GB2038798A

GB2038798A - (Hydroxymethyl imidazolyl) methylthioethyl guanidine derivatives

Info

Publication number: GB2038798A
Application number: GB7931198A
Authority: GB
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1978-12-06
Filing date: 1979-09-07
Publication date: 1980-07-30
Also published as: GB2038798B

Abstract

Compounds of the formula <IMAGE> wherein R<1> is a C3-9 alkynyl group and non-toxic pharmaceutically acceptable acid addition salts thereof, are potent anti-ulcer agents. The compounds may be prepared by reacting appropriate N-cyano N' mercaptoethyl-N'' C3-9 alkynyl guanidines with suitable imidazole derivatives.

Description

SPECIFICATION Chemical compounds The present invention relates to certain N-cyano-N'-42-[(4-hydroxymethyl-5-imidazolyl)methylthio]ethyl}-N'- alkynylguanidines which are H2-receptor blocking agents, which inhibit gastric acid secretion and which are useful in the treatment of ulcers.

The clinical objective in the treatment of peptic ulcer disease is to decrease gastric acid secretion, based on the principle "no acid, no ulcer". Traditional peptic ulcer disease therapy involves control of diet and the use of antacids and anticholinergics.

There is evidence indicating that histamine may be the final common pathway for stimulation of gastric secretion. This effect of histamine is mediated via H2-receptors and is not inhibited by the classical antihistamines, which are H1-receptor blockers. A number of specific H2-receptor blocking agents (H2-receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as secretion by other known gastric acid stimulants, and are useful in the treatment of pepetic ulcers.

Burimamide (Ila) was the first clinically effective H2-receptor antagonist. It inhibits gastric secretion in animals and man, but oral adsorption is poor.

Ia; R2=H, Z=CH2, X=S Burimamide b; R2=CH3, Z=S, X=S Metiamide c; R2=CH3, Z=S, X=NCN Cimetidine Metiamide (llb), a subsequently evaluated H2 antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (llc) is as effective an H2 antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug. The half-life of cimetidine is relatively short, thereby necessitating a therapeutic regimen of multi daily doses of 200-300 mg. tablets. There is thus a need for anti-ulcer agents which are longer acting andlor more potent than cimetidine.

Reviews on the development of H2 antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, etal., Federation Proceedings, 35,1924(1976), in Drugs of the Future, 1,13 (1976), and in references cited therein. Relevant patents are as follows: U. S.Patent 3,590,333 discloses inhibitors of histamine-stimulated gastric secretion having the formula

wherein A, taken together with the carbon atom, represents an unsaturated heterocyclic ring containing at least one nitrogen and may contain an additional hetero atom such as sulfur or oxygen; X1 is interalia hydrogen, (lower)alkyl, hydroxyl, trifluoromethyl, benzyl, halogen or amino; X2 is interalia hydrogen; k isO to 2 and m is 2 or3, provided that the sum of k and mis 3 or4; Y is oxygen, sulfur or NH; E is NR2 in which R2 is hydrogen, nitro or cyano; and R1 is hydrogen, (lower)alkyl or di(lower)alkylamino(lower)alkyl.

Belgian Patent 804,144 (Farmdoc 19437V) discloses inhibitors of histamine-stimulated gastric acid secretion having the formula

in which HET is a 5 or 6 membered heterocyclic ring containing nitrogen (imidazole is one of 12 named heterocycles), which may be substituted by halogen, (lower)alkyl, trifluoromethyl, hydroxyl or amino; m and n are 0-4 and the sum of m and n is from 2 to 4; Z is sulfur, oxygen, NH or CH2; and R1 is hydrogen or (lower)alkyl.

Belgian Patent 841,814 (Farmdoc 90568X) discloses inhibitors of histamine-stimulated gastric secretion having the formula

in which HET is one of eight named heterocyclic rings (including imidazole) which may be substituted by (lower)alkyl, hydroxyl, amino or halogen; Z is sulfur or CH2; X is S, CHNO2, NCN or NH; Y is NH2, (lower)alkylamino, di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl, trifluorethyl or (CH2)nR in which n is 1-12 and R is OH, (lower)alkoxy, NH2 or (lower)alkylamino; provided that, when X is NH, Y is trifluoroethyl or (CH2)nR; and when X is NCN, Y may not be amino or (lower)alkyl.

Belgian Patent 843,840 (Farmdoc 05613Y) discloses histamine H2-receptor antagonists having the formula

wherein Z is sulfur or CH2; n is 2 or 3; Xis sulfur, CHNO2 or NCN; and Y is interalia hydrogen or (lower)alkyl.

U. S. Patent 4,112,234 discloses histamine H2-receptor inhibitors of the formula

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, and processes for the preparation thereof.

The present invention provides histamine H2-receptor antagonists which are effective inhibitors of gastric secretion in animals, including man, which are useful in the treatment of peptic ulcer disease, and which have the formula:

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, or non-toxic pharmaceutically acceptable acid addition salts thereof.

A preferred embodiment of the invention is a compound of the formula:

wherein R3 is hydrogen or methyl, or a nontoxic pharmaceutically acceptable acid addition salt thereof.

Another preferred embodiment of the invention is a compound of the formula

wherein R3 is hydrogen or methyl and n is an integer of from 1 to 6, inclusive, or a nontoxic pharmaceutically acceptable acid addition salt thereof.

Another preferred embodiment of the invention is a compound of the formula

A more preferred embodiment of the invention is N-cyano-N'-{2-[(4-hydroxymethyl-5 imidazolyl)methylthio]ethyl)-N"-(2-buty -yl)guanidine or a nontoxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred embodiment of the invention is N-cyano-N'-{2-[(4-hydroxymethyl-5 imidazolyl)methylthio]ethyl)-N"-(3-buty -yl)guanidine or a nontoxic pharmaceutically acceptable salt thereof.

Another more preferred embodiment of the invention is N-cyano-N'-12-[(4-hydroxymethyl-5- imidazolyl)methylthiojethyl}-N"-(4-pentyn-1 -yl)guanidine or a nontoxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred embodiment of the invention is N-cyano-N'-(2-[(4-hydroxymethyl-5 imidazolyl)methylthio]ethylE-N"-(2-methyl-3-butyn-2-yl)guanidine or a nontoxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred embodiment of the invention is N-cyano-N'-(2-[(4-hydroxymethyl-5 imidazolyl)methylthio]ethyl}-N"-(3-butyn-2-yl guanidine or a nontoxic pharmaceutically acceptable acid addition salt thereof.

The most preferred embodiment of the invention is N-cyano-N'42-[4-hydroxymethyl-5- imidazolyl)methylthio]ethyl}-N"-propargylguanidine or a nontoxic pharmaceutically acceptable acid addition salt thereof.

In another aspect, this invention relates to a process for the preparation of a compound of the formula

wherein R' is a straight or branched chain alkynyl group containing from 3 to 6 carbon atoms inclusive, or a nontoxic, pharmaceutically acceptable salt thereof, which process comprises reacting a compound of the formula

wherein R1 is as described above, with about an equimolar amount of a compound of the formula

in which

is a conventional acyl group utilized to protect a hydroxyl group and Z is a conventional leaving group, and preferably an acid addition salt thereof, in an inert organic solvent, and preferably in the presence of a base; and subsequently removing the

Suitable leaving groups Z for use in this reaction are well-known to those skilled in the art.They include, for example, fluoro, chloro, bromo, iodo, -03SR5 wherein R5 is (lower)alkyl [e.g. methanesulfonate], aryl, substituted aryl [e.g. benzenesulfonate, p-bromobenzenesulfonate or p-toluenesulfonate], -O3SF, acetoxy and 2,4-dinitrophenoxy. For convenience and economy we normally prefer to utilize compound IV in which Z is chloro.

In the process of this invention, the compound of Formula IV preferably is utilized in the form of an acid addition salt. Compound IV is relatively unstable in its free base form and therefore is preferably prepared and stored as an acid addition salt. Although the free base of the compound of Formula IV may be re-generated prior to the reaction, no advantage is obtained by so doing. It will be appreciated by those skilled in the art that any inorganic acid or organic acid may be utilized to form the acid addition salt of compound IV, e.g. hydrochloric, sulfamic, sulfuric, oxalic, benzoic, succinic, acetic, nitric, citric or the like. For convenience and economy we normally prefer to utilize compound IV in the form of its hydrochloride.

The reaction of compounds Ill and IV to produce compound I may be conducted in any inert organic solvent such as an alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, or the like. We prefer to conduct the reaction in an alkanol such as ethanol or 2-propanol.

The reaction temperature is not critical; the reaction may be conducted at temperatures of from a bout 00 to about 200 . At low temperatures the reaction is slow, while high temperatures normally lead to less pure products due to decomposition and the formation of side-products. We normally prefer to conduct the reaction at room temperature.

The reaction of compounds Ill and IV to produce compound I is preferably conducted in the presence of a base, which facilitates the reaction by acting as an acid acceptor. Suitable bases for use in this reaction include both inorganic and organic bases such as NaOH, KOH, LiOH, triethylamine, dimethylaniline, sodium ethoxide and the like. If compound IV is utilized in its free base form, it is preferred to use at least about one equivalent of base. When compound IV is used in its acid addition salt form at least about two equivalents of base are used.

The preparation of the compounds of the present invention may be readily understood from Reaction Scheme I, which illustrates the preparation of the most preferred compound la.

Reaction scheme I A) Preparation of compound IV

B) Preparation of compound Ill

C) Preparation of compound I

Instep B above, cysteamine hydrochloride (X) is reacted with an N-cyano-N'-alkynyl-S-methylisothiourea (such as XI in which the alkynyl group is propargyl to produce an N-cyano-N'-alkynyl-N"-(2mercaptoethyl)guanidine (such as Illa in which the alkynyl group is propargyl). The compound of formula XI is prepared by the reaction of propargylamine with dimethyl cyanodithioiminocarbonate [the latter compound being prepared by the procedure described in J. Org. Chem., 32, 1566 (1967)]. It will be appreciated that the reaction of dimethyl cyanodithioiminocarbonate with different alkynylamines will produce N-cyano-N'-alkynyl-S-methylisothioureas with the correspondingly different alkynyl group.The reaction of these latter compounds with cysteamine will produce N-cyano-N'-alkynyl-N"-(2mercaptoethyl)guanidines of formula III with the correspondingly different alkynyl group. The reaction of such compounds of formula Ill in Step C above will produce compounds of formula I with the correspondingly different alkynyl group.

The alkynylamine starting materials used for the preparation of the compounds of formula Ill are either commercially available or may be prepared by methods described in Bull. Soc. Chim. Fr., 490 (1958); Bull.

Soc. Chim. Fr., 592 (1967) andAnnales de Chimie (Paris), 3,656(1958).

The compounds of formula Ill are disclosed in U. S. Patent 4,112,234 and are described and claimed in our colleagues U. S. patent application Serial No.906,901, filed May 1978, the complete disclosures of which are incorporated herein by reference.

Although the compounds of the present invention have been shown as having the structure of formula I, these compounds may exist in various tautomeric forms. Also, the compounds of formula I which contain a branched chain alkynyl group as substituent R1 may exist as their d- or 1-optical isomers as well as their racemic forms. Thus, for example, 3-amino-1-butyne of the formula

may be resolved into its d- and 1- isomers as described in Compt. rend., 242, 1046 (1956). The use of the d- or 1- isomer of the alkynylamine in the preparation of a compound of formula I produces the corresponding dor 1-isomer of the compound of formula I. The present invention includes within its scope all possible tautomericforms and optical isomers of the compounds of formula I as well as mixtures thereof.

As used herein, the term nontoxic pharmaceutically acceptable acid addition salt means the mono- or di-salt of a compound of Formula I with a nontoxic pharmaceutically acceptable organic or inorganic acid.

Such acids are well known and include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, ethanedisulfonic, benzenesulfonic, acetic, propionic, tartaric, citric, camphorsulfonic, and the like. The salts are made by methods known in the art.

As used herein, the term (lower)alkyl is intended to mean straight or branched alkyl groups containing from 1 to 6 carbon atoms.

For therapeutic use, the pharmacologically active compounds of this invention will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in the basic form or in the form of a nontoxic pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable carrier.

The pharmaceutical compositions may be administered orally, parenterally or by rectal suppository. A wide variety of pharmaceutical forms may be employed. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injection, or an aqueous or nonaqueous liquid suspension. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation.

Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg. to about 250 mg., and most preferably from about 100 mg. to about 200 mg., The active ingredient will preferably be administered in equal doses from two to four times a day. The daily dosage regimen will preferably be from 250 mg. to about 1000 mg., and most preferably from about 500 mg. to about 750 mg..

Histamine H2-receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and man, Brimblecombe petal., J. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the histamine H2-receptor antagonist cimetidine has shown it to be an effective therapeutic agent in the treatment of peptic ulcer disease, Grayeta/., Lancet, 1(8001), 4(1977). The compound prepared in Example 1 below (hereinafter referred to as BC-3639) has been found to be more potent than cimetidine as a histamine H2-receptor antagonist in isolated guinea pig atria.

Histamine H2-receptorantagonism - isolated guinea pig atria assay Histamine produces concentration-related increases in the contractile rate of isolated, spontaneously beating guinea pig right atria. Black eta!., Nature, 236, 385 (1972), described the receptors involved in this effect of histamine as histamine H2-receptors when they reported the properties of burimamide, a competitive antagonist of these receptors. Subsequent investigations by Hughes and Coret, Proc. Soc. Exp.

Biol. Med., 148, 127 (1975) and Verma and McNeill, J. Pharmacy!. Exp. Ther., 200, 352 (1977) support the conclusion of Black and coworkers that the positive chronotropic effect of histamine in isolated guinea pig right atria is medicated via histamine H2-receptors. Black et al., Agents and Actions, 3, 133 (1973) and Brimblecombe et al., Fed. Proc., 35, 1931 (1976) have utilized isolated guinea pig right atria as a means for comparing the activities of histamine H2-receptor antagonists. The present comparative studies were carried out using a modification of the procedure reported by Reinhardt et al.,Agents and Actions, 4, 217 (1974).

Male Hartley strain guinea pigs (350-450 gm.) were sacraficed by a blow on the head. The heart was excised and placed in a Petri dish of oxygenated (95% 02, 5% CO2) modified Krebs solution (g./liter: NaCI 6.6, KCI 0.35, MgS04-7 H20 0.295, KH2PO4 0.162, CaCI2 0.238, NaHCO3 2.1 and dextrose 2.09). The spontaneously beating right atrium was dissected free from other tissues and a silk thread (4-0) attached to each end. The atrium was suspended in a 20 ml. muscle chamber containing oxygenated modified Krebs solution maintained at 32"C. Atrial contractions were recorded isometrically be means of a Grass FT 0.03 force displacement transducer and recordings of contractile force and rate were made with Beckman RP Dynograph.

A resting tension of 1 g. was applied to the atrium and it was allowed to equilibrate for 1 hour. At the end of the equilibration period a submaximal concentration of histamine dihydrochloride (3 x 10-6M) was added to the bath and washed out to prime the tissue. Histamine was then added to the bath in a cumulative fashion using 1/2 log 10 intervals to give final molar bath concentrations of 1 x 10-7 to 3 x 10-5. The histamine-induced increase in atrial rate was allowed to plateau before the next successive concentration was added. The maximal response invariably occurred at the 3 x 10-5M concentration. The histamine was washed out several times and the atrium allowed to return to control rate.The test compound (3 x 10-5M) was then added and after a 30 minute incubation the histamine concentration-response was repeated adding higher concentrations as needed.

The histamine ED50 values (concentration of histamine which increased contractile rate 50% of maximum) and 95% confidence limits before and after the test compound were obtained by regression analysis as described by Finney, ProbitAnalysis, 3rd ed., Cambridge (1971). Concentration-response curve displacement factors were calculated as follows: EDSO factor - ED50 Histamine + Compound Displacement factor ED50 Histamine Alone ED50 Hlstamine Alone The factor obtained for BC-3639 was then expressed as a ratio of the factor obtained for cimetidine.

Activity Ratio = Test Compound Displacement Factor - 1 Cimetidine Displacement Factor - 1 The results obtained from these studies are summarized in Table 1. Cimetidine and BC-3639 displaced the histamine concentration-response curve to the right by factors of 25.26 and 57.27 respectively. Based on the concentration-response curve displacement of factors, BC-3639 was about 2.32 times as active as cimetidine as a histamine H2-receptor antagonist in isolated guinea pig right atria.

TABLE 1 Relative activity of cimetidine and BC-3639 in isolated guinea pig right atria Histamine ED50 Concentration- Activity Ratio With 95% Response Curve Relative to Compound N Concentration Confidence Limits Displacement Cimetidine (Ilgiml) Factor Histamine 8 .... 0.19 control 8 ~~~~~ (0.15 - 0.24) 4.80 Cimetidine 8 3x10-5M (3.9 -5.9) 25.26 1.0 Histamine 2 ----- 0.11 control 2 (0.012 - 0.60) BC-3639 2 3 X 105M 6.3 57.27 -7.4) 57.27 2.32 N = Number of experiments EXAMPLE 1 N-Cyano-N'-{2-[(4-hydroxymethyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine (la) [BC-3639] A.Dimethyl 1-(Triphenylmethyl)imidazole-4,5-dicarboxylate (VII) A mixture of dimethyl imidazole-4,5-dicarboxylate (5.52 g; 30 mmoles) [prepared by conventional means from imidazole-4,5-dicarboxylic acid], dry dimethylformamide (30 ml) and dry triethylamine (5.4 ml; 39 mmoles) was stirred under nitrogen and protected from moisture with a CaCI2 tube. To this mixture was added a solution of triphenylmethyl chloride (9.2 g; 33 mmoles) in 60 ml of dry dimethylformamide, and the mixture was stirred at room temperature. The reaction was monitored by thin layer chromatography on silica plates using 3% methanol in methylene chloride as eluent. After 4 hours, the reaction mixture was poured over a mixture of crushed ice and water (500 ml), and the solids were collected and washed with water. The crude product was dissolved in chloroform, dried over sodium sulfate and the solution evaporated.The solid residue was dissolved in 20 ml chloroform, the solution diluted with 40 ml petroleum ether, (b.p. 30-60C) and the crystalline precipitate was collected by filtration to give 11 g (86%) of the title product, m.p. 200-205 C. On tic it showed a single spot with Rf 0.45; i.r. (nujol) 1720 cm-1; n.m.r. (CDCI3) 6, 3.17(s, 1H, OCH3), 3.87 (s. 3H, OCH3), 7.33 (m, 15H ArH), 7.57(s, 1H, C-2H).

Anal. Calc'd for C26H22N204: C, 73.22; H, 5.19; N, 6.57 Found: C,73.24; H,5.52; N,6.57 The starting material, dimethyl imidazole-4,5-dicarboxylate, is a known compound. See, for example, Chem. Abst, 67, 3033g (1967). The above reaction follows the general procedure described in J. Med. Chem., 20,721(1977).

B. 4,5-Dihydroxymethyl- l-(triphenylmethyl)imidazole (VIII) To an ice-cold, stirred suspension of lithium aluminum hydride (9.0 g; 0.274 mole) in 1 liter of dry tetrahydrofuran, under a nitrogen atmosphere, was slowly added dimethyl 1 -(triphenylmethyl)imidazole4,5-dicarboxylate (58 g; 0.119 mmole). After the addition was completed (30 minutes) the cooling bath was removed and stirring was continued at room temperature for 3 hours. The reaction mixture was cooled in an ice-bath and treated successively with 60 ml water, 60 ml of 15% aqueous sodium hydroxide and 60 ml water. It was then filtered and the inorganic salts were washed with tetrahydrofuran. The combined filtrate and washings were evaporated to dryness.The residue was dissolved in methylene chloride, dried over sodium sulfate, filtered and evaporated to give 38 g (80%) of the title compound, m.p. 192-193'C. On tic (10% methanol-CH2CI2) it showed a single spot of Rf 0.4; i.r. (nujol), 3420 (OH) cm-1; n.m.r. (CDCI3) 6,7.3 (m, 16H, ArH and C-2H), 4.65 (s, 2H, CH2OH), 3.95 (s, 2H, CH20H).

Anal. Calc'd for C24H22N202: C,77.81;H, 5.99; N, 7.56 Found: C, 77.84; H, 6.15; N, 7.44 C. 5-Hydroxymethyl-4-trimeth ylacetoxymethyl- l-(triphenylmethyl)imidazole (IX) To a stirred suspension of 4,5-dihydroxymethyl-1-(triphenylmethyl)imidazole (29.6 g; 80 mmoles) in 250 ml methylene chloride and dry pyridine (8.3 g; 124 mmoles) at OOC was added dropwise (10 minutes) a solution of trimethylacetyl chloride (10.25 g; 85 mmoles) in 100 ml of methylene chloride. After the addition was completed all starting material had dissolved. The reaction mixture was stirred at room temperature for 2.5 hours and then stored at 0 C overnight.The reaction mixture was then washed with water (3 x 200 ml), dried (Na2SO4) and evaporated to give a syrup. On thin layer chromatography on silica plates using 10% acetone in methylene chloride as eluent, this syrup showed one major spot for the title product (Rf 0.45), one small spot for starting material (Rf 0) and three other small spots (Rf 0.62, 0.82, and 0.92). The syrupy crude product was dissolved in 200 ml of 10% acetone-methylene chloride solvent mixture and filtered through a sintered glass funnel packed with silica (a bed of 10 cm x 4 cm i.d.), and the silica bed washed with the same solvent system (200 ml). By this treatment, the unreacted starting material was removed.The combined filtrate and washings were evaporated to give 31 g of crystalline title product Recrystallization from benzene (70 ml)-petroleum ether (175 ml, b.p. 90-120"C) gave 21.6 g (59.5%) of product, m.p. 1 57-159'C. The mother liquor was evaporated and the residue was chromatographed on silica using acetone-chloroform (1:10) as eluent to give 7.0 g of product. The two crops were combined to a total yield of 28.6 g (79%). I.R. (CHCl3), 3580 (OH), 1720 (CO) cm-1; n.m.r. (CDC13) b,7.33 (m, 16H, ArH and C-2H), 0 5.15 (s, 2H, CH2Cr) 4.0 2H, CH2OH), 1.18 (s, 9H, C-Me3).

Anal. calc'd for C29H30N203: C, 76.62; H, 6.65; N, 6.16 Found: C,77.03; H,6.49; N,6.14 D. 5-Chloromethyl-4trimethylacetoxymethylimidazole Hydrochloride (IVa) To 25 ml of stirred thionyl chloride was slowly added (5 minutes) 5-hydroxymethyl-4 trimethylacetoxymethyl-1-(triphenylmethyl)imidazole (5.0 g; 11 mmoles) and the mixture was stirred at room temperature for 10 minutes and then at reflux temperature for 30 minutes. Removal of the excess thionyl chloride in vacuo left a syrupy residue which partly solidified on trituration with ether (50 ml).The ether was removed by evaporation; the solid residue was dissolved in 5 ml of 95% ethanol, the solution was diluted with 60 ml ether and the crystalline precipitate collected by filtration, washed with ether and dried to give 2.15 g (83.5%) of the title product, m.p. 275-280"C (dec.); n.m.r. (CD30D-CD3COCD3) b, 1.2 (s, 9H, CMe3), 5.03 (s, 2H, CH2CI), 5.37 (s, 2H, CH2O), 9.17 (s, 1 H, C-2H).

Anal. Calc'd for C10H15C1N202.HCl: C,44.96; H,6.04; N, 10.49; CI, 26.14.

Found: C, 44.81; H, 5.94; N, 10.47, Cl, 25.60.

E. N-Cyano-N'-prn,oargyl-N"-(2-merca,ntoethyliguanidine (I I Ia) 1. N- Cyano-N'-propargyl-S-methyliso thio urea A solution of dimethyl cyanodithioiminocarbonate (16.00 g; 0.109 mole) and propargylamine (6.03 g, 0.109 mole) in acetonitrile (320 ml) was stirred at reflux for 4 hours, and then at 25 for 12 hours. The mixture was cooled and filtered to yield the title compound (13.58 g, 81%), mp 160-164 .

2. N-Cyano-N'-propargyl-N"-r2-mercaptoethyl)guanidine (lila) To a solution of cysteamine hydrochloride (0.6 g; 5.3 mmoles), N-cyano-N'-propargyl-S-methylisothiourea (0.815 g; 5.3 mmoles) and hydroquinone (10 mg) in 12 ml of dimethylformamide was added 1.32 ml of 4N aqueous sodium hydroxide (5.3 mmoles) and the reaction mixture was stirred at room temperature, under a nitrogen atmosphere, for 18 hours. The resulting solution was used directly in Step F, below.

F. N-Cyano-N'-propargyl-N"-{2-[4-trimethylacetoxymethyl)methylthio]- ethyt\guanidine (XII) The solution obtained in Step E2, above, was cooled to 0 C and 10 ml of ethanol and 2.64 ml of 4N aqueous sodium hydroxide were added. To this mixture was added a solution of 5-chloromethyl-4 trirr+hX PtnxvmPthvlimidazole hvdrochloride (IVa) (1.34 g; 5 mmoles) in 2 ml of water, and the mixture was stirred at room temperature under nitrogen for 40 minutes. The reaction mixture was partioned between water (15 ml) and methylene chloride (30 ml), the organic phase was separated and the aqueous phase was extracted with methylene chloride (2 x 30 ml.) The combined extracts, after drying, were evaporated and the residue purified on a silica column (15 g).The column was eluted successively with methylene chloride (40 ml), 5% MeOH-CH2CI2 (180 ml) and 10% MeOH-CH2CI2 (80 ml). The fractions of eluent which contained the product were combined and evaporated to give 0.47 g (25%) of the title product as an oil. This product showed on thin layer chromalography (silica, 10% MeOH-CH2CI2) a single spot of Rf 0.4; n.m.r. (CDCI3-D2O) 6,7.68(s, 1 H, C-2H), 5.1 Is, 2H, CH2O), 4.1 (t, 2H, NCH2C), 3.80 (s, 2H, CH2S) 3.5 (m, 2H, CH2N), 2.70 (m, 2H, SCH2), 2.33 (t, 1H,---CH) 1.18(s, 9H, CMe3).

Anal. calc'd for C17H24N602S: C, 54.23; H, 6.43; N, 22.32.

Found: C, 53.10; H, 6.44; N, 21.82.

G. N-Cyano-N' -(2-J(4-h ydroxymethyl-S4midazolyl)methylthiolethyJ}-N"-propargylguanidine (la) [BC-3639] To a solution of N-cyano-N'-propargyl-N"-42-[(4-trimethylacetoxymethyl-5imidazolyl)methylthio)ethyl}guanidine (ILL} (0.37 g; 0.99 mmoles) in 10 ml of methanol was added 0.25 ml of 4N aqueous sodium hydroxide and the solution was stirred at 25"C for 15 minutes. The reaction mixture was evaporated and the residue extracted with a 10% CH3OH-CH2CI2 mixture (2 x 30 ml). The combined extracts, after drying, were evaporated to dryness and the residue was chromatographed on a silica column.The column was eluted successively with CH2CI2, 5% CH3OH-CH2CI2 and 10% CH3OH-CH2Cl2. The fractions containing the product were combined and evaporated to give 95 mg of the title product; ir (neat), 3300 (OH), 2170 (CN) cm-'; n.m.r. (CD3COCD3D2O) 6,7.75(s, 1 H, C-2H), 4.68 (s, 2H, CH2O), 4.19 (t, 2H, NCH2C-)3.87 (s, 2H, CH2S), 3.54 Im, 2H, CH2N), 2.78 (m, 2H, SCH2) 2.2 (t, 1 H,-CH).

Anal. Calc'd for C12H16N6O5: C,49.30;H,5.52 Found: C, 50.45; H, 6.02.

EXAMPLE 2 The general procedure of Example 1 is repeated except that the propargylamine utilized in Step El is replaced by an equimolar amount of 2-butyn-1 -amine, 3-butyn-1 -amine, 4-pentyn-1-amine, 1,1-dimethylpropargylamine and 1-methylpropargylamine, respectively, and there is thereby produced N-cyano-N '-42-[(4-hydroxymethyl-5-imidazolyl)methylthio]ethylE-N"-(2-butyn-1 -yl)guanidine, N-cyano-N '-(2-[(4-hydroxymethyl-5-imidazolyl )methylthio]ethyl)-N"-(3-butyn-l -yl)guanidine.

N-cyano-N '-{2-[14-hydroxymethyl-5-imidazolyl )methylthiojethyll-N"-14-pentyn-1 -yI)guanidine, N-cyano-N '-12-((4-hydroxymethyl-5-imidazolyl)methylthio]ethyl)-N"-(2-methyl-3-butyn-2-yI)guanidine and N-cyano-N '-{2-[(4-hydroxymethyl-5-imidazolyl)methylthio)ethyl}-N"-(3-butyn-2-yI)guanidine, respectively.

Claims

1. Acompound having the formula:

wherein R' is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive.

2. A compound as claimed in claim 1 having the formula

wherein R3 is hydrogen or methyl.

3. A compound as claimed in claim 1 having the formula:

wherein R3 is hydrogen or methyl and n is an integer of from 1 to 6, inclusive.

4. A compound as claimed in claim 1 having the formula

wherein R3 is hydrogen or methyl.

5. N-Cyano-N'-{2-[!4-hydroxymethyl-5-imidazolyl)methylthio]ethyl}-N"-(2-butyn-1-yl)guanidine.

6. N-Cyano-N'-{2-[14-hydroxymethyl-5-imidazolyl)methylthio]ethyl}-N"-13-butyn-1 -yI)guanidine.

7. N-Cyano-N '-{2-(4-hydroxymethyl-5-imidazolyl)-methylthio]ethyl}-N"-14-pentyn-1 -yl)guanidine.

8. N-Cyano-N '42-[(4-hydroxymethyl-5-imidazolyl)methylthio]ethyl}-N"-12-methyl-3-butyn-2-yI)- guanidine.

9. N-Cya no N-Cyano-N '42-[(4-hydroxymethyl-5-imidazolyl)methylthio]ethyl}-N"-13-buwn-2-yI)guanidine.

10. N-Cyano-N'42-[(4-hydroxymethyl-5-imidazolyl)methylthio]ethylYN"-prnpargylguanidine.

11. A nontoxic pharmaceutically acceptable acid addition salt of a compound as claimed in any one of claims 1 to 10.

12. A process for the preparation of a compound of the formula:

wherein R1 is as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting a compound of the formula:

wherein R' is as defined above with a substantially equimolar amount of a compound of the formula

wherein

is a conventional acvl group used to protect a hvdroxyl group and Z is a conventional leaving group, in an inert solvent, and subsequently removing the

13. A process as claimed in claim 12 wherein the compound of Formula (IV) is in the form of an acid addition salt thereof.

14. A process as claimed in claim 12 or claim 13 wherein the reaction is carried out in the presence of a base.

15. A process as claimed in any one of claims 12 to 14 wherein Z is a chlorine atom.

16. A process as claimed in any one of claims 12 to 15 wherein the organic solvent is an alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide or acetone.

17. A process as claimed in any one of claims 12 to 16 wherein the reaction is conducted at ambient temperature.

18. A process as claimed in claim 12 substantially as hereinbefore described with reference to Example 1 or Example 2.

i9. A compound of Formula I as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 12 to 18.

20. A pharmaceutical composition which comprises as active ingredient at least one compound as claimed in any one of claims 1 to 10, or claim 19, or a pharmaceutically acceptable acid addition salt thereof as claimed in claim 11, together with a pharmaceutically acceptable diluent or carrier.

21. A pharmaceutical composition as claimed in claim 20 which is in unit dosage form.

22. A pharmaceutical composition as claimed in claim 21 wherein each unit dosage contains from 50mg to 250mg of the active ingredient.