction can be carried out in the presence of a tertiary alkyl amine, such as triethylamine. The reaction conditions are preferably the same as those explained above for converting the thioureas of the general formula XVI into the alkylthio compounds of the general formula XVH and into the end products of the general formula I. The implementation can be explained by the following reaction scheme:

S SR '

Formula ArNHC-NHAr ', where Ar and Ar' are phenyl or substituted phenyl groups. These compounds are usually reacted with ammonia to the corresponding 20guanidines.

A further process for the preparation of guanidines of the general formula IV, in which R preferably denotes 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, preferably follows that of E. Kühle, Angew. Chemistry, boarding school Ed., Vol. 8 (1969), pp. 24 and 26. In this process, the chlorine atoms of the corresponding isocyanide-30 dihalide of the general formula XXIII are normally substituted in succession. The preparation of the isocyanide dihalide is described, for example, in Angew. Chemistry, boarding school Ed., Vol. 6 (1967), p. 649. The isocyanide dihalide is usually 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 XXIV. Treatment of the reaction mixture with excess anhydrous ammonia and subsequent treatment with dilute alkali, for example a solution of an alkali metal hydroxide or carbonate, generally gives the corresponding guanidine of the general formula IV. This reaction can be explained by the following reaction scheme:

CL

NR4R

• 4 »-5

50

55

RN = C-CL + HNR4Rs + Et3N - ♦ RN = C-Cl + Et3N-HCl (XXIII) (XXIV)

NR4R5

RN = C-C1 Ä ^ (IV)

(XXIV)

60

Et = C, H ,.

rnh-c-nh2

(XX)

R'X

rn = c-nh2hx

(Tautomer) (xxi)

hnr4r

4 ^ 5.

Another process for the preparation of the guanidines of the general formula IV, in which R is a phenyl or substituted phenyl group, consists, for example, in the reaction of an aniline of the general formula XXV with a cyanamide of the general formula XXVI. The guanidine salt of the general formula XXII is normally obtained; see.

635 073

8th

GB-PS-1 341 245 and US-PS-3 976 643. This reaction can be illustrated by the following reaction scheme:

R-NH2 + NC-NR4R5 (XXV) (XXVI)

HCl

(XXII)

alkali

(IV)

A further process for the preparation of the guanidines of the general formula IV, in which R denotes a phenyl or substituted phenyl group, preferably follows that described by W. Abraham and G. Barnikow, Tetrahedron, Vol. 29 (1973), pp. 691 and 699 Process of acidic hydrolysis of a 2-isothiocyanatoamidine of the general formula XXVII. These compounds are generally prepared by reacting the mono-halide of the general formula XXIV with ammonium thio-cyanate. The process can be illustrated by the following reaction scheme:

no

4r5

nr4r5

RN = C-C1

NH4SCN

(XXIV)

-> RN = C-NCS

(XXVII)

H +

to pierce this area. At 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. Then the Ta-s bakbag bag seam is 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 carrier substance 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 allowed to stabilize and recover for 30 minutes, the collection tube is discarded from the cannula and replaced with a clean tube for absorbing the gastric juice. The total amount secreted is

Another process for the preparation of the guanidines of general formula IV, in which R has the above meaning, usually follows that of H.G. Viehe & Z. Janousek, Angew. Chemistry, boarding school Ed., Vol. 12 (1973), p. 806, in which a dichloromethylene ammonium salt of the general formula XVIII, in which R4 and R5 have the above meaning, but the group NR4R5 is not a thia-morpholino-l-oxide group, is reacted with an amine of the general formula XXV to the monohalide of the general formula XVIII. This compound is then generally treated with excess ammonia and then with alkali in the manner described above. The corresponding guanidines of the general formula IV are usually obtained. This reaction can be explained by the following reaction scheme:

Cl

RNH2 + Cl-C = NR4R5®C1®— »RN = C-Cl (XXV) (XXVIII) '(XVIII)

The compounds of the general formula I and their salts with acids and quaternary ammonium salts are, for example, valuable medicinal substances which inhibit gastric juice secretion and lower the blood sugar level, as explained below:

The inhibition of gastric juice secretion was demonstrated in rats in the gastric fistula test. Female rats of the Sprague-Dawley strain were used for the experiments;

»(XXII) + COS» iiu ».Z.UÌ..VIIV 5 ^" '"

HÖH 'melt. 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 precipitate 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 acid 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 / liter is the amount of 0.01 N sodium hydroxide solution that is required to titrate the acid up to pH 7. The total acidity is the product of 35 titratable acid times volume. The results are given in% inhibition compared to 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 40 also generally lower blood sugar levels, i.e. they have hypoglycemic properties. This is preferably demonstrated using the glucose tolerance test on rats. The compounds of the general formula II usually have particularly pronounced hypoglycemic properties. 45 The glucose tolerance test in rats is generally an extremely sensitive standard test for the diagnosis of diabetes and hypoglycemic symptoms and is explained below:

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 of glucose / kg of body weight in 1 ml of water, they become 90 minutes after 0 minutes, 30 minutes, 60 minutes

no4r.

NH, alkali

(iv)

Compound to be investigated was injected intraduodenally in a dose of 2.5 to 40 mg / kg body weight. 24 hours before 55 minutes, 120 minutes, 150 minutes and 180 minutes 0.1 ml of the experiment, the rats are no longer fed, 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 have any blood vessels in

Blood drawn from the tail vein without anesthesia. The blood samples are immediately deproteinized with aqueous solutions of barium hydroxide and zinc sulfate, and the glucose levels are determined according to the L.P. Cawley et al. 60 employees, “Ultra Micro Chemical Analysis of Blood Glucose with Glucose Oxidase” 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 percent methyl cellulose solution. The control groups are given the same volume of carrier subcutaneously. Blood glucose levels are expressed at each time in

mg% (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 lowers the blood glucose level at all times with a confidence limit of 95%, the compound has hypoglycemic activity.

Embodiments

example 1

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

A mixture of 1.84 g (0.013 mol) of boron trifluoride etherate in anhydrous diethyl ether is mixed with nitrogen as a protective gas and with vigorous stirring with 1.02 g (0.011 mol) of epichlorohydrin and stirred for 3 hours. The crystalline triethyloxonium fluoroborate formed is then washed with fresh, anhydrous diethyl ether under nitrogen as a protective gas. The ether solution is decanted. The crystals are dissolved in anhydrous methylene chloride, and the solution is mixed with 1.09 g (0.011 mol) of l-methyl-2-pyrroîidinone and stirred for 2 hours. Then the solution obtained is mixed with ice cooling with 0.01 mol of N-phenyl-1-pyrrolidinecarboximidamide. The reaction mixture is stirred for about 16 hours, then evaporated to dryness under reduced pressure and diethyl ether is added to the residue. The crude crystalline HBF4 salt of N- (l-methyl-2-pyrrolidinylidene) -N'-

9 635 073

phenyl-1-pyrrolidine carboximidamide obtained. The crystals are recrystallized from acetone. The pure fluoborate salt of F. 164 to 166 ° C is obtained.

The fluoborate salt is converted into the free base in methylene chloride with ice cooling using 20 percent sodium hydroxide solution. The methylene chloride solution is dried over anhydrous potassium carbonate, then filtered and evaporated to dryness under reduced pressure. The remaining free base is dissolved in methanol and mixed with an equimolar amount of ioL - (+) - tartaric acid. The resulting solution is evaporated with the addition of isopropanol until practically all of the methanol has been distilled off. After cooling, the tartrate crystallizes out. The pure title compound is removed from the isF by recrystallization from isopropanol with a small amount of methanol. Get 153.5 to 156 ° C.

Example 2

Example 1 is repeated, but the corresponding lactam fluoborate of the general formula III-a is reacted with the corresponding guanidine of the general formula IV in the molar ratios indicated. The compounds of general formula I are obtained either as a free base or as a salt of an acid.

25 * 3 1— {ChVp NB

i

30 R1

Connection no.

1.

3rd

4th

5.

6.

7.

8th.

9.

10th

11.

12.

13.

No

1 -CHPh,

1 Ph

1 Ph

1 Ph

Ri

Me

Me

Me

Me

1 1-naphthyl Me

1 Ph

1 Ph

1 Ph

1 Ph

1 Ph

1 g ClPh

1 Ph

Ph

Me

•O

-CHUPh

Me me

Margin

H

H

Me

H

H

H

H

H

H

-CH, CH, OH H

1 1-naphthyl Me

Ph Ph H

r3

H

H

H

Ph

H

H

H

H

H

H

H

H

H

NR.R

4 ^ 5

X]

NHPh

-O - <j

-O <J

-NEt2 <]

/ —V.

-N ^> -N O

Molver product ratio

(HI): (IV)

1.1: 1 1.2: 1 1: 1 1: 1 1.2: 1 1.1: 1 1.2: 1

1.2: 1

-NHPh 1.1: 1

HJ

base

HJ

HJ

HJ

HJ

HJ

F., ° C

218-220

180-183

158-160

215-217

185-187

193.5-194.5

155-157

1.1: 1 saccharinate 165-166.5

1.2: 1 fumarate 208-210

base

HCl

128-130

204-207

-N O 1.08: 1 fumarate (220) 224-226

-NEt.

1.05: 1 fumarate 187-tS1)

635 073

10th

Connection no.

14.

15.

16.

17th

18th

19th

20th

21st

22.

23.

24th

25th

26.

27th

28

29.

30th

31

32.

33.

34.

35.

* inverse addition

R Rj

9-fluorenyl Me

Ph -CH2CH = CH2

Ph Me

Ph Me

£ -nC4H9Ph m-CFjPh -CHPh2 Ph g-MePh

Me Me Me Me Me

/ ° \

3.4CH2V / Ph Me

O

m-ClPh Me m-MePh Me

3,4- (OMe) 2Ph Me

4-PhCH20-Ph Me

3-OMePh Me

4-OMePh 4-SMePh 4-NMe2Ph Ph

3-pyridyl *

Ph

3-C (0) CH3Ph

S "17

Compound molar ratio, No. nis (III): (IV)

18th

19th

20th

21st

22.

23.

1.08 1.08 1

1.08 1.2 1.17

Me Me Mfe Me Me n-CRH Me

product

Fumarate Fumarate L - (+) - Tartrate HJ

Fumarate HJ

R2

H

H

H

n-C4Hy H H H H H H H H H H H H H H H H H H

r3

H H

û-C8Hi7 H

H H H H H H H H H H H H H H H H H H

F., ° C

no

<]

-O

-N O

<D

Molver product ratio

(III) :( IV)

1.1: 1 1.2: 1

1: 1

1: 1

-NEt: N (Me) <Q

-N O N /

-N (Me) <Q <]

-N

-n o v_y

-N (Me) <Q

-G

a

-N

-O

-n ^ O

-O

✓— \

-N NH \ /

Me

Me

-N O

-a -a

163-165

(135-137) 139-141

146-148.5

(120) 128.5-130

176-178

144-146

hj hcio4

Tosylat hj f., ° c

230-232

(Dec.)

105.5-107

(130) 133-135

130-131

11

635 073

Connection Moherhaltung-Nr. nis (I1I) :( IVJ

24th

25th

26.

27th

28

29.

30th

31

32.

33.

34.

35.

2: 1 1.2: 1 1.1: 1

2.5: 1 1.1: 1 2: 1 1.08: 1 1.08: 1 1: 1

1: 1.1 1: 1.1 1: 1.1

product

Fumarate fumarate phosphate

HC104

HNO3

Fumarate

HJ

HJ

2HJ

1.5 fumarate

Tartrate

Pamoat

F., ° C

177.5-179.5 133-136 201-204 (dec.)

(151) 152-154

104-109

179-180.5

142-144

171-172

269-270

(Dec.)

138-139.5

oil

158-164 (dec.)

Example 3

N- (2,6-dimethylphenyl) -N - (7-methyl-2-pyrrolidinylidene) -! -pyrrolidine carboximidamide fumarate

A solution of 3.47 g (0.035 mol) of anhydrous 1-methyl-2-pyrrolidinone in anhydrous methylene chloride is treated with 3.99 g (0.035 mol) of methyl fluorosulfonate under nitrogen. After 2 hours of reaction, a solution of 6.52 g (0.03 mol) of N- (2,6-dimethylphenyl) -l-pyrrolidinecarboximidamide in anhydrous methylene chloride is rapidly added at room temperature with stirring. The mixture is then stirred at room temperature for about 16 hours and then made alkaline with excess cold 20 percent sodium hydroxide solution. The methylene chloride solution is separated off and the aqueous phase is extracted twice with 50 ml of fresh methylene chloride each time. The methylene chloride extracts are combined, dried over anhydrous potassium carbonate, filtered and evaporated. The oily residue is dissolved in diethyl ether and the solution is filtered through diatomaceous earth. The filtrate is neutralized with a hot solution of fumaric acid in isopropanol.

20th

30th

The title compound crystallizes on cooling. It is recrystallized from isopropanol and melts at 182 to 184 ° C with weak decomposition.

Example 4

Example 3 is repeated, but the corresponding guanidine of the general formula IV is reacted with the corresponding compound of the general formula III-b in the molar ratios indicated. The compounds of general formula I are obtained either as a free base or as a salt of an acid.

35

C — NR4R5

Connection, no.

1.

2nd

3rd

4th

5.

6.

7.

9.

10th

R

Ph Ph

1-Naphthyl £ -N02-Ph 2,6-diCl-Ph Ph exo-2-norbornyl O

3.4CH2 Ph O

4-MePh 4-MePh

NR4R5.

-N S

NHCHjPh

N (Me) <Q> <]

do.

do.

/ - \

-N O

N (Me) <^>

-lO)

-N S

Ri

Me Me Me Me Me Me Me Me Me Me

Molar ratio (IIIb) :( IV)

1.09: 1

1.2: 1

1.2: 1

1: 1

1.14: 1

1: 1

1: 1

1.2: 1

1.2: 1

1.2: 1

product

HJ

Fumarate

HJ

base

F., ° C

188-190

130-132

225-226

113-114.5

Base 139-141.5

L - (+) - tartrate 153-155 fumarate 180-182

Fumarate

HJ

HJ

(161-4) 174

(Dec.)

190-191

(Dec.)

166-168

(Dec.)

635 073

12

Connection, no.

11.

12.

13.

14.

15.

r

3-MePh 3-OMePh

3-MePh

3-OMePh 3-MePh

NR4RS

-O

-N (Me) - <Q

-N ~ "o

/ \ -NwS

s ~ \

-n o

Ri

-ch2ch = ch2 -ch2ch = ch2

Molver

hell

(IlIb) :( IV)

1.17: 1 1.17: 1

Product hj

Fumarate xh h, 0

2 me

1 me

1.2: 1 fumarate

1.2: 1 HY 1.2: 1 fumarate

F., ° C

158-160

(Dec.)

120-122

(142-144) 148-151

185-186

161-164 (dec.)

20th

Example 5

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

A) N- (2,6-dichlorophenyl) -N - (1-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) -l-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-1-pyrrolidine-carboximidamidinium methoiodide

A solution of 0.05 mol of N- (1-methyl-2-pyrrolidinylidene-N'-phenyl-1-pyrrolidinecarboximidamide (Example 1-D) 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, giving the title compound of mp (156) 162 to 164 ° C.

c) The reaction of 0.05 mol of the compound from Example 1-D in anhydrous diethyl ether with 0.05 mol of methyl fluorosulfonate gives an oily precipitate which crystallizes. After recrystallization from tert-butanol, the product of Example 18-B is obtained in the form of the methofluorosulfonate with a melting point of 135.5 to 137 ° C.

Example 6

N-phenyl-N- (2-pyrrolidinylidene) -l-pyrrolidine carboximide amide hydroiodide

A solution of 0.07 mol of triethyloxonium fluoroborate in anhydrous methylene chloride is mixed with 6.08 g (0.070 mol) of 2-pyrrolidinone and stirred 2XU hours. The reaction mixture is then made alkaline with 50 percent sodium hydroxide solution while cooling with ice. The methylene chloride solution is separated off, dried over anhydrous potassium carbonate and filtered. 12.28 g (0.065 mol) of N-phenyl-1-pyrrolidinecarboximidamide are added to the filtrate. The methylene chloride is then distilled off and replaced by tert-butanol. The resulting solution is heated under reflux for 22 hours. The reaction mixture is then cooled to room temperature and neutralized with 47 percent hydroiodic acid.

The crude crystalline hydroiodide is recrystallized from tert-butanoi. The title link from f. Obtained 223 to 225 ° C (dec.).

25th

Example 7

N- (l-methyl-2-pyrrolidinylidene) -N '-phenyl-1-pyrrolidinecarboximidamide-L- (4-) -tartrate

A mixture of 0.99 g (0.01 mol) of 1-methyl-2-pyrrolidone 30 in anhydrous benzene is heated under reflux and stirred, and 1.26 g (0.01 mol) of dimethyl sulfate are slowly added. The mixture is then stirred for a further 5 hours. The reaction mixture is then slowly mixed with 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide. The mixture 35 is stirred for a further 16 hours at room temperature and then evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride and the solution is made alkaline with 50 percent sodium hydroxide solution while cooling with ice. The methylene chloride solution is dried over potassium carbonate 40, filtered and evaporated to dryness under reduced pressure. 2.7 g of an oil remain, which is dissolved in methanol and 1.5 g (0.01 mol) of L - (+) -tartaric acid are added. The crystals formed are filtered off and recrystallized from a mixture of methanol and isopropanol. > 5 The title link from f. Get 153 to 156 ° C.

Example 8

N- (l-methyl-2-pyrrolidinylidene) -N '-phenyl-1-pyrrolidinecarboximidamide- L - (+) - tartrate so A cooled solution of 1.98 g (0.02 mol) l-methyl-2-pyrrolidone 3.95 g (0.04 mol) of phosgene are added in anhydrous toluene. The mixture is stirred for 45 minutes at room temperature under nitrogen as a protective gas. White crystals fall out. Excess phosgene and solvent are then filtered off under nitrogen. Fresh toluene is added to the residue and the remaining phosgene is evaporated under reduced pressure to separate it. The remaining crystals are washed twice in the same way with toluene and then dissolved in anhydrous methylene chloride 60. The solution is mixed with 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide and 1.01 g (0.01 mol) of triethylamine. The resulting mixture is stirred for about 15 hours under nitrogen as a protective gas and then evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride and the solution is made alkaline with 50 percent sodium hydroxide solution while cooling with ice. The methylene chloride solution is separated off, dried over anhydrous potassium carbonate, filtered and concentrated under reduced pressure

13

635 073

steams. The oily residue is dissolved in isopropanol and adjusted to a pH of about 6 to 7 with L - (+) - tartaric acid. The crystals obtained on cooling are filtered off and recrystallized from isopropanol. The title compound of F. 155 to 156 ° C is obtained.

Example 9

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

A mixture of 1.29 g (0.0075 mol) of 2,2-diethoxy-l-methylpyrrolidine in anhydrous benzene is mixed with 1.42 g (0.0075 mol) of N-phenyl-l-pyrrolidinecarboximidamide and about 15 Heated under reflux for hours. The reaction mixture is then evaporated to dryness under reduced pressure. The residue is treated with 10% hydrochloric acid and then made alkaline with cold 20% sodium hydroxide solution. The free base is extracted with diethyl ether. The ether extract is dried over potassium carbonate and evaporated to dryness under reduced pressure. The oily residue is dissolved in isopropanol and 1 mol equivalent of L - (+) - tartaric acid is added. After recrystallization from a mixture of methanol and isopropanol, the pure title compound of mp 153 to 156 ° C. is obtained.

Example 10

N- (1-Methyl-2-pyrrolidinylidene) -N '-phenyl-1-pyrrolidine-carboximidamide 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 decomposition);

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

Example 13

N- (4-acetylaminophenyl) -N - (1-methyl-2-pyrrolidinylidene) -l-pyrrolidinecarboximidamide hydrobromide

3.4 g (0.0119 mol) of N- (4-aminophenyl-N '- (l-methyl-2-s pyrrolidinyidene) -1 - pyrrolidinecarboximidamide (the product of Example 12) are mixed with 25 ml of acetic anhydride to about 1 The reaction mixture is diluted with ethanol and heated for a further hour, after which the volatile constituents are distilled off under reduced pressure, the residue is treated with dilute sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract is dried over potassium carbonate , filtered and evaporated to leave an oil which is converted into the corresponding hydrobromide in a mixture of diethyl ether and ethanol with hydrogen bromide and after recrystallization from a mixture of ethanol and diethyl ether the title compound melts at 246 to 247 ° C.

Example 11

N- (l-methyl-2-pyrrolidinylidene) -N-phenyl-1-pyrrolidine-carboximidamide hydroiodide

A solution of 2.57 g (0.01 mol) of l-methyl-2-methylthio-l-pyrrolinium iodide in tert-butanol is mixed with 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide. The mixture is heated under reflux for 16 hours and the methyl mercaptan formed is absorbed in concentrated sodium hydroxide solution. After cooling and inoculation, 3.65 g (92% of theory) of the crude title compound are obtained, which is recrystallized from tert-butanol; F. 206 to 207 ° C.

Example 12

N- (4-aminophenyl) -N- (l-methyl-2-pyrrolidinylidene) -l-pyrro-lidincarboximidamide hydrobromide

2.46 g (0.0078 mol) of N- (l-methyl-2-pyrrolidinylidene) -N '- (4-nitrophenyl) -l-pyrrolidinecarboximidamide (product No. 4 from Example 4) in 50 ml of anhydrous ethanol is dissolved in Presence of Raney nickel hydrogenated at about 3 at hydrogen pressure. Hydrogen uptake is complete within about 30 minutes. The catalyst is then filtered off and washed out with ethanol. The filtrate and the washing solution are combined and evaporated under reduced pressure. The residue is dissolved in ethanol and neutralized with 1 equivalent of 48 percent hydrobromic acid. The crystals formed are filtered off and recrystallized from a mixture of ethanol and diethyl ether. The title compound of F. 241 to 241.5 ° C is obtained.

2o Example 14

N- (l-methyl-2-pyrrolidinylidene) -N- (4-methylsulfonylphenyl) -4-morpholine carboximidamide

A solution of 1.98 g (0.0006 mol) of N- (4-methylthiophenyl) -N '- (l-methyl-2-pyrrolidinylidene) -4-morpholine carboxamide 25 (compound 30 from Example 2) in anhydrous methylene chloride 3.6 g (0.018 mol) of m-chloroperbenzoic acid are added at 0 ° C. while stirring. The temperature should not rise above 5 ° C. The mixture is then stirred for 30 minutes at this temperature and then washed three times with 40 ml of saturated sodium bicarbonate solution and three times with 35 ml of saturated saline solution. The organic phase is dried over potassium carbonate and filtered through a filter aid. The filtrate is evaporated to dryness under reduced pressure. The residue is diluted with Me-35 ethanol. Insoluble substances are filtered off and discarded. The filtrate is evaporated almost to the dryness on a steam bath. The residue is diluted with diethyl ether. The crystals formed (F. 160 to 166 ° C) are recrystallized from diethyl ether. The pure title compound of F. (165) 167 to 170 ° C. is obtained.

Example 15

N- (l-Methyl-2-pyrrolidinylidene) -N- (4-methylsulfinylphenyl) -4-morpholine carboximidamide 45 A solution of 1.98 g (0.006 mol) of N- (4-methylthiophenyl) -N '- (l -methyl-2-pyrrolidinylidene) -4-morpholine carboximidamide (compound 30 from Example 2) in methylene chloride is mixed at 5 ° C with 1.22 g (0.006 mol) of m-chloroperbenzoic acid. The temperature should not rise above 5 ° C. Then the reaction mixture is warmed to room temperature and stirred for a further 2 hours. The organic phase is then washed three times in succession with 30 ml of saturated sodium bicarbonate solution and twice with in each case 30 ml of saturated sodium chloride solution and dried over anhydrous potassium carbonate 55. After filtering, the solvent is distilled off under reduced pressure. The residue is treated with a mixture of diethyl ether and hexane. The crystalline crude product is recrystallized from a mixture of diethyl ether and hexane. Pure title compound 60 of F. (115) 117 to 120 ° C. is obtained.

Example 16

N- (4-Hydroxyphenyl) -N - (1-methyl-2-pyrrolidinylidene) -l-pyr-65 rolidine carboximidamide hydroiodide

A solution of 26.6 g (0.071 mol) of N- (l-methyl-2-pyrro-lidinylidene) -N '- (4-benzyloxyphenyl) -l-pyrrolidinecarboximide-amide (compound 27 from Example 2) in 50 ml of acetic acid becomes

635 073

14

hydrogenated in the presence of 10% palladium-on-carbon for about 2 hours at 3 atm hydrogen pressure and at room temperature. As soon as the hydrogen uptake has ended, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. A viscous oil remains, which is dissolved in acetone and mixed with 1 equivalent of concentrated hydroiodic acid. The crude crystalline title compound obtained is recrystallized from a mixture of methanol, acetone and diethyl ether. The pure title compound melts at 174 to 178 ° C.

Example 17

N- (4-Acetoxyphenyl) -N- (l-methyl-2-pyrrolidinylidene) -l-pyrrolidinecarboximidamide hydroiodide

A solution of 5.15 g (0.0124 mol) of N- (4-hydroxyphe-

nyl) -N '- (l-methyl-2-pyrrolidinylidene) -l-pyrrolidinecarboximide amide hydroiodide (compound of Example 16) and 41.2 g (0.20 mol) of N, N'-dicyclohexylcarbodiimide in 400 ml acetone 12 g (0.20 mol) of glacial acetic acid are slowly added. The mixture is stirred for 72 hours at room temperature under nitrogen as a protective gas. The crystallized N, N'-di-cyclohexylurea is then filtered off and the filtrate is evaporated under reduced pressure. The remaining amber oil is digested several times with diethyl ether. A yellow solid is obtained, which is recrystallized from a mixture of acetone and diethyl ether. White crystals of F. (188) 195 to 197 ° C. are obtained. After further recrystallization from a mixture of methanol, acetone and diethyl ether, the pure title compound is obtained in white crystals from 15 F. 196 to 199 ° C.

C.

Claims (2)

635 073 2nd PATENT CLAIMS 1. Process for the preparation of heterocyclic guanidine derivatives of the general formula I (I) © CCH2) n {CH7) n L 5-Ni-alkyl (III-c) io and the pharmaceutically acceptable acid addition salts thereof, in which n has the value 1, 2 or 3, Rx is a hydrogen atom, a Qg-alkyl-, C3_ <rcycloalkyl-, 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 1-6 -alkyl radical or an aryl radical, R4 is a hydrogen atom, a methyl or ethyl group and Rs is a CM-alkyl radical, a C ^ - Cycloalkyl radical, an aralkyl radical or an aryl radical, or R4 and R5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, a 6-membered ring (a) still being an 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 which is bonded to the carboximide amide function and R is a C + ^ o-alkyl radical, a C5_8-cycloalkyl radical, a C7_10-bicycloalkyl radical, a C7_10-bicycloalkenyl radical, a Cg_10-tricycloalkyl radical, a l-adamantylmethyl group, a C9_10- Trieycloalkenylgrappe, a phenyl-C ^ alkyl or naphthyl-C ^ alkyl group, an a, a-tetramethylenephenethyl group, a diphenyl-C1_2-al-alkyl group, an a- or ß-naphthyl group, a condensed diarylcycloalkenyl group, a condensed arylcycloalkyl group a phenyl-Cs_7-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, methylethylamino , Diethylamino, lower alkanoylamino, thio lower alkyl, sulfinyl lower alkyl, sulfonyl lower alkyl, trifluoromethyl, hydroxyl, benzyloxy, lower alkanoyloxy, lower alkanoyl or Ni-trogruppe substi tuated phenyl group, a 3-pyridyl group 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 III wherein Y! 0 stands for an iodide, OSO2F0, methyl sulfate, tosylate or methanesulfonate anion, with a compound of the general formula IV NO H2N-C-NR4R5 (IV) wherein R, R4 and R5 have the above meaning, reacted in an organic solvent and the compounds of general formula V obtained -fCHOn 25 h (V) HY wherein R, R1; R2, R3, R4, R5 and n have the above meaning, and Y 'is either Y or YL, converted into the free base of the formula I and, if appropriate, into a pharmaceutically acceptable acid addition salt. 35. 2. Process for the preparation of quaternary salts of heterocyclic guanidine derivatives of the general formula I NO -C — N , R. (I) wherein the substituents are defined in claim 1, characterized in that compounds of the formula I are prepared in accordance with the process according to claim 1 and then compounds obtained are quaterized with an alkylating agent. -O (III) in which X represents a methoxy or ethoxy group or Cl and Ye represents a BR4 ©, C1®-CH30S03® or 0S02F® group, and Rj, R2, R3 and n have the above meanings, with the proviso that Y only then Cl ® means when X is chlorine, or a compound of general formula III-c 55