CA1075702A - Process for the preparation of substituted guanidine compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A process for the production of compounds having activity as histamine H2-receptor antagonists and having the formula

Description

1 This invention relates to pharmacologically active compounds, to methods for preparing these compounds, to pharmaceutical compositions containing these compounds and to methods of blocking histamine H2-receptors by administering these compounds. The compounds of the invention can exist as acid addition salts but, for convenience, reference will be made throughout this specification to the parent compounds.

Many physiologically active substances elicit ~heir biological actions by interaction with specific sites known as receptors. Histamine is such a substance and has-a number of biological actions.- Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines" of which mepyramine is a typical e~ample, and diphenhydramine and chlorpheniramine are other examples, are mediated through histamine Hl-; i receptors (Ash and Schild, Brit. J. Pharmac. Chemother, ¦ 27, 427, (1966). However, other of the biological actions 20 1 of histamine are not inhibited by "antihistamines" and actions of this type which are inhibited by a compound described by Black et al -~Nature, 236, 385 (1972)) and - -called burimamide are mediated through receptors which ~i are defined ~y Black et al, as histamine H2-receptors.
:- 25 Thus histamine H2-receptors may be defined as those histamine receptors which are not blocked by mepyramine ~-but are blocked by burimamide. Compounds which block ~- - histamine H2-receptors are referred to as histamine H2-antagonists.
Elockade of histamine H2-receptors is of utility in - inhibiting the biological actions of histamine which are not inhibited by "antihistamines". Histamine H2-antagonists - are t~erefore~useful, for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents ~hich act on the cardiovascular system, for example as inhibitors of the effects of histamine on blood pressure.

,~, .
-~ - -2- - -. ~. - - . ' " .

~r ' :.' ' . ' ' ' ' '. ': ' ' ' . , '' :. ~ - ', .

In the treatment of certain conditions, for example, inflammation and in inhibiting the actions of histamine on blood pressure, a combination of histamine Hl- and H2- antagonists is useful. The compounds of this invention are histamine H2- antagonists. These s compounds are represented by the following formula:

HOCH2 ~ CH2Z (CH2) nNH-c\

- ~ NHY

FO~MULA I

wherein n is 2 or 3; Z is sulphur or methyiene; X is sulphur CHNO2 or N.CN; Y is hydrogen, lower alkyl or HetCH22'(CH2)n,;
Z' is sulphur or methylene; n' is 2 or 3; and Het is 5-hydroxy- -methyl-4-imidazolyl, an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or an isothiazole ring.
. .
Thus, in accordance with the prese~t pro~ess, a process i5 provided for the produc~ion of a compound of the formula:

HOCH2 ~ CH2-s-cH2-cH2-NH-c-NHy H-N ~ N N-CN
~' wherein Y is a lower alkyl group; or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting an -~ amine of the formula:
'~'''~ ' ' .
. ~ .

~ -3-: ':

i~

.. ~ . ...... . .- .. . ~ - . . . .

. -.- :: ' . - , .
, - . - :
:. . - ,. ' .. ' ' .

.

` 107570Z

HOCH2~e~ CH2-s-cH2-cH2 NH2 H-N ~ N

with a di lower alkyl dithioiminocarbonate of the formula QS\
C--N-CH
QS
. 10 where Q is a lower alkyl group to produce a compound of the formula:
NCN
HOCH2 ~ C~I2SCH2CH2NH-C
H N
and the compound of formula IV produced is reacted with an amine of formula YNH2 wherein Y is as hereinbefore defined.
, .
~-` Throughout the present specification, by the term "lower Alkyln we mean an alkyl group containing from 1 to 4 carbon atoms.
.' . .
A useful group of compounds according to our invention are those wherein Y is lower alkyl, e.g., methyl. Another useful group is -that wherein Z is sulphur, and n is 2.

Z,~ i8 preferably sulphur, n' is preferably 2 and Het is preferably 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3-hydroxy-2-pyridyl, --~ 3-methoxy-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 2-thiazolyl or 3-isothiazolyl. Specific compounds within the scope of the present invention incl~de:
N-methyl-N'- 2-(5-hydroxymethyl-4-imidazolyl)-methylthio)ethyl thiourea and ~ 35 ...
. '~ .
-~;
~-~ -3a-.'~ ~j - .
., ~ ..

- . , . , . . . ~ . . . . .. .
,'. . . - , -' . ' : :
',~. . , ', - ,: . ' ~ .. . . . .

1 N-methyl-N'-cyano-N"-[2-((5-hydroxymethyl-4-imidazolyl)methylthio)ethyl]guanidine The compounds o~ the present invention~y.be produced ~r.om the amine of Formula II: .

HOCR2 _C~2Z (CH2)nNE~2 . HN~6~N .

.: ` 10 FOR~ULA_II -.- ~herein n and Z have the above significance by-reactions . such as those disclosed in our British specification : 15 Nos. 1338169, 1397436, 1421792 and 1431589 the particular ~ reaction used depending of course on the nature of X and -~. Y in Formula I. For example, the compounds wherein X is -~ I sulphur and Y is lower alkyl may be produced by- reaction I of the amine of Formula II with a lower alkyl isothiocyanate ~0 o~ Formula III:
. I - - .
.~ ~ Y'-N-C~S
~ : -. . -. FOR~ULA III
wherein Y' is lower alkyl. A similar reaction using benzoyl;isothiocyanate yields an N-benzoyl thiourea which, on acid hydralysis to remove the benzoyl group yields the . compounds of For.mula I wherein X is sulphur and Y is hydrogen. The compounds wherein X is sulphur and Y is ~ Het ~ Z':( ~ )n,~may be prepared by first reacting the :. ~ amine of Formula II with carbon disulphide to give a dlthlocarbàmic.acid of ~ormu}a I~: S

~ 35 ~ ~ SR
1::
FORMULA IV

.. . . . .
..... . . . ... . ~ : .. . .

~075'70Z
1 wherein Z and n have the above signlficance and R i9 hydrogen, ~hich compound is then reacted with methyl halide to give the corresponding methyl ester (Formula IV, R-methyl), and finally reacting this ester with an amine of formula HetCH2Z'(C~ )n,NH2 to yield the required compound.

The compounds wherein X is CEN02 or N.CN may be produced by reaction of the amine of Formula II with a di(lower alkyl) dithioimino carbonate o~ formula Va: .

, QS
~ C ~ X' , QS ~
FOR~ ~ A Va wherein Q is lower alkyl and X' is CHN02 or N.CN or, when X' is CEN02, the co,rresponding monosulphoxide compound of ', 20 ~3rmu:La Vb:

QSO
: ~ - C ~ X' . QS
, . , FORMULA Vb .:- X' to give a compound Vl: ~ - -- HOCH2 ~ .cH25tc~ )nNH SQ
HN~6~N
.-, . - '.
~ FORMULA VI
.,~
- ., ;, ~ , . i'ollowed by reaction o~ this latter compound with an amine oS formula. r ~ to'give the required compound,of Formula I.
~ ~ - - . ' , . . ' .
5_ - .

~. ~

1 Ihe amine o~ Formula II wherein Z is ~ulphur 18 conveniently prepared by reduction o~ the corresponding carbo~yl~c acid o~ Formula VII:

S HO-CO C~2S(CH2)nNH2 ~ ' ' FORM~LA VII

This reductio~ is conveniently c~rried ,out by electrolytic -mean~ or, alternatively by chemical reduction o~ the ' -corresponding ester ~ith lithium aluminium hydride.
.
The synthesis of the compound o~ Formula VII may suitably -.
commence irom ethyl ethoxyacetcacetate which is ~irst converted with nitrous acid to the known compound o~
iormula VIII: -C2H50CH2CO~ C2H5 ¦ ' OH

.. FOR~nLA VIII , .
Reduction of this compound with stannous chloride gives the corresponding amine which, without isolation, is reacted , ~ith ammonium thiocyanate to give,the.imidazo~e-2-thione of '. Formula IX: . ~
. _:
',~ . C2~50CO ~ OC2~5 :, ~ ' ' - S
' 35 - FORYDIA I~

.
~: ~ -6-` ~ ' ' - . ' ' . . . ' .
. ~

': - .
~. . -,, ~ ~ ' , '.. ' -' ' - - . , .

1 Desulphurisation oi this compound gives the imidazole derivative o~ Formula X:

C2H50Co~_C~I20C2H5 ~H

FORMULA X
.
~hen this compound is sub~ected to a series o~ reactions which can be effected without isolation of any intermediate and which comprise (a) hydrolysis of the ethyl ester to ~he acia (b) cleavage o-f th~e ethyl ether to the hydroxy compound and (c) reaction o~ the resultant, 4-hydro~ymethyl-5-carboxy compound with an aminothiol o~ the formula HS(CH2)nNH2, the required compound of Formula VII is produced.
Preparation of the amine o~ Formula II wherein Z is methylene may commence from a compound of Formula XI: -.E~N(CH2)n+
, .
FORMULA XI

~herein n has the same significance as in Formula I and E ~ N is a suitably protected amine group e.g., phthalimido.
Reaction of the compound of Formula XI with acetylene-~n a ~ - suitable solvent and in the presence of a Le~is acid e.g., -~ AlC13 gives the c--ompound of Formula ~II:

- E~N(C~2)n~2c~C~-cH
. - .
FORMULA XII
.
:
which, on treatment with triphenyl phosphine gives the compound o~ Formula XIII:

.. . .
~ .
. ~ .
, . ~-_.

, .
:''- . .

`` ` ~ i07570Z

E8N(CH2)n+2COCH'CHpph3 Cl FORMULA XIII

When this com~ound is reacted with S-methylisothiourea the product is the imidazole derivative of Formula XIV:

(CH2)n+2 ~ CH2PPh3 Cl-HN yN

,', .
FOR~DLA ~IV
-. and when this is treated with sodium methoxide (cf. the process described in German OL5 2,649,~591,. - -t~e.p~oduct is the compound of Formula XV~

A` E-N(CH2)n+2 CH20CH3 ~ ' ' ' ~ .
25 - SC~3 .~ FORMULA XV

Desulphurisation of the compound of Formula XV with Raney nickel to remove the 2-methylthio group and treatment with , ~ concentrated hydrochloric acid to convert the methoxymethyl .~ : to a hydroxymethyl group and to remove the amine protestin~g group yields the amine of Formula Il wherein Z is methylene.

The c~mpounds of Formula I block histamine H2-reccptors, that .

.~
.~

-' :'. " ~ ~ ' .
1 is they inhibit the biological actions of histamine which are not inhibited by "antihistamines" such as mepyramine but are inhibited by burimamide. For example, the compounds of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses o~ from 0.5 to 256 micromoles per kilogram intravenously. This - procedure is referred to in the above mentioned paper - 10 of Ash and Schild. The activity of these compounds as histamine H2-antagonists is also demonstrated by their ability to inhibit other actions of histamine which according to the above mentioned paper of Ash and Schild, are not mediated by histamine Hl-receptors.
For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.

.
The compounds of this invention inhibit the basal secretion of gastric acid and also that stimulated by pentagastrln or by food.

In addition, the compounds of this invention show anti-inflammatory activity in conventional tests such as the rat paw oedema test, wh-ere the oedema is induced by an irritant; the rat paw volume is reduced by subcutaneous injection of doses of a compound of Formula I. In a conventional test, such as the measurement of ~blood pressure in the anaesthetised cat, the action of the compounds o~ this invention-in inhibiting the vasodilator action of histamine can also be demonstrated. The level of activity of the- compounds of this invention is illustrated by the - effective dose producing 50% inhibition of gastric acid secretion in the anaesthetized rat and the dose producing 50% inhibition of histamine-induced tachycardia in the isolated guinea pig àtrium.
.
- -- _9_ .

...

1 For therapeutic use, the pharmacologically active compounds of the present 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 an addition salt with a pharmaceutically acceptable acid and in association with a pharmaceutical csrrier therefor. Such addition salts include those with hydrochloric, hydrobromic) hydri~dic, sulphuric and maleic acids and may conveniently be formed from the corresponding bases of Formula I by standard procedures, for example, by treating the base ~ith an acid in a lower alkanol oi by the use of ion exchange resins to form the required salt either directly from the base or from a different;addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and methods of blocking histamine H2-receptors which comprise administering a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof are also objects of this invention. The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra al-ba, sucrQse, talc, g~latin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. E~emplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed.
- Thus~ if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or loze~ge The amount of solid carrier will ~ary widely but preferably will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the ~orm of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or nonaqueous liquid suspension.

:

.

1 The pharmaceutical compositions are prepared by con-ventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredient~
as appropriate to the desired preparation.
The active ingredient will be present in the composition - in an effective amount to block histamine H2-receptors.
The route of administration may be oral or parenteral.

Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg to about 250 mg.

The active ingredient will pre~erably be administered one to six times per day. The daily dosage regimen will -preferably be from about 150 mg to about lS00 mg.

.
-~ j Advantageously the composition will be made up in a dosage I form appropriate to the desired mode of administration, for 201 example as a ~et, capsule, injectable solution or as a I cream or ointment for topic?l application.

The invention is illustrated but in no way limited by the following Examples in which all temperatures are in degrees Centigrade:

EXAMPLE l N-Methrl~ 2-((5-hydroxymethyl-4-imidazolyl)methylthio)-- ethyl]thiourea.
,, .
- (i) Ethyl a-oximino-~-oxo-y-ethoxybutyrate (24.8 g) was added slowly in 30 minutes to cooled (15), well stirred ~olution/suspension of stannous chloride dihydrate (58.5g) in concentrated hydrochloric acid (97 ml) and then powdered tin (1.2 g) was added. After 2 hours the mixture was diluted with wa~er (300 ml), cooled to 0C and hydrogen sulphide .. , - ~ .

... .
. ~
._ .` ~' -: .

.

- ": ' ' passed into the solution which waq then filtered. The pH of the solution was adjusted to about 1.0 with sodium hydro~ide and an aqueous solution of ammonium thiocyanate (10.3 g) added together with further sodium hydroxide to adjust the pH to about 2Ø AIter warming with stirring to 95 for lS minutes the reaction mixture was cooled to 0 and, on standing, a sandy coloured precipitate was obtained which oll recrystallisation Irom water yielded 4-ethoxycarbonyl-5-ethoxymethyl-2-mercaptoimidazole, (11.9 g), m.p. 162.5 - 163.
(Found: C, 47.14; H, 6.04; N, 11.97; S, 13.6870 CgH14N203S
requires: C, 46.94; H, 6.13; N, 12.17; S, 13.9270).

(ii) To a stirred solution at 40 of 4-ethoxycarbonyl-5-ethoxymethyl-2-mercaptoimidazole (11.9 g) in ethanol (700 ml) was added Raney nickel tS5 g) and the mixture heated under reflux for 2.5 hours. After cooling, filtration and -evaporation of the filtrate the residue was recrystallised from water to give 4-ethoxycarbonyl-5-eth~xymethylimidazole t6.1 g) m.p. 143-144.
tFound: C, 54.71; H, 7.05; N, 14.00% CgH14N203 requires: C, 54.53; H, 7.12; N, 14.13O

(iii) 4-Ethoxycarbonyl-5-ethoxymethylimidazole (6.0 g) was dissolved in 48~o aqueous-hydrobromic acid t650 ml) and refluxed together with cysteamine hydrochloride t3.4 g) for - 17 hours. Evaporation of the reaction mixture to dryness and recrystallisation from butano}/ether tl5:85) gave 4-carboxy-5-~2-aminoethylthio~methylimidazole dihydrobromide (10.9 g), m.p. 219-220.
(Found: C, 23.11: ~I, 3.64; ~, 11.58; Br, 44.417c C7~ 30;,S;~IBr requires: C, 23.16; H, 3.61; N, 11.57; Br, 44.02aO.
- (iv) A solution o~ 4-carboxy-5-~2-aminoethylthio~methyl- -imidazole dihydrobromide (1.0 g) inlOaO by volume sulphuric acid t2~ ml) was electrolysed for 3 hours at constant curre~t (1.0 amp) a~d 8-10 volts over a stirred mercury cathode and plat~num anode separated by a porous disc.

-- , ~
.

:' ' ~ "'' ~075702 Adjustment OI the pH to 9-10 with potassium carbonate (8.3 g) and evaporation to dryness yielded a residue which was extracted with hot isopropanol and this extract evaporated to give 5-hydroxymethyl-4-[2-aminoethylthio~-methylimidazole (0.4 g).
(v) An aqueous ethanolic (1:5, 6 ml) solution of the 5-hydroxymethyl-4-[2-aminoethylthio~methylimidazole (0.4 g) was refluxed with methyl isothiocyanate (0.2 g) for 0.5 hours. After cooling a precipitate separated on standing and the supernatant liquid evaporated to yield an oil which was recrystallised from acetonitrile to give, as a white solid, N-methyl-N'-[2-((5-hydroxymethyl-4-imidazolyl)-methylthio)ethyl]thiourea (0.1 g), m.p. 138.5 - 139.5.
(Found: C, 41.59; H, 6.37; N, 21.38% CgH16N40S2 requires: C, 41.51; H, 6.19; N, 21.52%
: . ' . ~.
Ea~AlQPLE 2 .
N-Methyl-N'-cyano-N"-[2-((5-hydroxymethyl-4-imidazolyl)-methylthio)ethyl]guanidine.
.
To a solution of 5-hydroxymethyl-4_(2-aminoethylthio)-methylimidazole (0.4 g) in ethanol (3 ml) was added an ethanolic solution of dimethyl cyanodithioimidocarbonate (0.3g) and stirred at 15 for 2 hours. Evaporation of - the solvent yielded, as an oil, S-methyl-N-cyano-N'-~2-((5-hydroxymethyl-4-imidazolylmethylthio?ethyl]isothiourea - to which was added excess of an ethanolic solution of methylamine (7 g). ;~fter stirring for 70 hours, the reaction ` 30 mixture was purified by preparative thin layer chromato-graphy to yield the title product, as an oil (0.1 g). The structure of the product was confirmed ~y the n.m.r.
spectrum in D20 which showed the following resoIlances: -imidazole-2-H ; Singlet at~; 8.69 integral 0.7 protons calculated 1.0 protons ' .'. - - `

.

. . .

~07570Z

.
1 imidazole-CH2-0 ; singlet at ~4.72 integral obscured by HDO .
imidazole-CH2-S ; singlet at ~ 3.92 integral 1.9 proton~
calculated 2.0 protons -CH2-N ; triplet at ~ 3.34 integral 1.9 protons calculated 2.0 protons CH3-ND ; singlet at ~ 2.78~ integral 5.0 protons S- ~ CH2 ; triplet at 62.71~ calculated 5.0 protons When 5-hydroxymethyl-4-(2-aminoeth~lthio)methyl imidazole is reacted ~ith l-nitro-2,2-bis-methylthioethylene the ''- 15 product is 1-nitro-2-methylthio-2-[2-((5-hydroxymethyl-4- -' imidazolyl)methylthio)ethylamino]ethylene.

EXA~PLE 4 .~ j' ', . . .
' ' ~hen, S-methyl-N-cyano-N'-[2-((5-hydroxymethyl-4-imi-dazolyl)-- '¦ methylthio)ethyl]isothiourea is re~luxed in pyridine for ! 7 hours with'the following compounds:
. :
.' 5-hydroxymethyl-4-(~-aminoethylthio)methylimidazole, '~ 25 ~.j 5-~ethylJ4-(2-aminoethyLthio)methylimidazole, '5-brbmo-4-(2-am'inoethylthio)methylimidazole, ~- 3-hydroxy-2-(2-aminoetkylthio)methylpyridine, -`~ ~ ' 3-methoxy-2-(2-aminoethylthio)methylpyridine, 3-chloro-2-(2-aminoethylthio)methyl~pyridine, 3-bromo-2-(2-aminoethyithio)methylpyridine, --~
-'~` - - 2-(2-aminoethylthio)methylthiazole, .
3-(2-aminoethylthio)methylisothiazole and' 4-(4-aminobutyl)imidazole ~ ' the products are, respectively:
:
~- 35 H:~ . N-cyano-N,N'-bis-12-((~-hydroxymethyl-4-imidazolyl)- . ~:
methylthio)ethyl]guanidine, - -14- - _ , _ . ~ ' : .
-~, - .

- - - . . . -1~7570Z

1 N-cyano-N'-~2-((5-hydroxymethyl-4-imidazolyl)methyl-thio)ethyl]-N"-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl]guanidine, N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-S thio)ethyl]-N"-[2-((5-bromo-4-imidazolyl)methylthio)-ethyl~guanidine, N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-thio)ethyl]-N"-[2-((3-hydroxy-2-pyridyl)methylthio)-ethyl]guanidine, N-cyano-N'-~2-((5-hydroxymethyl-4-imidazolyl)methyl-thio)ethyl]-N"-[2-((3-methoxy-2-pyridyl)methylthio)-ethyl~guanidine, .N-cyano-N'-~2-((S-hydroxymethyl-4-imidazolyl)methyl- . .
thio)ethyl]-N"-[2-((3-chloro-2-pyridyl)methylthio)-ethyl~guanidine, N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-thio)ethyl]-N"-[2-((3-bromo-2-pyridyl)methylthio?ethyl]-guanidine, : . N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-`~ 20 thio)ethyl]-N"-[2-(2-thi-azolylmethylthio)ethyl~guanidine, N-cyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-thio)ethyl]-N"-[2-(3-isothiazolylmethylthio)ethyl]- :-guanidine and N-eyano-N'-[2-((5-hydroxymethyl-4-imidazolyl)methyl-thio)ethyl]-N"-~4-(4-imidazolylbutyl)~guanidine.

~' .
Reaction of 5-hydroxymethyl-4-.[2-aminoethylthio)methyl-., imidazole with benzoylisothiocyanate and acid hydrolysis of the product to remove the N-benzoyl group yields N-[2-((5-hydroxymethyl-4-imidazolyl)methylthio)ethyl]thiourea.

. EXAMPLE 6 ~hen in the process of Example 1, 3-mercaptopropylamine hydrochloride is used in place of cysteamine hydrochloride . , - -.~ . ' .
r_ .~

-~`
.

1 (see Ex. 1 tiii)), the resultant product is N-methyl-N'-[3-((5-hydroxymethyl-4-imidazolyl)methylthio)propyl]-thiourea.

. -EXA~PLE 7 i Reaction of 5- hydroxymethyl-4-(4-aminobutyl)imidazole with dimethyl cyanodithioimidocarbonate and subsequently with methyliamine according to the process of Example 2 IO yields`N-methyl-N'-cyano-N"-[4-(5-hydroxymethyl-4-imidazolyl)-butyl]guanidine.
, ., ~ .
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-~- 30 -.
, ~, .

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Claims (3)

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

1. A process for the production of a compound of the formula:

I

wherein Y is a lower alkyl group; or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting an amine of the formula:
II

with a di lower alkyl dithioiminocarbonate of the formula III

where Q is a lower alkyl group to produce a compound of the formula:

IV

and that the compound of formula IV produced is reacted with an amine of formula YNH2 wherein Y is as hereinbefore defined.

2. A process according to claim 1 for the production of N-methyl-N'-cyano-N"-[2-((5-hydroxymethyl-4-imidazolyl)methylthio)ethyl] guanidine wherein 5-hydroxymethyl-4-(2-aminoethylthio) methylimidazole is reacted with dimethylcyanodithioimido-carbonate and the product of this reaction reacted with methylamine.

3. N-Methyl-N'-cyano-N"-[2-((5-hydroxymethyl-4-imidazolyl)methylthio) ethyl] guanidine whenever prepared or produced by the process of claim 2 or by any obvious chemical equivalent thereof.