DE2824066A1 - NEW COMPOUNDS USED FOR ULCUS TREATMENT, METHODS FOR THEIR PRODUCTION, MEDICINAL PRODUCTS AND INTERMEDIATES - Google Patents

Description

PATENT LAWYERS J. REITSTÖTTER W. KINZKEACH

PROP. DR. DR. DIPL. ING. DR. PHIL. DIPL. CHEM.

W. BUNTE U958-1Ö76) K. P. HÖLLER 2824066

DR. ING. ^ DR. RER. NAT. DIPL. CHEM. REITSTÖTTER 8: KINZEUACH TELEPONl (08β) 3Τ66 88 POST BOX 7HO. D-8OOO MUNICH 43 TELEXl ES162O8 IBAH D BAUERSTRASSB 22, SOOO MUNICH 40

M / 19135 1 * ^{Jurn 1978}

SY-155OX

BRISTOL-MYERS COMPANY

345 Park Avenue »

New York, N.Y. 10022, USA

New compounds and methods useful for treating ulcers for their manufacture, pharmaceuticals and intermediates

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POSTAL ADDRESS! POST BOX 78O. D-8O0O MUNICH 4a

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The invention relates to what is specified in more detail by the claims Object.

The N-cyano-N ^t -f2 - [(4-methyl-5-imidazolyl) -methylthio] -äthylT-N "-alkynylguanidines are Hp receptor blocking agents which inhibit gastric acid secretion and are used in the treatment of Ulcers are useful.

Used in the treatment of peptic ulcer disease the clinical goal is »to reduce gastric acid secretion. This is based on the principle "no acid - no Ulcus ". Traditional therapy for peptic ulcer disease is diet control and use of antacids and anticholinergics.

There is evidence to suggest that histamine ultimately stimulates gastric acid secretion could. This effect of the histamine is via Hp receptors conveyed. It is enhanced by the classic antihistamines » which are H ^ receptor blocking agents, not inhibited. A number of specific -receptor blocking agents (Hg receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as the secretion produced by other known gastric acid stimulants and are useful for Treatment of peptic ulcer.

The invention relates to histamine Hg receptor antagonists » which prove to be effective inhibitors of gastric secretion when

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Humans and "turn out to be" in animals. These compounds are useful for the treatment of peptic ulcer diseases. They correspond to the formula:

NCN CH ₂ SCh ₂ CH ₂ NHCNH-R ¹

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

A preferred embodiment of the invention are the compounds the general formula:

N <

y 1

/ ^CH 3

wherein R ^{4- is} hydrogen or methyl, as well as their non-toxic, pharmaceutically acceptable acid addition salts.

Another preferred embodiment of the invention are the compounds of the formula:

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SY-155OX -jv \ - 282A066

NCN CH ₂ SCH ₂ CH ₂ NHCNh- (CH ₂ ) _η 0Ξ

where R is hydrogen or methyl and η is a whole Number from 1 to 6 inclusive "means, as well as their non-toxic» pharmaceutically acceptable acid addition salts.

Another "preferred embodiment of the invention are the compounds of the general formula:

CH,

NCN j °

* | ^ CH ₂ SCH ₂ CH ₂ NHCNH-C-ChCR ⁴ "

where Ή7 stands for hydrogen or methyl »and their non-toxic» pharmaceutically acceptable acid addition salts.

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

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

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

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N "- (4-pentin-1-yl) -guanidine, as well as its non-toxic» pharmaceutically acceptable acid addition salts.

Another preferred embodiment of the invention is the N-cyano-N '- (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.

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

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

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

CH ₂ SCH ₂ Ch ₂ NHCNH-R ¹

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

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CH ₂ SCH ₂ CH ₂ NHR ₅

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

R ₆ NHR ¹ (III)

wherein R is as previously defined and R _c and 1L _C are from each other

ρ ο

are different and are either for H or the group

NCN
11
-C-SR

wherein R is any substituent, provided that the group -SR is a suitable leaving group ("Leaving group") forms, unsets and, if desired, the one obtained Compound of general formula I in basic form or in the form of an acid addition salt in the corresponding, non-toxic, pharmaceutically acceptable acid addition salts or converted into the free base form. ·

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

This process is illustrated by Reaction Schemes I and II below using a preferred compound of the invention explained:

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SCHEME I

NCN

CH ₂ SCH ₂ CH ₂ NHC-Sr + H ₉ NCH ₂ C = CH

NCN

CH ₂ SCH ₂ CH ₂ NHCNHCH ₂ CsCH

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 the radical R can be any substituent, provided that the group -SR represents a suitable leaving group. For example, R can represent (lower) alkyl, aryl, substituted aryl (for example p-nitrophenyl), aralkyl, -CH ₂ CN, -CH ₂ COOH, -CH ₂ COOR ¹ , or the like. The H-cyano-lT'-tZ-l ^ -methyl-S-imidazolyl) -methylthio J-ethyl3-SR-isothiourea starting materials can be prepared according to the procedures described in BE-PS 804 144. The alkynylamine starting materials are either commercially available or can be prepared according to the procedures described in Bull.Soc.Chim.Fr. 490 (1958), Bull.Soc.Chim.Fr. 592 (1967) and Annales de Chimie (Paris), J5, 656 (1958).

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-As-

SCHEME II

NCN
+ RS-CNHCH ₀ 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 can have the meaning given in Scheme I above. The 2 - [(4-methyl-5-imidazolyl) -methylthioj-ethylamine starting material can be prepared as described, for example, in US Pat. No. 3,950,353. The disubstituted Cyandithioiminocarbonate, which is used as the starting material for the production of N-cyano-N'-propargyl-SR-isothiourea is used (see step b) of example 2)

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can be prepared according to the procedures described in J. Org. Chem., 32., 1566 (1967).

In addition, it was found according to the invention that in the preparation of N-cyano-H'-f2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyli-N "-propargylguanidine according to the reaction scheme I certain reaction conditions in the last Stage to significantly improved product yields, as well as result in a product with fewer impurities. The latter circumstance leads to the additional advantage that you get the initial product (crude product) as crystalline Can isolate solid, which can be subjected to further purification by a simple recrystallization. This avoids chromatographic purification of the initial crude product, which was previously considered desirable was considered when other reaction conditions were chosen.

The aforementioned specific reaction conditions are to use methanol as a solvent in which Reaction uses a more concentrated solution (approximately 1 g of substituted isothiourea to 5 ml of methanol), while For the reaction, a stream of nitrogen is passed through the reaction vessel and freshly distilled propargylamine for the reaction begins.

Research has found that the use a nitrogen purge during the reaction results in the formation of small amounts of two as yet unidentified by-products which would otherwise be formed in the absence of a nitrogen purge. When these by-products are present, they cannot be removed by column chromatography and recrystallization. It is believed, that by flushing with nitrogen the formation of these secondary problems

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products is avoided by the fact that the methyl mercaptan so is quickly removed »as it is formed.

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

-CH

NCN

N "CH ₉ SCH ₉ CH ₉ NHCNh-R ¹

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

(V)

CH ₂ SCH ₂ CH ₂ NH ₂

with a compound of the formula:

S = C = NR ¹

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

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^M / ¹⁹¹⁵⁵ \ 9 - -too / nfifi

SY-155OX -Ao 2o24Ubb

(VI)

reacts with methyl iodide and cyanamide, the compound of the general formula I is formed in base form and, if desired, the product in a manner known per se in transferred to a corresponding, non-toxic, pharmaceutically acceptable acid addition salt.

This process is illustrated by Reaction Scheme III below for the preparation of a preferred one according to the invention Connection explained in more detail.

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-ft-

SCHEME III

N-

+ S = C = NCH ₂ C = CH

-CH-

Il

-N-H

.CH. DH / CH ₃ J 2) H ₂ NCN

NCN 'CH ₂ SCH ₂ Ch ₂ NHCNHCH ₂ C = CH

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

NCN H CH ₂ SCh ₂ CH ₂ NHCNH-R ¹

where R is a straight-chain or branched alkynyl group with 3 to 9 carbon atoms »or a non-toxic» pharmaceutically acceptable acid addition salt »which is characterized in that one is a compound of the general formula VII

(VII)

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

NCN HSCH ₂ Ch ₂ NHCNH-R ¹ (VIII)

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

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compatible acid addition salt or in the free base form convicted.

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

In a preferred embodiment, equimolar ones are used Amounts of the compounds of the formulas VII and VIII and carries out the reaction in the presence of a base.

Suitable leaving groups ¹¹ X "for this reaction are known to the person skilled in the art. These include, for example, fluorine, chlorine, bromine, iodine, -0 ~ SR ² , where R ^{2 is} (lower) alkyl (for example methanesulfonate), -O ₅ SR, where R ^ is aryl or substituted aryl (for example benzenesulfonate, p-bromobenzenesulfonate or p-toluenesulfonate), -O, SF, acetoxy and 2,4-dinitrophenoxy. For reasons of simplicity and economy, the compound of the formula II used, in which X stands for chlorine.

The compound is used in the process according to the invention of the formula VII, preferably in the form of an acid addition salt. Compound VII is in its free base form relatively unstable and is therefore preferably produced and stored as an acid addition salt. Although one can regenerate the free base of the compound of the formula II before the reaction, this does not lead to any advantage. For the It is obvious to those skilled in the art that any inorganic or organic acid can be used to form an acid addition salt to form the compound of formula VII. For example, hydrochloric acid, sulfamic acid, Sulfuric acid,. Oxalic acid, benzoic acid, succinic acid, acetic

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W-Vdoz - <& 2824086

W-Vdoz

acid, nitric acid »citric acid or similar» use. For the sake of simplicity and economy According to the invention, it is normally "preferred to use the compound of the formula II in the form of its hydrochloride.

The reaction of the compounds VII and VIII to form the compound of general formula I can be in any one of inert organic solvents are carried out. Here you can use an alkanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, Use 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. The reaction is slow at low temperatures. At higher temperatures, on the other hand, it usually leads to less pure products due to decomposition and formation of by-products. It is normally 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 preferred carried out in the presence of a base. The base facilitates the reaction by acting as an acid acceptor. To suitable Bases for this reaction include inorganic and organic bases. You can, for example, NaOH, KOH, IiOH, triethylamine, Use dimethylaniline, sodium ethylate, and the like.

The procedure is followed by Reaction Scheme IV below for the preparation of a preferred compound according to the invention explained in more detail:

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SCHEME IV

CH-

H CH ₂ OH / H

NCN + HSCH ₂ CH ₂ NHCNHCh ₂ C = CH

^ -CH.

N-H

CH ₂ SCH ₂ Ch ₂ NHCNHCH ₂ C = CH

(I)

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

NCN
HSCH ₂ Ch ₂ NHCNH-R ¹ '

(VIII)

Where R is a straight-chain or branched alkynyl group with 3 "to 9 carbon atoms, and their addition _{salts. These compounds are useful for the preparation of the histamine H 2} receptor antagonists of the general formula I.

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

-CHC = CR ⁴ , CH *

where R is hydrogen or methyl. In a further preferred embodiment, the radical R is ~ ( ^σΗ 2 ^ η ^0Ξ ° ' ^{where n is} an integer from 1 to 6 and R ^{4 is} hydrogen or methyl. In a further preferred embodiment, the radical R is

CH ₅

where 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 one. Embodiment, the radical R is the 3-butyn-1-yl-G group. In a further, more preferred embodiment, the radical R is the 4-pentyn-1-yl group. In a further, more preferred embodiment, the R ¹ radical is the 2-methyl-3-butyn-2-yl group. In a further, 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 the general formula VIII is the propargyl group.

The invention also relates to a process for the preparation of the new intermediates of the general formula VIII:

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HSCH ₂ CH ₂ NHCNh-R

which is characterized by »that a compound of the general formula IX:

P-SCH ₂ CH ₂ NH ₂ (IX)

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

NCN
RSCNH R " ¹ (X)

wherein R " ^{1 has} the above meanings,

reacted and then the sulfhydryl protective group removed from the compound obtained, the intermediate product of the general formula VIII is formed.

This procedure is illustrated by scheme V below:

SCHEME V

NCN HCISCH ₂ CH ₂ NH ₂ + RSCNHCH ₂ C = CH

1) heating

2) Unblock

NCN

HSCH ₂ CH ₂ NHCNHCH ₂ CScH

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The dimethylcyanedithioiminocarbonate used as the starting material for the preparation of the N-cyano-N ¹ -alkynyl-S-methylisothioureas can be prepared by the procedures described in J. Org. Chem., 32 , 1566 (1967). The alkynylamine starting materials are either commercially available or can be prepared by methods described in Bull. Soc. CMm. Pr., 490 (1958), Bull. Soc. Chim. Pr. _T 592 (1967) and Annales de Chimie (Paris), 3, 656 (1958).

When you use cysteamine hydrochloride with an N-cyano-N'-alkynyl-S-methylisothiourea with formation of an N-cyano-N'-alkynyl-N "- (2-mercaptoethyl) -guanidine of the general formula VIII, it is found to be desirable to carry out the reaction in the presence of a small amount of hydroquinone and bubbling nitrogen through the reaction mixture (see, for example, step B of Example 14). It was found that these reaction conditions lead to the formation of compounds of Formula VIII in higher yield and lead with higher purity. It is believed that the nitrogen purge removes the methyl mercaptan formed in the reaction removed, thereby avoiding side reactions caused by the addition of the methyl mercaptan to the carbon-carbon triple bond originate. It is believed that the hydroquinone prevents the formation of free radicals and side reactions resulting from their presence .

As used herein, "non-toxic, pharmaceutically acceptable acid addition salts" means a mono- or Disalt of a compound of the invention with a non-toxic, pharmaceutically acceptable organic or inorganic acid. Such acids are known. These include hydrochloric acid, hydrobromic acid, sulfur

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acidic acid »sulfamic acid, phosphoric acid, nitric acid» Maleic acid, fumaric acid, succinic acid, oxalic acid, benzoic acid, methanesulphonic acid, ethane disulphonic acid, benzenesulphonic acid, Acetic acid, propionic acid, tartaric acid, citric acid, camphorsulfonic acid, and the like. The salts will be on produced in a manner known per se.

The term (lower) alkyl used here is intended to be straight-chain or branched alkyl groups of 1 to 6 carbon atoms.

In the therapeutic application, the inventive, pharmacologically active compounds normally administered as a pharmaceutical agent, which as the (or a) essential 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.

The pharmaceutical agents can be administered orally, parenterally, or through rectal suppositories. One can Use a variety of pharmaceutical dosage forms. For example, if you need a solid support, so the preparation can be put into tablets, in a hard gelatin capsule, in powder or pellet form, or they can be in the form of a lozenge or in lozenge form. If a liquid carrier is used, the preparation can in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile solution for injection or a aqueous or non-aqueous liquid suspension. The pharmaceutical agents are prepared according to the usual techniques that are suitable for the respective desired preparation, manufactured.

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Preferably, each dosage unit contains the active ingredient in an amount from about 50 mg to about 250 mg, most preferably in an amount of from about 100 mg to about 200 mg. The active ingredient is preferred given in equal doses two to four times a day. The daily dose prescription is preferably between 250 mg and about 1000 mg, most preferably between about 500 mg and about 750 mg.

It has been shown that histamine Hp receptor antagonists are effective gastric acid secretion inhibitors in humans and animals, see Brimblecombe et al., J. Int. Med.Res., 3. » ⁸⁶ (1975). The clinical evaluation of the histamine Hp receptor antagonist cimetidine has shown that it is an effective therapeutic agent for the treatment of peptic ulcer diseases, cf. Gray et al., Lancet, J_ (8001), 4 (1977) . The compound prepared in Examples 1 and 2 below (hereinafter referred to as BL-5641) was compared with cimetidine in various studies. It was found here that the compound according to the invention is superior to cimetidine. This superiority manifested itself as a histamine H ^ 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 tests in the dogs indicate that the compound according to the invention has a longer duration of action than cimetidine at the same doses.

Histamine Hp Receptor Antagonism

Examination in the isolated atrium of the guinea pig.

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

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(1972) describe the receptors involved in this histamine effect as histamine H ₂ receptors when they reported the properties of burimamide, 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 by Black and coworkers that the positive chronotropic effect of histamine in the isolated right atrium of the guinea pig is mediated by histamine Hq receptors. Black et al. " Agents and Actions, 3. » 133 (1973) and Brimblecombe et al., Fed. Proc, 55. " 1931 (1976) used the isolated right atrium of the guinea pig as a means of comparing the activities of histamine H ₂ ~ receptor antagonists. The present comparative studies were carried out using a modification of the procedure reported by Reinhardt et al., Agents and Actions, 4 »217 (1974).

Male Hartley strain guinea pigs (350-450 g) were killed by a blow to the head. The heart was excised and placed in a Petri dish with oxygenated (95 # O ₂ , 5 ^ CO ₂ ) modified Krebs solution (g / liter: NaCl 6.6; KCl 0.35; MgSO ₄ .7 H ₂ O 0.295; KH ₂ PO ₄ 0.162; CaCl ₂ 0.238, NaHCO ₃ 2.1 and dextrose 2.09). The spontaneously beating right atrium was cleared of other tissues. A silk thread (4-0) was attached to each end. Was suspended the atrium in a 20 ml muscle chamber containing oxygenated modified Krebs solution and was kept at 32 ⁰ C. The atrial contractions were recorded isometrically using a Grass ' 0.03 strain gauge'. The recording of the force and speed of contraction was made with a Beckman RP dynograph.

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Resting tension of 1 g was applied to the atrium and allowed to equilibrate for 1 hour. After the equilibration period, a submaximal concentration of histamine dihydrochloride (3 x 10 "M) was added to the bath and washed to prep the tissue. Then histamine was added cumulatively to the bath using 1/2 log 10 intervals to finally molar Bath concentrations of 1 χ 10
up to 3 x 10 ^J. You waited until it got through
Histamine-related increase in heart rate reached a plateau until the subsequent concentration was established. In each case, the maximum response

-5
chen 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 χ 10 " ⁵ M) was added, and after a 30-minute period
Incubation period, the histamine concentration response was repeated, adding higher concentrations than required.

The ED, -Q- ¥ ¥ ¥ ¥ ¥ ¥ of the histamine (concentration of histamine which leads to an increase in the contraction frequency of 50 $> the maximum
Frequency led) and the 95 % confidence limits before and
after the test compound were determined by regression analysis as described by Finney, Probit Analysis, 3rd Edition,
Cambridge (1971). The concentration response curve shift factors were calculated as follows:

ED50 histamine + compound

Displacement factor =

₀ histamine alone

The factor obtained for BI-5641 was then used as a ratio

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of the factor obtained for the cimetidine expressed:

BL-5641 Shift Factor - 1st

Activity ratio =

Cimetidine Shift Factor - 1

The "results obtained in these studies are compiled in Table I. Cimetidine or BI-5641 shifted the histamine concentration response curve to the right by a factor of 6.6 and 32.7, respectively. Based on the Concentration response curve shift factors were compound BL-5641 as histamine Hp 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 effectiveness of cimetidine and the compound according to the invention BL-5641 in the isolated right atrium of the guinea pig

Compound N concentra- histamine ED5O various activity with 95 % application factor activity confidence limits of the concentration

(UK / ml) ^{tration νμ6} ' response curve

Histamine 0.21

Control 3 (0.18-0.25)

1.39 cimetidine 3 1 ac 10 " ⁵ M (1.08-1.85) 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

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Determination of gastric antisecretory activity in rats with a 2-hour pyloric ligature (Shay)

The "pyloric ligation method" in the rat was developed by Shay et al., Gastroenterology, £, 53 (1945) to study perforating gastric ulcers. When this method became known, however, it was also used as a means of studying gastric secretion in the Rat (see. Shay et al., Gastroenterology, 2j5, 906 (1954) »Brodie, DA, Am.J.Dig.Dis., _1_1_» ² 31 (1966). A modification of this procedure for evaluating compounds applied for their gastric antisecretory activity.

Male Long Evans rats weighing 280 to 300 g are used. The animals are in individual cages given and fasted for 24 hours. However, drinking water is available. Under ether anesthesia the stomach is through exposed a central incision and placed a cotton thread ligature around the pylorus. After closing The administration of ether is interrupted at the wound and either BL-5641 »cimetidine or carrier liquid is intraperitoneally administered administered at a volume of 1 mg / kg. BL-5641 and cimetidine are dissolved in one equivalent of HCl and brought to the right volume with water. The animals are returned to their cages that make up the water bottles were removed and then killed with ether 2 hours later. You remove the stomach and put it in the Gastric acid was collected in graduated test tubes for 2 hours to determine the volume. Titratable acidity is measured by titrating a 1 ml sample with 0.02N NaOH to pH 7.0. An automatic one is used here Burette (autoburet) and an electrometric pH meter (Radiometer). The amount of titratable acid is calculated in microequivalents by dividing the volume in ml

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with the acid concentration in milliequivalents per liter multiplied. The percent inhibition of acid production is calculated as follows:

Control acid production

percentage - acid production with the substance inhibition _ χ 100

of acid ~ acid production in control production

The results obtained with compound BL-5641 of the present invention and the cimetidine are shown below Table II listed.

The results show that with the 2 hour pyloric ligature preparation in the rat, the compound according to the invention BL-5641 with regard to the inhibition of gastric acid production at least as effective as the cimetidine is.

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TABLE II

Effect of BL-5641 and of cimetidine on gastric acid production "in the rat at 2-hour Pyloric ligature

link Dose ( 11.1 percentage In ED50 5.53 hibernation of
Acid production μΜοΐ / kg BL-5641 μΜοΐ / kg mg / kg 2.76 80 40 10 61 -v / 11 20th Ul 37 Cimetidine 10 2.5 66 40 1.25 60 -v / 14 20th 40 10 34 5

* At least 5 animals are used for each dose.

Determination of gastric antisecretory activity in dogs with a gastric fistula

Stainless steel cannulas according to Thomas (Thomas, J.E., Proc.Soc.exp.Biol.Med., 46 »260 (1941)) into the stomachs of Beagle dogs (10 to 12 kg) immediately in the area of the pylorus near the greater curvature one »around one creating chronic gastric fistula. The animals are then left

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recover at least two months before doing any tests. The dogs are in front Fasted each experiment overnight (approximately 18 hours) with water given ad lib. One gives put the dogs in a sling and attach an 8 in. catheter with an inner needle (CR. Baird Inc.) Insert a 5 cm long needle (gauge 17) into a vein in the leg to administer the drug. The gastric secretions are emptied every 15 minutes by gravity collected from the opened cannula. The basal secretions are collected for two consecutive periods of 15 min each. If these turn out to be excessive (> 4 ml / 15 min .; pH <5 »0), the animal will not used. In carrying out this investigation, a modification of that of Grossman and Konturek, Gastroenterology, 6 x 5, 517 (1974) applied. Immediately after the second basal collection, a 90-minute infusion of histamine (100 μg / kg / hour) is made with a Harvard infusion pump with a volume of 6 ml / hour. carried out. At this point, you either give the according to the invention BL-5641 »the cimetidine (dissolved with one equivalent of HCl and adjusted to the correct one with normal saline Volume) or normal saline is injected quickly (within 50 seconds) to a volume of 0.1 ml / kg. Then the infusion of the histamine is continued for another 150 minutes (total infusion time = 4 hours). Every Sample taken after 15 min. Gastric juice is measured to the nearest 0.5 ml and the titratable acidity is determined Determined against 0.02N NaOH (end point pH 7 »0) with an automatic burette and a pH meter (radiometer). the percent inhibition of acid production is as in the procedure for measuring the rat with pyloric ligation described, calculated.

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M / 19135

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

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

- 37 809850 / Θ906

TABLE III

Effect of
unaesthetized BL-5641 and cimetidine
Dogs with gastric fistula 24136 15th on gastric acid production 60 ; Inhibition of acid
(N = 1) 90 105 120 minutes _AVO
VJl - *
VJlOJ
Ουί Pharmacon and dose dog no.
(μΜοΐ / kg iv) 24136 66 percentage
production 99 75 93 91 73 PS 22619 63 30th 45 76 99 48 41 14th BL-564 ¹ (12) 22619 82 99 99 95 54 76 52 53 Cimetidine (12) 23606 84 99 89 67 78 54 40 32 </, BL-5641 (6) 23606 60 99 99 34 65 42 24 (P *
O Cimetidine (6) 24895 43 96 73 0 32 38 8th 0 BL-5641 (3) 24895 82 59 36 49 17th 7th 0 0 Cimetidine (3) 23553 73 27 15th 29 33 18th 0 0 BL-5641 (1.5) 23553 51 72 53 28 0 43 42 46 Cimetidine (1.5) 50 57 60 17th 31 27 25th 19th BL-5641 (0.75) 38 28 35 Cimetidine (0.75) 10 24 282 ^ 990 *

SY-155OX -> Q, ^ o ^ huv

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

example

N-cyano-N ^I - {2 - [(4-methyl-5-iniidazolyl) -methylthioJ-ethyl} · N "-propargylguanidine

NCN CH ₂ SCH ₂ CH ₂ NHC-SCh ₅ + Η ₂ Ν0Η ₂ 0Ξ0Η

NCN CH ₂ SCH ₂ CH ₂ NHCNHCH ₂ CsCH

A mixture of 3.00 g (0.0111 mol) of N-cyano-N ¹ - {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyl} -S-methyl-isothiourea and 2, 50 g (0.045 mol) of propargylamine in 60 ml of acetonitrile 65 hrs. under reflux, and then heated in a pressure vessel made of stainless steel 38 h. at 120 to 130 ⁰ C. It is cooled, the reaction mixture at> decanted from a tar-like product, and then evaporates, leaving 3.75 g of a rubbery material. This material is placed on silica gel (0.15 mm to 0.074 mm (100 to 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 aceto-

- 39 809850 / Θ906

Μ / 19135 » _Λ , _{oo / ncc}

SY-155OX-HO - 282406b

recrystallized nitrile. Here, one 0.236 g (7.7%) of the title compound with melting point of 146 to 149.5 ⁰ receives G.

Analysis C ₁₉ H ₁ ^ -N, S:

12 16 6 _{c HN}

ber .: 52, 15th 5, 83 30, 41 found: 51, 86 5, 81 30, 70

Example 2

N-cyano-N '- {2- [(4-methyl-5-imidazolyl) -methyl thio I-ethyl} · N "-propargylguanidine

(CH ₅ S) ₂ C = NCN + H ₂ NCH ₂ ChCH

NCN ^
CH ₅ SCNHCH ₂ ChCH;

CH ₂ SCH ₂ CH ₂ NH ₂ + A.

, CH,
N-

NCN CH ₂ SCH ₂ CH ₂ NHCNHCH ₂ CSCh

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

A solution of 16.00 g (0.109 moles) dimethylcyanedithioiminocarbonate and 6.03 g (0.109 mole) propargylamine in

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M / 19135

320 ml of acetonitrile. Stirred for 4 hours at reflux and then stirred for 12 hrs. At 25 ⁰ C. Work-up gives 13 »58 g (81 #) of title compound A with a melting point of 160 to 164 ^° C.

b) N-cyano-N ^l - [2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyl} -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 64 hours on Heated to reflux. The solvent is removed by evaporation, the residue is poured onto silica gel (0.15 mm to 0.074 mm (100 to 200 mesh)) and chromatographed by gradient elution using methylene chloride / methanol. The later fractions yield 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 is identical to the product prepared according to Example 1 (Infrared analysis, nuclear magnetic resonance, thin layer chromatography).

41 -

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M / 19135 SY-155OX

example

-HI-

-N'-te-C (4-methyl-5-imidazolyl) -methylthioJ-ethyl} - N "- (2-butyn-1-yl) -guanidine

(CH ₅ S) ₂ C = NCN + H ₂ NCH ₂ C = CCH ₅

NCN

CH ₂ SCH ₂ CH ₂ NH ₂ + B

NCN CH ₂ SCH ₂ CH ₂ NHCNHCH ₂ C ^ CCh

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

A solution of 10.00 g (0.0684 mol) of dimethylcyandithioiminocarbonate and 4.73 g (0.0684 mol) of 2-butyn-1-amine in 200 ml of acetonitrile is 0.5 hours at 25 ^° C. and then 2, Stirred under reflux for 5 hours. The mixture is cooled and filtered, the title compound B having a melting point of 180 to 183 ^° C. being obtained.

- 42 -

8098Β0 / Θ906

% -Vdox _1β. 28 2 A 06 6

b) N-Cyano-H '- ^ - C (4-methyl-5 ~ imidazolyl) -methylthio] -ethylS N "- (2-T3utin-1 -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) -methylthioj-ethylamine in 140 ml of methanol is 40 hours. heated to reflux. The work-up and chromatography described in Example 2 above yields the title compound. If the title compound is prepared according to the general procedure of Example 1, it melts at 128 to 130 ^° C.

example

N-cyano-N · -i 2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl} - N "- (5-butyn-1-yl) -guanidine

The general procedure of Example 1 is repeated with the exception that the propargylamine used there replaced by an equimolar amount of 3-butyn-1-amine "whereby the title compound is obtained",

example

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

Repeat the general procedure of Example 1 with the exception that one replaces the propargylamine used therein an equimolar amount of 4-pentyn-1-amine, thereby obtaining the title compound with melting point from 99 to 103 ⁰ C.

- 43 809850 / Θ906

SY-155OX j .. 2824

Example 6

N-cyano-NM2 - [(4-methyl-5-imidazolyl) -methylthio] -ethylI- N "- (2-methyl-3-butyn-2-yl) -guanidine

The general procedure of Example 3 is repeated with the exception that the 2-butyn-1-amine used there replaced by an equimolar amount of 1,1-dimethylpropargylamine » thereby obtaining the title product.

example

N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyl} - Ijii - (3-butyn-2-yl) -guanidine

The general procedure of Example 3 is repeated with the exception that the 2-butyn-1-amine used there is replaced by an equimolar amount of 1-methylpropargylamine to give the title compound.

Example 8

N-cyano-N'-t2 - [(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-butyn-1-amine in 60 ml of propionitrile is stirred under reflux for 40 hours. Thin layer chromatographic Examination of an aliquot of the reaction mixture reveals a trace of the isothiourea -Materials to make the mix Is refluxed for a further 6 hours and then stirred for 64 hours at room temperature. One removes the solution

- 44 -809850 / Θ90Β

SY-155OX &quot; J ^ Q ^ UOQ

medium (together with excess amine) at reduced pressure and gives the remaining gummy residue on silica gel (0.15-0.074 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 Ithylacetat 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 C. The yield is 1.072 g of product with melting point 128 to 130 ⁰ C.

Analysis C ₁ -H ₁₈ NgS:

53 C. 6th H N 94 1 S. 08 * ber .: 53 , 77 6th , 25 28, 62 1 1, 34 found ι , 72 , 29 29 1,

Example 9

N-cyano-N · - {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyl> N "- (3-butyn-1-yl) -guanidine

A mixture of 3.00 g (0.0111 mol) N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyli-S-methyl-isothiourea and 3.13 g (0 * 0453 mol) 3-butyn-1-amine in 60 ml of propionitrile is stirred under reflux for 40 hours. The solvent is evaporated, giving 5.40 g a syrup is obtained which is placed on 70 g of silica gel (0.15 mm to 0.074 mm (100 to 200 mesh)) and by gradient elution chromatographed using methylene chloride / methanol.

- 45 809850/0906

M / 19135
SY-155OX 99 -Her Eluent MeOH volume 28240 f fraction CH ₂ C1 _2/1 100 ml weight 1 Il 70 ml - CVl Il 50 ml - 3 Il 30 ml 0.117 G 4th Il 75 ml - 5 It 150 ml 0.067 G 6th 98 Il MeOH 325 ml 0.080 G 7th CH ₂ Gl _2/2 50 ml 0.168 G 8th ti 150 ml - 9 Il 250 ml 0.125 G 10 97 Il MeOH 250 ml 0.811 G 11 CH ₂ Cl _2/3 175 ml 0.72 G 12th Il 225 ml 0.125 G 13th It - 0.133 G H 95 It
ti MeOH 225 ml
200 ml 0.027 G 15th
16 CH ₂ Cl _2/5 250 ml 0.002 G 17th ti 250 ml 0.035 G 18th 0.236 G

TLC (silica gel, 90 GH ₂ Cl _2/10 MeOH) indicates that the fractions are purely 9 to 12, and must be combined. Fractions 1 to 8 contain rapidly migrating impurities. Fractions 13 and 14 show some post-migration contamination. Fractions 9 to 12 are combined and evaporated. This gives 1.72 g of a yellow, rubbery product. This product comes in 11 ml

809850 / Θ ⁴ 90 ~ 6

Nitromethane dissolved and crystallized at -15 ⁰ C to give 1.18 g of pale yellow Peststoff obtained. This is recrystallized from 9 ml of nitromethane, 0.987 g of product having a melting point of 86 to b9 ° G (softening at fa5 ° C) being obtained. The infrared and HMH (100 MHz) spectra are clean and in agreement with the desired structure. NMR shows the product to be solvated with approximately 0.08 moles of nitromethane.

Analysis G ₁₅ H ₁₈ N ₆ S 0.08 (CH ₅ NO ₂ ):

CHNS

ber .: 53 , 21 6, 22nd 28 , 84 10 , 86 found: 52 , 68 6, 28 29 , 39 11 , 22 52 , 87 6, 02 29 , 50

Example IjO

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

A mixture of 3.00 g (0.0111 mol) N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyli-S-methyl-isothiourea and 3.69 g (0.0445 mol) of 4-pentyne-1-amine in 60 ml Acetonitrile is stirred under reflux for 24 hours and then left to stand for 96 hours at room temperature. That Solvent and the excess amine are removed under reduced pressure. The remaining yellow rubbery Product is chromatographed on 50 g silica gel (0.15 mm to 0.074 mm (100 to 200 mesh)) using a gradient elution with methylene chloride / methanol (99: 1 to 96: 4). By thin layer chromatography the middle fractions are found to be pure. They are combined and evaporated to give 1.91 g of a yellow rubbery product. This is at

- 47 809850/0908

SY-155OX ^ ^ O ^ huuw

-15 ⁰ C crystallized from 18 ml of ethyl acetate. (G 1.25) v / ill be recrystallized The white Peststoff obtained at -15 ⁰ C in 10 ml of acetonitrile. In this case, one obtains 1.063 g of product having melting point of 99-103 ⁰ C.

Analysis C ₁ -Hp ₀ NgS:

CHNS

ber .: 55.24 6.52 27.61 10.53 # gel.-. 55.43 6.58 28.26 10.97 f>

Example 1_1_

N-cyan-N ^! - {2 - [(4-methyl-5-imidazolyl) -methylthio J-ethyl] -N "-propargylguanidine

A mixture of 10.0 g (0.0371 mol) of N-cyano-N'-i2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl-S-methyl-isothiourea and 20 ml (0.325 mol) is stirred distilled propargylamine in 50 ml of methanol at reflux under a nitrogen atmosphere (nitrogen purge) with positive pressure for 20.5 hours. The solvent and excess amine are then removed by evaporation, leaving a tan oil which crystallizes easily. 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 product (79 $>) with melting point 146 to 148.5 ⁰ C.

Example 12_

N-cyano-N · -i2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl} - N "-propargylguanidine

A mixture of 100 g (0.371 mol) .N-cyano-N'-12 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl3-S-methyl-isothiourea and

- 48 809850/0906

M / 19135 SY-155OX

150 ml (2.44 mol) of distilled propargylamine in 500 ml of methanol is stirred under reflux under a nitrogen atmosphere (nitrogen flushing) with positive pressure for 22 hours. The reaction mixture is cooled and the solvent and excess amine are removed by evaporation. What remains is an amber-colored oil that easily crystallizes. The crude product is triturated under 250 ml of isopropanol, cooled to ⁰ ° C. for 2 hours and collected by filtration. Wash the filter cake with cold isopropanol and dried in vacuum for 16 h. Over P2 ° 5 * ■ ^The gei ^ ⁰⁰ ^ "designated title product is in the form of an almost white, dense solid before. The yield is 73.5 g (71 7 $>) with melting point 147 to 149 ⁰ C.

Example 1J5

Recrystallization of N-Cya ^ i-N'-te-C ^

methylthio] -ethyl3 -Ν "-propargylguanidine

The end products obtained in Examples 11 and 12 are combined (81.3 g in total), dissolved in 1000 ml of hot isopropanol, filtered through "Super-Gel" 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% recovery). The melting point is 149 to 151 ^° G. High pressure liquid chromatography (HPLC) shows that the purity is approximately 99.5%. The HMR (100 MHz) spectrum is clean and consistent with structure.

Analysis C ₁₀ H ^ IL-S:

12 16 6 _c HN S.

ber .: 52 , 15 5, 83 30, 41 11 found: 52 , 42 5, 94 30, 51 11

M / 19135 oQo / naa

SY-155OX h "28z4Ubb

-50-

Example 14

N-cyano-N'-12 - [(4-methyl-5-imidazolyl) -methylthioJ-ethylI-N "-propargylguanidine

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

A solution of 16.00 g (0.109 koi) Dimethylcyandithioiminocarbonat and 6.03 g (0.109 mol) of propargylamine in 320 ml of acetonitrile is 4 hrs. Under reflux, and then stirred for 12 hrs. At 25 ⁰ C. The mixture is cooled and filtered, 13.58 g ($ 81) of the title compound having a melting point of 160 to 164 ^° C. being obtained.

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

A mixture of 1.136 g (1C mmol) of cysteamine hydrochloride, 1> 53 g (10 mmol) of the product from step A) above and 0.055 g of hydroquinone in 10 ml of DMF is easy to dissolve warmed up. 10 ml of 1N aqueous sodium hydroxide are added to this solution and nitrogen is bubbled through the solution. After standing at room temperature for 17 hours, the reaction mixture is evaporated to dryness, whereby a mixture of title product and sodium chloride is obtained. The title product is made from this mixture with 10 ml of ethanol extracted, and the ethanolic solution is used in the subsequent stage C).

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

The ethanolic solution of the product from step B) above (approximately 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 ^° C. After 5 minutes, a solution of 1.67 g (10 mmol) of 4-methyl-5-chloromethylimidazole.HCl in 14 ml is added

- 50 809850/8906

M / 19135

Ethanol is added and the mixture is stirred under nitrogen for 70 minutes 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 the product is purified by chromatography on a silica gel column (20 g silica gel 3.2 × 4.5 cm bed) with ethanol / chloroform mixtures as the solvent. The ethanol content is gradually increased from 2 to 15 9 ^. The eluent is evaporated to dryness and 1.906 g of crystalline product are obtained. Recrystallization from 2-propanol gives 1.49 g (54%) of the title product with a melting point of 144 to 145 ^° C.

Example 1_5

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

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

A solution of 10.00 g (0.0684 mol) of dimethylcyanedithioiminocarbonate and 4.73 g (0.0684 mol) of 2-butyn-1-amine in 200 ml of acetonitrile is 0.5 hours at 25 ^° C. and then 2, Stirred under reflux for 5 hours. The mixture is cooled and then filtered, the title compound having a melting point of 180 to 183 ^° C. being obtained.

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

The general procedure of Example 14 B) is repeated with the exception that the K-cyano-N'-propargyl-S-methyl-isothiourea used there by a

- 51 - 809850/6908

M / 19135 SY-I55OX

an equimolar amount of N-cyano-N '- (2-butyn-1-yl) -S-methyl-isothiourea replaces »whereby you get the title product.

C) N-cyano-N ^l -i2 - [(4-methyl-5-imidazolyl) -methylthioJ-ethyl * · N "- (2-butyn-1-yl) -guanidine

The general procedure of Example 14 0) is repeated with the exception that the IT-cyano-N'-propargyl-N "- (2-mercaptoethyl) -guanidine used there is replaced by an equimolar amount of N-cyano-N ^l - ( 2-butyn-1-yl) -N "- (2-mercaptoethyl) -guanidine replaced, whereby the title product is obtained.

Example 16

N-cyano-N ^f - {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyl 1- N "- (3-butyn-1-yl) -guanidine

A) N-cyano-N '- (3- "butyn-1 -yl) -N" - (2-mercaptoethyl) guanidine

The general procedures of Example 14, steps A) and B) are repeated, with the exception that this is done there Propargylamine used in step A) is replaced by an equimolar amount of 3-butyn-1-amine, whereby the title product is obtained receives.

B) iJ-Cyano-N ^f - {2- [(4-methyl-5-imidazolyl) -methylthio J- ethyl-N "- (3-butyn-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'- (3-'butin-1-yl) -N "- (2-mercaptoethyl) -guanidine replaced, whereby the title product is obtained.

- 52 - 809850/9906

-SB-

Example 17

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

A) N-cyano-N '- (4-pentin-1-yl) -N "- (2-mercaptoethyl) -guanidine

The general procedures of Example 14> steps A) and B) are repeated with the exception that the procedure in Step A) replaced propargylamine used with an equimolar amount of 4-pentyn-1-amine, whereby the title product is obtained.

B) N-Gyan-N'-12 - [^ - methyl-S-imidazolyl) -methylthio] -ethyll-N "- (4-pentin-1-yl) -guanidine

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

Example 18

N-cyano-N'-i 2 - [(4-methyl-5-imidazolyl) -methylthio I-ethyli N "- (2-methyl-3-butyn-2-yl) guanidine

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

The general procedures of Example 14> steps A) and B) are repeated with the exception that this is done there Propargylamine used in stage A) replaced by an equimolar amount of 1,1-dimethylpropargylamine, whereby the Title product receives.

- 53 -

809850/8906

SY-155OX Γη i.uz.Hwww

B) N-cyano-N ¹ -? 2- [(4-methyl-5-imidazolyl) -methylthio] -ethyl] -N "- (2-methyl-3-butyn-2-yl) -guanidine

The general procedure of Example 14 C) is repeated with the exception that that is used there N-cyano-N · propargyl-N "- (2-mercaptoethyl) -guanidine an equimolar amount of N-cyano-N '- (2-methyl-3-butyn-2-yl) N "- (2-mercaptoethyl) -guanidine replaces» whereby the title product is obtained.

Example 19

N-cyano-N '- {2 - [(4-methyl-5-imidazolyl) -methylthio] -ethyli-N "- (3-butyn-2-yl) -guanidine

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

The general procedures of Example 14, steps A) and B) are repeated, with the exception that this is done there Propargylamine used in stage A) replaced by an equimolar amount of 1-methylpropargylamine, whereby the title product is obtained.

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

The general procedure of the example 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 ¹ - (3-butyne -2-yl) -N "- (2-mercaptoethyl) -guanidine is replaced, whereby the title product is obtained.

- 54 -

809850 / Ö906

Claims (24)

PATENT CLAIMS K ₁ (D wherein R is a straight-chain or branched alkynyl group having 3 to 9 carbon atoms, and their non-toxic, pharmaceutically acceptable acid addition salts. 2. The acid addition salts of the compounds according to claim 1 with hydrochloric acid, hydrobromic acid, sulfuric acid, Sulfamic acid, phosphoric acid, nitric acid, Maleic acid, fumaric acid, succinic acid, oxalic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Acetic acid, propionic acid, tartaric acid, citric acid or camphorsulphonic acid. 3. Compounds according to any one of claims 1 and 2, wherein R corresponds to the following formulas: CH ₃ -CHCsCR ⁴ , - (CH ₂ ) _n CS0R ⁴ or -C-CsCR ⁴ 809850/0906 Μ / 19135 Π where R ^{4 is} H or CEU and η is an integer from 1 to 6 inclusive » 4. Compounds according to any one of claims 1 »2 or 3» wherein R ¹ for -CHC = CR ⁴ CH ₃ where R ⁴ "is H or CH. 5. Compounds according to any one of claims 1 _f 2 or 3 »wherein R ^{1 is} - (CH ₂ ) _n C = CR ⁴ , where R ⁴ "is H or CH ₅ . 6. Compounds according to claim 5 »in which η is 1 or 2. 7. Compounds according to any one of claims ^{1, 2 or 3 »wherein R 1 is} CH ₃ -CC = CR ⁴ CH ₅ where R ^{4 is} H or CH ₅ . 8. Process for the preparation of the compounds of general formula I according to Claims 1 to 7 or their phar ^ Pharmaceutically acceptable acid addition salts, characterized in that a compound of the general formula II: - 3 809850/0906 Μ / 9135, Ο. CH ₉ SCH ₉ CH ₀ NHR ₁ . <- CC. O or their acid addition salt with a compound of the general formula III: R ₆ NHR ¹ (III) wherein R has the meanings given in claim 1 and Rc and Rg are different from one another and either for H or the group NCN Il -C-SR wherein R is any substituent, with the proviso that the group -SR is a suitable leaving Represents group, reacts in a non-reactive solvent at a temperature above room temperature, and, if desired, the compound of formula I obtained in the basic form or its acid addition salt in a corresponding, non-toxic pharmaceutical compatible acid addition salt or in the free Base form transferred. 9. The method according to claim 8, characterized in that ■ equimolar amounts of the compounds of the formulas II and III are reacted with one another. 10. The method according to any one of claims 9 and 10, characterized in that R is (lower) alkyl, aryl, substituted aryl, aralkyl, -CH ₃ CN or -CH ₂ COOR ", where R" is hydrogen or (lower) Alkyl owns, stands. - 4 8098 5 0/6906 M / 19155. _λ 11. Process for the preparation of the compounds of general formula I according to any one of claims 1 to 7 or their non-toxic pharmaceutically acceptable
Acid addition salts, characterized in that a compound of the formula V: H -r CI CH ₃ (V) CH ₂ SCH ₂ CH ₂ NH ₂ with a compound of the general formula: S = C = NR ¹ wherein R has the meaning given in claim 1, and the resulting compound of the formula VI: CH ₂ SCH ₂ Ch ₂ NHCNHR ¹ reacts with methyl odide and cyanamide, whereby the compound of the general formula I is obtained in the basic form, and, if desired, the product in a manner known per se Way converted into an appropriate, non-toxic, pharmaceutically acceptable acid addition salt . 12. Process for the preparation of the compounds of the general - 5 809850/0906 M / 19135, r- NEN formula I according to one of claims 1 to 7 or their non-toxic, pharmaceutically acceptable acid addition salts, characterized »that a compound of the formula VII: (VII) wherein X is hydroxy or a conventional leaving group, or one of its acid addition salts with a Compound of the general formula VIIIs NCN
HSCh ₂ CH ₂ NHCNH-R ¹ (VIII) wherein R has the meanings given in claim 1, is reacted in an inert organic solvent and, if desired, the compound obtained of the general formula I in the basic form or its acid addition salt into a corresponding, non-toxic pharmaceutical acid addition salt or converted into the free base form. 13. The method according to claim 12, characterized in that X is for the following common exiting groups stands: fluorine, chlorine, bromine, iodine, -O, SR, where R is (lower) alkyl, -0, SR, where R is aryl or substituted aryl, O, SF, acetoxy and 2,4-dinitrophenoxy. 14. The method according to any one of claims 12 and 13 »thereby 809850/0906 Μ / 19135, characterized in that equimolar amounts of the compounds of formulas VII and VIII in the presence of a base. 15. Compounds of the general formula: NON HSCH ₂ CH ₂ NHCNh-R ¹ wherein R is a straight-chain or branched alkynyl group with 3 "to 9 carbon atoms, and their acid addition salts. 16. The acid addition salts of the compounds according to claim with hydrochloric acid, hydrobromic acid, sulfuric acid, Sulfamic acid »phosphoric acid, nitric acid, Maleic acid, fumaric acid, succinic acid, oxalic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Acetic acid, propionic acid, tartaric acid, citric acid or camphorsulphonic acid. 17. Compounds according to any one of claims 15 and 16, wherein R the formulas: CH ₃ -CHCSCR ⁴ , - (CH ₉ ) C ^ CR ⁴ or -CC = CR ⁴ ι * - η ι CH ₃ CH ₃ corresponds to, wherein R ^{4 is} H or CH, and η is an integer from 1 to 6 inclusive. 18. Compounds according to any one of claims 15 to 17, wherein R ^{1 is} - 7 809850/0906 M / 19135, h -CHC = CR ⁴ CH ₅ in which R is H or CH. 19. Compounds according to any one of claims 15 to 17 »wherein S ¹ for in which R ^{4 has} the meanings H or CH. 20. Compounds according to claim 19 »wherein η is 1 or 2 stands. 21. Compounds according to any one of claims 15 to 17 »wherein R ^{1 is} CH ₅ -C-CSCR ⁴ CH ₅ in which ΈΓ has the meanings H or CH. 22. Pharmaceutical agent for inhibiting gastric acid secretion, containing a compound according to any one of claims 1 to 7 together with a suitable carrier or diluents. 23. Composition according to claim 22 for oral administration. 24. Composition according to claim 22 for parenteral administration. _ 8 - 809850 / Θ906