NO772669L - PROCEDURES FOR THE PREPARATION OF PHARMACOLOGICAL ACTIVE COMPOUNDS - Google Patents

Description

"Procedure for the manufacture of

pharmacologically active compounds"

This invention relates to the preparation of pharmacologically active compounds. The compounds produced according to the invention block histamine t^ receptors. These compounds can exist as acid addition salts, but for practical reasons reference will be made below to the parent compounds.

Many physiologically active substances trigger their biological effects by impact with special points known as receptors. Histamine is one such substance and has a number of biological effects. The biological actions of histamine which are inhibited by agents commonly called "antihistamines", of which mepyramine, diphenhydramine and chlorpheniramine are typical examples, are mediated through histamine H 2 receptors (Asn and Schild, Brit, J. Pharmac. Chemother, 21_, 427 (1966)). However, other biological actions of histamine will not be inhibited by "antihistamines", and actions of this type that are inhibited by a compound described by Black et al (Nature, 236, 385 (1972)) called burimamide are mediated through receptors that are defined by Black et al as histamine F^ receptors. Thus, histamine P^ receptors can be defined as those histamine receptors which are not blocked by mepyramine, but are blocked by burimamide. Compounds which block histamine I^ receptors are referred to as histamine f^ antagonists.

Blocking histamine F^ receptors is useful for inhibiting the biological effects of. histamine that is not inhibited by "antihistamines". Histamine H2_antagonists are therefore e.g. useful as agents for inhibiting gastric acid secretion, as anti-inflammatory agents and as agents acting on the cardio-vascular system, e.g. as inhibitors of the effects of

histamine on blood pressure. When treating certain conditions,

e.g. inflammations and in inhibiting the effects of histamine on blood pressure, a combination of histamine H-^- and P^-antagonists is useful.

The compounds produced according to the invention are histamine F₂ antagonists. These compounds have the following formula 1:

where Het is a pyridine, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, pyrimidine, pyrazine or pyridazine ring, which ring is optionally substituted with lower alkyl, lower alkoxy, hydroxy, halogen or amino; Y is hydrogen, . hydroxy or lower alkyl, and X is sulfur, CHNC>2 or NY' where Y' is hydrogen, hydroxy, lower alkyl, cyano or CONH2;

W. is NH or, when NY and X are both NH, sulfur; q is an integer from 2 to 12; n is 2 or 3 and m is 0, 1 or 2, such that the sum of m and n is 3 or 4, or, except when X is NH, NOH, NC0NH2 or N(lower alkyl) and Het' is imidazole, pyrazole or triazole, 2; Z is sulfur or a methylene group; Het<1>is a nitrogen-containing 5- or 6-membered heterocyclic ring such as an imidazole-, pyridine-, thiazole-, isothiazole-, oxazole-, isoxazole-, pyrazole-, triazole-, thiadiazole-, pyrimidine-, pyrazine- or pyridazine ring, which ring is optionally substituted with lower alkyl. lower alkoxy, hydroxy, halogen or amino; .and pharmaceutically acceptable acid addition salts thereof.

It will be understood that the structure shown in formula 1 is only one of various forms, and that other tautomeric forms are also encompassed by the formula. Hydrates and hydrated pharmaceutically acceptable salts of the compounds of formula 1 are also prepared according to the invention.

It is preferred that W is NH and that Y is hydrogen. It is particularly preferred that NY and X are both NH. A preferred group of compounds is that where q is 6 to 10 and NY and X are both NH.

It is preferred that Het is selected from a 2-pyridyl ring which is optionally substituted with hydroxy, chlorine, bromine or methoxy, a 2-thiazolyl ring or a 3-isothiazolyl ring.

It is preferred that Z is sulfur. Preferably m is 1 and n 2. Preferably Het' is selected from a 4-imidazolyl ring which is optionally substituted with methyl or bromine, a 2-pyridyl ring which is optionally substituted with hydroxy, chlorine, bromine or methoxy, a 2-thiazolyl ring or a 3-isothiazolyl ring.

Examples of special compounds that are produced

according to the invention, are:

1,8-bis-[N<1->(3-(2-thiazolyl)propyl)guanidino]octane

and

1-[N1 -(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]-8-[N'-(3-(2-thiazolyl)propyl)guanidino]octane Compounds of formula 1 where W is NH, Y is hydrogen or lower alkyl and X is sulphur, CHNQ2, NH, Ndavere alkyl), NCN or NCONH,,, can be prepared by a method described in scheme 1:

On form 1, Het, W, n, m and Het<1> are as indicated below

2 •

formula 1, Y is hydrogen, lower alkyl or a guanixidine protecting group such as benzoyl, benzyloxycarbonyl or '33 ethoxycarbonyl, and X' is sulfur, CHN02 or NY where Y is hydrogen, cyano, lower alkyl or a guanidine protecting group such as benzoyl, benzyloxycarbonyl or ethoxycarbonyl.

In Path A on Form 1, Y 2 is preferably not hydrogen or

lower alkyl unless Het'-(CHz „)' m Z(CH_2 ) n- is the same as Het-CCH,,)^-- Compounds with formula 1 where Y is hydrogen and

X is NY and Het'-(CH~) Z(CHJ is not the same as Het-(CHJ,-,

2 m 2 n 2 3

can be prepared by acid hydrolysis of ..compounds of formula 5 where Y 2 is CN and X<1> is NCN, or by removing the guanidine-protecting groups from compounds of formula 5 where X' is NY 3 and Y 2 and Y 3 are guanidine protecting groups. Compounds of formula 1 where X<1> is NCONH2 can be prepared by hydrolysis under mild acid conditions of the corresponding cyanoguanidine.

In the case of pathway A in scheme 1, the order of the reactions can be reversed, i.e. a compound of formula 4 can be treated with

an amine of the formula NH~(CH„) NH„, and the product is treated with a

2 2 q 2' ^r

compound with formula 2. Correspondingly, the order of the reactions at path B in scheme 1 can be reversed, i.e. the compound with formula 6

can first be treated with the amine of the formula Het'(CH~) Z(CH_) NH„

2 m 2 n 2

and the product is treated with the amine of the formula Het (CH2) ^NH,,.

Step 1 of Path A can be carried out in the presence or absence of a solvent. Preferably, this reaction is carried out using an excess of the amine NH 2 (CH 2 )^NH 2 as solvent. Preferably, step 2 of route A is carried out in the absence of a solvent or in the presence of a polar solvent such as a lower alcohol or pyridine. This reaction is preferably carried out at an elevated temperature, e.g. 100°C. When Het'(CH2)mZ(CH2)n is the same as Het(CH2)3, and NY and X are equal, step 1 and step 2 of pathways A and B can be carried out simultaneously without isolating the intermediates of formula 3 or 7 .

Preferably, both steps of pathway B are carried out in one polar solvent such as a lower alcohol or pyridine, and at

an elevated temperature, e.g. 100°C. When Het'(CH0) Z(CH0) -

Jr 2 m 2 n

is not the same as Het(CH2)^-, preferably one equivalent of the amine Het(CH2).2NH2 is used in the first step of path B, and

an excess of the mine Het' (CH~) m Z(CH~) nNH_ is used in the second step.

zmln 2

Amines of the formula Het1(CH_) Z (CH~) NH„ can be prepared

2 m2n 2

by methods described in British patents 1305547, 1338169 and 1421999 and German publication 2634433.

The compounds of formula 1 where W is sulfur and NY and X are both NH can be prepared by alkylating a thiourea with the formula Het(CH_)-NHCSNH- or. Het1 (CH~) Z(CH„) NHCSNH,,

2 3 2 2 m 2 n 2

with a dihaloalkane of the formula Hal(CH2)^Hal, where Hal means chlorine, bromine or, iodine, and treatment of the product with a thiourea of the formula Het'(CH_) Z(CH-) NHCSNH-2 m 2 n2 respectively. or Het (CH2) ^NHCSNH,,. Preferably, the reaction is carried out with an acid addition salt of the thiourea. Preferably, Hal is bromine,

and the reaction is carried out in a solvent such as ethanol. Preferably there will be an excess of the compound of formula Hal(CH2 ~) pHal in the first stage of the reaction.

The compounds of formula 1 block histamine H2 receptors, i.e. they inhibit the biological effects of histamine which are not inhibited by "antihistamines" such as mepyramine, but which are inhibited by burimamide. It is e.g. found that the compounds produced according to the invention inhibit histamine-stimulated secretion of gastric acid from lumen-perfused stomachs in rats anesthetized with urethane, in doses from 0.5 to 256 micromol per kg intravenously. This method is described in the above-mentioned article by Ash and Schild. . The activity of these compounds as histamine H₂ antagonists is also demonstrated by their ability to inhibit other effects of histamine, which, according to the above-mentioned article by Ash and Schild, are not mediated by histamine H₂ receptors. E.g. inhibit the effects of histamine on isolated guinea pig atrium and isolated rat uterus.

The compounds produced according to the invention inhibit the basal secretion of gastric acid and also that which is stimulated by pentagastrin or by food.

In a common test, such as measuring blood pressure in an anesthetized rat, the effect of the compounds to inhibit the vasodilator effect of histamine can also be demonstrated. The potency of the compounds' activity is illustrated by the effective dose that produces 50% inhibition of gastric acid secretion in an anesthetized rat, and the dose that produces 50% inhibition of histamine-evoked tachycardia in an isolated guinea pig atrium.

For therapeutic use, the pharmacologically active compounds produced according to the invention will normally be administered as pharmaceutical preparations containing as the only or as a substantially active ingredient at least one such compound in base form or in the form of an addition salt with a pharmaceutical

acceptable acid and together with a pharmaceutical carrier. Such addition salts include the salts with hydrochloric acid, hydrobromic acid,

hydroiodic acid, sulfuric acid and standard acid, and can suitably be prepared from the corresponding bases with formula 1 by standard methods, e.g. by treating the base with an acid in a lower alkanol or by using ion exchange resins to form the desired salt, either directly from the base or from another addition salt.

Pharmaceutical preparations containing a pharmaceutical carrier and a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof can be used to block histamine H2 receptors by administering a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof in suitable preparation form. The pharmaceutical carrier used can e.g. be a solid or a liquid. Examples of solid carriers are lactose, corn or potato or modified starch, dicalcium phosphate, terra alba, sucrose, celluloses, talc, gelatin, microfine silicic acid, agar, pectin, gum acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil. alcohol, propylene glycol, polyethylene glycols, water and the like.

A number of different pharmaceutical forms can be used.

If a solid carrier is thus used, the preparation can

tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a lozenge or lozenge. The amount of solid carrier will vary widely, but will preferably be from approx. 25 mg to approx. 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile, injectable liquid or an aqueous or non-aqueous liquid suspension. Other additives, such as preservatives, e.g. antioxidants

or antibacterial agents, and/or flavorings or coloring agents can also be introduced. The liquid forms can also be prepared in soft gelatin capsules or microcapsules. The sterile solution can be prepared in ampoules, bottles with several doses or

disposable syringes with unit dbs. The preparation can also be in a semi-solid form such as a cream, paste, ointment or gel', or a liquid or aerosol for local administration.

The pharmaceutical preparations are produced by usual

methods that include e.g. mixing, granulating and compressing or dissolving the components as appropriate for . the desired preparation.

The active ingredient will be present in the preparations.

in an amount effective to block histamine F^ receptors. The route of administration can be oral or parenteral.

Preferably, each unit dose contains the active ingredient in an amount from approx. 50 to approx. 250 mg.

The active ingredient is preferably administered

1 to 6 times daily. The daily dosage amount will preferably

be from approx. 150 to approx. 1500 mg..

Appropriately, the preparation is prepared in a dosage form

which suits the desired administration method, e.g. as a tablet, capsule, injectable solution or as a cream or ointment' for local administration.

The following examples, where all temperatures are in °C,

shall serve to further illustrate the invention:

Example 1

a) A mixture of. dimethyl-N-cyanodithioimidocarbonate (6.0 g), 1,8-diaminooctane (2.85 g) and ethanol (50 ml) were stirred at room temperature for 5 hours. Water was added and the mixture was filtered to give 1,8-bis-[N<1->cyano-S-methylthioureido]octane, sm.p. 193-195°.<C>14<H>24N6<S>2 requires: c 49.4, H 7.1,'N .24.7, S 18.2% found: C 49.4, H 7.2, N 24.5, S 18.7%. b) 3-(2-thiazolyl)propylamine dihydrochloride (15.0 g) was . treated with an excess of 40% aqueous sodium hydroxide, and the mixture was extracted with chloroform, and the chloroform extracts were dried and evaporated to a residue. 1,8-bis-[N'-cyano-S-methylthioureido]octane (11.0 g) was added to this residue and the mixture was heated at 140° for 3 hours. The mixture was chromatographed on silica gel eluting with ethyl acetate/iso-propanol (4:1) to give 1,8-bis-[N'-(3-(2-thiazolyl)propyl)-N"-cyanoguanidino]octane, m .p. 93-94°. c) 1,8-bis-[N,'-(3-(2-thiazolyl)propyl)-N"-cyano6guanidino]-octane was refluxed. with concentrated hydrochloric acid for 24 hours,

and the hydrochloric acid was removed by evaporation to give 1,8-bis-[N1-(3-(2-thiazolyl)propyl)guanidino]octane tetrahydrochloride which can be purified via the dipicrate derivative.

Example 2

a) A mixture of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (3.25 g), 1,8-bis-[N1-cyano-S-methylthioureido]octane (6.8 g) and

pyridine (50 mL) was heated under reflux for 12 h. The pyridine was removed by evaporation, and the residue was purified by chromatography on silica gel eluting with ethyl acetate to give 1-[N<1->cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl-guanidino] -8-[N'-cyano-S-methylthioureido]octane, m.p. 65-72°. b) 3-(2-thiazolyl)propylamine and 1-[N'-cyano-N"-(2- (5-Methyl-4-imidazolyImethylthio)ethylguanidino]-8-[N<1->cyano-S-methyl-thioureido] octane was refluxed together in pyridine. The pyridine was removed by evaporation, and the residue was purified by chromatography on silica gel to give give 1-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]-8-[N'-cyano-N"-[(3-(2-thiazolyl)propyl )guanidino]octane.

c) 1-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]-8-[N'-cyano-N"-(3-(2^-thiazolyl ) propyl) guanidino] octane

was refluxed with concentrated hydrochloric acid to give 1-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]-8-[N'-(3-(2-thiazolyl)propyl)guanidino] octane.

Example 3

Application of

(a) - 2-(2-imidazolylmethylthio)ethylamine

(b) 2-(4-imidazolylmethylthio)ethylamine,

(c) 2-(5-bromo-4-imidazolylmethylthio)-ethylamine,

(d) 2-(5-trifluoromethyl-4-imidazolylmethylthio)-ethylamine, (e) 2-(5-hydroxymethyl-4-imidazolylmethylthio)ethylamine, (f) . 2-(2-pyridylmethylthio)ethylamine,

(g) 2-(3-methyl-2-pyridylmethylthio)ethylamine,

(h) 2-(3-methoxy-2-pyridylmethylthio)ethylamine,

(i) 2-(3-chloro-2-pyridylmethylthio)ethylamine,

(j) 2-(3-amino-2-pyridylmethylthio)ethylamine,

(k) 2-(3-hydroxy-2-pyridylmethylthio)ethylamine,

(1) '2-(3-isothiazolylmethylthio)ethylamine,

(m) 2-(4-bromo-3-isothiazolylmethylthio)ethylamine,

(n) 2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamine,

(0) 2-(4-chloro-3-(1,2,5)-thiadiazolylmethylthio)ethylamine,

(p) 2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio)ethylamine instead of 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the method according to example 2 (a) and treatment of the products by.

the general procedure according to example 2 (b and c) gives respectively the following guanidines:

(a) 1-[N'-(2-(2-imidazolylmethylthio)ethyl.)guanidino]-8-[N'~(3-(2-thiazolyl)propylguanidino)]octane, (b) 1-[N' -(2-(4-imidazolylmethylthio)ethyl)guanidino]-8-[N'-(3-(2-thiazolyl)propylguanidino)]octane, (c) 1-[N'-(2-(5-bromo- 4-imidazolylmethylthio)ethyl)-guanidino] -8- [N 1 - ( 3-(2-thiazolyl) propylguanidino).] octane , (d) 1-[N'-(2-(5-trifluoromethyl-4-imidazolyl) -methylthio)-ethyl)guanidino]—8-[N'-(3-(2-thiazolyl)propylguanidino)]octane, (e) 1-[N'-(2-(5-hydroxymethyl-4-imidazolylmethylthio)- ethyl)guanidino]-8-[N<1->3-(2-thiazolyl)propylguanidino)]octane, (f) 1-[N'-(2-(2-pyridylmethylthio)ethyl)guanidino]-8-[ N'-3-(2-thiazolyl)propylguanidino)]octane (g) 1-'[N' - (2-(3-methyl-2-pyridylmethylthio)ethyl)guanidino]-8-[N'-3-( 2-thiazolyl)propylguanidino)]octane, (h) 1-[N'-(2-(3-methoxy-2-pyridylmethylthio)-guanidino]-8-[N'-3-(2-thiazolyl)propylguanidino)] octane, (1) 1-[N1-(2-(3-chloro-2-pyridylmethylthio)ethyl)-guanidino]-8-[N<1->3-(2-thiazolyl)propylguanidino)]octane, (j ) 1-[N<1->(2-(3-amino-2-pyridylmethylthio)ethyl)guanidino]-8-[ N<1->3-(2-thiazolyl)propylguanidino)]octane, (k) 1-[N'-(2-(3-hydroxy-2-pyridylmethylthio)ethyl)-•guanidino]-8-[N' -3-(2-thiazolyl)propylguanidino)]octane, (1) 1-[N'-(2-(3-isothiazolylmethylthio)ethyl)guanidino].-8-[N'-3-(2-thiazolyl)propylguanidino )]octane, (m) 1-[N'-(2-(4-bromo-3-isothiazolylmethylthio)-ethyl)]-guanidino-8-[N'-3-(2-thiazolyl)propylguanidino)]octane,

(n) 1-[N'-(2-(3-(1,2,5)-thiadiazolylmethylthio)-ethyl)-guanidino]-8-[N<*->3-(2-thiazolyl)propylguanidino)] octane,

(o) 1-[N'-(2-(4-chloro-3-(1,2,5)-thiadiazolyl-methylthio)-ethyl)guanidino]-8-[N'-3-(2-thiazolyl) propylguanidino)]octane,

(p) 1-[N'-(2-(5-amino-2-(1,3,4)-thiadiazol-1-methylthio)-ethyl)guanidino]-8-[N<1->3-(2- thiazolyl)propylguanidino)]octane.

Example 4

Use of 3-(2-pyridyl)propylamine instead of 3-(2-thiazolyl)-propylamine in example 2 (b and c) gives 1-[N<1->(2-(5-methyl-4-imidazolylmethylthio) ethyl)guanidino]-8-[N1-(3-(2-pyridyl)propyl)-guanidino]octane.

Example 5

Application of

(a) 1,2-diaminoethane

(b) , 1,6-diaminohexane

(c) 1,12-diaminododecane

instead of 1,8-diaminooctane in the method according to example 1 leads to the production of respectively:

(a) 1,2-bis-[N<1->(3-(2-thiazolyl)propyl)guanidino]-ethane tetrahydrochloride, (b) 1,6-bis-[N'-(3-(2 -thiazolyl)propyl)guanidino]-hexane tetrahydrochloride, (c) 1,12-bis-[N<1->(3-(2-thiazolyl)propyl)guanidino]-dodecane tetrahydrochloride.

Example 6

A solution of S-methyl-N-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]dithiocarbamate (5 g) in absolute ethanol (60 ml) is added to a solution of sodium (0.3 g ) in ethanol (100 ml), and after filtration, a solution of excess 1,8-diaminooctane (1.4 g) in ethanol (30 ml) is added, and the mixture is refluxed for 24 hours. Concentration of this reaction mixture gives N-(8-aminooctyl)-N'-[2-((4-methyl-4-imidazolyl)methylthio)ethyl]-thiourea, which upon reaction first with N-benzoyldimethyl-dithioimidocarbonate and then with 3 -(2-thiazolyl)propylamine under the conditions according to example 1 (b) gives 1-[N'-((2-(4-methyl-5-imidazolyl)methylthio)ethyl)thioureido]-8-[N'-benzoyl- N"-(3-(2-thiazolyl)propyl)guanidino]octane. Hydrolytic removal of the N-benzoyl group finally yields 1-[N<1->((2-(4-methyl-5-imidazolyl)-methylthio) ethyl)thioureido]-8-[N1-(3-(2-thiazolyl)propyl)guanidino]octane.

Example 7

(a) Addition of a solution of 3-(2-thiazolyl)propylamine in ethanol to carbon disulfide with stirring at room temperature gives N-[3-(2-thiazolyl)propyl]dithiocarbamic acid. Treatment of this dithiocarbamic acid with methyl iodide in methanol gives S-methyl-N-[3-(2-thiazolyl)propyl]dithiocarbamate hydroiodide. (b) Reaction of N-(8-aminooctyl)-N1 -[2-((4-methyl-5-imidazolyl)

methylthio)ethyl],thiourea (see Example 6) with S-methyl-N-[3-(2-thiazolyl)propyl]dithiocarbamate gives 1-[N'-(2-((4-methyl-5-imidazolyl)methylthio ) ethyl) thioureido[-8-[N 1 -(3-(2-thiazolyl)propyl)-thioureido]octane.

.. (c) When dry hydrogen chloride is bubbled through a solution

of the above octane in methanol at 80°C and the solvent is removed, the product is 1-[N<1->(2-((4-methyl-5-imidazolyl)methylthio)-ethyl)-S-methylisotibureido]-8- [N 1 -(3-(2-thiazolyl)propyl)-S-methyl-' isothioureido]octane. (d) Treatment of 1-[N'-(2-((4-methyl-5-imidazolyl)methylthio)-ethyl)-S-methylisothioureido]-8-[N'-(3-(2-thiazolyl)propyl )-S-methyl-isothioureido ] octane with at least two equivalents of hydroxylamine hydrochloride gives 1-[N'-hydroxy-N"-(2-((4-methyl-5-imidazolyl)-methylthio)ethyl)guanidino]- 8 -[N1-hydroxy-N"-(3-(2-thiazolyl)propyl)-guanidino]octane.

Example 8

Reaction of 1-[N1 -(2-((4-methyl-5-imidazolyl)methylthio)-ethyl)-S-methylisothioureido]-8-[N'-(3-(2-thiazolyl)propyl)-S- methyl1-isothioureido]octane (see example 7 (c)) under reflux treatment on a steam bath for 3 hours with a 33% solution of at least two equivalents of methylamine in ethanol gives 1-[N'-methyl-N"-(2-( 4-methyl-5-imidazolyl)methylthio)ethyl)guanidino]-8-[N<1->methyl-N"-(3-(2-thiazolyl)propyl)guanidino]octane.

Example 9

Reaction of 3-(2-thiazolyl)propylamine in methanol with an equimolar amount of N-benzoyldimethyldithioimidocarbonate gives N-benzoyl-S-methyl-N'-[3-(2-thiazolyl)propyl]isothiourinstbf f, which

by reacting an excess of 1,8-diaminooctane yields N-benzoyl-N'-(8-aminooctyl)-N"-[3-(2-thiazolyl)propyl]guanidine. Reflux-

treatment of this compound in ethanol with 1-nitro-2-methylthio-. 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]ethylene gives 1-[N<1->benzoyl-N"-(3-(2-thiazolyl)propyl)guanidino]-8-(1-( 2-(4-Methyl-5-imidazolylmethyltib)ethylamino)-2-nitrovinyl-1-amino]-octane Hydrolytic removal of the N-benzoyl group finally gives 1-[N'~(3-(2-thiazolyl)propyl) guanidino]-8-[1-(2-(4-methyl-5-imidazolylmethylthio)ethylamino)-2-nitrovinyl-1-amino]octane.

Example 10

Hydrolysis of N-benzoyl-N1 -(8-aminooctyl)-N"-[3-(2-thiazolyl)propyl]guanidine (see example 9) gives N-(8-amino-octyl)-N'-[3- (2-thiazolyl)propyl]guanidine which, on reaction with N-cyano-S-methyl-N1 -[2-(4-methyl-5-imidazolylmethylthio)ethyl]-isothiourea, gives 1-[N'-(3- (2-thiazolyl)propyl)guanidino]-8-[N<1->cyano-N"-(2-(4-methyl-5-imidazolylmethylthio)ethyl)guanidino]-octane. Mild hydrolysis of this compound with dilute hydrochloric acid at 40°C affords 1-[N'-(3-(2-thiazolyl)propyl)guanidino]-8-[N'-carbamoyl-N"-(2-(4-methyl -5-imidazolylmethylthio)ethyl)guanidino]-octane.

Example 11

A solution of the hydrobromide salt of N-[3-(2-thiazolyl)-propyl]-thiourea in ethanol was heated under reflux with 1,3-dibromopropane to give 1,3-bis-[S-(N-(3-(2-thiazolyl)-propyl)isothioureido]propane.

Claims (14)

1. Procedure for preparing a compound of the formula: where Het is a pyridine, thiazole, isothiazole, oxazole, isoxazole, thiadiazole, pyrimidine, pyrazine or pyridazine ring, which ring is optionally substituted with lower alkyl, lower alkoxy, hydroxy, halogen or amino; Y is hydrogen, hydroxy or lower alkyl, and X is sulphur, CHNC^ or NY' where YV is hydrogen, hydroxy, i.lower alkyl, cyano or CONH 2 ; W is NH or, when NY and X are both NH, sulfur; q is an integer from 2 to 12; n is 2 or 3, and m is 0, 1 or 2, such that the sum of m and n is 3 or 4, or, except when X is NH, NOH, NC0NH2 or N(lower alkyl) and Het' is imidazole , triazole or pyrazole, 2; Z is sulfur or a methylene group; Het' is a nitrogen-containing 5- or 6-membered heterocyclic ring such as an imidazole-,' pyridine-, thiazole-, isothiazole-, oxazole-, isoxazole-, pyrazole-, triazole-, thiadiazole-, pyrimidine-, pyrazine- or pyridazine ring, which ring is optionally substituted with lower alkyl, lower alkoxy, hydroxy, halogen or amino; and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula: where E is hydrogen, or 2 A is lower alkyl;' Y is hydrogen, lower alkyl or a guanidine-3 3 protecting group; and X' is sulfur, CHN02 or NY, where Y is hydrogen, cyano, lower alkyl or a guanidine protecting group, is reacted with a suitable compound of the formula: hydrogen. 2. Method as stated in claim 1, characterized in that a compound with the formula is reacted in a first step with an amine with the formula I^N(CH^)gNH2' and the product from this reaction is treated in a second step with a compound of the formula: 3. Method as stated in claim 2, characterized in that the first step is carried out using an excess of the amine H_N(CH„) NH„ as an up-2 2 q 2 L solvent, and the second step is carried out in the absence of a solvent agent or in the presence of a polar solvent. ■4. Method as stated in claim 1, characterized in that a compound with the formula: is reacted in a first step with a compound of the formula Het (CH2)3NH2, and the product from this reaction is reacted in a second step with a compound of the formula: 5. Method as stated in claim 4, characterized in that both steps are carried out in a polar solvent. 6. Method as stated in claim 2 or 4, where Het'(CH„) Z(CH0) is the same as Het(CH0)n, and NY <2> is the same as X', characterized in that first and second steps are carried out simultaneously without isolation of any intermediate product. 7. Process for producing a compound with the formula specified in claim 1 where W is sulfur and NY and X are both NH, characterized in that a thiourea with the formula Het(CH-) -,NHCSNH0 or Het'(CH_) Z (CH-)NHCSNH„ is alkylated with et z 5 Z 2 m 2 n Z dihaloalkane with the formula Hal(CH2 )^ Hal where Hal is chlorine, bromine or iodine, and the product is reacted with the appropriate thiourea with the formula Het'(CH„) Z(CH_) NHCSNH- or 2 m 2 n 2 Het(CH2)3NH CS NH2 . 8. Process for producing a compound with the formula stated in claim 1 where NY and X are both NH, characterized by acid hydrolysis of the corresponding compound where Y 2 is cyano and X' is NCN. 9. Process for the preparation of a compound with the formula specified in claim 1 where NY and X are both NH, characterized in that the guanidine protecting groups are removed from the corresponding compound where X <1> is NY <3> 2 3 and Y and Y are guanidine protecting groups. 10. Method as stated in one of the preceding claims, characterized by - that q is from 6 to 10. 11. Method as stated in one of the preceding claims, characterized in that Het is a 2-pyridyl ring which is optionally substituted with hydroxy, chlorine, bromine or methoxy, one 2-thiazolyl ring or one 3-isothiazolyl ring. 12. Method as stated in one of the preceding claims, characterized in that Z is sulphur, m is 1 and n is 2 and Het' is a 4-imidazolyl ring which is optionally substituted with methyl or bromine, a 2-pyridyl ring which is optionally is substituted by hydroxy, chlorine, bromine or methoxy, a 2-thiazolyl ring or a 3-isothiazolyl ring. 13. Method as stated in claim 1 for use in the production of 1,8-bis-[N1-(3-(2-thiazolyl)propyl)guanidino]octane. 14. <v> Process as stated in claim 1, for use in the preparation of 1-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]-8-[N'-(3- (2-thiazolyl)propyl)guanidino]octane.