CH632994A5 - Process for preparing guanidine derivatives - Google Patents

Description

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

30 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 unsub-35 substituted on the amino nitrogen atom of the guanidine residue.

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

The process according to the invention for the preparation of heterocyclic guanidine derivatives of the general formula 40 I

No

I!

r-

- (cnj

2 n

45

L

n-

-N

re

(I)

so 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 radical, a C 1-4 cycloalkyl radical, preferably a cyclopentyl or cyclohexyl group, a Cj_5-alkene-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

Alkyl radical or an aryl radical, preferably a phenyl group, R3 is a hydrogen atom, a C 1-6 alkyl radical 60 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 or a C3-7 - Cycloalkyl, preferably a cyclopentyl or cyclohexyl group, 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 a Oxygen or sulfur ring atom or an optionally by a lower alkyl radical, a phenyl or

632 994

Benzyl group substituted nitrogen ring atom contains 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, in particular an aziridinyl, azetidinyl, pyrrolidinyl -, Piperidino-, 2,3,4,5,6,7-hexa-hydroazepinyl-, morpholino-, thiamorpholino-, thiamorphopholino-l-oxide-, thiamorpholino-1,1-dioxide or 2,6-di -Lower 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-nie-der -alkylpiperazinyl group, preferably a 2,6-dimethyl-piperazinyl group, and R is a C4_I0-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 C7_10 bicycloalkyl, 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 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 -Octa-hydro-4,7-methanoindanyl) group, a 1-adamantyl-methyl group, a C9_10-tricycloalkenyl group, such as a 3- (2,3,6,6a-tetrahydro-lH-l, 3a-ethanopentalenyl) - or 5- (3a, 4,5,6,7,7a-hexahydro-4,7-methanoindenyl) group, a phenyl-CN4-alkyl or naphthyl-CM-alkyl radical, such as a benzyl, d- or 1 -a-phenethyl, a, a-dimethylbenzyl, a, a-dimethyl-ß-phenethyl, d- or l- (a-naphthyl) ethyl group, an a, a-tetramethylenephenethyl group, a diphenyl -C ^ alkyl radical, such as a diphenylmethyl or 2,2-diphenylethyl group, an a- or β-naphthyl group, a condensed diarylcycloalkenyl radical, such as a 9-fluorenyl or 5-azenaphthyl group, a condensed arylcycloalkyl radical such as a 4- (2,3-dihydro-1H-indenyl) -, 1- (1,2,3,4-tetrahydronaphthyl) - or 7-bicyclo [4.2.0] octa-1,3,5-trie -nyl) group, a phenyl-C5_7-cycloalkyl radical, such as a cis or trans-2-phenylcyclopentyl, eis or trans-2-phenyl-cyclohexyl or eis or trans-2-phenylcycloheptyl group, a C ^ - Cycloalkyl-C ^ -cycloalkyl radical, such as a cis or trans-2-cyclohexylcyclopentyl or cis or trans-2-cyclopentylcyclopentyl group, a phenyl or methylenedioxyphenyl group, a mono-, di- by halogen atoms, lower alkyl or alkoxy radicals or trisubstituted phenyl group, 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 nitro group substituted phenyl group, a 3-pyridyl group or a 3-pyridyl group mono- or disubstituted by halogen atoms, lower alkyl or alkoxy groups, 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 one 5-membered heterocyclic radical, such as a 2-furyl or 2-thienyl group, is characterized in that a compound of the general formula XVII

HZ

(XVII)

in which R 'represents an ethyl or methyl group and HZ represents an acid and Rls R2, R3 and n have the above meanings, with an amine of the general formula s HNR4R5

in which R4 and R5 have the above meanings, reacted in a lower aliphatic alcohol at the reflux temperature and the salt obtained of the compound of the general formula I is converted into the free base and, if appropriate, the compounds obtained are converted into the pharmaceutically acceptable acid addition salts thereof.

The term “lower” means that the corresponding group preferably contains 1 to 4 carbon atoms. Fluorine, chlorine, bromine and iodine atoms are usually suitable as 15 halogen 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 -, amber, maleic, fumaric, apple, wine, lemon, Ben-30 zoe, cinnamon, almond, methane sulfone, ethane sulfone, benzene sulfone, p-toluenesulfone, cyclohexane sulfamine , Salicylic and p-aminosalicylic 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- Methyl toluenesulfonate and methyl fluorosulfonate. The quaterization can be carried out in the presence or absence of a solvent at room temperature or under 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 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

55

R11 RIO '

- (CH2) n nro

■ N-C-N

"R-

48

(II)

and preferred their salts with acids and quaternary ammonium salts. In this formula, n is 1 or 2, R6 is a lower alkyl or hydroxyalkyl radical, an alkyl or benzyl group, R7 is a methyl or ethyl group, R8 is a Q- to C4-alkyl radical, a cyclopentyl or cyclo-

632994

hexyl group or R7 and Rs together with the nitrogen atom to which they are attached, a pyrrolidino, piperidino-no, morpholino or thiamorpholino group, R9 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, cyclo-hexyl, diphenylmethyl, naphthyl or 9-fluorenyl group, R10 is a hydrogen atom or a C1_3-alkyl radical and Rtl is a hydrogen atom or a CI_3 -Alkylrest, wherein at least one of the radicals RI0 to Rlt represents a hydrogen atom.

Starting materials of formula XVII are obtained e.g. from a 2-imino compound of the general formula given below, in which n, Rls R2 and R3 have the meaning given above. Most of these 2-imino compounds are known or can be prepared by the process described in CAPS 950 464, for example in accordance with Example 14 of this PS. These 2-imino compounds are preferably treated with an isothiocyanate of the general formula XV, in which R has the meaning given above and preferably does not represent a 9-fluorenyl group, in an inert organic solvent, such as benzene, methylene chloride or chloroform, at temperatures of 0 to room temperature in about 2 to 24 hours in approximately equimolar amounts. Then, in general, the thio group in the thio-ureas of the general formula XVI obtained, several of which are described in US Pat. No. 3,717,648, by reacting the compounds of the general formula XVI with an alkylating agent of the general formula R'X, in the R 'represents an ethyl or preferably methyl group

R

R.

- (CH2> n and X denotes a tosylate, methosulfate, methanesulfonate, fluorosulfonate or preferably an iodide ion, is converted into an alkylthio group (-SR '). The reaction is preferably carried out in a solvent. Examples s of usable solvents are ethers, preferably diethyl ether, tetrahydrofuran or dioxane, lower ketones, such as acetone or 2-butanone, halogenated hydrocarbons and lower aliphatic alcohols, preferably methylene dichloride and methanol.

io Methyl iodide is particularly suitable as an alkylating agent in methanol. In general, the alkylating agent is used in at least an equimolar amount. The amount normally depends on the reactivity of the thiourea of the general formula XVI or its solubility in the solvent used. The alkylation reaction can be carried out at room temperature or at higher temperatures in a closed reaction vessel. The alkylthio compounds of the general formula XVII are then reacted in the form of their salts with a 20 acid (HX), preferably at temperatures from room temperature to the reflux temperature or in a closed reaction vessel at higher temperatures with an amine of the general formula HNR4RS, in which R4 and R5 are the have the meaning given above. 25 The reaction is carried out in a lower aliphatic alcohol, such as isopropanol or tert-butanol, and at the reflux temperature of the reaction mixture. The guanidine derivatives of the general formula I are obtained in the form of their salts, which are converted into the corresponding free bases with alkali 30. This process can be illustrated by the following reaction scheme:

N

I.

'R-NCS,

(XV)

R-

• (CH2} n

N

I.

Marg

■ VER

(XIV)

(xvi)

R'X y

* HX-

hsr4r5

* 3 "

! II

N * *

I.

(I). salt

(xvii)

Alkali ■ hx ->

Rh

-V

- (ch) 2 n

■ N

i r

1

(I)

No

I!

-nr r 4 s

5

632 994

The isothiocyanates of the general formula XV, of which numerous compounds are known, can be prepared in a manner known per se.

When the compounds of the general formula XVII are reacted with the amine of the general formula HNR4R5, the amine is preferably used in excess over the stoichiometric amount, for example in a molar ratio of 1: 1.05 to 1: 2.0. If only a small excess of the amine is used, it may be expedient to add a stoichiometrically equivalent amount of a tertiary alkylamine, such as triethylamine, in order to increase the reaction rate. By-products, for example of the general formula, can form during the reaction

H2N-

-nr4r hx or r.

R '

(CB2> n

J = NR ^ 5 N "

i ©

x

0

form. These compounds can be separated from the compounds of the general formula I by fractional recrystallization.

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. 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. 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. 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 65 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 in order 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 / 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 titrable 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 generally also lower the blood sugar level, 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.

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, 0.1 ml of blood is withdrawn from the tail vein without anesthesia after 0 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes and 180 minutes. Blood samples are immediately deproteinized with aqueous solutions of barium hydroxide and zinc sulfate, and glucose levels are measured using the L.P. Cawley et al. Collaborator, “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. The blood glucose values are printed out at all times in mg% (mg glucose / 100 ml blood). The mean glucose values of the control groups are statistically based on Student's t-test with the mean values of Ver25

30th

35

40

45

50

55

632 994

6

search group compared at each corresponding time. If the compound to be tested significantly reduces blood glucose at all times with a confidence limit of 95%, the compound has hypoglycemic activity.

Exemplary embodiments Example 1

A) N- (1-methyl-2-pyrrolidinylidene) -N'-phenylthiourea A suspension of 6.73 g (0.05 mol) of 2-imino-l-me-

thyl-pyrrolidine hydrochloride in benzene is mixed with stirring with 5 ml of 50 percent sodium hydroxide solution. After stirring for 2 minutes, the benzene solution is decanted onto anhydrous potassium carbonate and the aqueous phase is extracted twice with fresh benzene. The benzene extracts are combined and, after drying, are quickly filtered through a bed of diatomaceous earth with as little air access as possible. 6.76 g (0.05 mol) of phenyl isothio-cyanate are rapidly added to the filtrate. After stirring for 3 hours, the solid obtained is filtered off. A further amount of the title compound is obtained from the mother liquor. After crystallization from ethyl acetate, the compound melts at 142 to 143.5 ° C.

B) N- (l-Methyl-2-pyrrolidinylidene) -N'-phenylcarbamimidothiomethyl ester hydroiodide

A solution of 34.86 g (0.15 mol) of the compound obtained in (A) in 500 ml of acetone is mixed with a solution of 21.3 g (0.15 mol) of methyl iodide in acetone. The solution is refluxed for 30 minutes and left at room temperature for an additional hour. When cooling in an ice bath, crystallization takes place. The crystals are filtered off and recrystallized from a mixture of methanol and isopropanol. The title compound of F. 145 to 147 ° C is obtained.

C) The reaction of the compound obtained in (A) in a lower aliphatic alcohol, acetone or a lower halogenated hydrocarbon with methyl p-toluenesulfonic acid, dimethyl sulfate, methyl fluorosulfonate, trimethyloxonium fluoroborate or methanesulfonic acid methyl ester gives the methylthio compound (B) as the corresponding salt.

D) N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidine-carboximidamide hydroiodide (I)

A solution of 15.02 g (0.04 mol) of the compound obtained in (B) and 4.31 g (0.06 mol) of 99 percent pyrrolidine in 100 ml of isopropanol is heated under reflux for 24 hours. When cooling in an ice bath, crystallization takes place. The crystals are filtered off and the mother liquor is saved; see. Example 26. The crystals are recrystallized from isopropanol and a mixture of methanol and diethyl ether. The title compound of F. 206 to 208 ° C is obtained.

Preparation A

The following salts of the 2-imino compounds of the general formula XIV are prepared by the process described in CA-PS 950 464:

a. 2-imino-l-methyl-5-phenylpyrrolidine fluoborate, mp 128-131 ° C;

b. 2-imino-l-methylpyrrolidine fluoborate, mp 109-111 ° C;

c. 2-imino-l-ethylpyrrolidine hydrochloride, mp 181-185 ° C;

d. 2-imino-l-n-butylpyrrolidine cyclohexane sulfamate, mp 110-114.5 ° C;

e. 2-imino-l-benzylpyrrolidine fluoborate, mp 112-114 ° C;

f. 2-imino-l, 5-dimethylpyrrolidine fluoborate, mp 100-102 ° C;

G. 2-imino-l-methylpiperidine hydrochloride;

H. Hxahydro-2-imino-1-methyl-1 H-azepine-cyclohexansulfate, m.p. 143-145 = C;

i. 1-hydroxyethyl-2-iminopyrrolidine-cyclohexanesulfamate,

M. 105-108 ° C.

These salts are converted into the free bases by treatment with 50 percent sodium hydroxide solution according to Example 1-A.

Preparation B

According to the by J. C. Jochims and A. Seeliger, Angew. Chemistry, boarding school Ed., Vol. 6 (1967), p. 174, the following isothiocyanates are prepared:

a. 1- and 2- (2,3,3a, 4,5,6,7,7a-octahydro-4,7-methanoin-danyl) isothiocyanate;

b. 1,1-dimethylphenethyl isothiocyanate;

c. 1-a-phenethyl isothiocyanate;

d. d-a-phenethyl isothiocyanate;

e. 1-benzylcyclopentyl isothiocyanate;

f. 7- (bicyclo [4.2.0] octa-l, 3,5-trienyl) isothiocyanate;

G. 1-adamantyl methyl isothiocyanate;

H. 2-adamantyl isothiocyanate;

i. trans-2-phenylcyclopentyl isothiocyanate; j. cis-2-phenylcyclopentyl isothiocyanate;

k. trans-2-cyclohexylcyclopentyl isothiocyanate; 1. cis-2-cyclohexylcyclopentyl isothiocyanate and m. cis-2-phenylcycloheptyl isothiocyanate.

Preparation C

According to Example 1-A, but using an equivalent amount of the 2-imino compound obtained in preparation A, the following thioureas of the general formula XVI are obtained in the reaction with an equivalent amount of the corresponding isothiocyanate:

a. N-2- (hexahydro-1H-1-methyl-azapinylidene-N'-phenyl-thiourea, mp 157-159 ° C;

b. N-1-methyl-2-pyrrolidinylidene-N'-diphenyimethylthio-urea, mp 112-114 ° C (polymorphic), 119-120 ° C;

c. N-1-methyl-2-pyrrolidinylidene-N'-p-nitrophenylthio-urea, mp 179-180.5 ° C (dec.);

d. N-1-methyl-5-phenyl-2-pyrrolidinylidene-N'-phenylthio-urea, mp 135-140 ° C;

e. N-1-methyl-2-pyrrolidinylidene-N'-p-fluorophenylthio-urea, mp 152-154 ° C;

f. N-1-methyl-2-pyrrolidinylidene-N'-benzylthiourea, F.

(71) 74-81 ° C;

G. N-1-methyl-2-pyrrolidinylidene-N'-2-naphthylthiourea, mp 159-162 ° C (dec.);

H. N-1-methyl-2-pyrrolidinylidene-N'-cyclohexylthiourea, mp 88-93 ° C;

i. N-1-methyl-2-pyrrolidinylidene-N'-p-methoxyphenylthio-

urea, m.p. (149) 150-152 ° C (dec.); j. N-1-methyl-2-pyrrolidinylidene-N'-p-chlorophenylthio-

urstolf, mp 154-156 ° C (dec.); k. N-1-methyl-2-pyrrolidinylidene-N'-2,6-dimethylphenyl-

thiourea, m.p. (164) 165-168 ° C; 1. N-1-methyl-2-pyrrolidinylidene-N'-1, 1,3,3-tetramethyl-

butylthiourea, F. 115-116.5 ° C; m. N-l-methyl-2-pyrrolidinylidene-N'-l-adamantyIthio-

urea, mp 150-152 ° C; n. N-1-ethyl-2-pyrrolidinylidene-N'-phenylthiourea, mp 158 ° C;

o. N-1-ethyl-2-pyrrolidinylidene-N'-p-methoxyphenylthio-

urea, mp 128-130 ° C and p. N-1-methyl-2-piperidinylidene-N'-phenylthiourea, mp 132-134 ° C.

Preparation D

According to Example 1-B, but using the solvents listed below, the pre-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

632 994

C thioureas listed in the corresponding methylthiohydroiodides of the general formula XVII converted.

S-CH, • HJ

Product of

Formula I.

F., "C

Thiourea from Example 4

Solvent s-CH3 • HJ, F., ° C 5

a b c d e f g h i m n o P

ch2c12

acetone

CH3OH

CH3OH

CH3OH / acetone

Acetone ch2c12

ch2c12

ch2c12

ch2c12

ch2ci2

CH30H

CH30H

ch2c12

acetone

acetone

157-159

122-123

150-152 104-105

123-125 Glass

(Oil)

124-125 165-168 189-192 (dec.) (Oil)

145-148 117-119 (oil)

164-165

Example 2

Example 1-D is repeated, but the corresponding methylthio-hydroiodides from Example 1-B and preparation D and the corresponding amines of the general formula HNR4R5 in a molar ratio of 1: 1.5 to 1: 3 in refluxing isopropanol or preferably tert-butanol converted to the corresponding compounds of general formula I in the form of the hydroiodides. The hydroiodides are isolated as such or converted into the free bases with aqueous alkali or converted into another salt by reacting the free base with the specified acid. The guanidines of the general formula IV can be formed as by-products and isolated from the reaction mixture, for example by fractional crystallization, as free bases or as salts of an acid. The abbreviations used below have the following meanings:

Me = CH3; Ph = C6H5; Et = C2H5; Bu = C4H9.

30th

Example 1-B Example 1-B Example 1-B Example 1-B

Example 1-B Example 1-B

2o Example 1-B Example 1-B

Example 5-a

Example 5-b Example 5-d Example 5-e Example 5-f

-O

-NH ~ Q -N ^ N-Ph

-N ^ O

-nh- £)

-N ^ N-Me Me

- * Q

i-le me

NH - \

Me

- <]

Example 5-g 35 Example 5-h Example 5-i Example 5-j Example 5-1 Example 5-m ■ to Example 5-n Example 5-o Example 5-p Example 5-p Example 5-h Base hj

Base hj hj 2hj hj hj hj hj hj hj hj hj hj hcio4

hj hj hj hj

193-200

186-188.5

131-133

(163-164) 171-173

82-84

161-161.5

(193)

197-199 (dec.)

269-270 (dec.)

192-193

218-220

201-203

190-192

(165)

167-171

187-189

203-204

142-144

183-185

154-155

171-173

142-143

164-166

151-153

r

R,

r2

R3

p-nC4H9Ph

Me

H

H

m-CF3Ph

Me

H

H

-CHPh2

Me

H

H

Ph

Me

H

H

p-MePh

Me

H

H

3.4CH ,. Ph

Me

H

H

m-ClPh

Me

H

H

m-MePh

Me

H

H

3,4- (OMe) 2Ph

Me

H

H

4-PhCH20-Ph

Me

H

H

3-OMePh

Me

H

H

NR4R5

product

F., ° C

-NEt2

. -N (Me) "/ I

~ ir \>

-N (Me) / ~ |

3rd

-O

-N (Mc) Q

'"h v_.

O

-N -N

Fumarate Fumarate L - (+) - Tartrate hj

Fumarate hj

Fumarate

Fumarate

Phosphate HC104

HNO3

163-165

(135-137) 139-141

146-148.5

(120) 128.5-130

176-178

144-146

177.5-179.5

133-136

201-204 (dec.)

(151) 152-154

104-109

632 994

8th

R

NR4RS

r *

product

F., ° C

4-OMePh

Me

H

H

4-SMePh

Me

H

H

4-NMe2Ph

Me

H

H

Ph

Me

H

H

3-pyridyl

Me

H

H

Ph

n-C8HI7

H

H

3-C (0) CH3Ph

Me

H

H

O

1

■ n (me> <^)

-O

Ph

1-naphthyl p-NO2-Ph

2,6-diCl-Ph Ph exo-2-norbornyl

3.4C {h ^ '

4-MePh ^^

4-MePh

3-MePh

3-OMePh

3-MePh

3-OMePh

3-MePh

N

■ a

- \ _ p

/ - \ "Nv_y °

-N 'S \ /

-O

-N (MeHQ

-o -o

-A

- Me NH-

l ~ me r ~~ \

~ N 0 * \ _ /

h -n

- «n

Me

Me

Me

Me me

Me

Me

Me

Me

-ch2ch = ch2 -ch2ch = ch2

Me Me Me

Fumarate HJ HJ 2HJ

1,5-fumarate tartrate

Pamoat HJ HJ Base Base

L - (+) - tartrate

Fumarate

Fumarate

HJ

HJ

HJ

Fumarate ■ Vz HzO

Fumarate

HJ

Fumarate

179-180.5 142-144 171-172 269-270 (dec.)

138-139.5

01

158-164 (dec.) 188-190 225-226 113-114.5

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.)

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) -1-pyrrolidinecarboximidamidinium methofluorosulfonate A mixture of 6.83 g (0.02 mol) of N- (2,6- Dichlorophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide 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. 148-150 ° C is obtained.

so 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 (Example 1-D) in 30 ml of acetone is mixed with 0.05 mol of methyl iodide. After 55 hours, 48 hours The resulting crystals are filtered off and recrystallized from acetone to give the title compound of mp (156) 162-164 ° C.

c) The reaction of 0.05 mol of the compound from Example 1-D in anhydrous diethyl ether with 0.05 mol of 6o 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 135.5-137 ° C.

65 Example 4

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, m.p. (106) 207-109 ° C;

Oxalate, mp 129-131 ° C;

Pamoat, m.p. 153-156 ° C (dec.);

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

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

The following examples illustrate substituent conversions, always within the scope of the compounds of the formula I.

Example 5

N- (4-aminophenyl) -N '- (l-methyl-l-pyrrolidinylidene) -l-pyr-rolidinecarboximidamide hydrobromide

2.46 g (0.0078 mol) of N- (l-methyl-2-pyrrolidinylidene) -N '- (4-nitrophenyl) -l-pyrrolidinecarboximidamide in 50 ml of anhydrous ethanol are in the presence of Raney nickel at about 3 at Hydrogen pressure hydrogenated. The 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 mp 241-241.5 ° C is obtained.

Example 6

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

3.4 g (0.0119 mol) of N- (4-aminophenyl-N '- (l-methyl-2-pyrrolidinylidene) -l-pyrrolidinecarboximidamide (the product of Example 5) are mixed with 25 ml of acetic anhydride for about 1 hour The reaction mixture is then 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. An oil remains, which is converted into the corresponding hydrobromide in a mixture of diethyl ether and ethanol with hydrogen bromide After recrystallization from a mixture of ethanol and diethyl ether, the title compound melts at 246 to 247 ° C.

Example 7

N- (1-Methyl-2-pyrrolidinylidene) -N '- (4-methylsulfonylphenyl) -4-morpholine carboximidamide

A solution of 1.98 g (0.0006 mol) of N- (4-methylthio-phenyl) -N '- (l-methyl-2-pyrrolidinylidene) -4-morpholine carboximidamide in anhydrous methylene chloride is at 0 ° C under 3.6 g (0.018 mol) of m-chloroperbenzoic acid were added while stirring. The temperature should not rise above 5 ° C. The mixture is then stirred at this temperature for 30 minutes 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 methanol. Insoluble substances are filtered off and discarded. The filtrate is almost on a steam bath

632 994

evaporated to dryness. The residue is diluted with diethyl ether. The resulting crystals (F.

160-166 ° C) are recrystallized from diethyl ether. The pure title compound of F. (165) 167-170 ° C is obtained.

Example 8

N- (l-Methyl-2-pyrrolidinylidene) -N '- (4-methylsulfinylphenyl) -4-morpholine carboximidamide

A solution of 1.98 g (0.006 mol) of N- (4-methylthio-phenyl) -N '- (l-methyl-2-pyrrolidinylidene) -4-morpholine carboximidamide in methylene chloride is at 5 ° C with 1.22 g (0.006 mol) of m-chloroperbenzoic acid are added. The temperature should not rise above 5 ° C. The reaction mixture is then 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 30 ml of saturated sodium chloride solution and dried over anhydrous potassium carbonate. 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. The pure title compound of F. (115) 117-120 ° C. is obtained.

Example 9

N- (4-Hydroxyphenyl) -N '- (l-methyl-2-pyrrolidinylidene) -l-pyrrolidinecarboximidamide hydroiodide

A solution of 26.6 g (0.072 mol) of N- (l-methyl-2-pyrrolidinylidene) -4 '- (4-benzyloxyphenyl) -2-pyrrolidinecarboximidamide in 50 ml of acetic acid is in the presence of 10% palladium hydrogenated on carbon for about 2 hours at 3 at 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 174-178 ° C.

Example 10

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

A solution of 5.15 g (0.0124 mol) of N- (4-hydroxyphenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide and 41.2 g (0 , 20 mol) N, N'-di-cyclohexylcarbodiimide in 400 ml acetone is slowly mixed with 12 g (0.20 mol) glacial acetic acid. The mixture is stirred for 72 hours at room temperature under nitrogen as a protective gas. The crystallized N, N'-dicyclo-hexylurea 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) 195-197 ° C. are obtained. After further recrystallization from a mixture of methanol, acetone and diethyl ether, the pure title compound is obtained in white crystals of mp 196-199 ° C.

According to the method according to the invention, e.g. produce the following compounds (Me = methyl; Et = ethyl; Ph = phenyl):

9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

632994

10th

Compounds of formula I.

R

Ri

R,

R3

no "r5

product

F., ° C

-CHPh2

Ph

Ph

1-naphthyl

Ph

Ph

Ph

Ph

Ph

Ph

1-naphthyl

9-fluorenyl

Ph

Ph

Ph

Me Me Me Me Ph Me

-O

-CH2Ph

-ch2ch2oh

Me

Me

Me

-ch2ch = ch2

Me me

H

Me

H

H

H

H

H

H

H

Ph

H

H

H

H

n-C4.II 5

H H Ph H H H H H H H H H H

n-C8H17 H

'<] - «□ ■ <]

-NJ

-N'J-

-NEt2

-N Y

"Nv_y ° -N .0

-NEt2 - <]

-O

-'C °

-o hj hj hj hj hj hj

Saccharinate

Fumarate

base

Fumarate

Fumarate hj hcio4

Tosylat hj

218-220

158-160

215-217

185-187

193.5-194.5

155-157

165-166.5

208-210

128-130

(220) 224-226

187-189

230-232 (dec.)

105.5-107

(130) 133-135

130-131

s

Claims (2)

632 994 2nd PATENT CLAIMS 1. Process for the preparation of heterocyclic guanidine derivatives of the general formula I . (OUÌ NO (IJ and the pharmaceutically acceptable acid addition salts thereof, in which n is 1, 2 or 3, Rt is a hydrogen atom, a C 1-6 alkyl, C 1- 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 C 1-4 alkyl radical or one C3_7-cyclo-alkyl 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 attached to the carboximidamide radio tion, and R is a C4-C10-alkyl radical, a C 1-6 -cycloalkyl radical, a C7_10-bicycloalkyl radical, a C 7_10-bicycloalkenyl radical, a C9_10-tricycloalkyl radical, a 1-adamantylmethyl group, a C9_I0-tricycloalkenyl group, a Phenyl-C ^ -alkyl or naphthyl-C ^ -alkyl radical, an a, a-tetramethylene-phenethyl group, a diphenyl-C ^ -alkyl radical, an a- or β-naphthyl group, a condensed diarylcycloalkenyl radical, a condensed arylcycloalkyl radical, a phenyl-C5_7-cycloalkyl radical, a C ^ -cycloalkyl-C ^ -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, di-ethylamino, lower alkanoylamino, thio lower alkyl, sulfinyl lower alkyl, sulfonyl lower alkyl, trifluoromethyl, hydroxyl, benzyloxy, lower Alkanoyloxy, lower alkanoyl or nitro group substituted phenyl group, is a 3-pyridyl 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 : N-C = NO HZ HNR4R5 in which R4 and R5 have the above meanings, reacted in a lower aliphatic alcohol at the reflux temperature and the salt of the compound of the general formula I obtained is converted into the free base and, if appropriate, the compounds obtained are converted into the pharmaceutically acceptable acid addition salts thereof. 2. Use of the heterocyclic guanidine derivatives of the general formula I 15 (XVII) in which R 'represents an ethyl or methyl group and HZ represents an acid and Rls R2, R3 and n have the above meanings, with an amine of the general formula (I) 20 wherein the substituents are defined in claim 1, for the preparation of quaternary salts thereof, characterized in that these compounds are quaternized with an alkylating agent. 25th