Novel compounds of the formula ##STR1## wherein each R.sup.1 is the same and is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, which are useful intermediates in the preparation of anti-ulcer agents, are prepared by reacting cystamine (VI) with an N-cyano-N'-alkynyl-S-methylisothiourea of the formula ##STR2## in which R.sup.1 is as defined above.

SUMMARY OF THE INVENTION 
This application relates to certain novel 
N,N'-bis[(N-cyano-N'-alkynyl)methanimidamidyl]cystamines of the formula 
##STR3## 
wherein each R.sup.1 is the same and is a straight or branched chain 
alkynyl group containing from 3 to 9 carbon atoms, inclusive, which are 
useful as intermediates in the preparation of anti-ulcer agents of the 
formula 
##STR4## 
wherein R.sup.1 is as defined above. 
BACKGROUND AND PRIOR ART 
The clinical objective in 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 H.sub.2 receptors and is not inhibited by the classical 
antihistamines, which are H.sub.1 receptor blockers. A number of specific 
H.sub.2 receptor blocking agents (H.sub.2 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 
peptic ulcers. 
Burimamide (Va) was the first clinically effective H.sub.2 receptor 
antagonist. 
##STR5## 
Va; R.sup.2 .dbd.H, Z.dbd.CH.sub.2, X.dbd.S--Burimamide B; R.sup.2 
.dbd.CH.sub.3, Z.dbd.S, X.dbd.S--Metiamide 
C; R.sup.2 .dbd.CH.sub.3, Z.dbd.S, X.dbd.NCN--Cimetidine 
It inhibits gastric secretion in animals and man, but oral absorption is 
poor. Metiamide (Vb), a subsequently evaluated H.sub.2 antagonist, is more 
potent than burimamide and is orally active in man. Clinical utility was 
limited, however, owing to toxicity (agranulocytosis). Cimetidine (Vc) is 
as effective an H.sub.2 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 and/or more 
potent than cimetidine. 
Reviews on the development of H.sub.2 antagonists, including those 
discussed in the preceding paragraph, may be found in C. R. Ganellin, et 
al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 
13 (1976), and in references cited therein. 
Our colleagues' co-pending application Ser. No. 848,959, filed Nov. 7, 
1977, now U.S. Pat. No. 4,112,234, (the disclosure of which is 
incorporated herein by reference) describes and claims novel histamine 
H.sub.2 receptor antagonists of the formula 
##STR6## 
wherein R.sup.1 is a straight or branched chain alkynyl group containing 
from 3 to 9 carbon atoms, inclusive, and nontoxic, pharmaceutically 
acceptable salts thereof, which are effective inhibitors of gastric 
secretion in animals, including man, and which are useful in the treatment 
of peptic ulcer disease. 
Our colleagues' co-pending application Ser. No. 906,901 filed May 18, 1978 
(the disclosure of which is incorporated herein by reference) discloses 
and claims novel intermediates of the formula 
##STR7## 
wherein R.sup.1 is as described above, and a novel process for the 
preparation of anti-ulcer compounds of Formula I by reacting a compound of 
Formula III with a compound of the formula 
##STR8## 
wherein X is a conventional leaving group, and wherein the compound of 
Formula II preferably is in the form of an acid addition salt. 
Cystamine (VI) is a known compound, being described 
##STR9## 
for example, on page 363 of The Merck Index, ninth edition (1976), as 
compound 2775. 
Pantethine, a derivative or cystamine having the formula 
##STR10## 
is described in The Merck Index, ninth edition (1976) as compound 6817. 
The compound N,N'-bis(p-tolylsulfonylcarbamoyl)cystamine having the formula 
##STR11## 
is listed in the Alfred Bader Chemicals Library of Rare Chemicals, Aldrich 
Chemical Company, Inc. (1971) by structure on page 114 and by name on page 
275. 
The Journal of The American Chemical Society, 79, 5663-6 (1957) discloses 
guanidinoethyldisulfide [N,N'-bis(guanyl)cystamine], having the formula 
##STR12## 
Complete Disclosure 
In its broadest aspect, this invention relates to novel 
N,N'-bis[(N-cyano-N'-alkynyl)methanimidamidyl]cystamines of the formula 
##STR13## 
wherein each R.sup.1 is the same and is a straight or branched chain 
alkynyl group containing from 3 to 9 carbon atoms, inclusive, and acid 
addition salts thereof. 
In a preferred embodiment the compounds of Formula IV have the structure 
##STR14## 
wherein each R.sup.4 is the same and is hydrogen or methyl, or an acid 
addition salt thereof. 
In another preferred embodiment the compounds of Formula IV have the 
structure 
##STR15## 
wherein each R.sup.4 is the same and is hydrogen or methyl, and n is an 
integer of from 1 to 6 inclusive, or an acid addition salt thereof. 
In yet another preferred embodiment the compounds of Formula IV have the 
structure 
##STR16## 
wherein each R.sup.4 is the same and is hydrogen or methyl, or an acid 
addition salt thereof. 
In a more preferred embodiment the compound of Formula IV is 
N,N'-bis[{N-cyano-N'-(2-butyn-1-yl)}methanimidamidyl]cystamine, or an acid 
addition salt thereof. 
In another more preferred embodiment the compound of Formula IV is 
N,N'-bis[{N-cyano-N'-(3-butyn-1-yl)}methanimidamidyl]cystamine, or an acid 
addition salt thereof. 
In another more preferred embodiment the compound of Formula IV is 
N,N'-bis[{N-cyano-N'-(4-pentyn-1-yl)}methanimidamidyl]cystamine, or an 
acid addition salt thereof. 
In still another more preferred embodiment the compound of Formula IV is 
N,N'-bis[{N-cyano-N'-(2-methyl-3-butyn-2-yl)}methanimidamidyl]cystamine, 
or an acid addition salt thereof. 
In yet another more preferred embodiment the compound of Formula IV is 
N,N'-bis[{N-cyano-N'-(3-butyn-2-yl)}-methanimidamidyl]cystamine, or an 
acid addition salt thereof. 
In the most preferred embodiment the compound of Formula IV is 
N,N'-bis[(N-cyano-N'-propargyl)methanimidamidyl]cystamine, or an acid 
addition salt thereof. 
The compounds of Formula IV may be prepared by reacting cystamine (VI) with 
an N-cyano-N'-alkynyl-S-methylisothiourea of the formula 
##STR17## 
in which R.sup.1 is an defined above, in a ratio of about 2 moles of 
compound VII per mole of cystamine, in an inert organic solvent. Suitable 
inert organic solvents include, for example, (lower)alkanols, 
acetonitrile, DMF, DMSO, acetone and the like. We normally prefer to 
conduct the reaction in DMF. 
The reaction temperature is not critical; the reaction may be conducted at 
temperatures of from about 0.degree. to about 200.degree.. 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. 
When reacting cystamine with an N-cyano-N'-alkynyl-S-methylisothiourea of 
Formula VII to produce a compound of Formula IV it has been found 
desirable to conduct the reaction in the presence of a small amount of 
hydroquinone and to bubble nitrogen through the reaction mixture. These 
reaction conditions were found to produce compounds of Formula IV in 
higher yield and of higher purity. The nitrogen sweep is believed to 
remove the methyl mercaptan produced in the reaction and thereby avoid 
secondary reactions arising from the addition of methyl mercaptan to the 
carbon-carbon triple bond. It is believed that the hydroquinone prevents 
the formation of free radicals and secondary reactions arising from their 
presence. 
The acid addition salts of a compound of Formula IV referred to herein are 
intended to include salts of a compound of Formula IV with any 
conventional inorganic or organic acid, e.g. hydrochloric, hydrobromic, 
sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, 
acetic, propionic, tartaric, citric, camphorsulfonic, and the like. The 
acid addition salts are prepared by conventional methods. 
As used herein the term "(lower)alkanol" means a straight or branched chain 
aliphatic alcohol containing from 1 to 6 carbon atoms. The abbreviations 
DMF and DMSO represent dimethylformamide and dimethylsulfoxide, 
respectively. All temperatures herein are given in degrees centigrade. 
Celite is a registered trademark of the Johns-Manville Products 
Corporation for diatomaceous earth. 
Preparation of Starting Materials 
The N-cyano-N'-alkynyl-S-methylisothiourea starting materials of Formula 
VII utilized herein may be prepared by reacting dimethyl 
cyanodithioiminocarbonate with about an equimolar amount of the 
appropriate alkynylamine, as described in our colleagues' application Ser. 
No. 848,959, now U.S. Pat. No. 4,112,234. The dimethyl 
cyanodithioiminocarbonate which is used as a starting material for the 
preparation of the N-cyano-N'-alkynyl-S-methylisothioureas may itself be 
prepared by procedures described in J. Org. Chem., 32, 1566 (1967). The 
alkynylamine starting materials are either commercially available or may 
be prepared by methods described in Bull. Soc. Chim. Fr., 490 (1958); Bull 
Soc. Chim. Fr., 592 (1967) and Annales de Chimie (Paris), 3, 656 (1958). 
The compounds of Formula IV may be converted to compounds of Formula III by 
the general procedure for the reduction of disulfides to thiols, as 
described by J. J. D'Amico in J. Org. Chem., 26, 3436 (1961), as shown in 
the following reaction scheme: 
##STR18## 
wherein R.sup.1 is as described above. 
The compounds of Formula III may subsequently be converted to the 
anti-ulcer agents of Formula I by the process described in our colleagues 
co-pending application Ser. No. 906,901, as shown in the following 
reaction scheme. 
##STR19## 
in which R.sup.1 and X are as described above. The reduction of compounds 
of Formula IV to compounds of Formula III, and the subsequent reaction of 
compounds of Formula III with a compound of Formula II to produce 
anti-ulcer agents of Formula I are further described in the following 
Illustrative Procedures. 
Illustrative Procedure 1 
N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidi 
ne 
A. N-Cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine 
To a solution of 0.082 g (0.226 m mole) of 
N,N'-bis[(N-cyano-N'-propargyl)methanimidamidyl]cystamine in 4 ml ethanol 
was added a solution of 0.082 g sodium borohydride in 2 ml ethanol and the 
mixture was stirred at room temperature for 1.5 hours. Acetic acid (1 ml) 
was added to decompose excess borohydride, the solution was poured into an 
8% solution of sodium bicarbonate in water (50 ml) and extracted with 
chloroform (3.times.15 ml). The chloroform solution, after drying 
(Na.sub.2 SO.sub.4), was evaporated to dryness to give 0.056 g of the 
title product as a syrup. I.R. (nujol): 3410 and 3270 (NH), 2540 (SH), 
2160 (C.tbd.N), 1590 (C.dbd.N) cm.sup.-1 ; n.m.r. (CDCl.sub.3 --CH.sub.3 
OD) .delta., 4.21 (NH), 4.03 (d, 2H, CH.sub.2 C.tbd.C, J.dbd.2.5 Hz), 3.43 
(m, 2H, CH.sub.2 N), 2.73 (m, 2H, SCH.sub.2), 2.45 (t, 1H, C.tbd.CH, 
J.dbd.2.5 Hz). 
This product, without further purification was used in step B. 
B. 
N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanid 
ine 
A solution of 0.029 g (0.16 m mole) of the product of step A, in 1 ml 
ethanol containing 0.42 m mole sodium ethoxide, was placed under a 
nitrogen atmosphere and cooled to 4.degree. C. with stirring. After 5 
minutes, 0.035 g (0.21 m mole) of solid 4-methyl-5-chloromethylimidazole 
was added. The mixture was stirred for 40 minutes, poured into brine (30 
ml) and then extracted with chloroform (3.times.15 ml). After drying 
(Na.sub.2 SO.sub.4), the solvent was removed by evaporation. The residue 
was purified by thin layer chromatography on silica gel plates using a 
methanol-chloroform (1:4) solvent system to give 0.022 g (50%) of the 
title compound as a syrup which crystallized on standing at room 
temperature. Trituration with chloroform gave the crystalline product, 
m.p. 147.degree.-149.degree. C. I.R. (nujol): 3360 (NH), 3300 (C.tbd.CH), 
2160 (C.tbd.N), 1600 and 1585 (C.dbd.N) cm.sup.-1 ; n.m.r. (acetone 
D.sub.6): .delta. 8.53 (1H, NH), 7.68 (s, 1H), 7.00 (1H, NH), 4.13 (q, 2H, 
J.dbd.2.5 Hz), 3.73 (s, 2H), 3.53 (m, 2H), 2.73 (m, 3H), 2.21 (s, 3H). 
Illustrative Procedure 2 
The general procedure of Illustrative Procedure 1 is repeated except that 
the N,N'-bis[(N-cyano-N'-propargyl)methanimidamidyl]cystamine utilized 
therein is replaced by 
N,n'-bis[{N-cyano-N'-(2-butyn-1-yl)}methanimidamidyl]cystamine, 
N,n'-bis[{N-cyano-N'-(3-butyn-1-yl)}methanimidamidyl]cystamine, 
N,n'-bis[{N-cyano-N'-(4-pentyn-1-yl)}methanimidamidyl]cystamine, 
N,n'-bis[{N-cyano-N'-(2-methyl-3-butyn-2-yl)}methanimidamidyl]cystamine and 
N,n'-bis[{N-cyano-N'-(3-butyn-2-yl)}methanimidamidyl]cystamine, 
respectively, 
and there is thereby produced 
N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-butyn-1-yl)gu 
anidine, 
N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-1-yl)gu 
anidine, 
N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(4-pentyn-1-yl)g 
uanidine, 
N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-methyl-3-buty 
n-2-yl)guanidine and 
N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-2-yl)gu 
anidine, respectively. 
This invention is illustrated by, but in no way limited to, the following 
Examples.

EXAMPLE 1 
N,N'-bis[(N-Cyano-N'-propargyl)methanimidamidyl]cystamine 
Cystamine hydrochloride (2.25 g, 10 m moles) (Aldrich Chemical Co. Ltd) was 
treated with 1 N aqueous sodium hydroxide (20 ml) to liberate the base and 
then evaporated to dryness. The residue was stirred with 2-propanol and 
the suspension filtered through a bed of Celite filter aid to remove the 
inorganic salts. The filtrate was evaporated to dryness to give cystamine 
free base as an oil. This oil was dissolved in 5 ml DMF and added to a 
solution of 3.06 g (20 m moles) of 
N-cyano-N'-propargyl-S-methylisothiourea and 0.11 g hydroquinone in 5 ml 
DMF, and the reaction mixture was allowed to stand at room temperature for 
16 hours while nitrogen was bubbled through the solution. The reaction 
mixture was diluted with ethyl acetate saturated with water (150 ml) and 
washed first with water saturated with ethyl acetate (2.times.100 ml) and 
then with brine (100 ml). After drying over sodium sulfate, the solvent 
was removed by evaporation. The solid residue was triturated with carbon 
tetrachloride (50 ml), filtered and washed with carbon tetrachloride (50 
ml) to give 2.68 g of the title product, m.p. 134.degree.-136.degree. C. 
Extraction of the sodium sulfate drying agent with methanol (150 ml) 
afforded an additional 0.41 g of the title product, thus increasing the 
yield to 3.09 g (85.5%). I.R. (nujol), 3290 (C.tbd.CH), 3270 (NH), 2160 
(C.tbd.N), 1595 and 1580 (C.dbd.N) cm.sup.-1 ; n.m.r. (CD.sub.3 OD): 
.delta., 4.00 (d, 4H, N--CH.sub.2 C.tbd.CH, J=2.6 Hz), 3.60 (m, 4H, 
CH.sub.2 N), 2.90 (m, 4H, --SCH.sub.2 --), 2.66 (t, 2H, C.tbd.CH, J=2.5 
Hz). 
Anal. Calc'd for C.sub.14 H.sub.18 N.sub.8 S.sub.2 : C, 46.38; H, 5.00; N, 
30.91; S, 17.69. Found: C, 46.12; H, 4.91; N, 31.21; S, 17.41. 
EXAMPLE 2 
N,N'-bis[{N-Cyano-N'-(2-butyn-1-yl)}methanimidamidyl]cystamine 
The general procedure of Example 1 is repeated except that the 
N-cyano-N'-propargyl-S-methylisothiourea utilized therein is replaced by 
an equimolar amount of N-cyano-N'-(2-butyn-1-yl)-S-methylisothiourea, and 
the title product is thereby produced. 
EXAMPLE 3 
N,N'-bis[{N-Cyano-N'-(3-butyn-1-yl)}methanimidamidyl]cystamine 
The general procedure of Example 1 is repeated except that the 
N-cyano-N'-propargyl-S-methylisothiourea utilized therein is replaced by 
an equimolar amount of N-cyano-N'-(3-butyn-1-yl)-S-methylisothiourea, and 
the title product is thereby produced. 
EXAMPLE 4 
N,N'-bis[{N-Cyano-N'-(4-pentyn-1-yl)}methanimidamidyl]cystamine 
The general procedure of Example 1 is repeated except that the 
N-cyano-N'-propargyl-S-methylisothiourea utilized therein is replaced by 
an equimolar amount of N-cyano-N'-(4-pentyn-1-yl)-S-methylisothiourea, and 
the title product is thereby produced. 
EXAMPLE 5 
N,N'-bis[{N-Cyano-N'-(2-methyl-3-butyn-2-yl)}methanimidamidyl]cystamine 
The general procedure of Example 1 is repeated except that the 
N-cyano-N'-propargyl-S-methylisothiourea utilized therein is replaced by 
an equimolar amount of 
N-cyano-N'-[(2-methyl-3-butyn-2-yl)methanimidamidyl]cystamine, and the 
title product is thereby produced. 
EXAMPLE 6 
N,N'-bis[{Cyano-N'-(3-butyn-2-yl)}methanimidamidyl]cystamine 
The general procedure of Example 1 is repeated except that the 
N-cyano-N'-propargyl-S-methylisothiourea utilized therein is replaced by 
an equimolar amount of N-cyano-N'-(3-butyn-2-yl)-S-methylisothiourea, and 
the title product is thereby produced.