DD140038A5 - METHOD FOR PRODUCING NEW GUANIDINE COMPOUNDS - Google Patents

Description

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Field of application of the invention

The invention relates to a process for the preparation of novel guanidine compounds having an alkynyl radical. The compounds obtainable according to the invention are useful for the treatment of ulcers because of their action as H ₂ -receptor blocking agents which inhibit gastric acid secretion.

Characteristic of the known technical solutions

In the treatment of peptic ulcer disease, the clinical objective is to reduce gastric acid secretion. This is based on the principle "no acid - no ulcer". The traditional therapy for peptic ulcer disease is diet control and the use of antacids and anticholinergics.

There is evidence to suggest that histamine may ultimately stimulate gastric acid secretion. This effect of the histamine is mediated via H2 receptors. It is not inhibited by the classical antihistamine ₅ which are Hi receptor blocking agents. A number of specific H ₂ receptor blocking agents (Hp receptor antagonists) are now known. These compounds inhibit basal acid secretion as well as secretion caused by other known gastric acid stimulants and are useful in the treatment of peptic ulcer.

Representatives of the known compounds used in this field may be cimethidine. This connection

M / 19 147. -3- 2 0 5 794

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however leaves something to be desired in terms of effect and duration of action.

Object of the invention

The aim of the invention is to provide a novel process for the preparation of novel guanidine compounds, which are effective in the aforementioned sense.

Explanation of the essence of the invention

The compounds obtainable according to the invention correspond to the following formula:

* i / i9 147 -3- 20 5 79 4

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NCN

wherein R represents a straight-chain or branched alkynyl group having 3 to 9 carbon atoms inclusive, including, their pharmaceutically acceptable acid addition salts. ·

Preferred compounds obtainable according to the invention are ^: the compounds of the general formula:

N ¹

wherein R is V or hydrogen or methyl, and their non-toxic pharmaceutically acceptable acid addition salts.

Preferred compounds obtainable according to the invention are also the compounds of the formula; ·

M / 19 147 '; '. - «* - 20'579 4

SY-155OX I

NCN CH ₂ SCH ₂ CH ₂ NHCNh- (CH

wherein R is hydrogen or methyl and η is an integer from 1 to 6 inclusive, "and their non-toxic, pharmaceutically acceptable acid addition salts.

Also preferred compounds obtainable according to the invention are the compounds of the general formula:

N

CH _x

ν NCN j '

H CH ₀ SCH ₀ Ch ₀ NHCNH-CC = CR ⁴

Xl cc c, ι

CH ₅

wherein R is Vihydrogen or methyl, and their non-toxic, pharmaceutically acceptable acid addition salts.

A more preferred embodiment of the invention is N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl} -N "- (2-butyn-1-yl) -guanidine, and its non-toxic, pharmaceutically acceptable acid addition salts.

, A further preferred embodiment of the invention is the N-cyano-N '\ 2 - [(4-methyl-5-imidazolyl) methylthio J-ethyl} -N' - (3-butyn-1-yl) guanidine, and its non-toxic, pharmaceutically acceptable salts.

A further preferred embodiment of the invention is the N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) methylthio-1-ethyl} -

M / 19 147 -5-. yAK7Q /

SY-1550X £ u ο / y ι *

N "- (4-pentyne-1-yl) -guanidine, and its non-toxic, pharmaceutically acceptable acid addition salts.

Another preferred embodiment of the invention is N-cyano-N ¹ - {2 - [(4-methyl-5-imidazolyl) -methylthio-ethyl] -N "- (2-methyl-3-butyn-2-yl) -guanidine , as well as its non-toxic, pharmaceutically acceptable acid addition salts.

A further preferred embodiment of the invention is the N-cyano-N ¹ - [2 - [(4-methyl-5-imidazolyl) methylthio] -ethyl-N '- (3-butyn-2-yl) -guanidine and its not -toxic, pharmaceutically acceptable acid addition salts.

The most preferred embodiment of the present invention is N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl} -N "-propargylguanidine and its non-toxic, pharmaceutically acceptable acid addition salts.

The invention thus provides a process for the preparation of the compounds of general formula I.

CH ₂ SCH ₂ Ch ₂ NHCNH-R

wherein R. is a straight-chain or branched alkynyl group having 3 to 9 carbon atoms inclusive, or a non-toxic, pharmaceutically acceptable acid addition salt, which is characterized in that a compound of general formula II:

_ _f _

205794

'N. CH ₀ SCH ₀ CH ₀ NHR ₁ - _H 2 2 2 5

or an acid addition salt thereof with a compound of general formula III:

R ₆ NHR ¹ (III)

wherein R is as previously defined and Er and Rg are different from each other and either H or the group

NCN

It

-C-SR

wherein R represents any substituent, provided that the group -SR forms a suitable leaving group, and, if desired, the resulting compound of general formula I in basic form or in the form of a Acid addition salt converted into the corresponding, non-toxic, pharmaceutically acceptable acid addition salt or in the free base form. ,

The reaction is carried out in a non-reactive solvent at a temperature above room temperature. In a preferred embodiment, equimolar amounts of the compounds of formulas II and III are used.

This process is illustrated by the following Reaction Schemes I and II with reference to a preferred compound of the invention:

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SCHEMA I

NCN

I!

CH ₂ SCH ₂ Ch ₂ NHC-SR

NCN

CH ₂ SCH ₂ CH ₂ NHCNHCh ₂ C = CH

The reaction is carried out in a non-reactive solvent at a temperature above room temperature It will be obvious to those skilled in the art that R may be any substituent provided that -SR is a suitable leaving group. For example, R may be (lower) alkyl, aryl, substituted aryl (e.g., p-nitrophenyl), aralkyl, -CH ₂ CN, -CH ₂ COGH, -CH ₂ COOR ', or the like '- [2 - [(4-Methyl-5-imidazolyl) -methylthioJ-ethyl} -SR-isothiourea starting materials can be prepared according to the procedures described in Belgian Pat. No. 804 144. The alkynylamine starting materials are either commercially available or can be prepared by the methods described in Bull.Soc.Chim.Fr. 490 (1958), Bull.Soc.CMm ₀ Fr. 592 (1967) and Annales de Chimie (Paris), 3_> ⁶ 56 (1958).

-β- 20 5 79 4

SCHEMA II

NCN + RS-CNHCH ₂ C = CH

NCN CH ₂ SCH ₂ CH ₂ NHCNHCH ₂ C = Ch

The reaction is carried out in a non-reactive solvent at a temperature above room temperature. The substituent R may have the meaning given in Scheme I above. The 2 - [(4-methyl-5-imidazolyl) methylthio] ethylamine starting material may be prepared as described, for example, in U.S. Patent 3,950,353. The disubstituted cyandithioiminocarbonate used as the starting material for the preparation of the N-cyano-N'-propargyl-SR isothiourea (see step b) of Example 2)

T - ³ ~ 2 0 5 7 9 4

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can be prepared by procedures described in J. Org. Chem., p. 2., 1566 (1967).

In addition, it was found according to the invention that in the preparation of N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) methylthio] ethyl} -N "-propargylguanidine according to the reaction scheme I certain conditions in the The last mentioned circumstance leads to the additional advantage that one can isolate the initial product (crude product) as a crystalline solid, which can be subjected to a further purification by a simple recrystallization This avoids chromatographic purification of the initial crude product which has heretofore been considered desirable when other reaction conditions have been chosen.

The aforementioned particular reaction conditions consist in using methanol as the solvent, using a more concentrated solution in the reaction (approx. 1 g of substituted isothiourea per 5 ml of methanol), passing a stream of nitrogen through the reaction vessel during the reaction and freshly distilled propargylamine for the reaction starts.

Itorch Investigations "it has been found that the use of a nitrogen purge during the reaction avoids the formation of small amounts of two as yet unidentified by-products, which are otherwise formed in the absence of a nitrogen purge Do not remove recrystallization It is assumed that the formation of this byproduct

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This is avoided by removing the methylmercaptan as quickly as it is formed.

The invention also provides the process for the preparation of a compound of general formula Ιί

NCN

in Ch ₉ SCH ₉ CH ₉ NHCNH-R ¹ H ά <L ά

wherein R is a straight-chain or branched alkynyl group having 3 to 9 carbon atoms, or a non-toxic, pharmaceutically acceptable acid addition salt, which is characterized in that a compound of the formula V :.

KX

W CH ₉ SCH ₉ CH ₉ NH. H 2 2 2,

with a compound der.Formel:

S = C = NR ¹

wherein R has the above meaning, and the resulting compound of formula VI:

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S (VI)

CH ₂ SCH ₂ CH ₂ IiHGMR ¹

reacted with methyl iodide and cyanamide »wherein the compound of general formula I is formed in the form of a base and» if desired, the product is converted in known manner into a corresponding, non-toxic pharmaceutically acceptable acid addition salt.

This process is further illustrated by the following Reaction Scheme III for the preparation of a preferred compound of the invention.

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SCHEMA III

N "

CH.

H ^ CH ₂ SCH ₂ CH ₂ NH ₂ + S = C = NCH ₂ C = CH

CH.

CH ₂ SCH ₂ CH ₂ NHCNHCH ₂ CHCH

CH ₃

D H

2). H ₂ NCN

NCN

Il

ι _ " ₃ _ 205 794

SY-155OX ';

The invention also provides a process for the preparation of a compound of general formula I:

wherein R represents a straight-chain or branched alkynyl group having 3 to 9 carbon atoms, or a non-toxic, pharmaceutically acceptable acid addition salt, which is characterized in that a compound of general formula VII

(VII)

Chox

wherein X is hydroxy or a common leaving group, or an acid addition salt thereof with a compound of general formula VIII:

NCN

HSCH ₂ Ch ₂ NHCNH-R ¹ (VIII)

wherein R has the above meaning, and if desired, the resulting compound of general formula I in its basic form or in the form of an acid addition salt in a corresponding non-toxic pharmaceutical

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acceptable acid addition salt or converted into the free base form.

The reaction is carried out in an inert organic solvent. ,

In a preferred embodiment, equimolar amounts of the compounds of formulas VII and VIII are used and the reaction is carried out in the presence of a base.

Suitable leaving groups "X" for this reaction are known to those skilled in the art. These include, for example, fluorine, chlorine, bromine, iodine, -O _x SR ² , wherein R is (lower) alkyl (for example, methanesulfonate), -O, SR, wherein R is aryl or substituted aryl (for example, benzenesulfonate, p-bromobenzenesulfonate or p-toluenesulfonate), -0, SF, acetoxy and 2,4-dinitrophenoxy. For reasons of simplicity and economy, the invention normally uses the compound of the formula II in which X is chlorine. ,

In the process according to the invention, the compound of the formula VII is preferably used in the form of an acid addition salt. Compound VII is relatively unstable in its free base form and is therefore preferably prepared and stored as an acid addition salt. Although one can regenerate the free base of the compound of formula II before the reaction, this leads to no advantage. It will be obvious to those skilled in the art that any inorganic or organic acid may be used to form an acid addition salt of the compound of formula VII. For example, hydrochloric acid, sulfamic acid, sulfuric acid, oxalic acid, benzoic acid, succinic acid, acetic acid

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acid »nitric acid! Use citric acid or the like ». For reasons of simplicity and economy, it is normally preferred according to the invention to use the compound of the formula II in the form of its hydrochloride.

The reaction of compounds VII and VIII to form the compound of general formula I can be carried out in any inert organic solvent. Here, one can use an alkanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, acetone, or the like. It is preferred to carry out the reaction in an alkanol, for example in ethanol or 2-propanol.

The reaction temperature is not critical. The reaction may be carried out at temperatures of about 0 ° to about 200 ⁰ C. At low temperatures, the reaction is slow. At higher temperatures, on the other hand, it usually results in less pure products due to decomposition and formation of by-products. It is usually preferred to carry out the reaction at room temperature. ·

The reaction of the compounds of formulas VII and VIII to form the compound of general formula I is preferably carried out in the presence of a base. The base facilitates the reaction by acting as an acid acceptor. Suitable bases for this reaction include inorganic and organic bases. For example, NaOH, KOH, LiOH, triethylamine, dimethylaniliri, sodium ethylate, and the like may be used. ,

The process is further illustrated by the following Reaction Scheme IV for the preparation of a preferred compound according to the invention:

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- " ⁶ - 20 5 7

SCHEME IV.

CH

3.

NCN

Il

+ HSCH ₂ CH ₂ NHCNHCh ₂ C = CH

CH ₂ OH / H "

-CH ₃

NCN'CH ₂ SCH ₂ CH ₂ NHCNHCH ₂ C = CH

(I)

The invention also relates to the novel intermediates of general formula VIII:

NCN • HSCH ₂ Ch ₂ NHCNH-R ¹

(VIII)

wherein R is a straight-chain or branched alkynyl group having 3 to 9 carbon atoms, and addition salts thereof These compounds are useful for preparing the histamine H ₂ receptor antagonists of general formula I.

- -ι? - 20 5 79 4

SY-155OX X. ν w »/ 7 fi»

In a "preferred embodiment, the radical R is the compound of general formula VIII

-CHC = CR ⁴ , CH.

wherein R is hydrogen or methyl. In a further preferred embodiment, the radical R is - (CHpO _n C ^ CR, where η is an integer from 1 to 6 and r4 is hydrogen or methyl. In a further preferred embodiment, the radical R is

CH ₃

CH ₃ wherein R is hydrogen or methyl.

In a more preferred embodiment, the radical R of the compound of the general formula VIII is the 2-butyn-1-yl group. In another more preferred embodiment, the radical R is the 3-butyn-1-yl group. In a further more preferred embodiment, the radical R is the 4-pentin-1-yl group. In another more preferred embodiment, the radical R is the 2-methyl-3-butyn-2-yl group. In another more preferred embodiment, the radical R is the 3-butyn-2-yl group. In the most preferred embodiment, the radical R of the compound of general formula VIII is the propargyl group. ,

The invention also relates to a process for the preparation of the novel intermediates of general formula VIII;

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ΐί ^0Ν _Λ (viii)

HSCH ₉ CH ₉ NHCNh-R ¹

characterized in that a compound of general formula IX:

P-SCH ₉ CH ₂ NH ₂ (IX)

wherein P represents any suitable sulfhydryl protecting group »with a compound of general formula X:

ESCNHR ⁴ . , (X)

wherein R ^{4 has} the above meanings,

and then removing the sulfhydryl protecting group from the resulting compound to form the intermediate of general formula VIII.

This process is illustrated by the following scheme V:

SCHEMA V

NCN PSCH ₂ CH ₂ NH ₂ - + RSCNHCH ₂ C = CH

1) heating 2.) unblocking

NCN

HSCH ₂ CH ₂ NHCNHCH ₂ C ^ cH

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The dimethylcyanedithioimino carbonate used as the starting material for the preparation of the N-cyano-N'-alkynyl-S-methylisothioureas can be prepared by the procedures described in J. Org. Chem., 32, 1566 (1967) The alkynylamine starting materials are either in the art 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).

When reacting gysteamine hydrochloride with an N-cyano-N'-alkynyl-S-methylisothiourea to give an N-cyano-N'-alkynyl-N "- (2-mercaptoethyl) -guanidine of general formula VIII, it proves For example, it is desirable to conduct the reaction in the presence of a small amount of hydroquinone and to spar nitrogen through the reaction mixture (see, for example, Step B of Example 14) It has been found that these reaction conditions produce the compounds of Formula VIII in higher yield and It is believed that the nitrogen purge removes the methyl mercaptan formed in the reaction, thereby avoiding side reactions resulting from the addition of the methyl mercaptan to the carbon-carbon triple bond. It is believed that the hydroquinone prevents the formation of free radicals and their side reactions resulting from their presence.

The term "non-toxic, pharmaceutically acceptable acid addition salts" as used herein means a mono- or di-salt of a compound of the invention with a non-toxic, pharmaceutically acceptable organic or inorganic acid. Such acids are known. These include hydrochloric, hydrobromic, hydro-

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ferric, suifamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, ethanedisulfonic, benzenesulfonic, acetic, propionic, tartaric, citric, campfire sulfonic, and the like. The salts are prepared in a manner known per se.

The term (lower) alkyl as used herein is intended to include straight-chain or branched alkyl groups having 1 to 6 carbon atoms. ,

For therapeutic use, the pharmacologically active compounds of the invention are normally administered as a pharmaceutical agent containing as the (or a) substantially active ingredient at least one such compound in the basic form or in the form of a non-toxic, pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable Carrier, contains.

The pharmaceutical agents can be administered orally, parenterally or by rectal suppositories. A variety of pharmaceutical administration forms can be used. For example, when using a solid carrier, the preparation may be tableted, placed in a hard gelatin capsule, in powder or pellet form, or it may be in the form of a troche or in a lozenge. When a liquid carrier is used, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile injection solution or an aqueous or non-aqueous liquid suspension. The pharmaceutical agents are prepared by conventional techniques suitable for the particular preparation desired. .

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Preferably, each unit dose contains the active ingredient in an amount of about 50 mg to about 25 mg, most preferably in an amount of about 100 mg to about 200 mg. The active ingredient is preferably administered in equal doses two to four times daily. The daily dose prescription is preferably between 25Ο mg and about 1000 mg, most preferably between about 5OO mg and about 750 mg.

Histamine Hp receptor antagonists have been shown to be potent gastric acid secretion inhibitors in humans and animals, cf. Brimblecombe et al., J. Int. Med.Res., 3. »86 j (1975) · The clinical evaluation of the histamine Hg receptor antagonist cimetidine has shown that. this is an effective therapeutic agent for the treatment of peptic ulcer diseases, cf. Gray et al., Lancet, 1_ (8001), 4 (1977). The compound prepared in Examples 1 and 2 below (hereinafter referred to as BL-5641) was compared to cimetidine in various studies. It was found that the compound of the invention is superior to cimetidine. This superiority manifested itself as a histamine Hp receptor antagonist in the isolated guinea pig atrium and as a gastric acid secretion inhibitor in rats and dogs. In addition, the gastric acid secretion studies in the dogs indicate that the compound of the invention has a longer duration of action than the cimetidine at the same doses.

Histamine Hp receptor antagonism

Investigation on isolated guinea pig atrium.

Histamine leads to concentration-dependent increases in the contraction rate of isolated, spontaneously beating right atrium in guinea pigs. Black et al., Nature, 236, 385

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(1972) describe the receptors involved in this effect of histamine as histamine H ₂ ~ receptors when they reported the properties of buriinamide, a competing antagonist of these receptors. Subsequent studies by Hughes and Coret, Proc. Soc. Exp. Biol. Med. 148 , 127 (1975) and by Verma and McNeill, J. Pharmacol. Exp. Ther., 200, 352 (1977) support the conclusion of Black and coworkers that the histamine's positive chronotropic effect in the guinea pig isolated right atrium is mediated by histamine Hp receptors. Black et al., Agents and Actions, 3rd, 133 (1973) and Brimblecombe et al., Fed. Proc, 355, ¹⁹³¹ (1976) have the isolated right atrium of the guinea pig is used as means for comparing the activities of histamine _H2 -receptor antagonists. The present comparative studies were conducted using a modification of the procedure reported by Reinhardt et al., Agents and Actions, 4, 217 (1974).

Male guinea pigs from the Hartley strain (350 to 450 g) were killed by a blow to the head. The heart was excised and placed in a petri dish with oxygenated (95% i ₂ O 5 / ° CO ₂ ) modified Krebs solution (g / liter: NaCl, 6.6, KCl 0.35, MgSO ₄ .7H ₂ O 0.295, KH ₂ PO, 0.162, CaCl ₂ 0.238, NaHCO ₅ 2.1, and dextrose 2.09). The spontaneously beating right atrium was freed from other tissues. At each end a silk thread (4-0) was attached. Was suspended the atrium in a 20 ml muscle chamber, the oxygenated, modified Krebs containing solution and was kept at 32 ⁰ C. The atrial contractions were recorded isometrically using a Grass FT 0.03 strain gage mediator. The contraction force and velocity were recorded with a Beckman RP-Dynograph.

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A resting tension of 1 g was applied to the atrium and allowed for 1 hour equilibration. After the equilibration period, a submaximal concentration of histamine dihydrochloride (3 x 10M) was added to the bath and washed out to prepare the tissue. Was then added to the bath cumulatively i histamine, wherein 1/2 log 10 intervals to Uses- i

-7 te, to finally molar bath concentrations of 1x10

to obtain 3 χ ^ 0 ~~ ^> . It was waited until the histamine-induced increase in heart rate reached a plateau until the respective subsequent concentration was established. In each case the maximal response was at a concentration of 3 x 10 M. The histamine was washed out several times and the atrium was allowed to return to the control frequency. Then, the test compound (1 × 10 M) was added, and after a 30-minute incubation time, the histamine concentration response was repeated, adding higher concentrations than required.

Histamine's EDp-Q (concentration of histamine causing an increase in the frequency of contraction of $ 50 at the maximum rate) and the 95 f ° confidence limits before and after the test compound were determined by regression analysis as described by Finney. Probit Analysis, 3rd Ed., Cambridge (1971). The shift factors of the concentration response curve were calculated as follows:

ED50 histamine + compound

Shift factor = _:

Q histamine alone

The factor obtained for Bl-5641 was then expressed as a ratio

~ ^1Η '20 579 A

of the factor obtained for cimetidine:

BL-5641 shift factor - 1

Activity ratio =

Cimetidine-Vex shift factor - 1

The results obtained in these studies are summarized in Table I. Cimetidine and BL-564I, respectively, shifted the histamine concentration response curve by a factor of 6t6 and 32.7 to the right, respectively. Based on the shift factors of the concentration response curve, the compound of the present invention was. BL-5641 as a histamine ELj receptor antagonist in the isolated right atrium of the guinea pig about 5 »7 times more effective than cimetidine.

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TABLE I

Relative efficacy of cimetidine and. the compound BL-5641 "according to the invention in the isolated right atrium of the guinea pig

Compound N concentra-histamine ED5O shift activity

tion with 95 % utilization factor confidence limits of the concentration

(μ _β / ιηΐ) trations response curve

Histamine 0.21

Control 3 (0.18 - 0.25) -

1.39 cimetidine 3 1 x 10 ^"5 M (1.08 to 1.85) 6.6 1.0

Histamine 0.38

Control 2 (0.27 - 0.53)

12,44 BL-5641 2 1 χ 10 " ⁵ M (7,81 - 20,28) 32,7 5,7

N = number of experiments

sT-, ₅₅ ox "* 20 5 79 4

Determination of Gastric Antisecretory Activity in Rats with 2-Hour Pylorus Ligation (Shay)

Rat pyloric ligation was developed by Shay et al., Gastroenterology, £, 53 (1945) for the study of perforating gastric ulcers. However, as this method became known, it has also been used as a means of studying gastric secretion in the rat (see Shay et al., Gastroenterology, 2β_, 906 (1954) "Brodle, DA, Am.J.Dig.Dis. Jj, 231 (1966). Currently, a modification of this procedure is used to evaluate compounds for their gastric presetic secretory activity.

One uses male Long Evans rats weighing 280 to 300 g. The animals are placed in individual cages and fasted for 24 hrs. Drinking water is available. Under anesthetic anesthesia, the stomach is exposed through a central incision and a cotton thread ligature is passed around the pylorus After closure of the wound, ather administration is discontinued and either BL-5641, cimetidine or carrier fluid is administered intraperitoneally at a volume of 1 mg / kg. 5641 and cimetidine are dissolved in one equivalent of HGl and brought to the correct volume with water, and the animals are returned to their cages, from which the water bottles are removed and subsequently killed 2 hours later with A'ther Stomach acidity is then transferred to graduated test tubes to determine the volume of gastric acid accumulation over the 2 hours Titrable acidity is measured by titrating a 1 ml sample with 0.02N NaOH to pH 7.0 using an automatic burette ( Autoburet) and an electrometric pH meter (radiometer) The amount of titratable acid is in microequiva calculated by dividing the volume in ml

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multiplied by the acid concentration in milliequivalents per liter. Percent inhibition of acid production is calculated as follows:

Acid production of the control

percentage - acid production with the substance inhibiting _ · 'χ 100

the acid-acid production in the control production

The results obtained with the compound BL-564I according to the invention and the cimetidine are shown in Table II below.

The results show that _f at the 2-hour pylorus-Ligaturpräparation the compound bij-5641 according to the invention is with regard to the inhibition of gastric acid production at least as effective as cimetidine in the rat.

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TABLE II

Effect of BL-5641 'and cimetidine on gastric acid production in the rat with 2-hour pylorus ligation.

connection Dose ( 11.1 percentage In ED50 Ip> * 5.53 hibernation of acid production μΜοΐ / kg BL-5641 μΜοΐ / kg mg / kg 2.76 ^: 80 40 10 61 - ^ 11 • .20 5 • 37 cimetidine 10 2.5 66 40 1.25 60 - ^ 14 20 40 10 34 5

* At least 5 animals are used at each dose.

Determination of gastric antisecretory activity in dogs with a gastric fistula

According to Thomas (Thomas, JE, Proc.Soc.exp.Biol.Med., 4_6> 260 (1941)), stainless steel cannulas are placed in the stomachs of beagle dogs (10 to 12 kg) directly in the vicinity of the pyloric gland greater curvature to create a chronic gastric fistula. You then leave the animals

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recover for at least two months »before any examinations are made. Me dogs are fasted overnight (about 18 hours) before each experiment »with water administered ad lib. Place the dogs in a sling and insert a 20.3 cm (8 in.) Inner needle catheter (CR Baird Inc.) into a leg vein using a 5 cm needle (gauge 17) to deliver each drug administer. The gastric secretions are collected every 15 min by gravity evacuation from the opened cannula. The secretions are collected for two consecutive periods of 15 min each. If these are found to be excessive (> 4 ml / 15 min, pH <5 »0), the animal is not used. In carrying out this study, a modification of the procedure described by Grossman and Konturek, Gastroenterology, & §_, 517 (1974) was used. Immediately after the second basal collection, a 90 min infusion of histamine (100 μg / kg / hr) is performed with a Harvard infusion pump at 6 ml / hr. At this time, either the 'BL-5641' of the present invention, the cimetidine (dissolved with one equivalent of HCl and made up to normal volume with normal saline) or normal saline is injected rapidly (within 30 seconds) to a volume of 0.1 ml / kg. Then the infusion of the histamine continued for another 150 min (total infusion time = 4 hrs). Each sample of gastric juice taken after 15 minutes is measured for the next 0.5 ml and titratable acidity is determined against 0.02N NaOH (endpoint pH 7> 0) with an automatic burette and a pH meter (radiometer). Percent inhibition of acid production is calculated as described in the rat pylorus ligation procedure.

ι -so-205794

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Equimolar doses of BL-5641 and cimetidine were administered to five different dogs. The results obtained are shown in Table III.

Both BI-5641 and cimetidine resulted in an immediate inhibitory effect on gastric acid production. However, the degree of inhibition at equimolar doses was consistently greater and longer in compound BL-5641 of the invention than in cimetidine. These results show that the BL-5641 of the present invention as an inhibitor of histamine-induced gastric acid production in dogs is more effective and / or more effective than cimetidine.

TABLE III

Effect of BL-5641 and cimetidine on gastric acid production in unvented dogs with gastric fistula

Pharmacon and dose (μΜοΐ / kg iv)

BL-564- ¹ (12) cimetidine (12)

-BL-5641 (6) Cimetidine (6)

BL-5641 (3) cimetidine (3)

BL-5641 (1,5) cimetidine (1,5)

BL-5641 (0.75) Cimetidine (0.75)

Dog no. 15 30 percentage production 60 Inhibition of (N = 1) .90. 105 Acid- 66 63 99 99 45 99 76 75 93 48 91 41 120 minutes 24136 24136 , 82 84 -99 96 cn cn cn co 95 67 99 54 76 54 52 40 73 14 22619 22619 60 43 59 27 99 73 34 0 78 65 42 38 24 8 53 32 23606 23606 82 73 72 57 36 15 49 29 32 17 7 18 0 0 0 0 24895 24895 VJl VJl 38 10 53 60 28 1-7 33 0 43 27 42 25 0 0 23553 .23553 28 24 31 35 46 19

(A

\ Q

20 5,794

The following examples serve to illustrate the invention! without restricting it.

example 1

N-cyano-N · - {2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl-3N-propargylguanidine

NCN CH ₂ SCH ₂ Ch ₂ NHC-SCH ₃ +

• NCN CH ₂ SCH ₂ CH ₂ NHCNHCH ₂ CHCH

A mixture of 3.00 g (0.0111 mol) of N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyl} -S-methyl-isothiourea and 2.50 g is stirred (0.045 mol) of propargylamine in 60 ml of acetonitrile for 65 hrs. Reflux and then heated in a pressure vessel made of stainless steel for 38 hrs. 120 to 1.30 ⁰ C. The reaction mixture a "b, decanted from a tarry product and evaporated This leaves a residue of silica gel (0.15 mm to 0.074 mm (100-200 mesh)) and eluted with a mixture of 97 parts of methylene chloride and 3 parts of methanol The product obtained from a middle fraction is crystallized by trituration under acetonitrile and then from acetone.

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nitrile recrystallized. This gives 0.236 g

(7 * 7%) of the title compound of melting point 146 to 149 »5 ° C.

Analysis C ₁₉

calc .: 52 15 5, 83 30 41 Found .: 51st 86 5th 81 30 70

Example 2

N-cyano-N'-12 - [(4-ethyl-5-imidazolyl) methylthio] J-ethyl-5-N-propargylguanidine

(CH ₃ S) ₂ C = NCN +

NCN CH ₃ SCNHCH ₂ CsCH

CH

CH ₂ SCH ₂ CH ₂ NH ₂ + A.

NCN

N-cyano-N'-propargyl-S-methyl-isothiourea (A)

A solution of 16.00 g (0.109 mol) of dimethyl cyanothione iminocarbonate and 6.03 g (0.109 mol) of propargylamine in

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320 ml of acetonitrile is stirred for 4 hrs. At reflux and then for 12 hrs. At 25 ⁰ C stirred. The workup gives 13.58 g (81 <o) of title compound A with melting point 160 to 164 ⁰ C.

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

A solution of 11.71 g (0.0765 mol) of Compound A and 13.10 g (0.0765 mol) of 2 - [(4-methyl-5-imidazolyl) methylthio] -ethylamine in 250 ml of methanol is added 64 hrs. heated to reflux. The solvent is removed by evaporation, the residue is placed on silica gel (0.15 mm to 0.074 mm (100-200 mesh)) and chromatographed by gradient elution using methylene chloride / methanol. The later fractions provide 4.0 g of the title compound. Recrystallization from acetonitrile gives a purified product with melting point of 150 to 152.5 ⁰ C, which identical with the product prepared according to Example 1 product. table (infrared analysis, nuclear magnetic resonance, thin-layer chromatography).

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Example 3

N-cyano-N · - {2 - [(4-methyl-5-imidazolyl) methylthio] J-ethylJ N "- (2-butyn-1-yl) -guanidine

• ζ

NCN

CH ₂ SCH ₂ CH ₂ NH ₂ + B

NCN CH ₉ SCH ₉ CH ₉ NHCNHCh ₉ C = CCH

a) N- (2-Butin-1-yl) -N'-cyano-S-methyl-isothiourea (B) _

.A solution of 10.00 g (Ό, 0684 mol) Dimethylcyandithioiminocarbonat and 4 »73 g (0.0684 mol) of 2-butyne-1-amine in 200 ml of acetonitrile is 0.5 hrs. At 25 ⁰ C and then 2 , Stirred for 5 hrs. Under reflux. The mixture is cooled and filtered, whereby the title compound B is obtained with mp 180 to 183 ⁰ C.

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b) N-Cyari-NM2- [(4-methyl-5-imidazolyl) -methylthlo] -ethyl-N, - (2-butyn-i-yl) -guanidine

A solution of 6.82 g (0.0407 mol) of Compound B and 6.98 g (0.0407 mol) of 2 - [(4-methyl-5-imidazolyl) methylthio] -ethylamine in 140 ml of methanol is added 40 hrs. heated to reflux. The work-up and chromatography described in Example 2 above gives the title compound. When the title compound is prepared according to the general procedure of Example 1, it melts at 128 to 130 ^° C.

At s ρ ie 1

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

Repeat the general procedure of Example 1, except replacing the propargylamine used there with an equimolar amount of 3-butyne-1-amine to give the title compound.

B ei s ρ i el

N-cyano-N '- {2- [(4-methyl-5- ^{1: 1} idazolyl) -methyl thi ο] ethyl} -N' - (4-pentyn-1-yl) guanidine

Repeat the general procedure of Example 1 with the exception that propargylamine is employed das'dort replaced with an equimolar amount of 4-Peritin-1-amine, thereby obtaining the title compound with melting point from 99 to 103 ⁰ C.

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B egg game

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

Repeat the general procedure of Example 3, with the exception that the 2-butyn-1-amine used there is replaced by an equimolar amount of 1,1-dimethylpropargylamine to give the title product.

Be i s ρ i e 1

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-amine used therein is replaced by an equimolar amount of 1-methylpropargylamine to give the title compound.

Example 8

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

A mixture of 3.00 g (0.0111 mol) of N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyl} -S-methyl-isothiourea and 3.07 g (0.0445 mol) of 2-butyne-1-amine in 60 ml of propionitrile is stirred for 40 hours under reflux. Thin-layer chromatographic analysis of an aliquot of the reaction mixture indicates a trace of the isothiourea starting material so that the mixture is refluxed for an additional 6 hours and then stirred at room temperature for 64 hours. Remove the solution

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medium (along with excess amine) under reduced pressure and the remaining gummy residue is placed on silica gel (0.15-0.74 mm (100-200 mesh)) and eluted with a mixture of 97 parts of methylene chloride and 3 parts of methanol. The middle fractions are combined and evaporated to give 1.81 g of a yellow gummy product. The product was dissolved in 20 ml Ä'thylacetat and crystallized at -15 ⁰ C. The pale yellow solid obtained (1.2 g) is dissolved in 11 ml of hot acetonitrile and recrystallized at -15 ⁰ O. The yield is 1.072 g of product with melting point 128 to 130 ⁰ C.

Analysis C ^ H ₁ glT ^ S:. ,

53 C 6 H 28 N 1 S 08 $> about ,: 53 77 6 25 29 , 94 1 1" 34 # ge f .: 72 , 29 , 62 1,

Example 9

N-cyano-N -i2 ^l - [(4-methyl-5-imidazolyl) methylthio] -äthyl3- N '- (3-butyn-1-yl) guanidine

A mixture of 3.00 g (0.0111 mol) of IT-methyl-imidazolyl-1-methylthio-1-ethyl-S-methyl-isothiourea and 3.13 g (0.0453 mol) of 3-butyne-1-amine in 60 ml of propionitrile is stirred for 40 hours under reflux. The solvent is evaporated to give 5 »40 g of a syrup which is added to 70 g of silica gel (0.15 mm to 0.074 mm (100 to 200 mesh)) and chromatographed by gradient elution using methylene chloride / methanol. -

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SY-155OX eluent MeOH volume mass G fraction 99 CH ₂ C1 _2/1 100 ml - 1 It 70 ml - G CVJ Il 50 ml 0,117 G 3 Il 30 ml - G 4 It 75 ml 0.067 5 It 150 ml 0,080 G. 6 Il MeOH 325 ml 0.168 G • 7 98 CH ₂ Cl _2/2 50 ml ^: - G 8th • ti 150 ml 0,125 G 9 Il 250 ml 0.811 G 10  < MeOH 250 ml 0.72 G 11 97 CH ₂ Cl _2/3 175 ml 0,125 G 12 Il 225 ml 0,133 G 13 ti -   0.027 G 14 It d MeOH 225 ml ) . 200 ml) 0,002 15 16 95 CH ₂ Cl _2/5 250 ml 0,035 17 It 250 ml 0.236 18

Thin layer chromatography (silica gel "90 CH ₂ Cl ₂ ZiO MeOH) indicates that fractions 9" to 12 are pure and need to be pooled Fractions 1 to 8 show rapidly migrating impurities Fractions 13 and 14 show some trailing impurity. Fractions 9 to 12 are combined and evaporated to give 1.72 g of a yellow gum-like product This product is dissolved in 11 ml

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Nitromethane dissolved and crystallized at -15 ⁰ C to give 1.18 g pale yellow solid. This is recrystallized from 9 ml of nitromethane, to give 0.987 g of product having a melting point of 86 to 89 ⁰ C (softening at 85 ⁰ C). The infrared and NMR (100 MHz) spectra are clean and consistent with the desired structure. The NMR shows that the product is solvated with approximately 0.08 mole of nitromethane.

Analysis C. ^ H ₁₈ N, -S.0.08 (CH ₅ NO ₂ ):

C H N S

calc .: 53 , 21 6 22 28 , 84 ' 1 0 , 86 * Found .: 52 , 68 • 6, 28 29 , 39 1 1 , 22 1 ° 52 , 87 6 02 29 50 la

I e: I 10

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

A mixture of 3.00 g (0.0111 mol) of N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) methylthio] ethyl 3-S-methylisothiourea and 3.69 g ( 0.0445 mol) of 4-pentyne-1-amine in 60 ml of acetonitrile is stirred for 24 hours under reflux and on. then allowed to stand at room temperature for 96 h. The solvent and the excess amine are removed under reduced pressure. The residual yellow gum is purified by chromatography on 50 g of silica gel (100 to 200 mesh) with a gradient elution with methylene chloride / methanol (99: 1 to 96: 4). By thin layer chromatography it is found that the middle fractions are pure. They are combined and evaporated to give 1.91 g of a yellow gummy product. This will be included

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-15 ⁰ C crystallized from 18 ml of ethyl acetate. The white solid obtained (1.25 g) is recrystallized at -15 ⁰ C in 10 ml of acetonitrile. This gives 1.063 g of product having a melting point of 99 to 103 ⁰ C.

Analysis C ₁₄ H ₂ QNgS:

C H NS

calc .: 55, 24 6 52 27 , 61 10 53 Found .: 55, 43 6 58 28 , 26 10 97

Example 11

N-cyano-N -i2 ^l - ^[(4-j methyl-5-imidazolyl) -methylthioJ-ethyl] -N "-propargylguanidin

A mixture of 10.0 g (0.0371 mol) of N-cyano-N ¹ -i2 - [(4-methyl-5-imidazolyl) methylthio] ethyl> S-methyl isothiourea and 20 ml (0.325 Mol) of distilled propargylamine in 50 ml of methanol at reflux under a nitrogen atmosphere (nitrogen purge) with positive pressure for 20.5 hrs. The solvent and excess amine are then removed by evaporation, leaving a yellow-brown oil which crystallizes readily. Trituration of the crude product under 30 ml of isopropanol gives the title compound as an off-white, friable solid. This gives 8.11 g of product (79 fi) with melting point of 146 to 148.5 ⁰ C.

Example 1_2

N-cyano-N ^f -i2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl} - N "-propargylguanidi n

A mixture of 100 g (0.371 mol) of N-cyano-N'-f2 - [(4-methyl-5-imidazolyl) -methylthioj-ethyl-3-S-methyl-isothiourea and

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150 ml (2.44 mol) of distilled propargylamine in 500 ml of methanol is stirred under reflux under a nitrogen atmosphere (nitrogen purge) with positive pressure for 22 hrs. The reaction mixture is cooled and the solvent and excess amine are removed by evaporation. What remains is an amber-colored oil that crystallizes easily. Rub the crude product under 250 ml of isopropanol, cooled for 2 hrs. On O ⁰ C and collected by filtration. Wash the filter cake with cold isopropanol and dried in a vacuum for 16 h. On Ρο ^ ς * ^ ^as dried title product is in the form of a nearly white, thick solid front. The yield is 73.5 g (71.7 ^) with melting point 147 to 149 ⁰ C.

B ic pie 1 1j5

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

The final products obtained in Examples 11 and 12 are combined (total 81.3 g), dissolved in 1000 ml of hot isopropanol, filtered through "Super-Cel" and allowed to cool for approximately 68 hours at room temperature. The resulting crystalline product is collected by filtration, washed with cold isopropanol, pulverized and dried under high vacuum for approximately 45 hours in a heated desiccator. The yield is 72.4 g (89% Y / recovery). The melting point is 149 to 151 ° C. By high pressure liquid chromatography (HPLC), the purity is found to be about 99.5%. The HMR (100 MHz) spectrum is clean and consistent with the structure. ·

analysis C 1 ^2H 1 6N ^{6S :} • 52 C 5 H . 30 N 1 1 S calc .: 52 15 5 , 83 30 , 41 1 1 60% Found .: , 42 , 94 , 51 , 35/0

-H3-

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Example 14

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

A) N-cyano-N'-propargyl-S-methylisothiourea

A solution of 16.00 g (0.109 mol) Dimethylcyandithioiminocarbonat and 6.03 g (0.109 mol) of propargylamine in 320 ml of acetonitrile is stirred for 4 hrs under reflux and then 12 hrs. At 25 ⁰ C. The mixture is cooled and filtered to give 13 »58 g (81 %) of the title compound of melting point 160 to 164 ⁰ C.

B) N-cyano-N'-propargyl-N "- (2-mercaptoethyl) -guanidine

A mixture of 1.136 g (10 mmol) of cysteamine hydrochloride 1: 53 g (10 mmol) of the product of step A above) and 0.055 g of hydroquinone in 10 ml of DMP is gently warmed to dissolve. To this solution is added 10 ml of 1N aqueous sodium hydroxide and nitrogen is bubbled through the solution. "Leave for 17 hours at room temperature, the reaction mixture is evaporated to dryness to give a mixture of title product and sodium chloride. The title product is extracted from this mixture with 10 ml of ethanol, and the ethanolic solution is used in the subsequent step C).

C) N-cyano-N ^{Γ -ί2} - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl} -N "-propargylguanidin

The ethanolic solution of the product of the above step B) (about 10 mmol) is added to a solution of 0.46 g of sodium '(0.02 g-atom) in 10 ml of ethanol under nitrogen at 4 ⁰ C. After 5 min, a solution of 1.67 g (10 mM) 4-methyl-5-chloromethylimidazole.HCl in 14 ml is added

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Ethanol, and the mixture is stirred under nitrogen for 70 min at room temperature The reaction mixture is filtered through a filter bed of Celite filter aid to remove the inorganic salts The celite is washed with ethanol The filtrate is evaporated to dryness and purified Product by chromatography on a silica gel column (20 g silica gel, 3.2-4 cm bed) with ethanol / chloroform mixtures as solvent The ethanol content is gradually increased from 2 to 15 $ The eluent is evaporated to dryness and retained 1.906 g of crystalline product. Umkristaliisation from 2-propanol gives 1.49 g (54%) of title product of melting point 144 to ⁰ C. 14.5

Example 1_5

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

A) N-cyano-N ^l - (2-butyn-1-yl) -S-methyl-isothiourea

A solution of 10.00 g (0.0684 mol) Dimethylcyandithioiminocarbonat and 4.73 g (0.0684 mol) of 2-butyn-1-amine in 200 ml of acetonitrile is 0.5 hrs. At 25 ⁰ C and then 2, Stirred for 5 hours under reflux. The mixture is cooled, and then filtered to give the title compound of melting point 180 to 183 ⁰ C won.

^B ) N-cyano-H '- (2-butyn-1-yl) -N "- (2-mercaptoethyl) -guanidine

Repeat the general procedure of Example 14 B) with the exception that the N-cyano-lT'-propargyi-S-methyl-isothiourea used there by a

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SY-155OX

replaced an equimolar amount of N-cyano-K '- (2-butyn-1-yl) -S-methyl-isothiourea to give the title product. , ·

C) N-cyano-K ¹ - {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyl · H "- (2- t-endin -1-yl) -guanidine _____

Repeat the general procedure of Example 14 C) except that the K-cyano-N ¹ -propargyl-N "- (2-mercaptoethyl) -guanidine used there is replaced by an equimolar amount of N-cyano-N '. Substituted for (2-butyn-1-yl) -iI "- (2-mercaptoethyl) -guanidine" to give the title product.

Example 16

N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) ethyl} -methylthioJ-

N '- (3-butyn-1-yl) -guanidin-

-N '- (3-butyn-1-yl) -IT "- (2-mercaptoethyi) -guanidine

The general procedures of Example 14, Steps A) and B) are repeated, except that the propargylamine used in step A) is replaced by an equimolar amount of 3-butyne-1-amine to give the title product ,

B) li-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthioJ- ethyl} -N' - (3 "but in-1-yl) guanidine ·

The general procedure of Example 14 (C) is repeated, except that the N-cyano-N'-propargyl-H "- (2-mercaptoethyl) -guanidine used there is replaced by an equimolar amount of cyan-Li ' (3-Butyn-1-yl) -l ⁱ i "- (2-mercaptoethyl) -

guanidine replaces "which gives the title product.

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Example 17

N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl} N "- (4-pentyne-1-yl) -guanidine

A) N-cyano-N '- (4-pentyne-i-yl) -N "- (2-mercaptoethyl) -guanidine

Repeat the general procedures of Example 14, Steps A) and B), except replace the propargylamine used in Step A with an equimolar amount of 4-pentyne-1-amine to give the title product. ·

B) N-cyano-N · -i2 - [(4-meth'yl-5-imidazolyl) -methylthio J- ethyl} -N "- (4-pentyne-1-yl) -guanidine

The general procedure of Example 14 C) is repeated with the exception that the N-cyano-N'-propargyl-N "- (2-mercaptoethyl) -guanidine used there is replaced by an equimolar amount of N-cyano-N '- (4-pentyne-1-yl) -N "- (2-mercaptoethyl) -guanidine to give the title product.

Example 18

N-cyano-N ^f - {2 - [(4-methyl-5-imidazolyl) -methylthio-ethyl- N, - (2-methyl-3-butyn-2-yl) -guanidine

A) N-cyano-N · - (2-methyl-3-butyn-2-yl) -N "- (2-mercaptoethyl) guanidine .

Repeat the general procedures of Example 14, Steps A) and B), except substituting an equimolar amount of 1,1-dimethylpropargylamine for the propargylamine used in Step A to give the title product.

20 5,794

B) N-cyano-N'-i2 - [(4-methyl-5-imidazolyl) -iiethylthio] -ethyl} -N '' - (2-methyl-3-butyn-2-yl) -guanidine

Repeat the general procedure of Example 14 C) with the exception that the N-cyano-N'-propargyl-N "- (2-mercaptoethyl) -guanidine used there by an equimolar amount of N-cyano-N ^l - (2-methyl-3-butyne-2-yl) -N "- (2-mercaptoethyl) -guanidine replaced by the title product.

Example 19

R-cyano-lT ^l - {2 - ^{[(4-methyl-5-imidazolyl)} methylthio] ethyl} · N '- (3-butyn-2-yl) guanidine

A) N-cyano-N '- (3-butyn-2-yl) -N "- (2-mercaptoethyl) -guanidine

Repeat the general procedures of Example 14, Steps A) and B), except substituting an equimolar amount of 1-methylpropargylamine for the propargylamine used in step A) to give the title product.

B) N-cyano-N M2 - [(4-methyl-5-imidazolyl) methylthio] ethyl} - N "- (3-butyn-2-yl) guanidine

The general procedure of the example is repeated, except that the N-cyano-N ¹ -propargyl-N "- (2-mercaptoethyl) -guanidine used there is replaced by an equimolar amount of H-cyano-N '- (3-butyne -2-yl), - N "- (2-mercaptoethyl) -guanidine is replaced to give the title product.

Claims (5)

- * »* - 20 5 79 invention claim 1. A process for the preparation of compounds of general formula I. ^ CH ₃ NCN H ^{2 2} wherein R is a straight-chain or branched alkynyl group with Represents 3 to 9 carbon atoms, and their non-toxic, pharmaceutically acceptable acid addition salts, characterized in that (a) a compound of general formula II: ^ CH-N- N ^ CHoCHoCHoNHR '2- 2 on nn \ r t- or their acid addition salt with a compound of general formula III: X-NHR ¹ (III) λ!, \\\) i -iQ7 Q> ^ ^; 'V ^ -! 9 * - M 9 -  20 5 79 4 wherein R has the meanings given above and R ₅ and R, are different from each other and either H or the group NCN Il -C-SR wherein R is any substituent, provided that the group -SR represents a suitable leaving group, in a non-reactive solvent at a temperature above room temperature, or (b) a compound of formula V: (l · Jl (V) N ^^ "" CHpSCH ₉ CH ₉ NH ₉ H ^ 2 2 2 with a compound of the general formula: S = C = NR ¹ . wherein R has the meaning given above, and the resulting compound of the formula VI: 1 _o N ^ ³ CH. (VI) ^ CH ₂ SCH ₂ CH ₂ NHCNHr ¹ H with methyl iodide and cyanamide, -So- 2 0 5 7 9 4 or
(c) a compound of formula VII: (VII). wherein X is hydroxy or a common leaving group, or one of its acid addition salts with a compound of general formula VIII NCN Il HSCH ₂ CH ₂ NHCNh-R ¹ (VIII) wherein R has the meanings given above, in an inert organic solvent, and, if desired, the resulting compound of the general formula I in the form of the free base or of an acid addition salt is converted into a corresponding, non-toxic pharmaceutically acceptable acid addition salt or into the free base. 2. The method according to item 1, characterized in that equimolar amounts of the compounds of formulas II and III are reacted together. - SA- 2 0 5 7 9 4 3. Method according to item 1 or 2, characterized that R is (lower) alkyl, aryl, substituted aryl, ^ aralkyl, -CH ₂ CN or -CH ₂ COOR ", wherein R" is hydrogen or (lower) alkyl. 4. The method according to item 1, characterized in that X for the subsequent conventional leaving groups 2 2 is fluorine, chlorine, bromine, iodine, -O-SR, wherein R is 3 3 (lower) alkyl, -O ₃ SR, wherein R is aryl or "substituted aryl, O_SF, acetoxy and 2,4-dinitrophenoxy. 5. The method according to item 1, characterized in that one reacts equimolar amounts of the compounds of formulas VII and VIII in the presence of a base.