NO791637L - INTERMEDIATE PRODUCTS FOR THE MANUFACTURE OF GUANIDINE DERIVATIVES - Google Patents

Description

The present invention relates to hitherto unknown intermediates for the production of certain N-cyano-N'-{2-[(4-methyl-5-imidazolyl)-methylthio]ethyl}-N"-alkynylguanidines, which are β-receptor blocking agents, which inhibits gastric acid secretion and which are valuable in the treatment of ulcers.

The clinical purpose in the treatment of pepsin ulcer is

to reduce gastric acid secretion based on the principle "no acid, no ulcer". The traditional therapy of pepsin ulcers involves dietary control and the use of antacids and anticholinergics.

There is some evidence that histamine may be the final common pathway in the stimulation of gastric acid secretion. This effect of histamine is mediated via I^-receptors and is not inhibited by the classic antihistamines which are I^-receptor blocking agents.

A number of specific β-receptor blocking agents (β-receptor antagonists) are now known. These compounds inhibit basal acid secretion as well as secretion by other known gastric acid stimulants and are valuable in the treatment of pepsin ulcers.

End products that can be produced using the intermediates according to the present invention are histamine β-receptor antagonists which are effective inhibitors of gastric acid secretion in mammals, including humans, and which are valuable for the treatment of pepsin ulcers. The final products in question have the general formula:

where R 1 denotes a straight-chain or branched alkynyl group containing from 3-9 carbon atoms, or are non-toxic, pharmaceutically acceptable acid addition salts thereof.

A preferred group of end products has the general formula:

where R 4 is hydrogen or methyl, or are non-toxic, pharmaceutically acceptable acid addition salts thereof. Another preferred group of end products has the j general formula: j

where R 4 denotes hydrogen or methyl, and n is an integer from 1-6, or are non-toxic, pharmaceutically acceptable acid addition salts thereof.

Another preferred group of end products has the general formula:

where R 4 denotes hydrogen or methyl, or are non-toxic, pharmaceutically acceptable acid addition salts thereof.

An even more preferred group of end products is N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N<->(2-butyn-1-yl)guanidine or non- toxic, pharmaceutically acceptable acid addition salts thereof.

Another preferred group of end products is N-. cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-1-yl)guanidine or non-toxic, pharmaceutically acceptable acid addition salts thereof.

Another preferred group of end products are N-cyano-N<1->{2-[(4-methyl-5-imidazoly1)methylthio]ethyl}-N"-(4-pentynyl)guanidine or non-toxic, pharmaceutically acceptable acid addition salts thereof.

Another preferred group of end products is N-cyano-N<1->{2-[(4-methyl-5-imidazol1)methylthio]ethyl}-N"-(2-methyl-3-butyn-2-yl) guanidine or non-toxic, pharmaceutically acceptable acid addition salts thereof.

Another preferred group is N-cyano-N<1->{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-2-yl)guanidine or non-toxic, pharmaceutically acceptable acid addition salts thereof.

The most preferred end products are N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine or non-toxic, pharmaceutically acceptable acid addition salts thereof.

The intermediates according to the present invention have

the general formula:

where R 1 has the meaning stated above and -SR 5 is a suitable leaving group, or is an acid addition salt thereof.

Preferred intermediates according to the invention are

such as lead to the above-mentioned preferred end products.

The conversion of the intermediate product according to the invention into the valuable end products can be carried out by reacting a compound with the formula: or an acid addition salt thereof, with a compound of the formula:

15

where R and R have the meaning indicated above, after which the prepared compound I is, if desired, converted into an acid addition salt thereof, or a prepared acid addition salt of the compound I is converted into the corresponding free base.

The conversion of the described intermediate to a preferred final product is described in the following reaction schemes.

The reaction is carried out in a non-reactive solvent at a temperature above room temperature. The substituent R can e.g. be lower alkyl, aryl, substituted aryl (eg p-nitrophenyl)aralkyl, -CHgCN, -CH2COOH, -Cf^COOR<1> or the like. The 2-[(4-methyl-5-imidazolyl)methylthio]ethylamine starting material can be prepared as described in US-PS 3,950,353.. The distributed cyanodithioiminocarbonate used as starting material in the preparation of N-cyano-N'-propargyl-SR-isothiourea (see step b in ex. 2) can itself be prepared using methods described in "J. Org. Chém." 32, 1566 (1967). where R 5 has the above meaning and P means a suitable sulfhydryl protecting group known per se.

In the present description, the term non-toxic, pharmaceutically acceptable acid addition salt means the mono- or di-salt of a compound produced according to the invention with a non-toxic, pharmaceutically acceptable organic or inorganic acid. Such acids are known and include e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, succinic acid, oxalic acid, benzoic acid, methanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, tartaric acid, citric acid and camphorsulfonic acid. The salts are produced in a manner known per se.

The term lower-alkyl refers to straight-chain or branched alkyl groups containing from 1-6 carbon atoms.

For therapeutic use, the pharmacologically active compounds referred to herein are usually administered as a pharmaceutical preparation comprising, as a substantially active ingredient, at least one such compound in base form or in the form of a non-toxic, pharmaceutically acceptable acid addition salt in connection with a pharmaceutically acceptable carrier.

The pharmaceutical preparations can be administered orally, parenterally or rectally as suppositories. A wide variety of pharmaceutical forms can be used. If a solid carrier is used, the preparation can thus be tableted, placed in a hard gelatin capsule in powder or pill form, or in the form of a pastille or a bolche. If a liquid carrier is used, the preparation can be a syrup, an emulsion, a soft gelatin capsule, a sterile injection solution or an aqueous or non-aqueous liquid suspension. The pharmaceutical preparations are produced using conventional methods, which are suitable for the desired preparation form.

Preferably, each dosage unit contains the active ingredient in an amount from approx. 50 mg to approx. 250 mg, and it is most preferred to use amounts from approx. 100 mg to approx. 200 mg. The active ingredient is preferably given in equal doses from 2-4 times a day. The daily dose interval will preferably be from 250 mg to approx. 1000 mg and most preferably from approx. 500 mg. to approx. 750 mg.

It has been demonstrated that histamine H2 receptor antagonists are effective inhibitors of gastric acid secretion in animals and humans,

see Brimblecombe et al., in "J. Int. Med. Res.", 3, 86 (1975). Clinical evaluation of the histamine H2 receptor antagonist, cimetidine, has shown that it is an effective therapeutic agent for the treatment of pepsin ulcers, see Gray et. al., in "Lancet", 1 (8001), 4

(1977). The compound prepared in examples 1 and 2 below (hereafter called BL-5641) has been compared with cimetidine in various tests and has been shown to be more potent than cimetidine both as a histamine H2 receptor antagonist in isolated guinea pig atria, and as an inhibitor of gastric secretion in rats and dogs. Furthermore, gastric secretion studies in dogs suggest that BL-5641 has a longer duration of action than cimetidine at the same doses.

Histamine H2 receptor antagonism studies

on isolated guinea pig atria',

Histamine evokes concentration-related increases in contractile velocity of isolated spontaneously beating guinea pig right atria. Black et al., described in "Nature", 236, 385

(.1972) involved receptors such as histamine H-receptors in this effect of histamine, when they reported the properties of burimamide, a competitive antagonist for these receptors. Subsequent investigations by Hughes and Coret, "Proe. Soc.

Exp. Biol. Med.", 148, 127 (1975) and Verma and McNeill, "J. Pharma-col. Exp. Ther.", 200, 353 (1977), supports the conclusion of Black et al., which states that the positive chronotropic effect of histamine in isolated right guinea pig atria is mediated via histamine H2 receptors. Black et al. in "Agents and Actions", 3, 133 (1973) and Brimblecombe et al. in "Fed. Proe.", 35, 1931

(1976) have used isolated right guinea pig atria as a means

to compare the activities of histamine H,, receptor antagonists. The present comparative studies were carried out using a modification of the method described by Reinhardt et al. in Agents and Actions, 4, 217 (1974).

Male guinea pigs of the Hartley strain with a body weight of 350-

450 g was killed by a blow to the head. The heart was excised and placed in a Petri dish with oxygenated (95% O^ t 5% CO 2 ) modified Krebs solution (g/l: NaCl 6.6, KCl 0.35, MgSO 4 -7H 2 O 0.295, KH 2 PO 40, 162, CaCl 2 O, 238, NaHCO 3 2.1 and dextrose 2.09). The spontaneously beating right atrium was dissected free of

other tissue, and a silk thread (4-0) was attached to each end. The atria were suspended in a 20 ml muscle chamber containing oxygenated modified Krebs solution, which was maintained at 32°C. Atrial contractions were recorded isometrically using a "Grass FT" 0.03 force displacement transducer, and recordings of contractile force and velocity were made with a "Beckman RP Dynograph".

The atrium is subjected to a resting tension of 1 g and allowed to equilibrate for 1 hour. After the equilibration period had expired, a submaximal concentration of histamine dihydrochloride (3 x 10 M) was added to the bath and washed out to prime the tissue. Next, histamine was added to the bath in a cumulative manner using one \log 10 intervals, so that obtained molar final bath concentrations of, 1 x 10~<7> to 3 x 10~<5>. The histamine-induced increase in atrial rate was allowed to stabilize before the next successive concentration was added. The maximum reaction invariably occurred at a concentration of 3 x 10 ^ M. The histamine was washed out several times, and the atrium was allowed to return to control--5

the speed. The test compound (1 x 10 M) was then added, and after 30 minutes of incubation, the histamine concentration reaction was repeated adding higher concentrations as needed.

The histamine ED^Q values (the concentration of histamine which increased the contractile velocity by 50% of the maximum) and 95% significance limits before and after addition of the test compound were obtained by regression analysis as described by Finney, in "Probit Analysis",

3rd ed., Cambridge (1971). The concentration-response curve shift factors were calculated as follows: The factor obtained for BL-5641 was then expressed relative to the factor obtained for cimetidine.

The results obtained in these studies are summarized in Table I. Cimetidine and BL-5641 shifted the histamine concentration-response curve to the right by a factor of, respectively. 6.6 and 32.7. Based on the concentration-response curve shift factors, BL-5641 was approx. 5.7 times more active than cimetidine as a histamine H2-receptor antagonist in isolated right guinea pig atria.

Determination of gastric antisecretory activity.

in the 2 Hour Pyloric Banded (Shay) Rat The pyloric ligation procedure in the rat was devised by Shay et al., "Gastroenterology", .5, 5.3 (1945) for the study of perforating gastric ulcers; when the method became known, however, it was also used, as a means of studying the gastric secretion of the rat, Shay et al., "Gastroenterology", 26, 906 (1954), Brodie, D.A., "Am. J. Dig. Dis." , 11, 231 (1966). A modification of this procedure is used today to assess compounds for gastric antisecretory activity.

Male Long Evans rats with a body weight of 280-300 g are used. The animals are placed in individual cages and starved for .24 hours with free access to water. Under ether anesthesia, the stomach' is accessed through a midline incision, and a ligature of cotton thread is placed around the pylorus. After closure of the wound, ether administration is stopped, and either BL-5641, cimetidine, or a vehicle is administered intraperitoneally in a volume of 1 mg/kg. BL-5641 and cimetidine were dissolved with one equivalent of HCl and brought to the correct volume with water. The animals are placed back in their cages from which the water bottles have been removed, and they are killed 2 hours later with ether. The stomach is removed, and the two-hour stomach collection is emptied into a graduated test tube to determine the volume. Titratable acidity is measured by titrating a 1 ml sample to pH 7.0 with 0.02N NaOH using an autoburette and an electrometric pH meter (Radiometer). The titratable amount of acid is calculated in microequivalents by multiplying the volume in ml by the acid concentration in milliequivalents per litres. The percentage inhibition of acid release is calculated as follows:

% inhibition of acid release =

The results obtained with BL-5641 and cimetidine are indicated

in table 2..

These results show that BL-5641 is at least as potent as cimetidine in the two-hour pyloric ligation test in rats for the inhibition of gastric acid secretion.

Determination of gastric antisecretory activity

in dogs with gastrocolic fistula

Thomas-type stainless steel cannulas [Thomas, J.E., “Proe.

Soc. exp. Biol. Med.", 46, 260 (1941)] was inserted into the stomach of beagle dogs of body weight 10-12 kg near the region of the pyloric gland at the greater curvature for the creation of a chronic gastrocolic fistula. The animals are allowed to rest at least for 2 months prior to any testing. Dogs are fasted overnight (approximately 18 hours) with water ad libitum prior to each trial. Dogs are placed in a sling and an approximately 20.3 cm needle insertion catheter with an approximately 5 cm needle no. 17 is inserted into a leg vein for use in administering the drug. Gastric secretions are collected every 15 minutes by gravity drainage from the open cannula. Basal secretions are collected in 2 successive 15 minute periods, and if these prove to be too large (>4 ml/15 min.; pH <5.0), the animal is not used. A modification of the method described by Grossmann and Konturek in "Gastroenterology", 66, 517 (1974) was followed. Immediately after the second basal collection, histamine was infused (100 pg/kg/hour) for 90 minutes using a Harvard infusion pump at a volume of 6 ml/hour. At this point, either BL-5641, cimetidine (dissolved with an equivalent of HG1 and brought to the correct volume with normal saline) or normal saline was injected rapidly (within 30 sec.) in a volume of 0.1 ml/ kg, and then the infusion of histamine was continued for a further 150 min. (total infusion time is 4 hours). Every 15 minute sample of gastric juice was measured to the nearest 0.5 ml, and titratable acidity against 0.02N NaOH (end point pH 7.0) was measured with an autoburette and pH meter (Radiometer). The percentage inhibition of acid release is calculated as described in connection with the pylorus-ays stringing experiment on rats.

Equimolar doses of BL-5641 and cimetidine were administered to

5 different dogs, and the results obtained are indicated in the table

III.

Both BL-5641 and cimetidine produced an immediate inhibitory effect on gastric acid secretion. However, the degree of inhibition at equimolar doses was consistently greater and of longer duration with BL-5641 than with cimetidine. These results show that BL-5641 as an inhibitor of histamine-induced gastric acid secretion

in dogs is more powerful and/or longer acting than cimetidine.

The invention shall be explained in more detail by means of the following examples.

Example 1

N-cyano-N'-{2-[(4-methyl-5-imidazoly1)methylthio]ethyl}-N"-propargylguanidine

A mixture of 3.00 g or 0.0111 mol of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea and 2.50 g or 0.045 mol of propargylamine in 60 ml of acetonitrile was stirred under reflux for 65 hours and then heated in a stainless steel pressure vessel to 120-130°C for 38 hours. The reaction mixture was cooled, decanted from a tar and then evaporated to obtain 3.57 g of a gum. This material was placed on silica gel (100-200 mesh) and eluted with

a mixture of 97 parts methylene chloride and 3 parts methanol. The product obtained from a middle fraction was crystallized by trituration under acetonitrile and then recrystallized from acetonitrile to give 0.236 g or 7.7% of. the title compound with melting point 146-149.5°C.

Analysis calculated for:<C>12H16<N>6S: C 52'15'' " H 5'83; N 30.41. Found: C 51.86; H 5.81; N 30.70.

Example 2

N- cyano- N'-{ 2-[( 4- methyl- 5- imidazolyl) methylthio 3-ethyl}- N"- propargylguanidine

a.. N- cyano- N'- propargyl- S- methylisothiourea ( A)

A solution of 16.00 g or 0.109 mol of dimethylcyanodithioiminocarbonate and 6.03 g or 0.109 mol of propargylamine in 320 ml of acetonitrile was stirred under reflux for 4 hours and then at 25°C for 12 hours. Workup gave the title compound A in an amount of 13.58 g or 81% and with a melting point of 160-164°C..

b. N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine

A solution of 11.71 g or 0.0765 mol of A and 13.10 g or 0.0765 mol of 2-[(4-methyl-5-imidazolyl)methylthio]ethylamine in 250 ml of methanol was heated under reflux for 64 hours.

The solvent was removed by evaporation, and the residue was applied to silica gel (100-200 mesh) and chromatographed by gradient elution using methylene chloride/methanol;

the latter fractions yielded 4.0 g of the title compound. Recrystallization from acetonitrile gave purified product with melting point 150-152.5°C which was identical (ir, nmr, tic) to the product prepared

in ex. 1.

Example 3

N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-2-butyn-1-yl)guanidine

a. N-(2-butyn-l-yl)-N'-cyano-S-methylisothiourea (B)

A solution of 10.00 g or 0.0684 mol of dimethylcyanodithioiminocarbonate and 4.73 g or 0.0684 mol of 2-butyn-1-amine.

in 200 ml of acetonitrile is stirred at 25°C for 0.5 hour and then below

reflux for 2.5 hours. The mixture is cooled and then filtered to obtain the title compound B with melting point 180-183°C. b. N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-butyn-1-yl)guanidine A solution of 6.82 g or 0, 0407 mol B and 6.98 g or 0.0407 mol 2-[(4-methyl-5-imidazolyl)methylthioethylamine in • 140 ml of methanol are heated under reflux for 40 hours Work-up and chromatography as described above in ex. 2 gave the title compound When the title compound was prepared according to the usual method of Example 1, it melted at 128-130° C. Example 4

N-cyano-N'-{2-[(4-methyl-5-imidazoly1)methylthio]ethyl)-N"-(3-butyn-1-yl)guanidine The usual procedure according to ex. 1 was repeated, except that the propargylamine used therein was replaced by an equimolar amount of 3-butyn-1-amine, and the title product was thereby prepared.

Example 5

N- cyano- N'-{ 2-[( 4- methyl- 5- imidazolyl) methylthio] ethyl}- N"-( 4- pentyn-1- yl) guanidine

The usual procedure according to, e.g. 1 was repeated, except that the propargylamine used therein was substituted. with an equimolar amount of 4-pentyn-1-amine, and the title product was thereby prepared with a melting point of 99-103°C.

Example 6

N- cyano- N'-{ 2-[( 4- methyl1- 5- imidazoly1) methylthio] ethyl}- N"-( 2- methyl- 3- butyn-2- yl) guanidine

The usual procedure according to e.g. 3 was repeated, except that the 2-butyn-1-amine used therein was replaced by an equimolar amount of 1,1-dimethylpropargylamine, and the title product was thereby prepared. •

Example 7

N- cyano- N'-{ 2-[( 4- methyl- 5- imidazolyl) methylthio] ethyl}- N"-( 3- butyn-2- yl) guanidine

The usual procedure according to e.g. 3 was repeated, except that the 2-butyn-1-amine used therein was replaced by an equimolar amount of 1-methylpropargylamine, and the title product was thereby prepared.

Example 8

N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio 3ethyl}-N"-(2-butyn-1-yl)guanidine

A mixture of 3.00 g or 0.0111 mol of N-cyano-N*-{2-[(4-methyl-5-imidazolyl)-methylthio3-ethyl}-S-methylisothiourea and

3.07 g or 0.0445 mol of 2-butyn-1-amine in 60 ml of propionitrile was stirred under reflux for 40 hours. TLC analysis of an aliquot of the reaction mixture showed traces of the isothiourine starting materials, so the mixture was refluxed for an additional 6 hours and then stirred at room temperature for 64 hours. The solvent together with an excess of amine was removed under reduced pressure, and the remaining gum was placed on silica gel (100-200 mesh) and eluted with a mixture of 97 parts methylene chloride and 3 parts methanol. The middle fractions were combined and evaporated to give 1.81 g of yellow gum. The gum was dissolved in 20 ml of ethyl acetate and crystallized at -15°C. The resulting pale yellow solid in an amount of 1.2 g was dissolved in 11 ml of hot acetonitrile and recrystallized at -15°C, and a yield of 1.072 g with melting point 128-130°C was obtained.

Analysis calculated for C12<H1>s<N>6<S:>

C 53.77; H 6.25; N 28.94; S 11.08.

Found: c 53.72; H 6.29; N 29.62; S 11,34. . Example 9 N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl)-N"-(3-butyn-1-yl)guanidin•

A mixture of 3.00 g or 0.0111 mol N-cyano-N'-{2-[(4-methyl-5-imidazolyl)-methylthio3ethyl}-S-methylisothiourea and 3.13 g or 0.453 mol 3-butyne -1-amine in 60 ml of propionitrile was stirred at reflux for 40 hours. The solvent was evaporated to give 5.40 g of a syrup which was applied to 70 g of 100-200 mesh silica gel and chromatographed by gradient elution using methylene chloride/methanol.

TLC (silica gel, 90 CH 2 Cl 2 /10 MeOH) indicated that fractions 9-12 were pure and should be combined. Fractions 1-8 showed fast moving impurities. Fractions 13 and 14 showed some subsequent impurities. Fractions 9-12 were combined and evaporated to 1.72 g of a yellow gum. The gum was dissolved in 11 mL of nitromethane and crystallized at -15°C to give 1.18 g of a pale yellow solid which was recrystallized from 9 mL of nitromethane to give 0.987 g, mp 86-89°C, after softening at 85°C.

IR and NMR (100 MHZ) were clean and consistent with the desired structure. NMR showed the product was solvated with c. 0.08 mol of nitromethane. ,

Analysis calculated for C13H18N6S'0'0'8(CH3N02J :

C 53.21; H 6.22; N 28.84; S 10.86. Found: C 52.68; H 6.28; N 29.39; S 11,22.

52.87; 6.02; 29.50;

Example 10

N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(4-pentyn-1-yl)guanidine

A mixture of 3.00 g or 0.0111 mol of N-cyano-N'-{2-

[(4-methyl-5-imidazolyl)-methylthio]ethyl)-S-methylisothiourea and 3.69 g or 0.0445 mol of 4-pentyn-1-amine in 60 ml of acetonitrile were stirred under reflux for 24 hours and then allowed allowed to stand at room temperature for 96 hours. The solvent and excess amine were removed under reduced pressure, and the remaining yellow gum was purified by chromatography on 50 g of 100-200 mesh silica gel using gradient elution with methylene chloride/methanol (99:1-96:4). The middle fractions which were found to be pure by TLC were combined and evaporated to give 1.91 g of yellow gum, which was crystallized from 18 ml of ethyl acetate at -15°C. The resulting white solid in an amount of 1.25 g was recrystallized at -15°C from 10 ml of acetonitrile, and 1.063 g of the product with melting point 99-103°C was obtained.

Analysis calculated for C^H^QNgS:

C 55.24; H 6.52; N 27.61; S 10.53. Found: C 55.43; H 6.58; N 28.26; P10.97. Example 11

N- cyano- N'-{ 2-[( 4- methyl- 5- imidazolyl) methylthio] ethyl}- N"-propargylguanidine

A mixture of 10.0 g or 0.0371 mol of N-cyano-N'-{2-[(4-methyl-1-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea and 20 ml or 0.325 mol of distilled propargylamine in 50 ml of methanol was stirred under reflux under a pressure of nitrogen atmosphere (nitrogen purge) for 20.5 hours. The solvent and excess amine were then removed by evaporation, leaving a tan oil which crystallized easily. Trituration of the crude product under 30 ml of isopropanol gave the title compound as a whitish fragile solid in an amount of 8.11 g or 79%. The melting point was 146-148, 5°C..

Example 12

N- cyano- N'-{ 2-[( 4- methyl- 5- imidazolyl) methylthio] ethyl}- N"-propargylguanidine

A mixture of 100 g or 0.371 mpl of N-cyanp-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea and 150 ml or 2.44 mol of distilled propargylamine in 500 ml of methanol was stirred under reflux under a pressure of nitrogen atmosphere (nitrogen purge) for 22 hours. The reaction mixture was cooled and the solvent and excess amine were removed by evaporation, leaving an amber oil which readily crystallized. The crude product was triturated under 250 ml of isopropanol, cooled at 0°C for 2 hours and collected by filtration. The filter cake was washed with cold isopropanol and dried in vacuum over ^2°s for 16 hours. The dried title product was an off-white dense solid in a yield of 73.5 g or 71.7%. The melting point was 147-149°C. Example 13

Recrystallization of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)-methylthio]ethyl}-N"-propargylguanidine

The final products obtained in ex. 11 and 12 are combined, giving a total of 81.3 g, and this amount is dissolved in 1000 ml of hot isoproanol, filtered through "Super-Cel" and allowed to cool at room temperature for approx. 68 hours. The resulting crystalline product was obtained by filtration, was washed with cold isopropanol, powdered and dried in a heated desiccator under high vacuum for approx. 4 5 hours. The yield was 72.4 g or 89%, the melting point was 149-151°C. HPLC analysis showed that the purity was approx. 99.5%. The NMR spectrum at 100 MHz was clean and consistent.

Analysis calculated for ci2Hl6<N>6S:

C 52.15; H 5.83; N 30.41; S 11.60.

Found: C 52.42; H 5.94; N 30.51; S 11.35.

Example 14

N-cyano-N'-(2-methyl-3-butyn-2-yl)-S-methylisothiourea A solution of dimethylcyanodithioimidocarbonate in an amount of 9.0 g or 0.0615 mol and 1,1-dimethylpropargylamine (90% amine, the rest water) in an amount of 5.68 g or 0.00615

moles in 125 ml of acetonitrile were converted under reflux

stirred for 13 days. The reaction mixture was evaporated under reduced pressure, and the residue was chromatographed on silica gel. The appropriate fractions were combined and the product recrystallized

from to.luen to obtain the title compound with a melting point of 128-130.5°C.

Analysis calculated for CgH^N^S '•

C 53.01; H 6.11; N 23.18; S 17.69. Found: C 52.89; H 6.13; N 23.15; S • 17/65.7 Example 15

N-cyano-N'-(2-prdpyn-l-yl)-S-benzylisothiourea Dibenzylcyanodithioimidocarbonate (prepared by means of the method described in "Ann.", 355, 196 (1907)) was reacted with approx. an equimolar amount of propargylamine according to . the one in ex. 14 described method, and the title compound was thereby prepared....

Example 16

N-cyano-N'-(2-propyn-1-yl)-S-(2,4-dinitrophenyl) isothiourea

Di-(2,4-dinotrophenyl)cyanothioimidocarbonate (prepared from 2,4-dinitrofluorobenzene and dipotassium cyanodithioimidocarbonate) was reacted with approx. an equimolar amount of propargylamine according to that in ex. 14 described general procedure, and the title compound was thereby prepared.

Claims (8)

1. Intermediate for the preparation of a compound of the general formula: where R" <*> " denotes a straight-chain or branched alkynyl group with from 3-9 carbon atoms, or a non-toxic, pharmaceutically acceptable acid addition salt thereof, characterized in that it has the general formula: ; where R has the meaning given above and R denotes any such substituent that -SR^ is a suitable leaving group or an acid addition salt thereof.;2. • Intermediate according to claim 1, characterized in that R means (lower) alkyl, phenylalkyl or phenyl with one or two substituents which can independently be nitro, chlorine or bromine.; 3. Method according to claim 2, characterized in that R"*" means: where n is an integer from 1-6 and R 4 is hydrogen or methyl. 4. Intermediate product according to claim 2, characterized in that R means: <...> where R 4 is hydrogen or methyl. 5. Intermediate product according to claim 2, characterized in that R1 means: where R 4 is hydrogen or methyl. 6. Intermediate product according to claims 1-5, characterized in that R 1 is (lower) alkyl. 7. Intermediate product according to claims 1-6, characterized in that it has the formula: where R 1 is (lower) alkyl, or an acid addition salt thereof. 8. Intermediate product according to claim 7, characterized in that it has the formula: or an acid addition salt thereof.