CH634557A5 - Process for preparing derivatives of guanidine - Google Patents

Abstract

The 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 pyrroline bases, which are substituted in the 2 position by methoxy or ethoxy, or pyrrolidone bases, which are acetalised in the 1 position, with a guanidine of the formula H2N-C(NR)-N(R4R5) in the presence of an anhydrous organic solvent. The bases which are obtained 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 60 new heterocyclic guanidine derivatives. These compounds are able to inhibit gastric juice secretion and lower blood sugar levels.

GS-PS 1 409 768 describes various heterocyclic derivatives of guanidine in which the 65 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.

^ 2> n

R.

L

■ N-

NO

II

-c — n;

, R,

Rr

3 (CH2) n R3

1 or

2 \ * R2

N

(IX)

3rd

634557

Other similar compounds are described in DT-OS 2,321,330 and 2,502,397.

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

i

Ri and its salts with acids and its quaternary ammonium salts, in which n has the value 1, 2 or 3, Rj is a hydrogen atom, a C 1-6 alkyl radical, a C3_6 cycloalkyl radical, preferably a cyclopentyl 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 is a hydrogen atom, a C, _6-alkyl radical or an aryl radical, preferably a phenyl group, R3 Hydrogen atom, a C 1-6 alkyl radical 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 means, or R4 and R5 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, where a membered ring (a) is also an oxygen or sulfur ring atom or a phenyl, optionally through a lower alkyl radical - 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 linked to the carboximidamide function, in particular an aziridinyl, azetidinyl, pyrrolidinyl -, Piperidino-, 2,3,4,5,6,7-hexahydroazepinyl-, morpholino-, thiamorpholino-, thiamorphoKno-l-oxide-, thiamorpholino-l, l-dioxide or 2,6-di-lower-alkylmorpho -lino 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 pe, preferably a 2,6-dimethylpiperazinyl group, and R is a C4_w-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_i0-bicycloalkyl radical, for example an exo- or endo-2-norbornyl, 2-bicyclo [2.2.2] octyl or endo-2-bicyclo-f3.2, l] octyl group, a C7_10 bicycloalkenyl group, such as an anti-7-norbornenyl group, a C9_10 tricycloalkyl group, 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, a 1-adamantylmethyl group, a Cg, 0-tricycloalkenyl group such as a 3- (2,3,6,6a-tetrahydro-1H-1 , 3a-ethano-pentalenyl) or 5- (3a, 4,5,6,7,7a-hexahydro-4,7-methano-indenyD group, a phenyl-C, 4-alkyl- or naphthyl-C] _4 - alkyl radical, such as a benzyl, d- or 1-a-phenethyl, a, a-di-

methylbenzyl, a, a-dimethyl-ß-phenethyl, d- or l- (a - naphthyD-ethyl group, an a, a-tetramethylenephenethyl group, a diphenyl-Ci_2-alkyl radical, such as a diphenyl-methyl or 2,2-diphenylethyl 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-dihydro-lH-inde- nyl) -, 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-phenylcyclo-heptyl group, a C5_7-cycloalkyl-C5_7-cycloalkyl radical, such as a cis or trans-2-cyclohexylcyclopentyl or eis 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 -, methyl ethylamino, diethylamino, lower alkanoyl amino, thio lower alkyl, sulfinyl lower alkyl, sulfonyl lower alkyl, trifluoromethyl, hydroxyl, benzyloxy, never-the-alkanoyloxy , lower alkanoyl or nitro group substituted phenyl group, a 3-pyridyl group 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-di-chloro-3-pyridyl or 2,6-dimethoxy-3-pyridyl group, or a 5-membered heterocyclic group 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 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, 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 and amber. , Malein, Fumar, Apples,

Tartaric, citric, benzoic, cinnamon, almond, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexane-sulfamic, 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-toluenesulfonyl and methyl methoxide 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 inert organic solvents which can be used 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, propano! 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.

Because of their very high blood sugar-lowering activity, compounds of the general formula II

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

634557

4th

R11 R10

- (CH2) n%

I "

j = n-c-n

I.

"R-

v8

(il)

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, R8 denotes a lower 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 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 Cj_3-alkyl radical, at least one of the radicals R10 and Rn Represents hydrogen atom.

The compounds of general formula I are prepared by using a free base of the formula

10th

15

20th

25th

r-

■ (ayn

N

(IX)

or r3

* 2

- (ch2) Ti

1.0-pieder-alkyl o ~ lower-alkyl

I.

R «

(XII-a)

wherein Rj, R2, R3 and n have the meanings already mentioned and X is methoxy or ethoxy, in an anhydrous organic solvent with a compound of the formula

NO

II

H2N — C — NR4R5 (IV)

in which R, R4 and R5 have the meanings already given, and the compound of the formula I obtained is optionally converted into the acid addition salt using an acid. Examples of usable solvents are lower aliphatic alcohols, such as methanol, ethanol, isopropanol and tert-butanol, ethers, such as diethyl ether, tetra-hydrofuran and dioxane, and lower halogenated hydrocarbons, such as chloroform, methylene chloride and 1,2-dichloroethane , and aromatic hydrocarbons such as benzene, toluene, and xylene.

The compounds of formula IX or Xlla used in the process can be obtained as follows, provided they are not already known; see. CA-PS 850 116 and 950 464, U.S. Patent 3,876,658, Chem. Bert., Vol. 89, (1956), p. 2063, and Org. Synth., Vol. 46 (1966), p. 113 and 120. In general, the lactams of the general formula VI are reacted with the corresponding trialkyloxonium fluoroborate of the general formula VII or a fluorosulfonic acid methyl ester of the formula VIII to give the corresponding lactam salts. The reaction is preferably carried out at temperatures from 0 ° C. to room temperature under one

40 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 ethers, such as diethyl ether, dioxane, tetra-45 hydrofuran and 1,2-dimethoxyethane, and aromatic hydrocarbons, such as benzene, toluene and xylene. These reactions are explained by the following reaction scheme:

5

634557

(VI)

(Et) 3OBF4

(VII)

3 ~ «2"

(CH.

N

I.

n

OEt

©

"1 (III-2)

BF

©

J

(VI)

+ MeQSO F 2

Cvrii)

(CK2> n

(Ill-b)

©

0S02F

©

Me = CH ,; Et = C, H,

The reaction of the salts of the general formula III with alkali, preferably in a halogenated hydrocarbon as solvent, such as methylene dichloride or chloroform, gives the free bases of the general formula IX, which then according to the invention with the guanidine derivative of the general formula IV, preferably in an anhydrous lower aliphatic alcohol as solvent, such as methanol, isopropanol or tert-butanol, are converted into 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 a stoichiometric excess. The reaction is preferably carried out during the last stage at the reflux temperature of the reaction mixture. The implementation proceeds according to the following reaction scheme:

R,

H

(III)

—X

©

R-.

Q

NaOH

(CH2> n

(IV)

CH2C12

N

(IX)

Alkanol

"(CH) 2 n

H

NO

l "11

/ = N-C-NO

4R5

Tautomer v

R-

(CH 1 NO

* n II.

N-C-NO.R N H 4 a

(X)

634557

6

An alternative process for the preparation of the compounds of the general formula I starts from lactams of the general formula VI, which are reacted with dimethyl sulfate of the formula XI to give the corresponding methosulfates of the general formula III; see. H. Bredereck 5 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 salt of the general formula XII can now be reacted with a lower alkali alkoxide, preferably sodium methoxide or ethoxide, in the corresponding lower aliphatic alcohol as solvent,

among those of H. Bredereck u. Mitarb., Chem. Bert., Vol. 97 (1964), pp. 3081 to 3087, reaction conditions described, to the corresponding lactam acetals of the general formula XH-a. These lactam talals are then reacted according to the invention with the corresponding guanidine of the general formula IV to give the free bases of the general formula I. These reactions are explained by the following reaction scheme:

-ICH2 »n

> 0

n

I.

R-.

(VI)

(Me0) 2S02 (XI)

~ ©

n

I #. /

■ (ch2),

'N

I.

r,

OS03Me

(XII)

M

Alkali metal alkoxide r3

4CH2) n

(iv)

0-nieçlêr-aikyl Q-lower alkyl

>

(I)

(free base)

R,

Me = CH,

7

634557

The preparation of a wide variety of guanidine derivatives is 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 alkylthio compound of the general formula XXI by alkylation with the alkylating agent of the general formula R'X. The alkylthio compound is then reacted with the corresponding amine of the general formula HNR4R5, where R4 and R5 have the meaning given above, but R5 represents a phenyl or substituted phenyl group. The guanidine derivatives of the general formula XXII are obtained as salts 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 alkylamine, such as triethylamine. The reaction conditions are the same as those explained above for converting the thioureas of the general formula XVI into the alkylthio compounds of the general formula XVII and into the end products of the general formula I. The implementation is illustrated by the following reaction scheme:

s

(I

rnh-c-nh r'x

10th

15

20th

rn =

sr '

i

= c-nh.

'hx hnr4rt

7 »

(Tautoraer-)

(xx)

(XXI)

NR4R5

i "

rn = c-nh "hx 2

Alkali nr4r5

rn = c-nh "

(Tautomer)

(xxii)

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 based on the corresponding N, N'-diarylthioureas of the general formula

S

II

ArNHC — NHAr '

from, where Ar and Ar 'are phenyl or substituted phenyl groups. These compounds are reacted with ammonia to give the corresponding guanidines.

A further process for the preparation of guanidines of the general formula IV, in which R is preferably an alkyl, cycloalkyl, aralkyl or diphenylalk radical, a phenyl group or one substituted by a lower alkyl or alkoxy radical, a halogen atom or a nitro group.

(IV)

stituiei te phenyl group, 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 iso-55 cyanide dihalide of the general formula XXIII are successively substituted. The preparation of the isocyanide dihalide is described in Angew. Chemistry, boarding school 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 meaning 60 above, but R5 is not a phenyl or substituted phenyl group, in the presence of a tri-alkylamine, such as triethylamine, in an inert aprotic anhydrous solvents, such as diethyl ether, a halogenated hydrocarbon, or an aromatic carbon-65 hydrogen, converted to the corresponding monohalide of the general formula XXIV. Treatment of the reaction mixture with excess anhydrous ammonia and subsequent treatment with dilute AI

634557

8th

kali, for example a solution of an alkali metal hydroxide or carbonate, provides the corresponding guanidine of the general formula IV. This reaction is illustrated by the following reaction scheme:

Cl i

RN = C-Cl hnr4r5

Et3N

NR.R,

l 4 5

} RN = C-Cl + Et ^ N • HCl

(xxiii)

(XXIV)

nr4r,

rn = c-cl

NH3

alkali

(iv)

(xxiv)

Et = CA.

Another process for the preparation of the guanidines of the general formula IV, in which R represents a phenyl or substituted phenyl group, consists in reacting an aniline of the general formula XXV with a cyanamide of the general formula XXVI. It will be the 30th

Guanidine salt of the general formula XXII obtained; see.

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

HCl

R-NH-

nc-nr4r5

(XXIIj ATkal: L> (IV)

(xxv)

(xxvi)

Another process for the preparation of the guanidines of the general formula IV, in which R represents a phenyl or substituted phenyl group, follows the process described by W. Abraham and G. Barnikow, Tetrahedron, Vol. 29 (1973), pp. 691 and 699 the acidic hydrolysis of a 2-isothiocyanatoamidine of the general formula XXVII. These compounds are prepared by reacting the monohalide of the general formula XXIV with ammonium thiocyanate. The process is illustrated by the following reaction scheme:

40

45

NR / Rc

I 5

RN = C-Cl nh.scn 4

NR4R5 RN = C-NCS

H"

-> (xxii) + cos

HEIGHT

(xxiv) (xxvii)

Another process for the preparation of the guanidines of the general formula IV, in which R has the above meaning, follows that of H.G. Viehe & Z. Janousek, An-gew. Chemistry, boarding school Ed., Vol. 12 (1973), p. 806, in which a dichloromethylene ammonium salt of the general formula XXVIII, in which R4 and R5 have the above meaning, but the group NR4R5 is not a thiamorpholino-1-oxide group, is reacted with an amine of the general formula XXV to the monohalide of the general formula XVIII. This compound is then treated with excess ammonia and then with alkali in the manner described above. The corresponding guanidines of the general formula IV are obtained. This reaction is illustrated by the following reaction scheme:

9

634557

Cl NRjRs

I ©, 0 v I ■ NH3 Alkali RNH2 + Cl-C = NR4R5WC1 ^ -} RN = C-C1> (IV)

(XXV) (XXVIII) (XVIII)

The compounds of the general formula I and their salts with acids and quaternary ammonium salts are valuable medicinal substances which inhibit gastric juice secretion and lower the blood sugar level.

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 they are offered water. 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. Then the bag of tobacco 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 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 absorbing 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 15 milliequivalents / liter 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 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 also lower blood sugar, i.e. they have 25 hypoglycemic properties. This is demonstrated using the glu-cosetolerance 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 hy-poglycemic 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 35th attempt, but water is offered to them. After oral administration of 1 g glucose / kg body weight in 1 ml water, 0.1 ml blood from the tail vein without anesthesia-40 is obtained after 0 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, and 180 minutes taken from them. 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. Collaborator, "Ultra Micro Chemical Analysis of Blood Glucose with Glucose Oxidase" 45 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 50 l percent methyl cellulose solution. The control groups are given the same volume of carrier subcutaneously. The blood glucose values are expressed at all times in mg% (mg glucose / 100 ml blood). The mean glucose values of the control groups are statistically compared 55 after Student's t-test with the mean values of the test group at each corresponding time. If the compound to be tested significantly lowers blood glucose at all times with a confidence limit of 95%, the compound has hypogly-60 comatic activity.

Preparation I

A) N- (4-tolyl) -N (R4Rs) carboximidamide hydroiodide

65 A solution of 33.2 g (0.2 mol) of 4-tolylthiourea in 200 ml of acetone is mixed with 31.4 g (0.221 mol) of methyl iodide and heated under reflux for 3 hours. The solvent is then distilled off under reduced pressure

634557

10th

and the remaining 2-methyl-1- (4-tolyl) -2-thiopseudo-urea hydroiodide dissolved in 200 ml of tert-butanol. 0.4 mol of an amine of the formula NHR4R5 is added to the solution and the mixture is heated under reflux for 18 hours. The reaction mixture is then cooled and diluted with diethyl ether. The crystals formed are filtered off and recrystallized from a mixture of acetone and diethyl ether.

Treatment of the salt in methylene chloride with 10 to 2% sodium hydroxide solution provides the free base. B) N- (2,6-dichlorophenyl-N (R4R5) carboximidamide hydrochloride

A mixture of 14:52 g (0.04 mol) of N-2,6-dichlorophenylcarbamimidothiomethyl ester hydroiodide and 0.08 mol of anhydrous amine HNR4RB in 30 ml of tert-butanol is heated under reflux for 72 hours. The solvent is then distilled off under reduced pressure and the remaining non-crystalline hydroiodide in methylene chloride is released into the free mixture with cold 20 percent sodium hydroxide solution

5 base transferred. The methylene chloride solution is dried over potassium carbonate and evaporated. The residue is converted into the hydrochloride with a solution of hydrogen chloride in isopropanol.

io C) The above processes are repeated, but an equivalent amount of the corresponding methylthio-hydroiodide of the general formula XXI is reacted with the corresponding amine of the general formula NHR4R5 in the stated molar ratios.

NR4R5

RN = C-NH ,. HX

-NR4R5

HX

Molar ratio added F., ° C base

Ph

X)

3,4-CH2 V> Ph

-N ^ S

O

HBr

HJ

1: 1.1 Et3N

1: 2

203-205

171-172.5.

_p-n-C4H9-Ph p-OH-Ph

-NEt,

- <]

Fumarate 1: 2

HJ

1: 2

96-98

216-218

m-me. Ph p-Me-Ph

-N (Me) -Q

C.

Cyclamate 1: 1.06 Et3N

HJ

1: 2

170-172

166-168

m-Cl-Ph

2,6-diCl-Ph

-nj-0 - <]

base

HCl

1: 2

1: 2

143.5-145.5

292-295

Ph

/ - <-N ^ O

HJ

1: 2

175-177

Ph p-NOz-Ph

(Ph), CH

Ph

-O

O

/ —V

"Nv_ / °

-N (Me) - (J

HNO3 1: 2

HJ

base

HJ

1: 2

1: 2

1: 1.3 Et3N

139-141

240-242 (dec.)

122-124

149-152

11

634557

R

-NR4R5

HX

Molar ratio of base added

F., ° C

p-Me-Ph (Ph) 2CH exo-2-norbornyl

Ph

3,4-diMeO-Ph m-CF3-Ph

1-naphthyl

9-fluorenyl 1-naphthyl 2,6-diMe-Ph

4-PhCH20-Ph

3-OMe-Ph

4-OMe-Ph

4-OMe-Ph

4-SMe-Ph

4-NMe2Ph

4-NMe2Ph

_ÎQ

-a - <]

- * C °

- <i

-a

-N (Me) -Q -N (Me) - ^^

-NEt2

- «a -a

- «0

-O

K {Me) -Çy

N (H) -CH2- ^

0 n— /

-o -o

HJ

HJ

HJ

HJ

HCl

HJ

base

HJ

HJ

HJ

base

base

HJ

base

HCl

1: 2

1: 2

1: 2

1: 2

1: 2

1: 2

1: 2

Fumarate 1: 4

1: 2

1: 2

1: 2

Tosylate 1: 2.1

Fumarate 1: 2

1: 2

1: 2

I: 1.1

1: 2

166-168

205-206

160-163

198-199.5

181-184

221-222

Fumarate 1: 1.3 Et, N 150-153

132-133

208-210 (dec.)

247-249 (dec.)

209-211

191-192

187-190

187-189

120-122

134-135

Et3N (1) 174-175.5

(111) 117-119

206-207 (dec.)

634 557

12

-NR4R5

HX

Molar ratio added F., ° C base

Ph

Me

-Ah n

2 HJ

1: 2.4

266 (dec.)

3-pyridyl

O

base

1: 2.1

188-190

/ ° \

3,4-CH, Ph o

-N (Me) - £)

base

1: 2

121.5-123

4-Me-Ph

/ - \ -N, 0

HJ

1: 2

197-204

4-Me-Ph

/ —V

•O

base

1: 1.2 Et3N (1) 119-120

119-123

4-Me-Ph

-O

HOAc polymorph (133) 134-137

3-Me-Ph

3-OMe-Ph

-iT \ j

\ t

-N (Me) -Q

base

base

1: 1

1: 2.6

Et, N (1) 105

Et3N (2.6) 93-95

3-Me-Ph

HJ

1: 2

(160) 168-191

3-OMe-Ph

/ - \

HJ

1: 1.2

Et3N (1) (188) 189-192

D) The salts obtained in part C are converted into the corresponding free bases with alkali.

example 1

N- (2,6-Dimethylphenyl) -N '- (l-methyl-2-pyrrolidinylidene) - 1-pyrrolidinecarboximidamide fumarate

A solution of 3.47 g (0.035 mol) of anhydrous 1-methyl-2-pyrrolidinone in anhydrous methylene chloride is mixed 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-dimethylphenylene) -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 hot with a

Neutralized solution of fumaric acid in isopropanol. The title compound crystallizes on cooling. It is recrystallized from isopropanol and melts at 182 to 184 ° C with weak decomposition.

50

Example 2

Example 1 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 and with the base. The compounds of general formula I are obtained as a free base. Some of the bases are converted into salts.

60

65

(CH_)

n

NO

u

N - C - NO., R

4 5

No.

1

2nd

3rd

4th

5

6

7

8th

9

10th

11

12

13

14

IR

NR1R5

I] Ri

Molar ratio (Illb): (IV)

product

F., ° C

Ph Ph

1-naphthyl p-NO2-Ph

2,6-diCl-Ph Ph exo-2-norbornyl 3,4CH / '' XPh

"O

4-MePh

4-MePh

3-MePh

3-OMePh

3-MePh

3-OMePh

3-MePh

NHCH2Ph

N (Me) ^

c

- \ _ p

N (Me) 0

/ - \ -Nw °

- »Ts

\ /

- * r *

\ ~ j -N (Mg

-O

-O

-iOO w

»C

Me

Me

Me

Me

Me me

Me

Me

Me me

-CH, CH = CH,

-CH2CH = CH2

| Me

Me

Me

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 1.17: 1 1.17: 1 1.2: 1 1.2: 1 1.2: 1

HJ

Fumarate HJ 'Base Base

L - (+) - tartrate

Fumarate

Fumarate

HJ HJ HJ

Fumarate. l / 3 HzO

Fumarate

HJ

Fumarate

188-190

130-132

225-226

113-114.5

139-141.5 153-155

180-182

(161-4) 174 (dec.)

'190-191 (dec.) 166-168 (dec.) 158-160 (dec.) 120-122

(142-144) 148-151 185-186 161-164 (dec.)

634557

14

Example 3

N- (l-methyl-2-pyrrolidinylenid) -N '-phenyl-1-pyrrolidine-carboximidamide-L - (+) - tartrate

A mixture of 0.99 g (0.01 mol) of l-methyl-2-pyrrolidone in anhydrous benzene is heated under reflux and stirred and slowly added 1.26 g (0.01 mol) of dimethyl sulfate. 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 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, 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. The title compound of F. 153 to 156 ° C is obtained.

Example 4

N- (l-methyl-2-pyrrolidinylidene) -N'-phenyl-l-pyrrolidine-carboximidamide-L (+) - tartrate

A mixture of 1.29 g (0.0075 mol) of 2,2-diethoxy-1-methylpyrrolidine in anhydrous benzene is mixed with 1.42 g (0.0075 mol) of N-phenyl-1-pyrrolidinecarboximidamide and about 15 hours heated under reflux. 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 5

N- (l-Methyl-2-pyrrolidinylidene) -N'-phenyl-l-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;

io Pamoat, mp 253-256 ° C (dec.);

Nitrate, mp 170-171 ° C (weak decomposition);

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

15

Example 6

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) - 1-pyrrolidinecarboximidamidinium methofluorosulfonate A mixture of 6.83 g (0.02 mol) of N- (2.6 -Dichlorphe-

25 nyl) -N '- (l-methyl-2-pyrrolidinylidene) -l-pyrrolidine carboximide amide in anhydrous methylene chloride is treated with nitrogen as a protective gas and with stirring 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.

35

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

A solution of 0.05 mol of N- (l-methyl-2-pyrrolidinyli-den-N'-phenyl-l-pyrrolidinecarboximidamide in 30 ml of acetone 40 is mixed with 0.05 mol of methyl iodide. After 48 hours of reaction, the crystals formed are filtered off and recrystallized from acetone to give the title compound of mp (156) 162 to 164 ° C.

v

Claims (2)

634557 2 PATENT CLAIMS or one possibly through a lower alkyl radical, *1 (Xll-a) wherein R1; R2, R3 and n have the meanings already mentioned and X represents methoxy or ethoxy, in a 40 anhydrous organic solvent with a compound of the formula NO II 45 H2N — C — NR4R5 (IV) in which R, R4 and R5 have the meanings already given, and the compound of the formula I obtained is converted into an acid addition salt with an acid, if appropriate. 1 1. A process for the preparation of heterocyclic gua- a phenyl or benzyl group-substituted nitrogen-nidine derivatives of the general formula I contains a ring atom or (b) the ring is replaced by a lower one Alkyl radical is substituted on a carbon atom which is not immediately adjacent to the nitrogen atom which is bonded to the carboximidamide function, and R is a C4_10-alkyl radical, a C5_8-cycloalkyl radical, a C7_10-bicyclo- ^ alkyl radical, a C7_10-bicycloalkenyl radical, a C9_10-tricyclo-alkyl group, a 1-adamantylmethyl group, a C9.10-tri-10 cycloalkenyl group, a phenyl-C 1-4 alkyl or naphthyl-C 1-4 alkyl group, an a, a-tetramethylene-phenethyl group, a diphenyl-C ^ -alkyl radical, an a- or β-naphthyl group, a condensed diarylcycloalkenyl radical, a condensed and their acid addition salts, in which n has the value 1, 2 or dense arylcycloalkyl radical, a phenyl-C5_7-cycloalkyl-3, Rx is a hydrogen atom , a C 1-6 alkyl, C3_6-cyclo-15 radical, a Cg-7-cycloalkyl-C5_7-cycloalkyl radical, a phenyl-alkyl-, C, _s-alkene-2-yl, lower hydroxyalkyl, aralkyl or Methylenedioxyphenyl group, one through halogen atoms, or aryl radical, R2 is a hydrogen atom, a C 1-4 alkyl radical lower alkyl or alkoxy radicals mono-, di- or trisubstituted or an aryl radical, R3 is a hydrogen atom, a C 1-4 -aluated phenyl group, one substituted by an amino, dimethyl alkyl radical or an aryl radical, R4 is a hydrogen atom, an amino, methylethylamino, diethylamino or lower alkane Methyl or ethyl group and R5 is a CM-alkyl radical, a 20-oylamino, thio-lower-alkyl, sulfinyl-lower-alkyl, sulfo-C3_7-cycloalkyl radical, an aralkyl radical or an aryl radical nyl-lower-alkyl, trifluoromethyl, Hydroxyl, benzyloxy, mean, or R4 and R5 together with the nitrogen-lower alkanoyloxy, lower alkanoyl or nitro group atom to which they are attached form a 3- to 7-membered substituted phenyl group, a 3-pyridyl or a by saturated heterocyclic ring , wherein a 6-membered halogen atom, lower alkyl or alkoxy radicals mono- or ring (a) or an oxygen or sulfur ring atom means 25 disubstituted 3-pyridyl group, or a 5-membered heterocyclic radical, characterized in that a free base of formula 4CH2) n lo-lower alkyl \ q-lower alkyl 2. Use of the heterocyclic guanidine derivatives of the formula I 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 55.