CA1130306A - N-cyano-n'-[2-[(4-methyl-5-imidazolyl) methylthio]ethyl]- n"-alkynylguanidines h.sub.2 receptor blocking agents - Google Patents

Abstract

ABSTRACT ABRIDGEMENT OF THE DISCLOSURE

Histamine H, receptor antagonists which inhibit gastric secretion in animals and are useful in the treatment of peptic ulcer disease having the formula I
wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, non-toxic pharmaceutically acceptable acid addition salts thereof, intermediates therefore and processes for their production.

Description

; ~ ~

This application relates to certain N-cyano-; N'-~2-[(4-methyl-5-imidazolyl)methylthio]ethyl~ -; N"-alkynylguanidines which axe H2 receptor blocking agents, which inhibit gastric acid secretion and which ` ~ are useful in the treatment of ulcers.
, :

' ~ 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 H2 receptors and is not inhibited by the classical antihist-amines, which are Hl receptor blockers. A number of ~pecific H2 receptor blocking agents (H2 receptor anta-gonists~ 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 ulcer~.

' ~3~306 Th2~ ~nyent~on relates to hista~ine H2 receptcr antagon~sts ~h~ch ~re ef~ecti~e inhlbitors of ~astric secretion in ani~als, including man, which are useful in the treatment of peptic ulcer disease, and which have the ~ormula ~CN
H CH2scH2cH2NHcNH-R
wherein Rl is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, and non-toxic pharmaceutically acceptable acid addition salts thereof.
A preferred embodiment of the invention is a compound o~ the formula N /

N ~ IlCN

H CH2SCH2CH2NHCNH-~HC--CR

wherein R4 is hydrogen or methyl, or a nontoxic pharmaceut-ically acceptable acid addition salt thereof.
Another preferred em~odiment of the invention is a compound of the formula ~L~ 3~)306 ~ CH2SCH2CH2NHCNH - (CH2)nC9 CR

wherein R4 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 N ~CH3 N ~ ~CN f 3 H CH2SCH2CH2NH NH - f-C -CR

.
wherein ~4 is hydrogen or methyl, or a nontoxic pharmaceut-ically acceptable acid addition salt thereof.

A more preferred embodiment of the invention is N-~; 20 cyano~ {2- r(4-methyl-5-imidazolyl)methylthio] ethyl} -N"-(2-butyn-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-methyl-5-imidazolyl~methylthio]ethyl}-; N"-t3-butyn-1-yl~guanidine or a nontoxic pharmaceutically acceptable ~alt thereof.

~ 4 -~13(~306 ~nother more p~e~erxed e,mbodiment o~ the invention is N~c~ano~N~-12-[(4~methy1~5~i~idazol~1),methylthio]-ethyl}-N"-(4-pentyn-1-yl)guanidine or a nontoxic pharm-aceutically acceptable acid addition salt thereof.

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

~10 Another more preferred embodiment of the invention is N-cyano-N'-{2- [t4-methyl-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'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargyl guanidine or a nontoxic phaxmaceutically acceptable acid addition salt thereof.
The present invention also provides for the prepara-tion of a compound of the formula N ~ ~
N / ~ ~CN

wherein Rl is a straight or branched chain alkynyl group containing from 3 to 9 caxbon atoms, inclusive, or a non-toxic pharmaceutically acceptable acid addition salt thereof characterized by reacting a compound of the formula ~3030~

N , ~
~1 1 II

- N ~ \

or an acid addition salt thereof with a compound of the formula R6NHRl III

wherein R is as defined above and R5 and R6 are non-identical and are either H or the group NCN
-C-SR
where R is any substituent such that -SR is a ~uitable leaving group, and, if desired, converting the resulting compound of formula I in basic form or an acid addition salt thereof to the corresponding non-toxic pharmaceutically acceptable acid addition salt or free base form.
The reaction is conducted in a non-reactive solvent at a temperature above room temperature. In a preferred embodi-ment equimolar quantities of the compounds of formulae II and III are used.
These processes are illustrated by the reaction schemes I and II below for a preferred compound of the invention.

Scheme I
~H3 N

N ~I\ CH25CH2CH2NNC-SR + H2NCH2C= CH

1:1303~G
~H3 N ~
[l ~, N ~CN
H CH2scH2cH2NHcNHcH2c = CH

The reaction is conducted in a non-reactive solvent at a temperature above room temperature. As will be appreciated by those skilled in the art, R may be any substituent such that -SR will be a suitable leaving group. Thus, R may be (lower) alkyl, aryl, substituted aryl (e.g. p-nitrophenyl), aralkyl, -CH2CN, -CH2COOH, -CH2COORI, or the like. The N-cyano-N~ [(4-methyl-5-imidazoly)methylthio~ethyl~-S-R isothiourea starting materials may be prepared by the procedures described in Belgian Patent 804,144. The alkynylamine starting materials are either commercially available or may be prepared by methods described in Bull. Soc. Chim. Fr., 490 (195B), Bull.Soc. Chim. Fr., 592 (1967) and Annales de Chimie (Paris), 3~ 656 (1958).

: ~
113~1306 Scheme II

N ~ ~CN
H CH2scH2cH2NH2 + S N 2 N ~

N \ ~CN

CH2NHcNHCH2c Z CH

The reaction is conducted in a non-reactive solvent at a temperature above room temperature. The substituent R may be as indicated in Scheme I, aboYe. The 2- r(4-methyl-5-imidazolyl)methylthio]ethylamine starting material may be prepared as described in U. S. Patent 3,950,353. The disubstituted cyanodithioiminocarbonate which is used as a starting material for thP preparation of the N-cyano-N'-propargyl-SR isothiourea (see step b of Example 2) may itself be prepared by procedures described in J. Org. Chem., 32, 1566 (1967) ~.

~13~306 .
It has additionally been di~covered that in the prep-aratlon o~ N~cyano-N~-{2- [(4-methyl~5-imidozolyl)methylthio]
ethyl`}-N"-propargylguanidine via Reaction Scheme I, selected reaction conditions in the last step thereof give greatly impro~ed yields of product as well as a product containing less impurities. The latter condition has the added advantage of permitting the initial ("crude") product to be isolated as a crystalline solid which may be more highly purified by simple recrystallization, and avoids the chromatographic purifica-tion of the initial crude product which we previously considered desirable when using other reaction conditions.
The selected reaction conditions referred to above consist of using methanol as solvent, utilizing a more concentrated solution in the reaction (approximately 1 gram of the substituted isothiourea per 5 ml of methanol), the use of a nitrogen sweep of the reaction apparatus during the reaction, and the utilization of freshly distilled propargylamine in the reaction.
Experiments have shown that the use of a nitrogen sweep during the reaction avoids the formation of small amounts of two as yet unidentified by-products which are formed in the absence of a nitrogen sweep. These by-products, when present, resisted removal by column chromatography and recrystallization. It is believed that the nitrogen sweep prevents the formation of these by-products by removing the methyl mercaptan gas as quickly as it is formed.

: ~

3L~L3V3~6 The pre~ent inventlon also pxovides the process for the production of a compound having the structure ~CN

H CH2scH2cE~2NH NH_R

; wherein Rl is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, or a non-toxic pharmaceutically acceptable acid addition salt thereof which comprises reacting a compound of the formula N

N
H CH2SCH2C~2NH2 V

with a compound of the formula S= C _NR
wherein Rl is as defined above, to produce the compound N /

which is then reacted with methyliodide and cynamide to pro-duce compound I in basic form and, if desired, converting the product by procPsses known ~ se to the corresponding non-toxic pharmaceutically acceptable acid addition salt.
This process is illustrated by the following reaction scheme III for a preferred compound of the invention.

`, ~ '!, ~3~3~Z6 Scheme III

CE~3 H CH2SCH2CH~NH2 ~ S=C=NCH2C--CH

C~3 \ /

N / ~ 11 ) H /CH 3 I

2 ) H 2NCN

N

H CH 2SCH 2CH 2NH NHCH 2C ~ CH

~3~)3~36 The ~nyentian of ~his ~pplication further provides a process for t~e prepa~tion ~f a compound o~ the formula Nl ~ CH3 N CH2SCH2CH2NH~NH-Rl wherein Rl is a straight or branched chain alkynyl group con-taining from 3 to 9 carbon atoms, inclusive, or a non-toxic pharmaceutically acceptable acid addition salt thereof characterized by reacting a compound of the formula VII

or an acid addition salt thereof in which X is hydroxy or a conventional leaving group with a compound of the formula ~CN
HSCH2CH2NH~NH R VIII
wherein R is as described above and, if desired, converting the resulting compound of formula I in basic form or an acid addition salt thereof to the corresponding non-toxic pharmaceu-tically acceptable acid addition salt or free base form.
The reaction is conducted in an inert organic solvent.
In a preferred em~odiment eguimolar quantities of the compounds of formulae VII and VIII are used and the reaction is carried out in the presence of a base.
Suitable leaving groups "X" for use in this reaction are well-known to those skilled in the art. They include, for example, fluoro, chloro, bromo, iodo, -O3SR2 wherein R2 is (lower)alkyl [e.g. methanesulfonate], -o3SR3 wherein R3 is aryl or substituted aryl [e.g. benzenesulfonate, p-bromobenæenesul-~1~3(~306 fonate or p~toluenesulfonate], -O3S~, acetoxy and 2,4-dinitro-phenoxy~. For convenience and econom~ we normally prefer to utilize compound I~ in which X is chloro.
In the process of this invention, the compound of Form-ula ~II preferably is utilized in the form of an acid addition salt. Compound VII is relatively unstable in its free base ~orm and therefore is preferably prepared and stored as an acid addition salt. Although the free base of the compound of ~ormula II may be re-gener~ted 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 VII, e.g. hydrochloric, sulfamic, sulfuric, oxalic, benzoic, succinic, acetic, nitric, citric or the like. For convenience and economy we normally prefer to utilize compound II in the form of its hydrochloride.
The reaction of compounds VII and UIII to produce compound I may be conducted in any inert organic solvent such as an alkanol, acetonitrile, dimethylformamide, dimethylsulfox-ide, 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 about to about 200. At low temperatures the reaction is slow, while high temperatures normally lead to less pure products due to de-composition and the formation of side-products. We normally prefer to conduct the reaction at room temperature.
The reaction of compounds VII and VIII to produce compound I is preferably conducted in the presence of a base, which facilitates the reaction by acting as an acid acceptor.
Suitable baais for use in this reaction include both inorganic and organic basis such as NaOH, KOH, LioH, triethylamine, ~13~306 ., di~eth~lan~line~ sodiu~ ethoxide and the like.
Th~s p~ocess is illustrated by the reaction scheme IV
illustrated below for a preferred compound of the invention.

Scheme IV
CH
~CN

N \ +
1: CH20EI/~: 1 \ N ~ ~CN
H CH2SCH2CH2NHCNHCH2C~ CH

1~3~30~;

Th~s inYent~on ~urther xel~tes to no~el intermediates of the fo~ula ~CN
HSCH2CH2NHCNH-Rl VIII
wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, and acid addition salts thereof, which are useful in the preparation of histamine H2 receptor antagonists of Formula I.

In a pre~erred embodiment, Rl of the compound of Form-ula VIII is -CHC_ CR4 in which R4 is hydrogen or methyl: in another preferred embodiment Rl is -(CH2)nC-- CR4 in which n is an integer of from 1 to 6 and R4 is hydrogen or methyl; in ~H3 another preferred embodiment Rl is -f-C - CR4 in which R is C~I3 hydrogen or methyl.

In a more preferred embodiment, ~1 of the compound of Formula VIII is the 2 butyn-1-yl group; in another more preferred embodiment Rl i8 the 3 butyn-1-yl group; in another more pref~rred embodiment Rl is the 4-pentyn-1-yl group; in another more preferred embodLment Rl is the 2-methyl-3-butyn-2-yl group; in another more preferred embodiment Rl is the

3-butyn-2-yl group. In the most preferred embodiment, Rl of the compound of Formula VIII is the propargyl group.

,. ~ ....

~3~3()6 This invention further relates to a process for preparing the novel intermediate compounds of the formula NCN
2CH2NHCNH-~ VIII
wherein R1 is a strai.ght or branched chain alkynyl group containing from 3 to 9 carbon atoms, characterized by reacting a compound of the formula wherein P is any of the group of suitable sulfhydryl protecting groups with a compound of the formula NICN
RSCNHR X
where R is any substituent such that -SR is a suitable leaving group, and thereafter removing the sulfhydryl ; protecting group of the resulting compound to produce the intermediate VIII.
This process is illustrated by the scheme V below.

Scheme V
INCN

1) heat 2) deblock HscH2cH2NHcNHcx2c=cH
NCN

;I When reacting cysteamine compound with. an N-cyano-N'-alkynyl-S-methylisothiourea to produce an N-cyano-N'-alkynyl-N"-(2-mercaptoethyllguanidine of Formula VIII, it ~as found desirable to conduct the reaction in the presence of a small amount of hydroqui.none and to bubble nitrogen ~L3~J13(~6 through the reaction mixture ~see, for example, step B of Example 14~. These reaction conditions were found to produce compounds of Formula VIII in higher yield and of higher purity. The nitrogen sweep is believed to remove the methyl mercaptan produced in the reaction and thereby avoid second-ary 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.
In another aspect, this invention relates to intermediates of the formula NCN
RS~CNH-R IV
wherein Rl is an alkynyl group containing from 3 to 9 carbon atoms, and R is Clower)-aIkYl, and acid addition salts thereof.

A preferred intermediate is a compound of the formula NCN
Rs-cNH-ccH2)nc 5CR IVa wherein R is as described above, R4 is hydrogen or methyl and n is an integer of from 1 to 6, inclusive, or an acid addition salt thereof.
A more preferred intermediate is a compound of Formula IVa in which R is methyl, or an acid addition salt thereof.
The most preferred intermediate is N-cyano-N'-(2-propyn-l-yl)-S-methyl lsothiourea or an acid addition salt thereof.

The invention further relates to a process for the preparation of a compound of the formula ~13~30~;

NCN

~ RS-CNH-R IV

¦ wherein Rl is an alkynyl group containing from 3 to 9 carbon atoms, inclusive, and R ls (lower~alkyl or an acid addition salt thereof, characterized by reacting a compound of the formula ~RS)2 C = NCN
- wherein R is as described above with a compound of the formula i wherein Rl is as described above, and, if desired, converting the product to the corresponding acid addition salt.
I The most preferred compound N cyano-N'-(2-propyn-! l-yl~-S-methyl isothiourea is prepared by reacting ~¦ dimethyl cyanodithio imLnocarbonate with propargylamine.
¦ The dimethyl cyanodithioiminocarbonate 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).
As used herein, the term nontoxic pharmaceutically acceptable acid addition salt means the mono- or di-salt of a compound of this invention with a nontoxic pharm-aceutically acceptable organic or inorganic acid. Such acids are ~ell known and include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric succinic, oxalic, benzoic, methanesulfonic, ethanedisulfonic, benzenesulfonic, acetic, propionic, tartaric, citric, -17a-~1303~6 ca~phQ~sul~on~c~ and the l~ke~ The ~alts are ~ade by ~ethDds kno~n ~n the art.

As used herein the term tlower~alkyl is intended to mean straight or branched alkyl groups containing from l to 6 carbon atoms.
Fbr 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 pharma-ceutically 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 pharma-ceutical compositions are pxepared 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 activP ingredient will preferably be administered in equal doses from two to four times a day. The daily dosage regimen will preEerably be from 250 mg. to about 1000 mg., and most prefer-ably from about 500 mg. to about 750 mg ~.

~31~30~

~2st~ne H~ece~t~ anta~Qnist~ hAve been ~hown to be ef~ect~e ~nhib~tors of gastric secretion in anLmals and man, Bri~lecombe et al., ~. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the his~amine H2-receptor antagonist cimetidine has shown it to be an effective thera-peutic agent in the treatment of peptic ulcer disease, Gray et al., Lancet, 1 (8001), 4 (1977~. The compound prepared in Examples 1 and 2 below (hereinafter referred to as BL-5641) has been compared with c~metidine 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 or gastric secretion in rats and dogs. Furthermore, the gastric secretion studies in dogs indicate that BL-5641 has a longer duration of activity than cimetidine at equal doses.

Histamine H2-Receptor Antagonism-Isolated Guinea_Pig Atria Assay Histamine produces concentration-related increases in the contractile rate of isolated, spontaneously beating guinea pig right atria. Black et al., 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) ~:13V306 and ~e~m~ ~na ~cNeill~ 3~ Rh~xm~cQl. Exp. Ther., 200, 352 (1~77~ support the conclusion o~ Black ~nd coworkers that the positive chronotropic e~fect of histamine in isolated guinea pig right atria is mediated via histamine H2-receptors. Black et al., Agents and Actions, 3, 133 (1973) and Bri~blecombe et al., ~ed. Proc., 35, 1931 (1976) have utilized isolated guinea pig right atria as a means for compar-ing the activities of histamine H2-receptor antagonists. The present comparative studies were carried ou~ using a modifica-tion of the procedure reported by Reinhardt et al., Agents and Actions, 4, 217 (1974].
Male Hartley strain guinea pigs (350-450 gm.) were sacrificed by a blow on the head. ~he heart was excised and placed in a Petri dish of oxygenated (95~ 2~ 5% C2) modified Krebs solution (g./liter: NaCl 6.6, KCl 0.35, MgSO4.7 H2O 0.295, KH2PO4 0.162, CaC12 0~238, NaHC03 201 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 sus-pended in a 20 ml. muscle chamber containing oxygenated modified Krebs solution maintained at 32C. Atrial contractions were recorded isometrically by means of a Grass FT 0.03 force displacement transducer and recordings of contractile force and rate were made with a 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 ~3~)3~)6 1/2 log lQ ~hte~yals to giVe final mo~ar bath concentrations o~ 1 x 10 7 to 3 x 10 5. The hista~ine-induced increase in atrial rate was allowed to plateau before the next succes-sive concentration was added. The maximal response invariably occurred at the 3 x 10 5M concentra~ion. The histamine was washed out several tLmes and the atrium allowed to return to control rate. The test compound ~1 x 10 5M) was then added and a~ter a 30 minute incubation the histamine concentration-response was repeated adding higher concen~
trations 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, Prohit Analysis, 3rd ed., Cambridge (1971). Concentration-response curve displacement factors were calculated as ~ollows:
ED50 Histamine~Compound Displacement Factor=
ED50 Histamine Alone The factor o~tained for BL-~641 ~as then expressed as a ratio of the factvr obtained f~r cimetidine.
BL-5461 Displacement Factor - 1 Activity Ratio =
Cimetidine Displacement Factor - 1 The results o~tained from these studies are summarized in ~able 1. Cimetidine and BL-5641 displaced the histamine concentration-response curve to the right by a factor of 6.6 ana 32.7, respectively. Based on the concentration-response curve displacemen~ fac~ors, BL-5641 was about -21_ 1~3~)3(~6 5.7 times more actlve than cimetidine as a histzmine ~ -receptor ant~30nis~ in ~sola~ed guine~ pi~ righ~ ætria.

T_ble 1 Relati~e Acti~ity o~ Cimet~dlne Pnd BL-5641 in Isola~ed -Guine? Pig Right Atria _ _ ~istam1ne ~D50 Concen~ration--: Wi~ 95~ Response Curve Conf~dence Displa~ement AC~ v : Co~ound N Concer.tra~ion Limits ~ 1.) _ Factor R~,ic . _ . _ _ _ . _ Histamine 0.21 Control ¦3 (0- 8 - 25) Cimetidine 3 1 x 10 5M(1.08 - 1.85) 6.6 1.0 __________ _ _________.~ _ ______________ ______________. . ______.
Histamine o .38 Control 121 1'- 7 ~ 53l ¦

12.44 6~l 2 ~ lC-5~ (7,81 - 20.28l 3~.7 5.7 .

N = n~mba~ o~ e.~Deriments.

1~30306 ' De'te'rmination'of Gastric Antisectory Acti'vity in the ~wo Hour Pylorous Ligated (Shay~ Rat The pyloric li~ation procedure in the rat was designed by Shay et al., Gastroenterology, 5,53 (1945) for the study of perforating gastric ulcers; however, as the method became known, it was also employed as a means of studyLng rat gastric secretion, Shay et al., Gastroenterology ! -26~
906 (1954~, Brodie, D. A., Am. J. Dig~ Dis " 11, 231 (1966~.
A modification of this procedure is presently used to eval-uate compounds for gastr;c antisecretory activity.
Male Long Evans rats, 280-300 gn~, are used~ The animals are placed in individual cages and fasted for 24 hours with free acess to water. Under ether anesthesia, the stomach is reached through a midline incision, and a cotton-thread ligature is placed around the pylorus~ After wound closure, ether administration is stopped and either BL-5641, cimetidine or vehicle are administared intra-peritoneally in a volume of 1 mg./kg, BL-5641 and cimetidine are solubilized with one equivalent of HCl and brou~ht to the proper volume with water. The animals are returned to their cages from which the water bottles have been removed and two hours later are sacrificed with ether. The stomach is removed and the two hour gastric collection is drained into a graduated test tube for volume determination.
Titratable acidity is measured by titrating a one ml.
sample to pH 7.0 with 0.02N NaOH, using an Autoburet and an electrometric pH meter (Radiometerl. Titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in millie~uivalents per liter. The percent inhibition of acid output is calculated as follows " ~L3~306 ~o Ir~ibition 4cid autput =
Acid Output-Control - Acid Output-Drua - - X lC~
Acid Output-Cor.trol The results o~tained ~Jith BL,5641 and ci~etidin~ ~re presented ;n Tzble 2.
Thes~ res~lts indicate ~hat~ in the two hou~ pylo~us ligæted rat: ~rep~r?t~.on5 BL-5641 i~ at leas~ as potent as c~m~tidine wit~ respect to t~le inh~ibiticn o~ g~stric acid outpu~.

Tablc 2 Ef~e~t o~ 5641 ard Ci~e~i.dine cn C~stric .4c~d Out~u~
~ . . ..
' the ~o Ho~r ~ylorus T igated Ra~ -.
Co~pound ¦ Dose (ip~a ¦ ~ Inhibition ED50 ~ ole/k~ ./k~.¦ of Acid Out~u~ ~Mole/kg, . =~. _ . - ....

BL-5641 40 11.1 80 5.~3 61 ~ 1 2~76 37 _____.____~_________________ ________________.. __________ C~ id~-lo !~o lO 66 20 5 6~ ~ 14 10 2.5 ~0 5 1.25 34 leas~ 5 ani~.? lS .~r~re emplo~ed at each dose.

~3~130~ii Determination of Gastric Antisecretory Acti~ity 'in th'e 'G'astric'Fistula Dog Thomas type [Thomas, J. E., Proc. Soc. exp. Biol. Med., 46, 260 (1941~ stainless steel cannulae are inserted into the stomachs of beagle dogs (10-12 kg.~ just orad to the pyloric gland area near the greater curvature to provide a chronic gastric fistula. Animals are allowed to recover for at least two months before any testing is done. Dogs are fasted overnight ~18 hours~ with water'ad-lib pr~or to each experiment. The dogs are placed in a sling and an eight inch inside needle catheter (C. R. Baird, Inc.~ with a two inch 17 gauge needle is inserted in~o a leg vsin for purposes of drug administration. Gastric secretions are collected every 15 minutes by gravity drainage from the opened cannula. Basal secretions are collected for two consecutive 15 minute periods and if these prove to be excessive (>4 ml./
15 min.; pH <5.0) the animal is not used. A modification of the procedure described by Grossman and Konturek~ Gastroenterolo- -gy, 66, 517 (1974) was followed. Immediately after the second basal collection, histamine ~100 ~g.~kg./hr.1 is infused for 90 minutes with a Harvard Infusion Pump in a volume of 6 ml./hr.
At this time either ~L-5641, cimetidine (solubilized with one equivalent of HCl and brought a proper volume with normal saliné) or normal saline is injected rapidly (within 30 seconds~
in a volume of 0.1 ml./~g. and then infusion of histamine con-tinues for an additonal 150 minutes (total time of infusion is 4 hours). Each 15 minute sample of gastric juice is measured to the nearest 0.5 ml. and titratable acidity against 0.02N NaOH (endpoint pH 7.0~ is measured with an Autoburet and pH meter (radiometer). The percent inhibition of acid 13L3~306 output is c~lculated as described in the Pylorus ligated rat procedure.
Equimolar doses of BL-5641 and cimetidine were administered to five different dogs and the results obtained are presented in Table 3.
Both BL-5641 and cimetidine produced an immediate in-hibitory effect on gastric acid output. However, the degree of inhibition at equimolar doses was consistently greater and of longer duration with BL-5641 than with cimetidine. These results indicate that as an inhibitor of histamine-induced gastric acid output in the dog, BL-5641 is more potent and/or longer acting than cimetidine.
The invention is illustrated but in no way limited by the following Examples.

~13~306 o C~l I ~ ~ ~ C~ o o o o o I ~ o ~ 0 o o c~
h 11 r-j~ ~tIr~ ~ ~1 ~ CU
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~ _ c~ ~ I ~ 0 ~ ~ C~J ~ ' ~ a~
_ ~ ~ O~
O O
Ll ~ J ~ ~ O r~
o ¢ t~
' ~i ~
O I O~ ~ ~ O G~
I C~ N N --I
g ~
t.~ ~ ~ '"1 ~ G~ O t~
~1 ~1 E~ ~
o o~ ~ 0 o G~ L'~ N ~ L~

~ ~1 ~ ~ o ~ c~ 1 o ~,1 5, '~
a~ ~D t~ ~~1 ~1 0 0 ~ C~ L'~
~ O O
'fi ~ Z ~ ~ N N ~t~
V C~ J ~ N N CJ C`J C\l cu N

_ l~ N ^~
O
u~ ~ V ~1 ~ O
~ ~o . ~ ~ ~ ~ ~1 ~ rt C~ Y ~ ~ ~O ~ ~O' ~ ~ ~ ~D ~
3 :~: ~ E ~ I fi ,~ F
h :~ . rl rJ ~ ~1 ~ .,1 ~1 ~ _ cq, c; a2 c) P:~ u ,~ c.~

~,. .

'I 9 3C~31)~

Example 1 N-Cvano-N ' -{ 2- [ ~Y-m2thvl-S-imidazolvl ) methvlthio] eth~1 } -.. .
N"-prooargylsuanidine ~ca3 CH2scH2c~l2l`~Lc-scH3 ~ C'~2C--C~

\ /
~CH3 ~( NCN
H CH25CH2C}I2NHCNHCH2C----CH

A mixture of N-cyano~ {2-~ (4 methyl-5-imidazolyl)-methy7 thio] ethyl}-S~methyl isothiourea ~3 . ~0 y, 0 . 011!
mole) and propargyl æ~ine t2.50 g, 0.0~5 mole) in acetonit-rile (60 ml~ was stirred at reflux for 65 hours j and tne~
~as ~.eate~ in a st2inl esa steel pressure vessel at 120~
13~ ~or 38 hou~s. The reaction mixture was coQle~, de-c3~ted from ~ ta_, and then evaporated to leave a ~Jum (3 . ;7 g) . Tnis material was placed on silica gel ~100-2CG

~csh) and el uted with a mixture o methylene chloride (3 /
par~s) a..d meth-nol ~3 parts). The product: ob~ained from a micdle ~^-action was crystallized by tritura~ion unde_ acetonitrile, and then was recrystallized ~rom ace~onitrile --2~--~3~3~:36 to yield the title co:n~oun;l (û..236 cJ; 7.7%); mp 146-149.5.
A~lal. Calc'd ~or C12E~16~6 Four.d: C, 51.86; H, 5.81; ~J, 30.70.

Example 2 N-Cyano-N ' -{ 2- [ (~-methyl-; im dazolyl ) methvltnio] etavl } -N"-~ro3argvlg,~anidine (CH3S) 2C-NCN ~ Y.2NC~2C--CH
'.

~JC21 CH3 SCNHCH2C _ CH
A

~3 N~;;~

El CH2SC C}12NH2 ~ A

I~N~\ NCN
H CH2scEl2cH22lHe~lHc}~2c ---CEI

~L3~30 ~, . a. NCyar.o-N'-~ro~argyl-S-methyl isothiour~a (A).

A solution of dimethyl cyanod1thioiminocarbonate tl6.00 g, 0.109 mole) and propargyl amine (6.03 g, 0.109 mole) in ace~onitrile (320 ml) was stirred at reflux for

4 hours, and .hen at 25 for 12 hours. Workup gave the title compound A ~13.52 g, 81%), mp 160~164o b. N-Cyano-~'-{2-[(4-methyl-5-imi~a~olyl)methvlthio]ethyl~- -N"-propargylguanidine A solution of A ~11.71 g, 0.0765 mole) ar~d 2-[(4-methyl-5-imida~olyl)me.hylthio] ethylamine (13.10 g, 0.0765 mole) in metha~.ol (250 ml) ~as heated at reflux for 64 ho~rs.
The solvent was removed by evapo_ation, the residue,'placed on silica gel (100-200 mesh) and chromatogr~phed by gradien~
elution using methylene chloride/methar.ol; the latter f~act-ions yielded 4.0 g of the ~itle compound. Rec-ystalli~a~ion from acetonitrile ~ave purified product mp 150-152.5~ ident-ical (ir~ ~mr, tlc) with the product prepared in Exam~le 1.

Exa~ple 3 : N-Cva~o ~'-{ -1(4-methY1~5 imidazolyl)methylthio]ethyl}-N~-~2-butyn-1-yl~guanidine .
(CH3S)2C--NCN ~ ~ NC~ C-CCH3 ~1 C~
CH3SCNHCH2C-- CC~3 ,~, .

1~;~3~6 H CH2scH2c~2~H2 ~ B

.
N~

N ~ ICN
H ~H2scH2cH2N~cNHcH2c aCC~3 a. N-(2-Butvn-l-yl)-~ cyano-S-meth~lisot~iourea (B) : A solution of dL~ethyl cyanodithioiminocar~onate (lO.C0 g, 0.0684 mole) and 2-butyn-1-amine (4.73 g, 0~068~ mole) in acetonitrile (200 ml) was s~irred at 25 for 0.5 hour, anZ then at reflux for 2.5 hours.

~he mixtu~e was cooled, then filtered to yield t:~ title compound ~, m? 180-183.

b. N-Cva~o-N'-{2-~(4 methvl-5-imidazolyl)me~hvlthio]-e~:n~l}~N"-(2-butyn-1-yl)guanidine ------..
A solution or B (6~82 g~ 0~0407 mole) ~nd 2-[(4-~,~thyl-~-Lmidazolyl)methylthio] ethylamine (6.g8 g, 0.0407 mole) in metha~.ol (140 ml) was heated at reflux for 40 hours. Workup and chromatography as described a~ove for Example 2 yieided the title compound. When the title compound was prepared according to the general proceduxe o_ Example 1, it melted at l28-130.

Example 4 N-Cvano-N'-{2-[~4-methyl-5-imidazolyl)methv~lthio]ethyl}-N"-(3-butvn-1-yl)guanidine The general procedure of ~xample 1 is repeated e~cept that the propargyl zmine utilized ther2in is replaced ~y an e~ui~.olar ~ount of 3-butyn-1-amine, and the title product is th~reby produced.

Exam~le 5 N-Cyano-N'-{2-~4-methyl-S-imidazolyl)methylthio]eth~l}-N"-~4-pentyn-1-vl)guanidine The gen~ral procedure of Example 1 is repeated except that the proparsyl amine utilized therein is replaced by an equimolar amount of 4-pentyn~l-a~ine, and the title product is tnereby produced; m.p. 99-103.

Example 6 N-Cyano-~'-{2-[t4 methyl-S-imidazolyl)methylthio]ethvl~-Nn-(2-metnyl-3-butyn~2-yl)guanidine _ _ The general procedure ~f Example 3 is repeated e~cept that tne 2-butyn-1-amine utilized therei~ is replaced by : an equimola~ ~mount of l,l-dimethylpropargylaminer and t*.e ~itie procuct is tnereby produced.

~32-3.~3~30~

ExamD~e 7 N-Cyano-N'-~2-~(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-2-yl)guanidine The general procedure of Example 3 is repeated except that the 2-butyn-1-æmine utilized therein is replaced by an equimola. æmount of l-methylpropargylamine, and the title produce is thereby produced.

Example 8 N-Cyano-N'-~2-tt4~methyl-5 imidazol~l)methylthio]ethyl}-N"-~2-butyn-1-yl)gu~nidine A mixture o N-cyano-N'-{2-[(4-methyl-5-Lmidazolyl)-methylthio~ethyl~-S-methyliso.hiourea (3.00 g. 0. a 11 1 mole~
and 2-~utyne-l-amin3 ~3.07 g,,0.0445 mole) in 60 ml. of propionit-ile was stirred at reflux for 4~ hou~s. TLC
assay of an a1iquot of the reaction mix~ure sho-~ed 2 trac~
of the isothiourea startiny material, so the mi:;ture was refluxed for an additionzl 6 hours and then stirred ~t rocm temperature fo~ 64 hours. The solvent (along with e~cess æ~ine) W25 removed at reduced pressure and the r~sidual gum was placed on silic~ gel (100-200 mesh~ and eluted with a mix'ure of methylene chloride ~97 parts3 and methar.ol (3 parts~

The mlddle frac'ion.s we~e combined and e~aporated ~o give 1,81 g. of yellow 5~. The gum was dissolved in 20 ml. of ethyl acetate and crystallized at -15C. The resulting pale yellow solld (1.2 g.) was dissolved in 11 ml. of hot acetonitrile and recrys'allized a~ -15C; yield 1.072 g., m.p. 128-130C.

1~3~3(~6 Anal. Calc'd ~or C13H18N6S: C, 53.77; ~I, 6.25; N, 28.94;
S, 11.08 Found: C, 53.7~; H, 6.29; N, 29.62;
S, 11.~4 Example 9 N-Cvano-N'-r2-[(4-methyl-5-imidazolyl)methylthio~e~hyl~-~i"-l3-~utyn~ l)guanidir.e A mixture of N-cyzno-N'-{2-~(4-methyl-S-i~idazolyl)-methylthio]ethyl}-S-methylisothiourea t3.00 g., 0.0111 mol~) and 3-butyn-l;amine (3~13 g., 0.0~53 mole) in 60 ml. o~
propionitril~ was stirred at reflux for 4~ nours. The solver.t was evaporated to give 5.40 g. o~ a syrup which was placed on 70 g. of 100-200 mesh silica gel and chromatographed b~
gradient elution using me hylene c~loride~methanol.

Fraction Eluan~ Volume _.
199 CH2C12/1 MeO~ 100 ml.
2 70 ml.
; 3 a ~0 ml. 0.l17 g.
4 ~ 30 ml~ -$ ~ 75 mlO 0.067 g.
6 " 750 ml. 0.080 g.
; 7 n 32~ ml. 0.168 g.
898 CU2Cl2~2 MeOH 50 ml.
g n 15~ ml. 00125 y.
~ 250 ml. 0.811 g.
11 ~ 250 ml. 0.72 y.

3~-~1303~

12 ~7 C~2C12!3 ~leOH 175 ml. 0.125 g.

13 n 225 ml~ 0.133 g.

14 ll ~ 0 ~ 027 g .

" 225 ml.
~ 0.002 g.
16 n 200 ml.J
1795 CH2C12/5 MeOH 250 ml. 0.035 g.
18 " 250 ml. 0,236 g.

TLC ~silica gel, 90 CH~C12/10 ~leOH) indicated fractio~s 9-1~ were pur~ and should be com~ined. Fractions 1-8 showed fzst moving im~urities. Frac~ions 13 and 14 s~.owed scme trailing impurities. Frac~ions 9-12 were combined and e~aporated to 1.72 g. of a yellow gum. The gu~ was dissolved in 11 ml. o nitromethane and crystallized at -15C (pale yellow solid, 1.18 g.), which was recrystallized fro~ 9 ml.
of nitromethane to give 0.~87 gm.; m.p. 86-89C (softens at 8~C~. Infrared and N~R ~100 ~Y.Z) were clean ar;d consistent wit~ ,ne desired structure. N~L~ showe~ ~hat the ~roduct was solvat~d with approxLmately 0.08 mole of nitromethane~
:',~ ., _13 18N6S-0.08~C~3NO2): C, 53021; ~, 6.22;
:~ N, 28.84; S, 10.86 Found: C, 52.68, 52~87; ~., 6.28, 6.02, N, 29.39, 29.50; Sr 11022 ~"~

3L~3~306 Example 10 N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethvl}-Nn-~4-pentyn-l~yl)guanidine A mixture of N-cyano-N'-{2-[(4-methyl-5.~ida7O1yl)-methylthio~e~hyl}-S-methylisothiourea (3.00 g., 0.0111 mole) ar.d 4-per.tyn-~-amine (3.69 g.,0.0445 mole) in 60 ml. of zcetonitrile was stirred at reîlux for 24 hours, and then allowed to stand at room temperature for 96 hours. The solvent and excess amine were removed under reduce~ pressure and the residual yellow gum was purified by chromatography on 50 g. of 100-200 mesh silica gel, using sradient elution with methylene chloride/~ethanol ~99:1-96:4). The middle fractions indicated by TLC to be pure were combined and evaporated to give 1.91 gO of yellow gum which ~as crystallized at -15C from 18 ml. of ethyl ace~ate. The resultins white solid (1.25 g.) ~as recrystallized at -1;C fro~ 10 ml. of aceto~itrile to glve 1.063 g. of product; m.p. 99 103C.

Anal. Calc'd for C14~0N65: C, 55.24; ~, 6.52, ~, 27~61; S, 10.53 Fou~d. C, 55.43; H, 6.58, N, 28.26; S, 10.97 .

~13~:)30~
EXamD1e 11 N-Cvano~ t2-~(4-methvl-5-imidazolvl)methvlthio]ethyl}-t~"-propar~lguanidine The mixture of l~-cyano~ 2-~(4-methyl-5-imidazolyl)-methylthio]ethyl~-S-methylisothiourea (10.0 g; 0.0371 mole) and distilled propargylamine t20 ml; 0.3~5 mole) in ~ethanol tS0 ~1) was stirred at reflux, under a positive pressure nitrogen at~osphere (nitrogen sweep~, for 20~5 hours. ~he solvent and excess amine were then rer.loved by evaporation to leave a yellow-brown oil that rea~ily crys~alliz~d.
Trituration of the crude product under isopropanol ~30 ml) gave the title compound as an off-white, friable solid (8.11 g, 79~); m.p..l46-148.5.

Example 12 N-Cyano~ t2-t[4-methyl-5-imidazolvl~meth~lthio]ethvl~-Nn-proeargvlsuanidin A mi~ure of N-cyano-N'-{2-lt4 me_hyl-5-imidazolyl~-m~thylthio3e~hyl}-S-methylisothiourea ~100 g; 0.371 mole) and ~ist~lled propargylamine ~1~0 ml; 2.~4 moles) in methanol ~500 ml) was s.irred at reflux under a positive pressure nitrog~n at~osphere ~nitrogen sweep~ for 22 hours. ~he r~ac _on ~ixtu-e was oooled, and the solvent and excess amine were removPd by e.vaporation to leave an amber oil that readily crys~alliz2d. The crude product was triturated under isopropanol (250 ml), cooled at O for 2 hours and collected by filtration. The fil~er cake was washed with cold isopropanol and dried in vacuo over P2O5 for 16 hours~ The dried title __ __ ~3~306 product was a near-white dense solid; yield 73.5 gm ~71.73) m.p. 147-149.

Exam~le 13 Recrvstalli~ation of ~I-CYano-N'-t2-[(4-meth~1-5-i~idazolvl)-methylthiolethyl}-~ln-pro~ar ~ lguanidine The final products obtained in Ex~ples 11 and 12 were combined (total 81.3 gl~ dissolved in hot isopropznol (1000 ml), filte_ed through"Super-Cel" and allowed to cool at room temperature for ca. 68 hours. The resultins crystalline product was recovered by filtr3tion, washed with cold isopropanol, pulverized and dried in a heate~ d~sicca~or under high vacuum for ca. 45 hours. Yield 72.4 g (89~
recovery); m.p. 149-151o IiPLC assay showed the purity ~o be ca. 99.5~. The N~I~ (100 MI~z) spectrum was clean and consiste~t.

An 1- Calc'd for C12~16N6S~ 2.15; II, 5-8~; ~l, 30~4~;
~, 11.60 Found: C, 52~4~; ~I, 5.9~; N, 30.51;
S, 11.35 1~3~;3C)~;
Exa'mp'le''14 N-Cyano'-N'-'~'2-[~('4'-methy'1-'5'-imi'd'a'zo`lyl'~methyl'thio]ethyl~-N"-propargylguanidine A. N-Cy'ano-N'-prop'a'rgy'l-'S-me'thylisothiourea 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.

B. N-Cyano-N'-propargyl-N"-(2-mercaptoethyl~guanidine A mixture of 1.136 g (10 m moles) of cysteamine hydro-chloride, 1.53 g (10 m moles) of the product of step A, above, and 0.055 g of hydroquinone in 10 ml DMF was slightly warmed to dissolve. To this solution was added 10 ml of lN aqueous sodium hydroxide and nitrogen was bubbled through the solution~
After standing at room temperature for 17 hours, the reaction mixture was evaporated to dryness to give a mixture of the title product and sodium chloride. The title product w~s extracted from this mixture with 10 ml of ethanol and the ethanolic solution was used in step C, below.

C. N-Cyano-N'-{2-[(4-met~y__5-'imidazolyl~methy_thio]-ethyl}-N"-proparg~guanidine The ethanol solution of the product of step B, above, (about 10 m moles) was added to a solution of 0.46 g sodium (0.02 g-atoms) in 10 ml ethanol at 4C under nitrogen. After

5 minutes, a solution of 1.67 g (10 m moles~ of 4-methyl~5-chloromethylimidazole-HCl in 14 ml eth~nol was added and the ~3~:306 mixture was stirred at room temperature under nitrogen ~or 70 minutes. The reaction mixture was filtered through a bed of celite filter aid to r~move the inorganic salts and the celite was washed with ethanol. The filtrate was evaporated to dryness a~d the product was purified by chroma-tography on a silica gel colu~n (20 g silica, 3.2 x 4.5 cm bed) with ethanol-chloroform mixtures as the sol~ent. The ethanol content was gradually increased fro~ 2 to 15~. The eluant was evaporated to dryness to give 1.906 g of crystal'ine prod-~ct. Recrystallization from 2-prop~no~ gave 1.49 g ~54~) of ~he title product, m.p. 144 - 145C.

Exam?le 1~

N-Cyano-~J'-{2-~(4-methyl-5-imidazolyl)methylthio]eth~l}-Nn-butyn-l-yl)guanidine A ~J-Cvano-?J'-~2-butvn-l-vl)-S-meth~lisothiourea A solution o~ dime'hyl cya~odithioiminocarbonate (lO.00 g, 0.0684 ~ole) and 2-butyn-1-amir.e (4.73 5, 000684 mole) in acetonitrile (~00 ml) was stirred at 25 for 0.5 hour, and then at reflux ~or 2.5 hours. The mixt~re W2S cooled, then fil~ered to yield the title compou~d, mp 180-183.

B. N-Cyano~ (2-butvn-1-yl~-~ln-(2-merca~toethvl)-...
guanidi~e The general procedu-e of Exa~ple~B is repeated ~cept that the N-cyano-N'-propargyl-S-methylisotniourea utilized 1~ 3~ 3~

therein is replaced by an equimolar umoun~ of ~-cyano-~J'-~2-butyn-1-yl)-S-methyl~sothiourea, an~ the ~itle pr~duct ls thereby produced.

C N-Cyano-N'-{2-~4-methYl-5-imidazolyl)~ethylthioJ-l}-N~-(2-butvn-1-yl)guanidine ~ he general procedure of Examplel~c is repeated except ~hat the N-cyano-N'-propargyl-~t"-(2-me~capto~thyl)guanidine utilized therein is ~eplaced by an equ~molar ~r.ount of N-cyano-N'-(2-butyn-1-yl)-N~-~(2-mercap~oethyl)guanidine, and the title product is thereby produced.

Exam~lel5 ~-CY~nO-N '-{ 2-~4-methyl-S~imiaazolyl~methvlthio]etny ~3-butvn~ gua~idine A. N-C~ano-~J'~3-butYn-l-Yl)-N"-(2-merca~toethvl)g~ar.i~ine The general procedures of Exa~ple 14 steps A and B, are repeated except that th propargylamine utilized in step ~
thereof is rep~aced ~y an ecuimolar 2mount of 3-butyn-1-a~ine, ar.d the title product is thereby produced.

N-Cyano-N'-{2-[(4-metnY1 5-imidazolyl)methvlthio]-ethvl}-Nn-(3-butyn-1-yl)~uan~dine The gPneral procedure of Examplel~C is repea.ed except that the N-cyano-N'-propargyl-N~-~2-mercaptoethyl)guanidine ~ 3~ 3~

utilized therein ~ replaced by ~n equimolar amount of N-cyano-N'-~3-butyn-1-yl~-N~-(2-mercap~oethyl)guanidine, and the title product is thereby produced.

~Z
~J-Cvano-N'~{2-r(4-met~yl 5-i~idazolYl)me~h~lthio~ethyl}-?l"-(4-pentyn-l~yl~suanidine A. N-CYano~ (4-pentyn-1-yl)-N~-~2-me-~aptoethyl)-guanidine The ge~eral procedures o~ Example14, steps A and B, axe repeated e~cept that the proparsylamine utilized in ~tep : thereo~ is replaced by ~n equimolar ~ount of 4-pentyn-1-amine, and the title product is thereby produced.

. N-Cyano~ {2-~(4-methvl-5-imiaazolyl)methylth~oi-The ge~eral procedura o ~xamplel~C is repe~t~d except that the ~-cyano-N'-propargyl-Nn-l2-mercaptoethyl3guar.idine utilized therei~ is ~eplaced by a~ e~uLmolar amoun~ of N-cyano-N~-(4-pentyn-l-yl)-N~2-mercaptoethyl)gu2~id~ne, and the title product is thereby produced.

~xam~
-Cyano-N'-{2-t(4-methyl-5-imidazolyl)methvlthio~eth~l}-N"-l2 methyl-3~butvn-2-yl~guanidine A. N-Cvano-N' (2-methyl-3-butyn~2-yl)-N" (2-me~caDto-ethyl)guanidine ,,,;~

~L3(~306 ~ he general procedures of Exzmpl~14, steps A and B, are repeated except that the propargyla~ine utilized in step A thereof is replaced by an equimolar amount of 1, l-dimethylpropaxgylEmine, and the tit~e product is thereby produced.

B. N-C~ano-N'-{2-[(4-methyl-5-imidazolyl~methylthio~-ethvl}-Nn-(2-meth~ 3-butyn-2-y~uanidi~e .

~ he general procedu~e of Example14c is repe3ted except that the ~-cyano-N'-propargyl-Nn-~2-mercaptoethyl)suanidine utilized therein is replaced ~y an equimolar amount of N-; cyano-N'-~2-methyl-3-butyn-2-yl)-N~-~2-mer-aptoethyl)guznidine, nd the title product is thereby produce ExamDle 19 N-Cvano-N ' -~ 2- ~ (4-meth~1-5-i~nidazolyl)methylthio; ethvl}-~ln-t3-butvn-2-yl)suanidine A N-Cyar.o-~'-(3-butYn-2 yl)-M"-(2 mercaptoeth~l)guan~dine The general procedures of Exælnple 14 steps A and B, are ~epeated except that the propargylamine utilized in step A
thereof is replaced by an equimolar amount o~ l-methyl propargylamine, znd the title product is thereby produced.

.~

~13(~306 B. N-Cyano-N'-{2-~4 methvl-5 imidazolvl)methvlthiol-eth~l}-N~-(3-butyn-2-yl)guanidine The general procedure of Examplel4 is repeated except that the N-cyano~N'-propargyl-N"-~2-mercaptoethyl)guanidine utill2ed therein is replaced by an e~ui~olar amoun~ of N-cyano-Nl-(3-butyn-2-yl)-N~-(2-mercaptoethyl)guaniaineJ ar.d the title product is thereby produced.

-4~-

Claims (14)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the formula IV
wherein R1 is an alkynyl group containing from 3 to 9 carbon atoms, inclusive, and R is (lower)alkyl or an acid addition salt thereof, characterized by reacting a compound of the formula (RS)2C =NCN
wherein R is as described above with a compound of the formula wherein R1 is as described above, and, if desired, converting the product to the corresponding acid addition salt.

2. The process of claim 1 wherein R1 is -(CH2)nC ? CR4 wherein n is an integer of from 1 to 6, inclusive, and R4 is hydrogen or methyl.

3. The process of claim 1 wherein R1 is -CH2C?CH

4. The process of claim 1 wherein R is -CH2C?CCH3

5. The process of claim 1 wherein R1is methyl.

6. The process of claim 1 wherein R1 is -CH2C?CH
and R is methyl.

7. The process of claim 1 wherein R1 is -CH2C?CCH3 and R is methyl.

8. A compound of the formula IV
wherein R1 is an alkynyl group containing from 3 to 9 carbon atoms, inclusive, and R is (lower)alkyl or an acid addition salt thereof, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.

9. A compound of claim 8 wherein R1 is -(CH2)nC=CR4 wherein n is an integer of from 1 to 6, inclusive, and R4 is hydrogen or methyl, or an acid addition salt thereof, whenever prepared by the process of claim 2 or an obvious chemical equivalent thereof.

10. A compound of claim 8 wherein R is -CH2C=CH
or an acid addition salt thereof, whenever prepared by the process of claim 3 or an obvious chemical equivalent thereof.

11. A compound of claim 8 wherein R1 is -CH2C==CCH3 or an acid addition salt thereof, whenever prepared by the process of claim 4 or an obvious chemical equivalent thereof.

12. A compound of claim 8 wherein R is methyl, or an acid addition salt thereof, whenever prepared by the process of claim 5 or an obvious chemical equivalent thereof.

13. A compound of claim 8 wherein R1 is -CH2C=CH
and R is methyl, or an acid addition salt thereof, whenever prepared by the process of claim 6 or an obvious chemical equivalent thereof.

14. A compound of claim 8 wherein R is -CH2C=CCH3 and R is methyl, or an acid addition salt thereof, whenever prepared by the process of claim 7 or an obvious chemical equivalent thereof.