CS257287B2 - Process for the preparation of N- [2- (2-guanidinothiazol-4-yl) methylthio] ethyl / ethanediimidamides - Google Patents

Abstract

A process for the preparation of N-[2-[(2-guanidinothiazol-4-yl)-methylthio]ethyl]ethanediimidamides of the general formula II, where R* and R5 independently of each other each represent hydrogen or C1-4-alkyl, and their acid addition salts, characterized in that the compound of the general formula IV is treated with a strong mineral acid, and the resulting product is isolated, optionally in the form of an acid addition salt. The substances produced are useful as intermediates for the preparation of pharmacologically active substituted 3,4-diamino-1,2,5-thiadiazoles.

Description

The invention relates to a process for the preparation of N- [2- (2-guanidinothiazol-4-yl) methylthiethyl] ethanediimidamides which are useful intermediates.

In our related Czechoslovak Pat. No. 257,276 describes the preparation of substituted 3,4-diamino-l, 2,5-thiadiazole of formula I, R ^b NH

CHjSCHjCHjNH

NHn

NHR ¹ (I) wherein

R ¹ and R 5 independently of one another are alkyl having 1 to 4 carbon atoms, consisting of cyclizing compounds of formula II R ^b -NH NH ₂ .CH ₂ SCH ₂ CH ₂ NH. .NHR ¹ \ _c = n-7Y M (II) in which

R ¹ and R ⁵ are as defined above, or acid addition salts thereof.

The compounds of formula I and their non-toxic, pharmaceutically acceptable salts are potent histamine H 1 -receptor antagonists, inhibit gastric acid secretion, and useful in the treatment of peptic ulcers and other conditions associated with pathological hypersecretion.

The present invention relates to a process for the production of starting materials for work according to our above-cited Czechoslovak patent specification.

Accordingly, the invention provides a method for producing N- / 2- £ (2-guanidithiazol-4-yl) metylthiojetyl / etandiimidamidů formula II R ^b NH, C = N _NH2 '

ch ₂ sch ₂ ch ₂ nh. , nhr ¹

HN NH (II) in which r! and r5 are each independently hydrogen or C1-C4alkyl, and their acid addition salts, characterized in that:

R ¹ and R ⁵ are as defined above, with a strong mineral product is isolated, optionally in the form of an acid addition salt.

acid and resulting

Hydrochloric acid is preferably used as a strong mineral acid. The reaction according to the invention can be carried out in an inert solvent, preferably in methanol. The reaction temperature is not critical; most conveniently the reaction is carried out at room temperature. The compounds of formula (IV) are known or can be readily prepared by the methods described in our U.S. Patent No. 4,494,508.

At present, N- [2- (2-guanidinothiazol-4-yl) methylthio] ethyl] ethanediimidamide appears to be the most preferred intermediate of formula (II).

/

The compounds of formula (II) are normally isolated and stored as acid addition salts, for example, trihydrochlorides. When these salts are used, the corresponding free base must be liberated from the salt according to our above-cited Czechoslovak patent specification, which is preferably done in situ by simply adding the appropriate amount of organic base to the solution of the compound of formula II.

For example, when 1 mole of a compound of formula (II) is used in the form of the trihydrochloride, 3 mole of a suitable organic base is added. Suitable organic bases include tertiary amines such as trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, pyridine, N-methylmorpholine, N-methylpiperidine, 1,4-diazabicyclo [2.2.2] octane , 1,8-diazabicyclof5,

4,0] undec-7-ene-1,5-diazabicyclo [4,3-a] non-5-ene and the like.

The invention is illustrated by the following non-limiting example. This example describes a two-step reaction in which, in the first reaction step, the desired intermediate of formula (II) is prepared by the process of the invention, which is then reacted in crude state according to our above-cited Czechoslovak patent specification to produce the corresponding compound of formula (I).

Example

A. N- [2- (2-Guanidinothiazol-4-yl) methylthio] ethyl] ethanediimidamide trihydrochloride

To a suspension of 5.25 g (13.7 mmol) of 3-amino-4- [2- (2-guanidinothiazol-4-yl) methylthio] ethylamino) -1,2,5-thiadiazole-1-oxide (prepared according to the published British No. 2,067,987) in 105 ml of methanol, 80 ml of concentrated hydrochloric acid is added, immediately forming a yellow solution. The solution was stirred at room temperature for 4.25 hours, then evaporated to near dryness and the residue triturated with acetone. After filtration and drying, the title compound is obtained.

B. 3-Amino-4- [2H (2-guanidinothiazol-4-yl) methylthio] ethylamino] -1,2,5-thiadiazole

To a mixture of 5.65 g (13.7 mmol) of crude N- [2- (2-guanidinothiazol-4-yl) methylthio-ethyl] ethanediimidamide trihydrochloride (prepared in Step A), 50 mL of dichloromethane and 5.7 mL of triethylamine was added. 5.44 g (13.7 mmol) of Ν, Ν'-thiobisphthalimide (dimethylformamide solvate) are added and the resulting mixture is stirred for 1 hour. To the resulting thick suspension was added 40 ml of 2N sodium hydroxide and the solvents were decanted off from the gum residue.

The resinous residue was isolated, washed with 40 ml of 2N sodium hydroxide and water and then dissolved in methanol. After concentration of the solution, 3.0 g of crude product is obtained which, after purification by flash chromatography on 90 g of silica gel (0.07-0.038 mm), eluting with ethyl acetate / methanol (97: 3), gives 2.44 g ( 54%) of the title compound. This product was treated with one equivalent of cyclohexylsulfamic acid in 35 mL of acetone to give the corresponding salt, which was then recrystallized from 95% aqueous ethanol. The title compound is obtained as cyclohexyl sulfamate, m.p. 171-173.5 ° C.

For C 5HHj ^NgSS · CgHH; ^NO ^ S requires C, 35.34; H, 5.34; N, 24.73; S, 25.16; Found: C, 35.39; H, 5.28; N, 24.23; S, 24.89.

object of the invention

Claims (1)

object of the invention Preparation of N- / 2 £ (2-guanidinothiazol-4-yl) metylthioJetyl / etandiimidamidů formula II R ^b NH. nh ₂ ^ ch ₂ sch ₂ ch ₂ nh NHR ¹ // Λ HN NH (II) wherein R ¹ and R ³ are each independently hydrogen or C 1 -C 4 alkyl, and their acid addition salts, characterized in that the compound of the formula IV R ⁵ NH _x ^ nh / i (IV) wherein R ¹ and R ⁵ are as defined above, act with a strong mineral acid, preferably hydrochloric acid, optionally in an inert solvent, and the resulting compound of formula II is isolated, optionally in the form of an acid addition salt. Severography, n. P., MOST Price 2,40 Kčs