DE3512084A1 - Guanidine derivatives, processes for their preparation and medicaments containing these compounds - Google Patents

Abstract

Novel guanidine derivatives of the general formula <IMAGE> are described which, as a result of their agonistic action on H2 receptors and partly their additional H1-antagonistic receptor activity, can be employed in disorders of the heart, in certain forms of hypertension and in arterial occlusive diseases.

Description

DESCRIPTION

The invention relates to new guanidine derivatives due to their agonistic effects on H2 receptors as well as in part because of their additional ones H1-antagonistic receptor activity in diseases of the heart, in certain Forms of hypertension as well as arterial occlusive diseases are used can.

Histamine as a specific stimulator of the H2 receptors triggers because of its H1 agonistic effect negative, sometimes fatal effects in the form of a Bronchospasm and anaphylactic shock, so that therapeutic use of histamine is not possible in the treatment of the diseases mentioned.

The invention is therefore based on the object, the disadvantageous To compensate for the effects of histamine and create better and more selectively more effective H2 agonists to provide those in which the harmful side effects are caused by an H1 agonist Active component - possibly

by an additional H1-antagonistic profile of action - avoided can be.

This object is achieved by the invention.

The invention therefore relates to new guanidine derivatives of the general formula I in the R the grouping denotes, where R1 and R2, which can be the same or different, each represent hydrogen, linear C1-C10-alkyl or C5-C6-cycloalkyl, or R1 and R2 together with the nitrogen atom to which they are bonded represent a 5- to Form a 10-membered nitrogen-containing alicyclic heterocyclic ring, R3 represents a hydrogen atom, a halogen atom or a lower alkoxy group, A represents the grouping -0- (CH2) k-, -O-CH2CH (OH) CH2-, -O-CH2-CH (CH3) -CH2-, -CH2-O-CH2-CH (OH) -CH2 or -O-CH2-CH (OH) -CH (OH) -CH2- denotes, in which k has the value 3 or 4, or in which R the grouping or where R4 is a hydrogen atom, a halogen atom bonded preferably in the para position to A, a lower alkoxy or lower alkyl group and A has the meaning given above, or in which R is the grouping where R5 and R6, which can be identical or different, each represent a hydrogen atom, a halogen atom or a linear lower alkyl or a linear lower alkoxy group, B denotes the grouping or - (CH2) m-, where 1 has the value 3 or 4 and m has the value 3, 4 or 5 and Y stands for a linear lower alkyl group, or in which R is the group means where R7 represents the group (R1R2) N-CH-, (HN) C = N-, where R1 and R2 are as defined above, D is the grouping CH2-S- (CH2) n- or - (CH2) o-, where n is 2 or 3 and o is 2, 3 or 4 have, or in the R the grouping where R8 is a hydrogen atom, a benzyl group optionally substituted by a halogen atom, the grouping (R1R2) N-CH2- or an amino group, where R1 and R2 are as defined above, R9 is a hydrogen atom, a linear lower alkyl or thio-lower alkyl group means, E for the groupings -CH2-S- (CH2) n-, or stands, where n has the value 2 or 3 and Y has the abovementioned meaning, or in which R is the grouping where Z is a hydrogen atom or a linear lower alkyl group and E is as defined above, X is a hydrogen atom or a benzoyl group, p is 2 or 3 and R 'is a hydrogen atom or a methyl group, and their physiologically acceptable salts .

In a preferred group of compounds according to the invention, R represents the grouping where the substituents R1 / NCH2 and R ', the same or can be different, in each case a hydrogen atom, a linear Cl-Cl0-alkyl group, preferably a linear C1-C6-alkyl group, very particularly preferably a linear C1-C3-alkyl group, for example a methyl, ethyl or n-propyl group, especially a methyl group. However, R1 and R2, together with the nitrogen atom to which they are bonded, can also form a 5- to 10-membered nitrogen-containing alicyclic, heterocyclic ring. Preferred examples of the 5- to 10-membered heterocyclic ring thus defined are the pyrrolidine, piperidine and homopiperidine ring. R3 represents a hydrogen atom or a halogen atom, for example a bromine or chlorine atom, preferably a chlorine atom which is in the ortho, meta or para position, preferably in the ortho position, to the (R1R2) N — CH2 group is bound. R3 can also be a lower alkoxy group, for example a methoxy, ethoxy or propoxy group, preferably a methoxy group, which is also bonded in the ortho, meta or para position, preferably in the para position, to the (R1R2) N-CH2 group it's his. A means one of the following groupings: -O (CH2) k-, -0-CH2CH (OH) CH2, -O-CH2-CH (CH3) -CH2-, -CH2-O-CH2-CH (OH) -CH2 - or -O-CH2-CH (OH) -CH (OH) -CH2-. Here k has the value 3 or 4, the value 3 being preferred. X is a benzoyl group or a hydrogen atom, with the hydrogen atom being preferred.

p has the value 2 or 3, with the value 3 being preferred. R 'stands for a hydrogen atom or a methyl group, preferably for a hydrogen atom.

In a further preferred group of the compounds according to the invention, IR in the general formula represents the grouping or R4 denotes a hydrogen atom, a halogen atom bonded preferably in the para position to A, such as, for example, a bromine or chlorine atom, preferably a chlorine atom, a lower alkoxy group such as a methoxy or ethoxy group, a lower alkyl group such as a methyl or ethyl group, entirely particularly preferably a hydrogen atom. A has the above definition and is preferably the group -O- (CH2) 3- or -0-CH2CH (OH) CH2-; X also has the above definition and is preferably a hydrogen atom. p has the above definition and preferably has the value 3, R 'preferably denotes a hydrogen atom. In a further preferred group of the compounds according to the invention, IR in the general formula represents the grouping where R5 and R6, which can be identical or different, each represent a hydrogen atom, a halogen atom, for example a chlorine or bromine atom, preferably a bromine atom. The halogen atom can preferably be bonded in the 3- and / or 5-position of the pyridine ring. If R6 is a hydrogen atom, then R5 is preferably a halogen atom, for example a chlorine or bromine atom, in particular a bromine atom. The halogen atom can preferably be bonded in the 3- or 5-position, in particular in the 5-position, of the pyridine ring. R5 and R6 can furthermore each be a lower alkyl or lower alkoxy group, preferably a methyl or methoxy group bonded in the 3- and / or 5-position of the pyridine ring. If R5 stands for a hydrogen atom, then R6 preferably denotes a methyl or methoxy group bonded in the 3- or 5-position of the pyridine ring.

B stands for the grouping or - (CH2) m-, where Y is a linear lower alkyl group, preferably a methyl, ethyl, n-propyl or iso-propyl group, in particular a methyl group. 1 has the value 3 or 4, preferably 3, while m has the value 3, 4 or 5, preferably 4. X preferably denotes a hydrogen atom. p has the value 2 or 3, preferably 3. R 'preferably denotes a hydrogen atom.

In a further preferred group of the compounds according to the invention, R represents the grouping Therein, R7 can be the group (R1R2) N-CH2- as a substituent, in which R1 2 and R2, which can be the same or different, are a linear C1-Cl0-alkyl group, preferably a linear C1-C3-alkyl group, for example one Methyl, ethyl or n-propyl group, the methyl group being preferred. Furthermore, R7 can have the grouping (H2N) 2C = N-, or be, one of the last two groups mentioned is very particularly preferred. D denotes a link -CH2-S- (CH2) n- or - (CH2) 0-, where n is 2 or 3, preferably 2, and o is 2, 3 or 4, preferably 3.

In a further preferred group of the compounds according to the invention, IR in the general formula represents the grouping where R8 denotes a hydrogen atom, a benzyl group which is optionally substituted by a halogen atom, such as, for example, a bromine or chlorine atom, preferably a chlorine atom, in the para position. R8 can also mean a grouping (R1R2) N-CH2-, in which R1 and R2 have the meanings given above, but preferably each represent a methyl group. R8 can also be an amino group. Preferably R8 is a hydrogen atom. R9 represents a hydrogen atom, a linear lower alkyl group, such as, for example, a methyl or ethyl group, preferably a methyl group, or a thio-lower alkyl group, very particularly preferably a thiomethyl group. If R8 represents a hydrogen atom and R9 represents a thiomethyl group, then E preferably represents the grouping -CH2-S- (CH2) n-, where n is 2 or 3, preferably 2. R9 furthermore preferably denotes the grouping -, where Y is a lower alkyl group, for example a methyl or ethyl group, preferably a methyl group.

In a further preferred group of the compounds according to the invention, IR in the general formula represents the grouping where Z is a hydrogen atom or a linear lower alkyl group, preferably a methyl group, E is as defined above, but is preferably the grouping -CH2-S- (CH2) 2-. X and R 'preferably represent a hydrogen atom. However, p has the above definition preferably the value 3.

The invention also includes all stereoisomeric forms and hydrates of above-described compounds of the general formula I.

The compounds according to the invention can be prepared by a process which is characterized in that a) for the preparation of a compound of the general formula I in which R, p and R 'have the meanings given above and in which X is a benzoyl group, (a1) a compound of the general formula II in which R is as defined above, with an amine of the general formula III in which R 'and p are as defined above, preferably in equimolar amounts in a polar solvent such as an alcohol, for example methanol, ethanol or isopropanol, preferably ethanol, or in acetonitrile, dimethyl sulfoxide, dimethylformamide, preferably acetonitrile, in the case of space or Reacting the reflux temperature of the corresponding solvent to a compound of the general formula I, or that (a2) a compound of the general formula IV in which R 'and p are as defined above, with equimolar amounts of a compound of the general formula V R-NH2 (V) in which R is as defined above, in a polar solvent, as mentioned above, preferably in acetonitrile, at room temperature or the reflux temperature of the corresponding solvent is converted into a compound of the general formula I or that b) for the preparation of a compound of the general formula I in which R, p and R 'have the meanings given above and in which X is a hydrogen atom, ( b1) a compound of the formula Ia in which R, p and R 'have the above meanings, with the aid of an acid, for example dilute sulfuric acid or dilute hydrochloric acid, preferably hydrochloric acid, or a base, for example sodium hydroxide solution or potassium hydroxide solution, preferably sodium hydroxide solution, at elevated temperature, preferably at reflux temperature, hydrolyzed to a compound according to the invention or that (b2) a compound of the general formula VI in which R, p and R 'have the above meanings, hydrolyzed with the aid of an acid, for example dilute sulfuric acid or dilute hydrochloric acid, preferably hydrochloric acid, as indicated above to give a compound of the formula 1.

If appropriate, those obtained in production steps a) and b) are obtained Compounds chromatographed in a manner known per se, purified or in it converted to physiologically acceptable salt.

It is also possible to prepare compounds of the general formula Ib in the R "for the grouping where R1, R2, R3 and R4 have the meanings given above and p is as defined above, an amine of the general formula VII wherein R "is as defined above, with N-benzoyldiphenylimidocarbonate of formula VIII to a compound of the general formula IX in which R "is defined as above. The compound IX can be converted into a compound of the general formula X, with elimination of phenol wherein R "is as defined above.

The compound X can also, starting from the compound of the general formula VII, by reaction with benzoyl isocyanide dichloride of the formula XI are manufactured. The compound X is then with a compound of the general formula III in which R 'and p are as defined above, to a compound of the invention general formula Ic OH I 1 R "-o-CH2-CH-CH2NH-C-NH (CH2) (Ic) RI H in which R ', R "and p are as defined above, reacted, whereupon, in a manner known per se, as mentioned above, acidic or basic hydrolysis is carried out to give the compound of the general formula Ib according to the invention.

In addition to the stereoisomeric compounds and hydrates, the invention includes of the substances of general formula I also include the physiologically acceptable salts of these connections. These salts can, for example, with mineral acids such as chlorine, Bromic, hydroiodic, phosphoric, metaphosphoric, nitric acid or Sulfuric acid, or with organic acids such as formic acid, acetic acid, propionic acid, Phenylacetic acid, tartaric acid, citric acid, fumaric acid, methanesulfonic acid, emboxylic acid etc., are formed.

The compounds of the invention can be administered in any can be formulated in any way. The invention therefore also includes medicaments the at least one compound according to the invention for turn contained in human or veterinary medicine. Such drugs can conventionally using one or more pharmaceutical carriers or diluents getting produced.

The compounds according to the invention can therefore be used for oral, buccal, topical, parenteral or rectal administration, with oral Administration is preferred.

For oral administration, the drug can be in the form of, for example Tablets, capsules, powders, solutions, syrups or suspensions are available under Prepared in a conventional manner using acceptable diluents have been.

For buccal administration, the drug can be in the form of tablets or take letters that have been formulated in a conventional manner.

The compounds of the invention can be used for parenteral administration be formulated by bolus injection or continuous infusion. Formulations for injection may be in unit dose form as ampoules or in multi-dose containers with added preservatives.

The drugs can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and they may include formulation auxiliaries, such as suspending, stabilizing and / or dispersing agents.

Alternatively, the active ingredient can also be used in powder form for reconstitution with a suitable vehicle, for example sterile, pyrogen-free water, before Use.

The compounds according to the invention can also be used for rectal preparations, for example suppositories or retention enemas, which can be formulated for example conventional suppository bases such as cocoa butter or other glycerides.

For topical application, the compounds according to the invention can formulated as ointments, creams, gels, lotions, powders or sprays in a conventional manner will.

For oral administration, a suitable daily dose is according to the invention Compounds 1 to 4 doses up to a total of 5 mg to 1 g / day, preferably 5 to 250 mg / day, depending on the patient's condition. In individual cases it may be necessary be to deviate from the stated amounts, depending on the individual Behavior towards the active substance or the type of its formulation and the point in time or the interval at which the administration takes place. For example, there are cases where less than the minimum amount mentioned above can be used, while in other cases the upper limit mentioned must be exceeded.

Example 1 Preparation of the precursors a) N-benzoyl-diphenylimidocarbonate 21.0 g (104 mmol) of benzoyl isocyanide dichloride and 20.5 g (218 mmol) of phenol are dissolved in ethyl acetate, and 45 ml of pyridine are added dropwise with cooling. After 30 minutes, the approach is i. Vac. evaporated, the residue stirred with benzene and the precipitated pyridinium chloride filtered off. After evaporation of the benzene i. Vac. what remains is a brown U1, which crystallizes through when stored in the refrigerator.

The crude crystals are extracted with ether several times at room temperature and in each case the insoluble residue is filtered off. The combined ether extracts will be iVac. concentrated and stored in the refrigerator for crystallization. Yield: 23.7 g (72%) of colorless needles which, after recrystallization from ether, melt at 108.degree.

IR (KBr): 1710 (C = O), 1645 cm 1 C20H15t03 (317.3) Calc .: C 75.70 H 4.76 N 4.41 Found: C 75.72 H 4.70 N 4, 47 MS: m / z (rel. Int. [% 3) = 224 to - 9i +, 24), 105 ([C6H5C0J + 100), 94 ([C6H50H] +, 9), 77 ([C6H5] +, 83).

1 H NMR data: @ = 7.2-7.55 (m) 13 H, (CDCl3, Tt1S as 7.93 (m) 2 H, ppm.

internal standard) b) N-Benzoyl-O-phenyl-N '[3- (3-piperidinomethyl-phenoxy) propylS isourea 2.48 g (10 mmol) 3- (3-piperidinomethyl-phenoxy) propylamine and 3.17 g (10 mmol) N-benzoyl-diphenylimidocarbonate are stirred in 20 ml ether for 1 h at room temperature. The reaction mixture is i. Vac. evaporated, the residue dissolved in methanol and treated dropwise with water until cloudy. When stored in the refrigerator, 4.40 g (93%) of N-benzoyl-O-phenyl-N'-T - (3-piperidinomethyl-phenoxy) propyl-isourea crystallize out as colorless needles with a melting point of 67 ° C.

C29H33N303 (471.6) Calcd .: C 73.86 H 7.05 N 8.91 Found: C 73.82 H 7.15 N 8.89 MS: m / z (rel. Int. LJ) = 471 (M +, 7), 388 (LM-93i +, 35) 105 (LC6H5C0J +, 100), 94 ([C6H5OH], 45), 84 ([C5H10N] + 40), 77 (LC6H5J, 55).

IR (KBr): 1640 (C = O) cm-1.

1 H-NMR data: d = 1.2-1.8 (m) 6 H, (CDC13, TMS as 2.20 (m) 2 H, internal standard) 2.37 (m) 4 H, 3.40 (s) 2 H, 3.78 (dt) 2 H, 4.13 (t) 2 H, 6.60 - 7.55 (m) 12 H, 7.87 (m) 2 H, 10.25 (t, wide) 1 H, interchangeable with D20 ppm.

c) N-Benzoyl-N '- [2- (imidazol-4-yl) ethyl] -N "- [3- (3-pi peridinomethyl) phenoxy) propyg guanidine The base is liberated from 0.92 g (5 mmol) of histamine dihydrochloride with 10 mmol of sodium ethylate in 100 ml of ethanol, the precipitated sodium chloride is filtered off and the filtrate is concentrated to about 20 ml in vacuo. After adding 2.36 g (5 mmol) of N-benzoyl-O-phenyl-N '- (3-piperidinomethylphenoxy) propyg isourea, the mixture is heated under reflux for 1 h, i. Vac.

evaporated and the residue dissolved in hot acetonitrile. When cooling crystallize 1.2 g (49%) N-benzoyl-N '- [2- (imidazol-4-yl) ety0J -N "-03- [3-piperidinomethyl-phenoxy) propyl] guanidine from m.p.

136 ° C.

The use of pyridine, acetonitrile or tert. Butanol instead using ethanol as the reaction medium leads to comparable results with the same reaction time Exploit.

C28H36N602 (488.6) Calcd .: C 68.83 H 7.43 N 17.20 Found: C 69.07 H 7.61 N 17.29 MS: m / z (rel. Int. E) = 488 (M +, 11), 105 (100), 95 (33), 84 (57), 77 (75).

1H-NMR data: # = 1.15-1.85 (m) 6 H, (d6-DMS0, TMS as 2.00 (m) 2 H, internal standard) 2.28 (m) 4 H, 2.77 (t) 2 H, 3.32 (s) 2 H, 3.0 - 3.8 (m) 4H, 4.00 (t) 2H, 6.55-7.55 (m) 9H, 8.02 (m) 2H, ppm.

Example 2 N-Benzoyl-N '- [2- (5-methylimidazol-4-yl) ethyl] -N "[3- (3-piperidinomethylphenoxy) propyljguanidine 5 mmol of 5-methylhistamine, prepared from 0.99 g of dihydrochloride with 10 mmol of sodium ethylate in ethanol, are mixed with 2.36 g (5 mmol) of N-benzoyl-0-phenyl-N'-L3- (3-piperidinomethyl-phenoxy) propylgisourea (Example 1b) heated under reflux in 20 ml of acetonitrile for 1 h. After evaporation i. Vac. the reaction product is obtained by preparative layer chromatography (silica gel 60 PF254 contains gypsum, mobile phase: ethyl acetate / methanol.

Ammonia 90 + 10) isolated. The eluate is i. Vac. evaporated, the The residue was dissolved in a little acetonitrile, and ethyl acetate was added. When storing 0.25 g (10%) of N-benzoyl-N '- [2- (5-methylimidazol-4-yl) ethyl crystallize in the refrigerator (- 200 ° C.) C3- (3-piperidinomethylphenoxy) propyluguanidine from melting point 118-120 ° C.

C29H38N602 (502.7) Calcd .: C 69.29 H 7.62 N 16.72 Found: C 69.07 H 7.77 N 16.61 MS: m / z (rel. Int. L%) = 502 (M +, 1), 109 (6), 105 (8), 95 (25), 84 (42), 77 (7), 44 (100).

1 H-NMR data: to = 1.15 - 1.7 (m) 6 H, (d6-DMSO, TMS as 2.00 (m) 2 H, internal standard) 2.10 (s) 3 H, 2.27 (m) 4 H, 2.70 (t) 2 H, 3.33 (s) 2 H, 3.0-3.8 (m) 4H, 4.00 (t) 2H, 6.55-7.6 (m) 8H, 8.02 (m) 2H, ppm.

Example 3 ridinomethyl-phenoxy) N-Benzoyl-N '- [3- (imidazol-4-yl-propy- [3- (3-piperidinomethyl-phenoxy) propyl] guanidine The base is liberated from 0.99 g (5 mmol) 3- (imidazol-4-yl) propylamine dihydrochloride with 10 mmol sodium ethylate in ethanol, precipitated sodium chloride is filtered off, the filtrate i. Vac. evaporated and taken up in pyridine. After adding 2.36 g (5 mmol) of N-benzoyl-0-phenyl-N '- [3- (3-piperidinomethyl-phenoxy) propy] isourea (Example 1, preparation b), the mixture is heated under reflux for 1 h, then i. Vac. evaporated and the product isolated by prepared layer chromatography (see. Example 2). The I. Vac. The evaporated eluate is dissolved in hot acetonitrile and left to crystallize. Yield 1.4 g (56%) of colorless needles with a melting point of 115 ° C.

C29H38N602 (502.7) Calcd .: C 69.29 H 7.62 N 16.72 Found: C 69.47 H 7.72 N 16.76 t4S: m / z (rel. Int. [%]) = 502 (M +, 24), 109 (50), 105 (100), 84 (25), 77 (39).

IR (KBr): 1600 (C = 0) cm-1.

H-NMR data: or = 1.15 - 2.4 (m) 14 H, (d6, DMS0, TMS as 2.58 (t) 2 H, internal standard) 3.32 (s) 2 H, 2.75 - 3.8 (m) 4 H, 4.03 (t) 2 H, 6.55 - 7.55 (m) 9H, 8.06 (m) 2H, ppm.

Example 4 N- [3- (Imidazol-4-yl) propyl] -N '- [3- (3-piperidinomethyl-phenoxy) propyl] guanidine 0.90 g (1.79 mmol) of N-benzoyl-N'-C3- (imidazol-4-yl) propyl-N "- [3- (3-piperidinomethyl-phenoxy) propyl] guanidine (Example 3) are 7 After the reaction mixture has cooled, the benzoic acid which has precipitated is filtered off, the filtrate is extracted three times with ether and the aqueous phase is evaporated to dryness in vacuo. 0.8 g ( 88%) dry foam.

C22H34N6O 3 HCl (507.9) MS: m / z (rel. Int. [% 3) = 398 (M +, 3), 109 (39), 95 (50), 84 (67).

1 H NMR data: cr = 1.3-2.3 (m) 8 H, (d6-DMSO, TMS as 2.4-3.65 (m) 12 H, internal standard) 4.08 (t) 2 H, 4.18 (s) 2 H, 6.8 - 7.5 (m) 5 H, 7.6 (s, wide) 2 H, interchangeable with D20 7.75 - 8.25 (m) 2 H, interchangeable with D20 8.93 (d) 1H, ppm.

Example 5 N-02- (Imidazol-4-yl) ethyl -N '- [3- (3-piperidinomethyl-phenoxy) propyl] -guanidine 1.4 g (3.4 mmol) of N-cyano-N'-imidazol-4-yl) eth -N "- 3- (3-piperidinomethyl-phenoxy) propyl] guanidine are refluxed with 50 ml of concentrated hydrochloric acid for 4 hours The reaction mixture is then evaporated to dryness in vacuo and the residue is stirred three times with anhydrous acetone The combined extracts are evaporated in vacuo and give 1.5 g (89%) of the strongly hygroscopic trihydrochloride, which at 100.degree C sinters. The Tripikrat sinters at 95 - 100 ° C.

C21H32N60 3C6H3N307 (1071.8) Calc .: C 43.70 H 3.86 N 19.60 Found: C 43.65 H 3.71 N 19.43 C21H32N60 3 3 HC1 (493.9) MS: m / z (rel. Int. [%]) = 384 (M +, 40), 302 (82), 107 (100), 95 (21, 84 (98).

1 H NMR data: S = 1.2-2.4 (m) 8 H, (d6-DMSO, H-D exchange with 2.6 - 3.9 (m) 10H, CF3COOD; TMS as internal 4.13 (t) 2 H, standard) 4.27 (s) 2 H, 6.85 - 7.7 (m) 5H, 9.00 (d) 1H, ppm.

Example 6 N-Benzoyl-N '- [2-hydroxy-3- (3-piperidinomethyl-phenoxy) propyl] -N "- [3- (imidazol-4-yl) propy; 1guanidine 1.32 g (5 mmol) of 2-hydroxy-3- (3-piperidinomethyl-phenoxy) propylamine are stirred with 1.59 g (5 mmol) of N-benzoyl-diphenylimidocarbonate in 30 ml of acetonitrile for 40 minutes at room temperature. After adding 0.63 g (5 mmol) of 3- (imidazol-4-yl) propylamine, the mixture is refluxed for 1 h and the reaction product is then isolated by preparative layer chromatography (silica gel 60 PF254 contains gypsum, mobile phase: chloroform / methanol.

Ammonia, 94 + 6). After evaporation of the eluate one obtains through Crystallization from ethyl acetate 0.62 g (24%) of colorless crystals of mp.

75 - 77 ° C.

C29H38N603 (518.7) Calcd .: C 67.16 H 7.39 N 16.20 Found: C 66.89 H 7.50 N 15.91 MS: m / z (rel. Int. E) = 121 (47), 109 (5), 105 (51), 85 (18), 77 (77), 58 (100).

1 H NMR data: # = 1.15-1.7 (m) 6 H, (d6-DMSO, TMS as 1.83 (m) 2 H, internal standard) 2.27 (m) 4 H, 2.57 (m) 2 H, 3.32 (s) 2 H, 2.9 - 3.8 (m) 4 H, 3.95 (m) 3 H, 5.5 (m) 1 H, interchangeable with D20, 6.5 - 7.5 (m) 11 H, 2 H, interchangeable with D20, 8.03 (m) 2 H, 10.2 (m, wide) 1 H, interchangeable with D20, ppm.

Example 7 N- -Hydroxy-3- (3-piperidinomethylphenoxy) p -N'-II3-) -propyl] guanidine 0.4 g (0.77 mmol) of N-benzoyl-N'-02-hydroxy-3- (piperidinomethyl-phenoxy) -propyl] -N "- [3- (imidazol-2-yl) propyl] guanidine ( Example 6) are in 45 ml of 15 percent. Hydrochloric acid heated under reflux for 6 h. The reaction mixture is worked up as in Example 4. After the aqueous solution has been evaporated, the residue is crystallized from isopropyl alcohol / ether. After drying i. Vac. 0.42 9 (93%) of the hygroscopic trihydrochloride, which contains 1 mol of isopropyl alcohol and sinters at 75 ° C., at room temperature.

C22H34N602 3HCT C3H8 ° (584.0) MS: m / z (rel. Int. [%]) = 190 (20), 151 (17), 109 (78), 107 (71), 98 (48), 95 (37), 84 (100).

1 H NMR data: # = 1.03 (d) 6 H, isopropyl alcohol (d6-DDISO, TMS as 1.15 - 2.2 (m) 8 H, internal standard) 2.3 - 4.3 (m) 16 H, 5.6 (m, wide) 2 H, interchangeable with D20 6.7 - 8.1 (m) 8 H, 3 H interchangeable with D20 8.96 (d) 1 H, ppm.

Example 8 N1 - [3-F (5-methyl-pyrid-2-yl) -methylamini propyl] -N2- [2- [2H-imidazol-4-yl) ethyl] guanidine trihydrochloride Preparation of the precursors a) O- Phenyl-N1-cyano-N2- [3-N- (5-methyl-pyrid-2-yl) -methylamino propyH -isourea 3.60 g (20 mmol) of N-methyl-N- (5-methyl-pyrid-2-yl) -propane-1,3-diamine and 4.76 g (20 mmol) of diphenylcyanimidocarbonate are dissolved in 30 ml of i-propanol Stirred for 4 h at room temperature. After evaporation of the solvent i. Vac.

the residue is taken up in 200 ml of methylene chloride and extracted twice with 100 ml of 1N sodium hydroxide solution. After drying over sodium sulfate, the organ. Phase i. Vac. evaporated. The U1 obtained crystallizes after a short time to colorless crystals with a melting point of 185 ° C. (decomp.) Yield: 4.19 g (65%) C18H21N50 (323.4) Rf (CH2C12 / CH3OH 98: 2): 0.45 b ) N1-cyano-N2- [3- [N- (5-methyl-pyrid-2-yl) -methylamino propyl -N3-L- (1H-imidazol-4-yl) ethyl-guanidine 3.00 g (9.3 mmol) of O-phenyl-N1-cyano-N2- [3-N- (5-methyl-pyrid-2-yl) -methylaminipropyl0-isourea and 1.03 g (9.3 mmol ) Histamine are refluxed for 10 h in 60 ml of i-propanol. After the solvent has been evaporated off in vacuo, the residue is chromatographed on silica gel with ethyl acetate / ethanol (60:40). After evaporation of the solvent, the main fraction gives 1.76 g (56 / a) of the title compound.

Colorless solid with a melting point of 152-153 ° C. (from chloroform) C17H24Na (340.4) Rf (EtOAc / EtOH 60:40): 0.41 NMR data & d = 1.73 (p) 2 H, (CD3OD, TMS as 2.16 (s) 3 H, internal standard) 2.84 (t) 2 H, 2.96 (s) 3 H, 3.18 (t) 2 H, 3.36 - 3.69 (m) 4H, 5.0 (broad) 3H, 6.56 (d) 1H, 6.90 (s) 1H 7.37 (dd) 1H, 7.64 (s) 1 H, 7.99 (d) 1 H ppm.

c) N] - [3- [N- (5-Methyl-pyrid-2-yl) -methylamino] propyl] -N2- [2- (1H-imidazol-4-yl) ethylg-guanidine trihydrochloride 2.0 g (5.9 mmol) of N¹-cyano-N²- [3- [N- (5-methyl-pyrid-2-yl) -methylamino] propyl] -N³- [2- (1H-imidazol-4 -yl) ethyl] -guanidine are boiled in 20 ml of 4N hydrochloric acid for 9 h. The solution is i. Vac. evaporated, the remaining residue taken up in 10 ml of methanol and stirred with 3.3 ml of 5.5 N sodium methylate solution for 10 min. After suctioning off the precipitate, i. Vac. evaporated. The crude product obtained is purified on aluminum oxide (neutral) with ethyl acetate / methanol (1: 1). After evaporation, the main fraction yields 0.88 g of a colorless bis, which is dissolved in 20 ml of water. After adding 6.1 ml of 2N hydrochloric acid, the solution is i. Vac. evaporated and the residue dried in a high vacuum. 1.16 g (47%) of the title compound are obtained as a colorless, hygroscopic solid.

C16H28C13N7 (424.8) Rf (base, Alox, EtOAc / MeOH 1: 1): 0.2 1H-NMR data: # = 2.01 (q) 2 H, (CD30D, TMS as 2.29 (s) 3 H, internal standard) 3.10 (t) 2 H, 3.34 (s) 3H, 3.40 (t) 2H, 3.52-3.94 (m) 4H, 4.8 (wide) 7H, 7.38 (d) 1H, 7.60 (s) 1H, 7.86 (d) 1H, 7.99 (dd) 1H, 9.00 (s) 1H, ppm.

Example 9 N1 - [2- (1H-imidazol-4-yl) ethyl] -N2- [2 - [[(5-methylthio-1H-imidazol-4-yl) methyl] thio] ethyguanidine trihydrochloride Preparation of precursors a) O-phenyl-N¹-cyano-N²- [2 - [[- methytio-1H-imidazol-4-yl) methyl] thio] et -isourea 5.50 g (20 mmol) of 2 - [[5-methylthio-1H-imidazol-4-yl] methylthio] ethylamine dihydrochloride are added to a solution of 0.92 g (40 mmol) of sodium in 60 ml of dry ethanol. After stirring for 30 minutes, the precipitate formed is filtered off with suction.

The filtrate is cooled with 4.76 g (20 mmol) of diphenylcyanimidocarbonate while cooling with ice added in 10 ml of ethanol and stirred for 3 h at room temperature. The solution is evaporated and the residue is freed from residual solvent in a high vacuum. The obtained oil crystallizes after brief stirring with 150 ml of methylene chloride.

Yield 5.77 g (83%) of colorless crystals with a melting point of 158-159 ° C C15H17N50S2 (347.5) Rf (CH30H / N (C2H5) 3 97: 3): 0.76 1 H NMR data: # = 2.24 (s) 3 H, (d6-DMSO, TMS as 2.57 - 2.89 (m) 2 H, internal standard) 3.31 - 3.68 (m) 2 H, 3.75 (s) 2 H, 7.12 - 7.58 (m) 5 H, 7.63 (s) 1 H, 8.9 (wide) 1 H, interchangeable with D20, ppm.

b) N1-cyano-N2- [2- (1H-imidazol-4-yl) ethyl] -N3-02- [[(5-methylthio-1H-imidazol-4-yl) methylg -thio] ethyl] methyl guanidine 2.68 g (7.7 mmol) of O-phenyl-N 1 -cyano-N 2 - [2 - [[(5-methylthio-1H-imidazol-4-yl) methyl] thio] ethyl] isourea and 0.86 g (7.7 mmol) of histamine are stirred in 40 ml of i-propanol for 8 h at 70.degree. After evaporating the solution i. Vac. the residue obtained is chromatographed on silica gel with ethyl acetate / ethanol (60:40). After evaporation, the main fraction gives 1.86 g (71%) of the title compound in the form of a colorless amorphous solid. Mp. 80-82 ° C C14H20N8S2 (364.5) Rf (EtOAc / EtOH 60:40): 0.42 H-NMR data: S = 2.32 (s) 3 H, (CD30D, TMS as 2, 68 (t) 2 H, internal standard) 2.88 (t) 2 H, 3.32 - 3.63 (m) 4 H, 3.84 (s) 2 H, 5.46 (wide) 4 H, 6.95 (s) 1H, 7.68 (s) 1H, 7.71 (s) 1H ppm.

c) N1 - [2- (1H-imidazol-4-yl) ethyl- N2 - [2 - [[(5-methylthio-1H-imidazol-4-yl) methylthiloethyl] guanidine trihydrochloride 1.82 g (5.0 mmol) of N 1 -cyano-N 2 - [2- (1H-imidazol-4-yl) ethyl] -N 3 - [2 - [[(5-methylthio-1H-imidazol-4-yl) methyl) ] thio] ethyl] guanidine are boiled in 20 ml of 4N hydrochloric acid for 14 h. After evaporation, the residue is dissolved in 12 ml of methanol, 4 ml of 5.5 N sodium methylate solution are added and the mixture is stirred for 10 minutes. After suctioning off the precipitate, 3.6 g (15 mmol) of picric acid in 50 ml of methanol are added to the filtrate and the mixture is briefly boiled. After resinous additions had been decanted off several times, 1.07 g of tripicrate of the title compound crystallized and was taken up in 6 ml of 2N hydrochloric acid. After the picric acid has been extracted with 6 × 10 ml of toluene, the aqueous phase is filtered and concentrated using a rotary evaporator. 0.44 g (20 °) of the trihydrochloride of the title compound is obtained in the form of a colorless, hygroscopic solid.

C13H24C13N7S2 (448> 9) Rf (base, Alox, EtoAc / MeOH 1/1): 0.26 1H-NMR data: = Z, 47 (s) 3 H, (CD30D, TMS as 2.61-3.22 (m) 4 H, internal standard) 3.37-3.78 (m) 4H, 3.99 (s) 2H, 4.9 (broad) 8H, 7.50 (s) 1H, 8.89 (s) 1H, 8.99 (s) 1H , ppm.

Example 10 N1 - [3- (Imidazol-4-yl) propyl] -N2- [2 - [[(5-methylthio-1H-imidazol-4-ylmethyl-thioj] ethy1-guanidine 1.02 g (5 mmol) 2- 05-methylthioimidazol-4-yl) methylthi; ethylamine, prepared from the dihydrochloride with sodium ethylate in methanol, is dissolved in 20 ml of acetonitrile, mixed with 1.59 g (5 mmol) of N-benzoyl diphenylimidocarbonate and stirred for 30 minutes at room temperature. After adding 0.63 g (5 mmol) of 3- (imidazol-4-yl) propylamine, the mixture is heated under reflux for 60 minutes and then the benzoylguanidine by preparative layer chromatography (silica gel 60 PF254> contains gypsum; mobile phase: chloroform / methanol. Ammonia, 94 + 6) isolated. The evaporated eluate is in 45 ml 20 percent. Hydrochloric acid heated under reflux for 7 h and worked up analogously to Example 4. The residue obtained after evaporation of the aqueous solution crystallizes on stirring with isopropanol / acetone. 0.25 g (11%) of the trihydrochloride is obtained as a hygroscopic solid.

C14H23N7S2 3HCl (462.9) MS: m / z (rel. Int.% 2) = 203 (33), 127 (100), 109 (8), 95 (94) 1 H NMR data: # = 1.87 (m) 2 H, (d6-DMSO, TMS as 2.48 (s) 3 H, internal standard) 2.6 - 2.9 (m) 4 H, 3.22 (m) 2 H, 3.48 (m) 2 H, 3.93 (s) 2 H, 7.50 (m) 1H, 9.07 (d) 1H, 9.20 (s) 1H, ppm.

Example 11 N- [2- (Imidazol-4-yl) ethyl] -N '- [3 - [(5-methylimidazol-4-yl) methylthio] propyl guanidine Preparation of precursor a) N-cyano-N' - [ 2- (imidazol-4-yl) ethyl-N "- [3 - [(5-methylimidazol-4-yl) methylthio] propyl] guanidine The base is liberated from 1.74 g (5 mmol) of 3-LcJ-methylimidazol-4-yI) methylthio1 propylamine dihydrobromide in ethanol with 10 mmol of sodium ethoxide, concentrated to half its volume and sodium bromide is separated off.

1.18 g (5 mmol) of N-cyano-diphenylimidocarbonate are added to the filtrate and stirred for 1 h at room temperature. For the i. Vac. evaporated reaction mixture 0.72 g (6.5 mmol) of histamine base in 30 ml of abs. Given pyridine, 1.5 h under reflux cooked and i. Vac. evaporated. Isolation by column chromatography (neutral Aluminum oxide, eluent: methanol / chloroform 4:96). The I. Vac. evaporated Eluate solidifies as a dry foam, which by stirring with ether 0.8 g (46%) N-cyano-N '- [2- (imidazol-4-yl) -ethyl] -N "- [(5-methylimidazole- 4-yl) methylthio] propyl] guanidine with a melting point of 135-137 ° C.

C15H22r48S (346.5) Calcd .: C 52.00 H 6.40 N 32.34 Found: C 52.47 H 6.64 N 31.85 IR (KBr): 2180 cm (C = N) 1 H NMR data: cf '= 1.70 (m) 2 H, (d6-DMSO, H-D exchange 2.14 (s) 3 H, with D2C, TMS as internal 2.24 (t) 2 H, standard) 2.73 (t) 2 H, 3.18 (t) 2H, 3.36 (t) 2H, 3.64 (s) 2H, 6.89 (s) 1H, 7.48 (s) 1H, 7.62 (s) 1H , ppm.

b) N- [2- (Imidazol-4-yl) ethyl] -N '- [3 - [(5-methylimidazol-4-yl) methylthio) propyl] guanidine 0.79 (2.02 mmol) N-cyano-N'- [2- (imidazol-4-yl) ethyg -N "- [3 {(5-methylimidazol-4-yl) methylthio] propyl] guanidine heated under reflux in 30 ml of 18 percent hydrochloric acid for 6 h and evaporated to dryness, whereby 0.98 g (100%) of a cloudy ul from ammonium chloride and N-2- (imidazol-4-yl) ethyl -N '- [ 3 - [(5-methylimidazol-4-yl) methylthio] propyl guanidine trihydrochloride remain.

C14H23N7S 3 HC1 .NH4Cl (484.3) The base is converted into the tripicrate of Mp. 171-174 ° C (decomp.) Transferred.

C14H23N7S 3C6H3N307 (1008.8) Calc .: C 38.10 H 3.20 N 22.22 Found: C 37.95 H 3.28 N 22.30 1 H NMR data: to = 1.78 (m) 2 H, (d6-DMSO, 2.30 (s) 3 H, H-D exchange with CF3COOD, 2.52 (t) 2 H, TMS as internal standard) 2.95 (t) 2 H, 3.24 (t) 2 H, 3.51 (t) 2H, 3.86 (s) 2H, 7.50 (s) 1H, 8.72 (s) 6H, 8.96 (s) 1H, 9.05 (s ) 1 H, ppm.

Example 12 N-Benzoyl-N'- 3- (imidazol-4-yl) propyl -N "-C2 (1-methylimidazol-2-yl) -methylthio] ethyl guanidine The base is liberated from 1.67 g (5 mmol) 2- 2 - [(1-methylimidazol-2-yl) methylthio] ethylamine dihydrobromide with sodium ethylate in ethanol.

The filtered solution is i. Vac. evaporated, tert in 20 ml. Butanol added and after the addition of 1.59 g (5 mmol) of N-benzoyl diphenylimidocarbonate 20 min. At room temp. touched. After adding 0.63 g of 3- (imidazol-4-yl) propylamine, dissolved in 10 ml of tert. Butanol, the reaction mixture is heated under reflux for 1 h i. Vac. evaporated and prepared by preparative layer chromatography (see. Example 2) isolated (mobile phase: ethyl acetate / methanol ammonia, 80:20). After evaporation of the eluate, the oily residue crystallizes through on stirring with ethyl acetate.

After recrystallization from acetonitrile, 1.1 g (52%) of N-benzoyl-N '- [3- (imidazo] yl) propyl] -N "- [2 - [(1-methylimidazol-2-yl) methylthio] ethyl guanidine with a melting point of 151-152 ° C.

C21H27N70S (425.6) Calc .: C 59.27 H 6.40 N 23.04 Found: C 59.18 H 6.46 N 23.12 MS: m / z (rel. Int.]) = 425 (M +, 2), 109 (55), 105 (100), 95 (87), 77 (63).

IR (KBr): 1600 cm (C = O) 1 H-NMR data: d? = 1.85 (m) 2 H, (d6-Dt4S0, TMS as 2.3 - 3.8 (m) 8 H, internal standard) 3.60 (s) 3 H, 3.87 (s) 2 H, 6.75 (m) 2H, 7.03 (d) 1 7.35 (m) 3H, 7.52 (s) 1H, 8.03 (m) 2H, ppm.

Example 13 N- [3- (Imidazol-4-yl) propyl -N '- [12- (1-methylimidazol-4-yl) methylthio] ethyl guanidine 0.6 g (1.41 mmol) of N-benzoyl-N'- [3- (imidazol-4-yl) propy 0 -N "- [2 - [(1-methylimidazol-4-yl) methylthio] ethyl] guanidine (Example 12) are refluxed in 45 ml of 20 percent hydrochloric acid for 3 hours and worked up as in Example 4. Yield 0.4 g (66%) of dry foam.

C14H23N7S 3 HC1 (430.8) MS: m / z (rel. Int. [%]) = 321 (M +, 1), 194 (34), 151 (22), 109 (60), 95 (100).

1 H NMR data: # = 1.85 (m) 2 H, (d6-DMSO, TMS as 2.72 (m) 4 H, internal Standard) 2.95 - 3.65 (m) 4 H, 3.85 (s) 3 H, 4.33 (s) 2 H, 7.43 (m) 1 H, 7.58 (d) 1 H, 7.68 (d) 1 H, 7.7 2 H, interchangeable with D20 7.95 (t) 1 H, interchangeable with D20 8.17 (t) 1 H, interchangeable with D20 9.02 (d) 1 H, ppm.

Example 14 N-Benzoyl-N '[2- [2- (4-chlorobenzyl) -5-methylimidazol-4-yl] methylthiol ethyl-N "- [3- (imidazol-4-yl) propyl] guanidine 0.74 g (2.5 mmol) 2 - [[2- (4-chlorobenzyl) -5-methylimidazol-4-yil-methylthiogethylamine, prepared from the dihydrobromide with sodium ethylate, and 1.59 g (2.5 mmol) N-Benzoyl-diphenylimidocarbonate are 20 min.

at room temperature in 20 ml of tert. Butanol stirred. After adding 0.63 g of 3- (imidazol-4-yl) propylamine, dissolved in 10 ml of tert. Butanol, is under for 1 h Heated to reflux and the reaction product by preparative layer chromatography isolated (mobile phase: ethyl acetate / methanol.

Ammonia, 90:10).

When the evaporated eluate is stirred with water, 0.15 g (11th %) of a solid obtained which sinters from 90 ° C.

C28H32C1N70S (550> 1) Calculated: C 61.13 H 5.86 N 17.82 Found: C 61.12 H 6.02 N 17.57 MS: m / z (rel. Int. [%]) = 219 (2), 109 (2), 105 (16), 95 (5), 77 (10), 43 (100).

H-NMR data: cr = 1.83 (m) 2 H, (d6-DMSO, TMS as 2.05 (s) 3 H, internal Standard) 2.3 - 2.7 (m) 4 H, 3.0 - 3.8 (m) 4 H, 3.60 (s) 2H, 3.80 (s) 2H, 6.72 (m) 1H, 6.9-7.6 (m) 8H, 8.00 (m) 2H, ppm.

Example 15 N-Benzoyl-N '- [2 - [(2-dimethylaminomethyl-5-methylimidazol-4-yl) methylthiodiethyl] -N "- [3- (imidazol-4-yl) propyl] guanidine From 1.14 g (5 mmol) of 2 - [[2-dimethylaminomethyl) -5-methylimidazol-4-yl) -methylthio]] - ethylamine and equimolar amounts of N-benzoyl-diphenylimidocarbonate and 3- (imidazol-4-yl) propylamine in acetonitrile.

Isolation is carried out by preparative layer chromatography (eluent: Ethyl acetate / methanol. Ammonia, 85:15). After evaporation of the eluate, one obtains a colorless 1> which when stirred with 10 ml of water and a few drops of ethanol solidified. After drying i. Vac. 0.25 g (10%) remain over calcium chloride of the dihydrate, which sinters at 51 - 52 ° C.

C24H34N80S 2H20 (518.7) Calculated: C 55.58 H 7.38 N 21.60 Found: C 55.35 H 7.43 N 21.49 MS: m / z (rel. Int. [7) = 153 (69), 109 (32), 108 (97), 105 (94), 43 (100).

1 H NMR data: d «= 1.87 (m) 2 H, (d, -Db50, TMS as 2.06 (s) 3 H, internal Standard) 2.13 (s) 6 H, 2.35 - 2.85 (m) 4 H, 3.28 (s) 2 H, 3.63 (s) 2 H, 3.05 - 3.7 (m) 4H, 6.73 (s) 1H, 7.2-7.6 (m) 4H, 8.03 (m) 2H, ppm.

Example 16 N-Benzoyl-N '- [2- [2-dimethylaminomethylthiazol-4-yl) methylthio] ethyl -N "- [3- (imidazol-4-yl) propyl) guanidine The base is liberated from 1.7 g (5 mmol) of 2 - [(2-dimethylaminomethylthiazol-4-yl) thiomethyl] ethylamine trihydrobromide with 15 mmol of sodium ethoxide in 100 ml of ethanol, the precipitated sodium chloride is filtered off and the filtrate i. Vac. evaporated. The oily residue is taken up in 20 ml of acetonitrile and, after adding 1.59 g (5 mmol) of N-benzoyldiphenylimidocarbonate, stirred for 35 minutes at room temperature. After adding 0.69 g (5.5 mmol) of 3- (imidazole-4- yl) propylamine is refluxed for 40 min. The reaction product is isolated by preparative layer chromatography (mobile phase: ethyl acetate / methanol.

Ammonia, 97: 3). The eluate is i. Vac. evaporated, in a little acetonitrile recorded, mixed with ether and stored in the refrigerator for crystallization. Yield 0.37 g (15 °, 0). M.p. 99-101 ° C.

C23H31N70S2 (485.7) Calc .: C 56.88 H 6.43 N 20.19 Found: C 56.84 H 6.51 N 20.24 MS: m / z (rel. Int. [%]) = 485 (M +, 10), 105 (100), 77 (83).

1 H NMR data: S = 1.85 (m) 2 H, (d6-DMSO, TMS as 2.23 (s) 6 H, internal Standard) 2.35 - 2.95 (m) 4 H, 2.95 - 3.75 (m) 4 H, 3.67 (s) 2 H, 3.83 (s) 2 H, 6.76 (s) 1H, 7.15-7.65 (m) 5H, 8.06 (m) 2H, ppm.

Example 17 N- [2 - [(2-Dimethylaminomethylthiazol-4-yl) methylthio]) methylthio] -N '- [3- (i mi -dazol-4-yl) propyl] guanidine 0.32 g (0.66 mmol) of N-benzoyl-N '- [2 - [(2-dimethylaminomethylthiazol-4-yl) metythio] ethyl] -N "- (imidazo] -4-yl) propyl] guanidine (Example 16) are in 45 ml of 20 percent. Hydrochloric acid heated under reflux for 7 h and worked up analogously to Example 4. The foam initially obtained is crushed, stirred with anhydrous acetone, filtered off with suction and i. Vac. dried. 0.21 g (60%) of hygroscopic solid is obtained.

C16H27N7S2. 4HC1 (527.4) MS: m / z (rel. Int. [% J) = 381 (M +, 7), 154 (21), 109 (100), 95 (47), 81 (55), 59 (41).

1 H-NMR data: = 1.87 (m) 2 H, (d6-DMSO, TMS as 2.4 - 2.9 (m) 4 H, internal standard) 2.82 (s) 6 H, 2.95 - 3.75 (m) 4 H, 3.97 (s) 2 H, 4.70 (s) 2 H, 7.50 (m) 1 H, 7.72 (s, wide) 2 H, interchangeable with D20 7.82 (s) 1 H, 8.05 (m) 1 H, interchangeable with D20 8.22 (m) 1 H, interchangeable with D20 9.03 (d) 1 H, ppm.

Example 18 N-Benzoyl-N '- [2 - [(2- (3,4,5,6-tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl) methylthiogethyl] -N "- [3 - (Imidazol-4-yl) propyl] guanidine Preparation of precursors a) 2 - [[2- (3,4,5,6-Tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl] methylthio] ethylamine 5.34 g (20 mmol) of 4-chloromethyl-2- (hexahydropyrimidin-2-ylidene) aminothiazole hydrochloride and 2.27 g (20 mmol) of cysteamine hydrochloride are dissolved in 50 ml of 48 percent strength. aqueous hydrobromic acid heated under reflux for 4 h. After evaporation i. Vac. the residue is boiled with ethanol. 6.57 g (76%) pyrimidin-2 (1H) -ylidene) aminothiazol-4-yl] methylthia-ethylamine crystallize out as dihydrobromide in chromatographically pure form. After recrystallization from ethanol / water, colorless needles with a melting point of 243 ° C. are obtained.

C1oHl7N5S2 2 HBr (433.2) Calc .: C 27.72 H 4.42 N 16.17 Found: C 27.53 H 4.46 N 16.07 MS: m / z (rel. Int. Cssl) = 271 (M +, 5), 227 ([M-C2H6N +, 100), 195 ([M-C2H6NS] +, 88).

1 H NMR data: = 1.92 (m) 2 H, (d6-DMSO, TMS as 2.5-3.75 (m) 8 H, internal standard) 3.80 (s) 2 H, 7.15 (s) 1 H, ppm.

b) N-Benzoyl-N'- [(2- (3,4,5,6-tetrahydropyrimidine-2 (1H) -ylidene) aminothiazol-4-yl) methylthio] ethyli -O-phenyl-isourea From 2.17 g (5 mmol) of 2- [[2- (3,4,5,6-tetrahydropyrimidine-2 (1H) -ylidene) aminothiazol-4-yl] methylthio] ethylamine dihydrobromide is mixed with 10 mmol of sodium ethylate in 100 ml of ethanol released the base. After evaporation of the ethanol i. Vac. the residue is taken up in acetonitrile, precipitated sodium bromide is filtered off and, after the addition of 1.59 g (5 mmol) of N-benzoyl-diphenylimidocarbonate, the filtrate is stirred at room temperature for 4 hours. The chromatographically pure solid which has precipitated is filtered off with suction and washed with acetonitrile. 1.5 g (61%) of N-benzoyl-N '- [2- [(2- (3,4,5,6-tetrahydropyrimidin-2 (1H-ylidene) aminothiazol-4-yl) methylthio] ethyl are obtained ] -O-phenyl-isourea, which, after recrystallization from hot acetonitrile, melts at 138-139 ° C.

C24H26N602S2 (494> 6) Calculated: C 58.28 H 5.30 N 16.99 Found: C 58.24 H 5.28 N 17.01 MS: m / z (rel. Int. [%]) = 494 (M +, 1), 105 (32), 94 (57), 77 (10), 66 (100).

H-NMR data d = 1.73 (m) 2 H, (d6-DMSO, TMS as 2.83 (t) 2 H, internal Standard) 3.05 - 3.45 (m) 4 H, 3.65 (s) 2 H, 3.70 (dt), 2 H, 6.40 (s) 1 H, 7.0 - 7.6 (m) 8 H, 7.80 (m) 2 H, 8.18 (wide) 2 H, interchangeable with D20, 10.06 (t) 1 H, interchangeable with D20, ppm.

c) N-BenzOyl-N '- [2 - [(2- (3,4,5,6-tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl) methylthiiethyl] -N "- [3 - (imidazol-4-yl) propyl] guanidine 1.3 g (2.63 mmol) of N-benzoyl-N '- [2 - [(2- (tetrahydropyrimidin-2-ylidene) aminothiazol-4-yl) methylthio] ethylate -O-phenyl-isourea and 0.38 g (3 mmol) 3- (imidazol-4-yl) propylamine are heated under reflux for 30 minutes in 20 ml of acetonitrile. After the solution has cooled and 20 ml of ether have been added, the oil that initially separated out solidifies on stirring. 1.1 g (80%) of solid are obtained which, after recrystallization from ethanol / water, melts at 175-176 ° C.

C24H31N90S2 (525.7) Calcd .: C 54.83 H 5.94 N 23.98 Found: C 54.96 H 6.09 N 24.00 MS: m / z (rel. Int. [%]) = 525 (M +, 1), 227 (23), 195 (21), 108 (10), 105 (100), 95 (35), 77 (61).

H-NMR data: = = 1.5-2.2 (m) 4 H, (d6-DMSO, TMS as 2.35-2.93 (m) 4 H, internal standard) 3.63 (s) 2 H, 2.95 - 3.85 (m) 8 H, 6.35 (s) 1 6.77 (s) 1H, 7.15-7.65 (m) 4H, 8.07 (m) 2H, ppm.

Example 19 iden) aminothiazol-4-yl) methylthio] ethyl] -N "- [3- (imidazol-4-yl) propyl] guanidine 0.6 g (1.1 mmol) of N-benzoyl-N'- 2 - [<2- (3,4,5,6-tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl) methylthio] ethyl ] -N '- [3- (imidazol-4-yl) propyl guanidine in 45 ml of 20 percent. Hydrochloric acid heated under reflux for 7 h and worked up analogously to Example 4. The residue obtained after evaporation of the aqueous solution is stirred with anhydrous acetone, filtered off with suction and i. Vac. dried. 0.59 g (97.0) of hygroscopic solid are obtained.

C17H27N9S2 '3HCl (531.0) MS: m / z (rel. Int. S]) = 421 (M +, 3), 195 (100), 109 (35), 95 (17), 81 (52, 59 (28).

1 H NMR data: # = 1.6-2.25 (m) 4 H, (d6-DMSO, HD exchange 2.4-3.0 (m) 4 H, with CF3COOD; 3.05-3 , 8 (m) 8 H, TMS as internal 3.87 (s) 2 H, standard) 7.17 (s) 1 H, 7.48 (m) 1 H, 9.07 (d) 1 H, ppm Example 20 N-Benzoyl-N '- {3- [2- (3,4,5,6-tetrahydropyrimidine-Z (1H) -ylidene) aminothiazol-4-yl] propyl) -N' 1- [3- ( imidazol-4-yl) propyl] guanidine Preparation of precursors a) N- {3- [2- (3,4,5,6-Tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl] proypl} phthalimide 4.75 g (30 mmol) (3,4,5,6-tetrahydropyrimidine-2 (1H) -ylidene) thiourea and 9.3 g (30 mmol) N- (5-bromo-4-oxopentyl) phthalimide are in 150 ml of acetone stirred for 5 h at room temperature. The precipitated solid is filtered off with suction, washed with acetone and recrystallized from ethanol / water. 12.3 g (91.degree. D) of colorless needles with a melting point are obtained.

244 OC.

C18H19N502S 'HBr (450.4) Calculated: C 48.00 H 4.48 N 15.55 Found: C 47.73 H 4.44 N 15.73 MS: m / z (rel. Int. [° 0] = 369 (M +, 36), 209 (30), 196 (100), 160 (7), 125 (13).

1 H-NMR data: 6 = 1.65-2.25 (m) 4H, (d6-DMS0, TMS as 2.65 (t) 2H, internal standard) 3.43 (m) 4H, 3.63 (t) 2H, 6.83 (s) 1H, 7.83 (m) 4H, 8.85 (wide) 2H, interchangeable with D20, 11.5 (wide) 1H, interchangeable with D20, ppm.

b) 3- [2- (3,4,5,6-Tetrahydropyrimidin-2 (1H) -ylidene) amine-thiazol-4-yl] propylamine 9.0 g (20 mmol of N- {3- [2- (3,4,5,6-tetrahydro-2 (1H) -ylidene) amino] thiazol-4-yl} propylphthal = imide are mixed with 2 ml of hydrazine hydrate 4 The reaction mixture is then evaporated under reflux in 150 ml of ethanol and the residue in 150 ml of 20%.

Hydrochloric acid heated under reflux for a further 2 h and after storage the precipitated phthalic acid hydrazide is filtered off in the refrigerator. The filtrate will i. Uak. concentrated, made alkaline with sodium hydroxide solution and extracted 3 times with methylene chloride.

The combined extracts are washed with water over sodium sulfate dried, i. Sak. evaporated and the residue crystallized from acetonitrile. 4.2 g (88.0D) 3- [2- (3,4,5,6-tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl] propylamine are obtained of m.p. 116 OC.

CloHl7N55 (239.3) Calc .: C 50.18 H 7.16 N 29.26 Found: C 49.73 H 7.22 N 29.06 MS: m / z (rel. Int. [] = 239 (M +, 24), 209 (66), 196 (100), 125 (26).

H-NtlR data: 6 = 1.23 (broad) 2H, interchangeable with D20 (CDC13, TMS as 1.5-2.15 (m) 4H, internal standard) 2.35-2.92 (m) 4H, 3.43 (t) 4H, 6.03 (s) 1H 8.45 (broad) 2H, interchangeable with D20, ppm.

The dihydrochloride melts at 259-260 after crystallization from ethanol OC.

£ 10I17N5S 2HC1 2H £ l (312.3) Calculated: C 38.46 H 6.13 N 22.43 Found: C 38.75 H 6.38 N 22.04 H-NMR data: 6 = 1.93 (m) 4H, (d6-DMSO, H-D exchange with CF3COOD, 2.45-3.05 (m) 4H, TMS as internal standard) 3.47 (t) 4H 6.88 (s) 1H, ppm.

c) N-Benzoyl-N '- {3- [2- (3,4,5,6-tetrahydropyrimidine-2 (1H) -ylidene) aminothiazol-a-yl] pro = pyl) -0-phenyl-isourea 1.2 g (5 mmol) 3- [2- (3,4,5,6-tetrahydropyrimidine-2 (1H) -ylidene) aminothiazol-4-yl] propyl: amine are dissolved in 10 ml methylene chloride and a solution of 1 , 59 g (5 mmol) of N-benzoyl diphenylimidocarbonate in 20 ml of methylene chloride. The reaction mixture is stirred for 15 min at room temperature, then i. Vac. evaporated and stirred for crystallization with acetonitrile. 2.2 g (95 Dó) of colorless solid are obtained, which melts at 165-167 ° C. after recrystallization from acetonitrile.

C24H26N6 ° 2S (462.6) Calcd .: C 62.32 H 5.67 N 18.17 Found: C 62.30 H 5.65 N 18.24 1H NMR data: 6 = 1.65-2.35 (m) 4H, (CDCl3, TMS as 2.70 (t) 2H, internal Standard) 3.15-3.75 (m) 6H, 6.13 (s) 1H, 6.95-7.55 (m) 8H, 7.90 (m) 4H, 2H interchangeable with D20, 10.3 (t) 1H, interchangeable with D20, ppm.

d) N-Benzoyl-N '- {3- [2- (3,4,5,6-tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl] pro = pyl} -N "- [3 - (imidazol-4-yl) propyl] guanidine 2.1 g (4.5 mmol) of N-benzoyl-N '- {3- [2- (3,4,5,6-tetrahydropyrimidin-2 (1H) -ylidene) aminothia = zol-4-yl] propyl } -0-phenyl-isourea and 0.6 g (4.8 mmol) 3- (imidazol-4-yl) propylamine are refluxed in 30 ml acetonitrile for 3 h. After evaporation i. Vac.

the reaction product is determined by preparative layer chromatography isolated (silica gel 60 PF254 contains gypsum; eluent: ethyl acetate / methanol. ammonia, 94: 6). The eluate is i. Sak. evaporated, the oily residue taken up in ethanol and crystallized by adding water. 1.3 g (59 m) are obtained colorless solid with a melting point of 158-159 ° C.

C24H31N905 (493.6) Calcd .: C 58.40 H 6.33 N 25.54 Found: C 58.23 H 6.34 N, 25.47 H NMR data: 6 = 1.5-2.35 (m) 6H, (CDC13, TMS as 2.68 (m) 4H, internal Standard) 3.05-3.65 (m) 8H, 6.13 (s) 1H, 6.74 (s) 1H, 7.05-7.55 (m) 4H, 7.75 (wide) 2H, interchangeable with D2û, 8.18 (m) 2H, 9.0 (wide) 1H, interchangeable with D20, ppm.

Example 21 N- {3- [2- (3,4,5,6-Tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl] propyl} -N1- [3- (imid = azol-4-yl ) propyl] guanidine 0.9 9 (1.8 mmol) N-benzoyl-N '- {3- [2- (3,4,5,6-tetrahydropyrimidin-2 (1H) -ylidene) aminothiazol-4-yl] propyl- N'1- [3- (imidazo1-4-yl) propylyguanidine in 30 ml of 20 per cent. Hydrochloric acid heated under reflux for 5 h. The reaction mixture is worked up as in Example 4.

0.65 g (93 ° Ó) of the trihydrochloride is obtained in the form of a hygroscopic amorphous solid.

£ 17H27N9 5 3HC1 (498.9) H-NMR data: 6 = 1.55-2.3 (m) 6H, (d6-DMSO, H-D exchange with CF3COOD, 2.5-3.0 (m) 4H, TMS as internal standard) 3.0-3.7 (m) 8H, 6.87 (s) 1H, 7.43 (m) 1H, 9.03 (d) 1H, ppm.

Example 22 N-Benzoyl-N '- {2 - [(2- (diaminomethyleneamino) thiazol-4-yl) methylthio] ethyl} -N "- [3- (imida = zol-4-yl) propyl guanidine Preparation of the precursor a) N-Benzoyl-N '- {2 [(2 (diaminomethyleneamino) thiazol-yl) methylthio] ethyl} -0-phenylisourea 1.15 g (5 mmol) 2 - [(2- (diaminomethyleneamino) thiazol-4-yl) methylthio] ethylamine and 1.59 (5 mmol) N-benzoyl-diphenylimidocarbonate are stirred in 40 ml acetone tril for 3 h at room temperature . The precipitated colorless solid is dc pure and can be used further directly. Yield 1.9 g (84 ° a). The substance crystallizes from ethanol / water in colorless needles with a melting point of 135 C.

C21H22N6O2S2 (454.6) Calc .: C 55.49 H 4.88 N 18.49 Found: C 55.24 H. 4.97 N 18.47 MR data: 6 = 2.80 (t) 2H, (d6-DMSO, TMS as 3.65 (s) 2H, internal Standard) 3.67 (m) 2H, 6.47 (s) 1H, 6.77 (s, wide) 4H, interchangeable with D20 7.0-7.6 (m) 8H, 7.75 (m) 2H, 10.0 (t) 1H, interchangeable with D20, ppm.

b) DJ-Benzoyl-N '- {2 - [(2- (diaminomethyleneamino) thiazol-4-yl) methylthio] ethyl} -N "- [3- (imidazol-4-yl) propyl] guanidine 1.0 g (2.2 mmol) of N-benzoyl-Nl- {2 - [(2-diaminomethyleneamino) thiazol-4-yl) methylthio] = ethyl) -0-phenyl-isourea are mixed with 0.35 g (2 , 8 mmol) 3- (imidazol-4-yl) propylamine in 30 ml acetonitrile heated under reflux for 3 h. The reaction product is isolated by preparative layer chromatography (silica gel 60 PF254 contains gypsum; mobile phase: ethyl acetate / methanol. Ammonia 95: 5). 0.28 g (26%) of colorless needles with a melting point of 133-134 ° C. crystallize from ethanol / water.

£ 21H27N9 S20 (485.6) 1H NMR data = 1.87 (m) 2H, (d6-DMSO, H-D exchange with D20, 2.3-2.95 (m) 4H, TMS as internal standard) 3.0-3.95 (m) 4H, 3; 65 (s) 2H, 6.43 (s), 1H, 6.77 (s) 1H, 7.1-7.7 (m) 4H, 8.05 (m) 2H, ppm.

Example 23 N-Benzoyl-N '- [3- (imidazol-4-yl) propyl] -N "- (3-phenoxypropyl) guanidine Preparation of precursor a) N-Benzoyl-N' - (3-phenoxypropyl) -0 -phenyl-isourea 1.0 g (6.6 mmol) of 3-phenoxypropylamine and 2.09 g (6.6 mmol) of N-benzoyl-diphenylimidocarbonate are stirred in 30 ml of ether at room temperature for 15 minutes. When constricting i. Vac.

the reaction product partially precipitates. Of this, 0.2 g are used for analytical Purpose removed, the entire remaining reaction mixture is as described under b) Further implemented. N-Benzoyl-Nl- (3-phenoxypropyl) -0-phenyl-isourea crystallizes out Ether in colorless needles of m.p. 75 C. C23H22N203 (374.4) Ber .: C 73.78 H 5.92 N 7.48 Found: C 73.63 H 5.85 N 7.44 1H- \ NR-Oatene: 6 = 2.13 (m) 2H, (d6-D'ISO, TMS as 3.70 (dt) 2H, internal standard) 4.10 (t) 2H, 6.7-7.65 (m) 13 H, 7.78 (m) 2H, 10.07 (t) 1H, interchangeable with D20, ppm.

b) N-Benzoyl-N '- [3- (imidazol-4-yl) propyl] -N "- (3-phenoxypropyl) guanidine The solution of 6.1 mmol of N-benzoyl-N '- (3-phenoxypropyl) -0-phenyl-iso = urea obtained according to a) is i. Vac. evaporated, the residue dissolved in acetonitrile and, after the addition of 0.8 g (6.4 mmol) 3- (imidazol-4-yl) propylamine, heated under reflux for 3 h. Then i. Vac. evaporated, the residue taken up in dilute hydrochloric acid and the aqueous solution extracted three times with ether. After alkalization with sodium hydroxide solution, the reaction product is extracted from the aqueous phase with methylene chloride and crystallized from the evaporated extract with ethyl acetate. 0.95 9 (38 ° ”) colorless solid is obtained which, after recrystallization from ethanol / water, melts at 149 ° C.

C23H27N502 (405.5) Calc .: C 68.13 H 6.71 N 17.27 Found: C 68.17 H 6.83 N 17.11 H-N data: 6 = 1.75-2.30 (m) 4H, (d6-DMS0, TMS as 2.35-2.8 (m) 2H, internal Standard) 3.0-3.75 (m) 4H, 4.07 (t) 2H, 6.7-7.6 (m) 10H, 8.08 (m) 2H, ppm.

Example 24 N- [3- (Imidazol-4-yl) propyl] -N '- (3-phenoxypropyl) guanidine 0.42 g (1 mmol) of N-benzoyl-N '- [3- (imidazol-4-yl) propyl] -N "- (3-phenoxypropyl) guanidine are refluxed in 30 ml of 20% hydrochloric acid for 5 hours. The reaction mixture is worked up in the same way as in Example 4. 0.35 g (94 ° ”) of the dihydrochloride is obtained as a hygroscopic amorphous solid.

C16H23N50 2H1 (374.3) 1H-R data: 6 = 1.95 (m) 4H, (d6-DMSO, TMS as 2.75 (t) 2H, internal standard) 2.95-3.6 (m) 4H, 4.05 (t) 2H, 6.7-7.5 (m (6H, 7.5-8.2 (m) 4H, interchangeable with D20, 9.00 (d) 1H, ppm.

Example 25 N- (2-Hydroxy-3-phenoxypropyl) -N '- [3- (imidazol-4-yl) propyl] guanidine 0.5 g (1.2 mmol) of N-benzoyl-N '- (2-hydroxy-3-phenoxypropyl) -N "- [3 (imidazo-4-yl) propyl] = guanidine are dissolved in 30 ml of 20% hydrochloric acid The reaction mixture is worked up as in Example 4. The dihydrochloride crystallizes from isopropyl alcohol / acetone in colorless crystals with a melting point of 165-166 ° C. Yield 0.45 g (96%).

C16H23N502. 2HC1 (390.3) Calcd .: C 49.24 H 6.46 N 17.94 Found: C 48.73 H 6.64 N 17.60 1H-NMR data: 6 = 1.85 (m) 2H (d6-DfrISO, H-D exchange with CF3COOD, 2.73 (t) 2H TMS as internal standard) 3.20 (t) 2H 3.35 (m) 2H 3.95 (m) 3H 6.7-7.5 (m) 6H 8.93 (d) 1H, ppm.

Claims (10)

Guanidine derivatives, process for their preparation and pharmaceuticals containing these compounds PATENT CLAIMS 1. Guanidine derivatives of the general formula I in the R the grouping denotes, where R1 and R2, which can be the same or different, each represent hydrogen, linear C1-C10-alkyl or C5-C6-cycloalkyl, or R1 and R2 together with the nitrogen atom to which they are bonded represent a 5- to Form a 10-membered nitrogen-containing alicyclic, heterocyclic ring, R3 stands for a hydrogen atom, a halogen atom or a lower alkoxy group, A the grouping -O- (CH2) k-, -O-CH2CH (OH) CH2-, -O-CH2-CH (CH3) ) -CH2-, -CH2-O-CH2-CH (OH) -CH2 or -O-CH2-CH (OH) -CH (OH) -CH2- denotes, in which k is 3 or 4, or in which R the grouping or where R4 is a hydrogen atom, a halogen atom bonded preferably in the para position to A, a lower alkoxy or lower alkyl group and A has the meaning given above, or in which R is the grouping where R5 and R6, which can be identical or different, each represent a hydrogen atom, a halogen atom or a linear lower alkyl or a linear lower alkoxy group, B denotes the grouping or - (CH2) m-, where 1 is 3 or 4 and m is 3, 4 or 5 and Y is a linear lower alkyl group, or in which R is the grouping means where R7 represents the group (R1R2) N-CH-, (HN) C = N-, where R1 and R2 are as defined above, D is the grouping CH2-S- (CH2) n- or - (CH2) 0-, where n is 2 or 3 and o is 2, 3 or 4 have, or in the R the grouping where R8 is a hydrogen atom, a benzyl group optionally substituted by a halogen atom, the grouping (R1R2) N-CH2- or an amino group, where R1 and R2 have the meanings given above, RP is a hydrogen atom, a linear lower alkyl or thio-lower alkyl group means, E for the groupings -CH2-S- (CH2) n-, or stands, where n has the value 2 or 3 and Y has the abovementioned meaning, or in which R is the grouping where Z is a hydrogen atom or a linear lower alkyl group and E is as defined above, X is a hydrogen atom or a benzoyl group, p is 2 or 3 and R 'is a hydrogen atom or a methyl group, and their physiologically acceptable salts . 2. guanidine derivatives according to claim 1, characterized gekennzeic hn et that R for the Grouping R3 stands 1 3 IP- A- R'R "NCH; 2 R1 and R2 together with the nitrogen atom form a pyrrolidine or piperidine ring, R3 stands for a hydrogen atom, A the grouping -O- (CH2) k-, -O-CH2CH (OH) CH2- or -O-CH2CH (CH3) CH2 - means, X and R each stand for a hydrogen atom and k and p each have the value 3. 3. guanidine derivatives according to claim 1, characterized gekennzeic hn et that R for the grouping where A has the meaning given in claim 1, X and R 'each represent a hydrogen atom and p has the value 3. 4. guanidine derivatives according to claim 1, characterized gekennzeic hn et that R for the grouping R5 stands for a halogen atom or hydrogen atom bonded in the 5-position of the pyridine ring, R6 stands for a hydrogen atom bonded in the 3-position of the pyridine ring or a methoxy group, B the grouping or - (CH2) 4-, X and R 'each represent a hydrogen atom and p has the value 3. 5. guanidine derivatives according to claim 1, characterized gekennzeic hn et that R for the grouping or D is the grouping -CH2-S- (CH2) 2- or - (CH2) 3, R 'is a hydrogen atom and p is 3. 6. guanidine derivatives according to claim 1, characterized gekennzeic hn et that R for the grouping E is as defined in claim 1, X and R 'each represent a hydrogen atom and p is 3. 7. guanidine derivatives according to claim 1, characterized gekennzeic hn et that R for the grouping E is the grouping -CH2-S- (CH2) 2-, or means, Y has the meaning given in claim 1, X and R 'each mean a hydrogen atom and p has the value 3. 8. guanidine derivatives according to claim 1, characterized qekennzeic hn et that R represents the grouping stands, D the grouping -CH2-S- (CH2) 3-, or where Y has the meaning given in claim 1, X and Rr each represent a hydrogen atom and p has the value 3. 9. Process for the preparation of guanidine derivatives according to Claims 1 to 8, characterized in that a) for the preparation of a compound of the general formula I in which X is a benzoyl group, (a1) a compound of the general formula II in which R has the meaning given in claim 1, with a compound of the general formula III in which R 'and p have the meanings given in claim 1, to form a compound of the general formula I or that (a2) a compound of the general formula IV in which R 'and p have the meanings given in claim 1, with a compound of the general formula V R-NH2 (V) in which R has the meaning given in claim 1, to form a compound of the general formula I or that b ) for the preparation of a compound of the general formula I in which X represents a hydrogen atom, (b1) a compound of the formula Ia in which R, p and R 'have the meanings given in claim 1, hydrolyzed under acidic or basic conditions or that (b2) a compound of the general formula VI in which R, p and R 'have the meanings given in claim 1, hydrolyzed with the aid of an acid to give a compound of the general formula I and that, if appropriate, the compounds obtained in preparation steps a) and b) are incorporated in it in a manner known per se converts physiologically acceptable salt. 10. Medicinal product, characterized in that it is a A compound according to claims 1 to 4 and at least one inert, pharmaceutical acceptable carrier or an inert, pharmaceutically acceptable diluent contains.