CY1229A - Guanidine derivatives - Google Patents

Description

PATENT SPECIFICATION ("> 1 598 628

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Application No. 23611/78 (22) Filed 26 May 1978 Convention Application No. 803009 Filed 3 June 1977

Convention Application No. 826796 Filed 22 Aug. 1977 Convention Application No. 848959 Filed 7 Nov. 1977 in United States of America (US)

Complete Specification published 23 Sept. 1981 INT CL3 C07D 233/64 A61K 31/415 Index at acceptance C2C 1410 202 215 246 247 250 252 25Y 30Y 320 326 373 37Y 703 747 758 802 80Y AA RH

(54) GUANIDINE DERIVATIVES

(71) We, BRISTOL-MYERS COMPANY, a Corporation organised and existing under the laws of the State of Delaware, United States of America, of 345 Park Avenue, State of New York, 10022, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:—

The present invention relates to certain N - cyano - N' - {2 - [(4 - methyl -5 - imidazolyl)methylthio]ethyl} - N" - alkynylguanidines which are H2 receptor blocking agents, which inhibit gastric acid secretion and which are useful in the treatment of ulcers.

The clinical objective in treatment of peptic ulcer disease is to decrease gastric acid secretion, based on the principle "no acid, no ulcer". Traditional peptic ulcer disease therapy involves control of diet and the use of antacids and anticholinergics.

There is evidence indicating that histamine may be the final common pathway for stimulation of gastric secretion. This effect of histamine is mediated via H2 receptors and is not inhibited by the classical antihistamines, which are H, receptor blockers. A number of specific H2 receptor blocking agents (H2 receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as secretion by other known gastric acid stimulants, and are useful in the treatment of peptic ulcers.

Accordingly, the present invention provides histamine H? receptor antagonists which are effective inhibitors of gastric secretion in animals, including man, which are useful in the treatment of peptic ulcer disease, and which have the formula

NCN

ch2sch2ch2n»

Unh-r1

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, and non-toxic pharmaceutically acceptable acid addition salts thereof.

A preferred embodiment of the invention is a compound of the formula ncn

II A

ch2sch2ch2nhcnh-chc=cr-

ch3

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BNSDOCID: <GB 1598628A_I_>

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wherein R4 is hydrogen or methyl, or a non-toxic pharmaceuticaily acceptable acid addition salt thereof.

Another preferred embodiment of the invention is a compound of the formula ch,

k

ncn II

h ck-sch_ch-nhcnh—(ch,) c.cr i /. 2. 2. n wherein R4 is hydrogen or methyl and n is an integer of from I to 6, inclusive, or a nontoxic pharmaceuticaily acceptable acid addition salt thereof. Preferably n is 1 or 2 in these compounds.

Another preferred embodiment of the invention is a compound of the formula

\ fiCN T3

h ch2sch2ce2nhcnk—c-c=cr4

^CK3

10 wherein R4 is hydrogen or methyl, or a nontoxic pharmaceuticaily acceptable acid 10

addition salt thereof.

A more preferred embodiment of the invention is N - cyano - N' - (2 - [(4 -methyl -5 - imidazolyl)methylthio] ethyl} -N" -(2 -butyn - 1 - yl)guanidine or a nontoxic pharmaceuticaily acceptable acid addition salt thereof.

15 Another more preferred embodiment of the invention is N - cyano -N' -{2 - 15

[(4 - methyl -5 - imidazolyl)methylthio]ethyl| -N" -(3 - butyn -1 - yl)guanidine or a nontoxic pharmaceuticaily acceptable salt thereof.

Another more preferred embodiment of the invention is N - cyano -N' - {2 -[(4 - methyl - 5 - imidazolyl)methylthio]ethyl] - N" - (4 - pentyn - 1 -20 yl)guanidine or a nontoxic pharmaceuticaily acceptable acid addition salt thereof. 20

Another more preferred embodiment of the invention is N - cyano - N' -12 -[(4 - methyl -5 - imidazolyl)methylthio] ethyl 1 -N" -(2 - methyl -3 - butyn - 2 -yl)guanidine or a nontoxic pharmaceuticaily acceptable acid addition salt thereof.

Another more preferred embodiment of the invention is N - cyano -N' -{2 -25 [(4 -methyl -5 - imidazolyl)methylthio]ethyl} -N" -(3 -butyn -2 -yl)guanidine 25 or a nontoxic pharmaceutially acceptable acid addition salt thereof.

The most preferred embodiment of the invention is N - cyano - N' - [2 - [(4 -methyl - 5 - imidazolyl)methylthio]ethyl} - N" - propargyl - guanidine or a nontoxic pharmaceuticaily acceptable acid addition salt thereof. 30 The present invention also provides for the preparation of a compound of the 30

formula ncn

CH2SCH2CH2NHi

Unh-r1 '

wherein R' is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, or a non-toxic pharmaceuticaily acceptable acid addition 35 salt thereof characterized by reacting a compound of the formula 35

II

ch2sch2ch2nhr5

BNSDOCID: <GB 1598628A_U

3

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3

10

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

RSNHR1 III

wherein R1 is as defined above and one of R5 and R6 is H and the other is the group

NCN

II

—C—SR

where —SR is a leaving group, and, if desired, converting the resulting compound of formula I in basic form or an acid addition salt thereof to the corresponding nontoxic pharmaceuticaily acceptable acid addition salt or free base form.

The reaction is conducted in a non-reactive solvent at a temperature above ambient temperature. In a preferred embodiment equimolar quantities of the compounds of formulae II and III are used.

This process is illustrated by the reaction schemes I and II below for a preferred compound of the invention.

Scheme I

10

N

Sr h

NCN

ch2sch2ch2nh!!- sr

+ h2nce2c=ch

-4/

ncn ch2sch2cb2nh<

&

hch2c=ch

The reaction is conducted in a non-reactive solvent at a temperature above 15 room temperature. As will be appreciated by those skilled in the art, R may be any substituent such that —SR will be a leaving group. Thus, R may be (lower)alkyl, aryl, substituted aryl (e.g. p - nitrophenyl), aralkyl, —CH2CN, —CH2COOH, or —CH,COOR', where R' is a C,_g alkyl group. The N - cyano - N' - {2 - [(4 -methyl - 5 - imidazolyl)methy!thio]ethyl| - S - R - isothiourea starting materials 20 may be prepared by the procedures described in Belgian Patent 804,144. The alkynylamine starting materials are either commercially available or may be prepared by methods described in Bull. Soc. Chim. Fr., 490 (1958), Bull. Soc. Chim. Fr., 592 (1967) and Annales de Chimie (Paris), J, 656 (1958).

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Scheme II

\

CH,

ncn ck2sch2ch2nh2 + rs-[!nhch2c=ch h ch2sch2ch2nhcnhch2c-ch

The reaction is conducted in a non-reactive solvent at a temperature above room temperature. The substituent R may be as indicated in Scheme I, above. The 2 - [(4 - methyl - 5 - imidazolyl)methylthio]ethylamine starting material may be 5 prepared as described in U.S. Patent 3,950,353. The disubstituted 5

cyanodithioiminocarbonate which is used as a starting material for the preparation of the N - cyano - N' - propargyl - S - R - isothiourea (see step a of Example 2) may itself be prepared by procedures described in J. Org. Chem., 32, 1566 (1967).

Our co-pending patent application No. 27637/79, (Serial No. 1598629) 10 describes and claims compounds of the formula 10

NCN

II

R2S—CNH—R1

wherein R' is as above defined and R2 is C,_9 alkyl, aryl, substituted aryl, aralkyl,

—CH2CN, —CH2COOH or —CH2COOR1

wherein R1 is C,_9 lower alkyl.

15 It has additionally been discovered that in the preparation of N - cyano -N' - 15

(2 - [(4 - methyl - 5 - imidazolyl)methylthio]ethyl) - N" - propargylguanidine via Reaction Scheme I, selected reaction conditions thereof give greatly improved yields of product as well as a product containing less impurities. The latter condition has the added advantage of permitting the initial ("crude") product to be 20 isolated as a crystalline solid which may be more highly purified by simple 20 recrystallization, and avoids the chromatographic purification of the initial crude product which we previously considered desirable when using other reaction conditions.

The selected reaction conditions referred to above consist of using methanol 25 as solvent, utilizing a more concentrated solution in the reaction (approximately 1 25 gram of the substituted isothiourea per 5 ml of methanol), the use of a nitrogen sweep of the reaction apparatus during the reaction, and the utilization of freshly distilled propargylamine in the reaction.

Experiments have shown that the use of a nitrogen sweep during the reaction 30 avoids the formation of small amounts of two as yet unidentified by-products which 30 are formed in the absence of a nitrogen sweep. These by-products, when present,

resisted removal by column chromatography and recrystallization. It is believed that the nitrogen sweep prevents the formation of these by-products by removing the methyl mercaptan gas as quickly as it is formed.

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5

The present invention also provides the process for production of a compound having the structure wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 5 carbon atoms, inclusive or a non-toxic pharmaceuticaily acceptable acid addition 5

salt thereof which comprises reacting a compound of the formula

H CE2SCH2CH2NH2 with a compound of the formula

S=C=NR1

10 wherein R1 is as defined above, to produce the compound 10

•Of . -

H "l

" CH2SH2CH2NHCNHRj-

which is then reacted with methyl iodide and cynamide to produce compound I in basic form and, if desired, converting the product to the corresponding nontoxic pharmaceuticaily acceptable acid addition salt.

15 This process is illustrated by the following reaction scheme III for a preferred 15

compound of the invention.

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Scheme III

h ch2sch2ch2nh2 + s=c=nch2c=ch

K Nnck

„ ch_sch0cr0nhcnhch0=ch « £ I Z 4

CH-

V

1) H /CH3I

2) h2ncn

I I

ncn ch0sch0ch_nhCnhch_c=ch n 2 2 2 I

The invention further provides a process for the preparation of a compound of the formula ch,

ncn i

CH2SCH CI^NHUNH-R1

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, or a non-toxic pharmaceuticaily acceptable acid addition salt thereof characterized by reacting a compound of the formula ck0

U

VII

CH2X

or an acid addition salt thereof in which X is hydroxy or a leaving group with a 10 compound of the formula

NCN

10

HSCH,CH2NHCNH—R1

VIII

BNSDOCID: <GB 1598628A_L>

,598,628

wherein R1 is as defined above and, if desired, converting the resulting compound of formula I in basic form or an acid addition salt thereof to the corresponding nontoxic pharmaceuticaily acceptable acid addition salt or free base form.

The reaction is conducted in an inert organic solvent.

5 In a preferred embodiment equimolar quantities of the compounds of 5

formulae VII and VIII are used and the reaction is carried out in the presence of a base.

Suitable leaving groups "X" for use in this reaction are well-known to those skilled in the art. They include, for example, fluoro, chloro, bromo, iodo, —O3SR1 •0 wherein R2 is (lower)alkyl [e.g. methanesulfonyloxy], —03SR3 wherein R3 is aryl or 10 substituted aryl [e.g. benzenesulfonyloxy, p - bromobenzenesulfonyloxy or p -toluenesulfonyloxy], —0,SF, acetoxy and 2,4 - dinitrophenoxy. For convenience and economy we normally prefer to utilize compound VIl in which X is chtoro.

In the process of this invention, the compound of Formula VII preferably is 15 utilized in the form of an acid addition salt. Compound VII is relatively unstable in 15 its free base form and therefore is preferably prepared and stored as an acid addition salt. Although the free base of the compound of Formula VII may be regenerated prior to the reaction, no advantage is obtained by so doing. It will be appreciated by those skilled in the art that any inorganic acid or organic acid may 20 be utilized to form the acid addition salt of compound VII, e.g. hydrochloric, 20 sulfamic, sulfuric, oxalic, benzoic, succinic, acetic, nitric or citric acid. For convenience and economy we normally prefer to utilize compound VII in the form of its hydrochloride.

The reaction of compounds VII and VIII to produce compound I may be 25 conducted in any inert organic solvent such as an alkanol, acetonitrile, 25 dimethylformamide, dimethylsulfoxide or acetone. We prefer to conduct the reaction in an alkanol such as ethanol or 2-propanol.

The reaction temperature is not critical; the reaction may be conducted at temperatures of from about 0° to about 200°. At low temperatures the reaction is 30 slow, while high temperatures normally lead to less pure products due to 30 decomposition and the formation of side-products. We normally prefer to conduct the reaction at room temperature.

The reaction of compounds VII and VIII to produce compound I is preferably conducted in the presence of a base, which facilitates the reaction by acting as an 35 acid acceptor. Suitable bases for use in this reaction include both inorganic and 35 organic bases such as NaOH, KOH, LiOH, triethylamine, dimethylaniline and sodium ethoxide.

This process is illustrated by the reaction scheme IV illustrated below for a preferred compound of the invention.

Scheme IV

40

ch,

ch2oh/h

NCN

HSCH2CH2NHCNHCH2CsCH

40

NCN

ch2sch2ch2nh{^nhc2c=ch

BNSDOCID: <GB •

1598628A L>

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The intermediates of the formula

NCN

II

HSCH2CH2NHCNH—R1 VIII

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, processes for their preparation and acid addition salts thereof, which are useful in the preparation of histamine H2 receptor antagonists of Formula I, are described and claimed in our co-pending patent application No. 18923/80, (Serial No. 1598630).

The dimethyl cyanodithioiminocarbonate which is used as a starting material for the preparation of the N - cyano - N' - alkynyl - S - methylisothioureas may itself be prepared by procedures described in J. Org. Chem., 32, 1566 (1967). The alkynylamine starting materials are either commercially available or may be prepared by methods described in Bull. Soc. Chim. Fr., 490 (1958); Bull Soc. Chim. Fr., 592 (1967) and Annales de Chimie (Paris), J, 656 (1958).

When reacting cysteamine hydrochloride with an N - cyano - N' - alkynyl -S - methylisothiourea to produce an N - cyano - N' - alkynyl - N" - (2 -mercaptoethyl)guanidine of Formula VIII, it was found desirable to conduct the reaction in the presence of a small amount of hydroquinone and to bubble nitrogen through the reaction mixture (see, for example, step B of Example 14. These reaction conditions were found to produce compounds of Formula VIII in higher yield and of higher purity. The nitrogen sweep is believed to remove the methyl mercaptan produced in the reaction and thereby avoid secondary reactions arising from the addition of methyl mercaptan to the carbon-carbon triple bond. It is believed that the hydroquinone prevents the formation of free radicals and secondary reactions arising from their presence.

As used herein, the term non-toxic pharmaceuticaily acceptable acid addition salt means the mono- or di-salt of a compound of this invention with a nontoxic pharmaceuticaily acceptable organic or inorganic acid. Such acids are well known and include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maliec, fumaric succinic, oxalic, benzoic, methanesulfonic, 1,2-ethanedisulfonic, benzenesulfonic, acetic, propionic, tartaric, citric and d-camphorsulfonic acids. The salts are made by methods known in the art.

As used herein the term "(lower) alkyl" is intended to mean straight or branched alkyl groups containing from 1 to 6 carbon atoms.

For therapeutic use, the pharmacologically active compounds of this invention will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in the basic form or in the form of a nontoxic pharmaceuticaily acceptable acid addition salt, in association with a pharmaceuticaily acceptable carrier or diluent.

The pharmaceutical compositions may be adminstered orally, parenterally or by rectal suppository. A wide variety of pharmaceutical forms may be employed. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injection, or an aqueous or nonaqueous liquid suspension. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation.

Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg. to about 250 mg., and most preferably from about 100 mg. to about 200 mg. The active ingredient will preferably be administered in equal doses from two to four times a day. The daily dosage regimen will preferably be from 250 mg. to about 1000 mg., and most preferably from about 500 mg. to about 750 mg.

Histamine H2-receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and man, Brimblecombe et al, J. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the histamine H2-receptor antagonist cimetidine has shown it to be an effective therapeutic agent in the treatment of peptic ulcer disease, Gray et al., Lancet, / (8001), 4 (1977). The compound prepared in Examples 1 and 2 below (hereinafter referred to as BL-5641) has been compared with cimetidine in various tests and has been shown to be more potent than cimetidine both as a histamine H2-receptor antagonist in isolated guinea pig atria and as an inhibitor or gastric secretion in rats and dogs. Furthermore, the gastric secretion studies in dogs indicate that BL-5641 has a longer duration of activity than cimetidine at equal doses.

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Histamine H2-Receptor Antagonism-isolated Guinea Pig Atria Assay

Histamine produces concentration-related increases in the contractile rate of isolated, spontaneously beating guinea pig right atria. Black et al., Nature, 236, 385

(1972), described the receptors involved in this effect of histamine as histamine H2-5 receptors when they reported the properties of burimamide, a competitive antagonist of these receptors. Subsequent investigations by Hughes and Coret, Proc. Soc. Exp. Biol. Med., 148, 127 (1975) and Verma and McNeill, J. Pharmacol. Exp. Ther., 200, 352 (1977) support the conclusion of Black and coworkers that the positive chronotropic effect of histamine in isolated guinea pig right atria is 10 mediated via histamine H2-receptors. Black et al., Agents and Actions, 3, 133

(1973) and Brimblecombe et al., Fed. Proc., 35, 1931 (1976) have utilized isolated guinea pig right atria as a means for comparing the activities of histamine H2-receptor antagonists. The present comparative studies were carried out using a modification of the procedure reported by Reinhardt et al., Agents and Actions, 4,

15 217 (1974).

Male Hartley strain guinea pigs (350—450 gm.) were sacrificed by a blow on the head. The heart was excised and placed in a Petri dish of oxygenated (95% 02, 5% C02) modified Krebs solution (g./liter: NaCI 6.6, KC10.35, MgSO„ • 7HzO 0.295, KH2P04 0.162, CaCl2 0.238, NaHC03 2.1 and dextrose 2.09). The spontaneously 20 beating right atrium was dissected free from other tissues and a silk thread attached to each end. The atrium was suspended in a 20 ml. muscle chamber containing oxygenated modified Krebs solution maintained at 32° C. Atrial contractions were recorded isometrically by means of a Grass FT 0.03 force displacement transducer and recordings of contractile force and rate were made with a Beckman RP 25 Dynograph.

A resting tension of 1 g. was applied to the atrium and it was allowed to equilibrate for 1 hour. At the end of the equilibration period a submaximal concentration of histamine dihydrochloride (3x 10~8M) was added to the bath and washed out to prime the tissue. Histamine was then added to the bath in a 30 cumulative fashion using 1/2 log 10 intervals to give final molar bath concentrations of lxlO-7 to 3xl0~5. The histamine-induced increase in a trial rate was allowed to plateau before the next successive concentration was added. The maximal response invariably occurred at the 3xlU"aM concentration. The histamine was washed out several times and the atrium allowed to return to control rate. The test compound 35 (1 x 10"5M) was then added and after a 30 minute incubation the histamine concentration-response was repeated, adding higher concentrations as needed.

The histamine ED50 values (concentration of histamine which increased contractile rate 50% of maximum) and 95% confidence limits before and after the test compound administration were obtained by regression analysis as described by 40 Finney, Probit Analysis, 3rd ed., Cambridge (1971). Concentration-response curve displacement factors were calculated as follows:

ED50 Histamine+Compound

Displacement Factor=

ED50 Histamine Alone

The factor obtained for BL-5641 was then expressed as a ratio of the factor obtained for cimetidine.

BL-5641 Displacement Factor—1

45 Activity Ratio=— —

Cimetidine Displacement Factor—1

The results obtained from these studies are summarized in Table 1. Cimetidine and BL-5641 displaced the histamine concentration-response curve to the right by a factor of 6.6 and 32.7, respectively. Based on the concentration-response curve displacement factors, BL-5641 was about 5.7 times more active than cimetidine as a 50 histamine H2-receptor antagonist in isolated guinea pig right atria.

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TABLE 1

Relative Activity of Cimetidine and BL-5641 in Isolated Guinea Pig Right Atria

Compound

N

Concentration

Histamine ED50 With 95% Confidence Limits (/zg/ml.)

Concentration-Response Curve Displacement Factor

Activity Ratio

Histamine Control

Cimetidine

3 3

lxlO~5M

0.21 (0.18—0.25)

1.39 (1.08—1.85)

6.6

1.0

Histamine Control

BL-5641

2 2

Ix 10~5M

0.38 (0.27—0.53)

12.44 (7.81—20.28)

32.7

5.7

N=number of experiments.

Determination of Gastric Antisecretory Activity in the Two Hour Pylorus Ligated (Shay) Rat The pyloric ligation procedure in the rat was designed by Shay et al.. Gastroenterology, 5, 53 (1945) for the study of perforating gastric ulcers; however, 20 as the method become known, it was also employed as a means of studying rat 20

gastric secretion, Shay et al., Gastroenterology, 26, 906 (1954), Brodie, D. A., Am.

J. Dig. Dis., 11, 231 (1966). A modification of this procedure is presently used to evaluate compounds for gastric antisecretory activity.

Male Long Evans rats, 280—300 gm., are used. The animals are placed in 25 individual cages and fasted for 24 hours with free access to water. Under ether 25

anesthesia, the stomach is reached through a midline incision, and a cotton-thread ligature is placed around the pylorus, After wound closure, ether administration is stopped and BL-5641, cimetidine or vehicle is adminstered intraperitoneally in a volume of 1 mg./kg. BL-5641 and cimetidine are solubilized with one equivalent of 30 HC1 and brought to the desired volume with water. The animals are returned to 30

their cages from which the water bottles have been removed and two hours later are sacrificed with ether. The stomach is removed and the two hour gastric collection is drained into a graduated test tube for volume determination.

Titratable acidity is measured by titrating a one ml. sample to pH 7.0 with 0.02N 35 NaOH, using an Autoburet and an electrometric pH meter (Radiometer). 35

Titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in milliequivalents per liter. The percent inhibition of acid output is calculated as follows

Acid Output-Control—Acid Output-Drug

% Inhibition Acid Output= xlOO

Acid Output-Control

40 The results obtained with BL-5641 and cimetidine are presented in Table 2. 40

These results indicate that, in the two hour pylorus ligated rat preparation, BL-5641 is at least as potent as cimetidine with respect to the inhibition of gastric acid output.

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TABLE 2

Effect of BL-5641 and Cimetidine on Gastric Acid Output in the Two Hour Pylorus Ligated Rat

Compound

Dose (ip)a ^Mole/kg. mg./kg.

% Inhibition of Acid Output

ED50 ,uMole/kg.

BL-5641

40

11.1

80

20

5.53

61

~11

10

2.76

37

Cimetidine

40

10

66

20

5

60

-14

10

2.5

40

5

1.25

34

10

"At least 5 animals were employed at each dose.

Determination of Gastric Antisecretory Activity in the 15 Gastric Fistula Dog 15

Thomas type [Thomas, J. E., Proc. Soc. exp. Biol. Med., 46, 260 (1941)]

stainless steel cannulae are inserted into the stomachs of beagle dogs (10—12 kg.)

just orad to the pyloric gland area near the greater curvature to provide a chronic gastric fistula. Animals are allowed to recover for at least two months before any 20 testing is done. Dogs are fasted overnight (~18 hours) with water ad lib prior to 20

each experiment. The dogs are placed in a sling and an eight inch inside needle catheter (C. R. Baird, Inc.) with a two inch 17 gauge needle is inserted into a leg vein for purposes of drug administration. Gastric secretions are collected every 15 minutes by gravity drainage from the opened cannula. Basal secretions are 25 collected for two consecutive 15 minute periods and if these prove to be excessive 25

(>4 mi/15 min.; pH <5.0) the animal is not used. A modification of the procedure described by Grossman and Konturek, Gastroenterology, 66, 517 (1974) was followed. Immediately after the second basal collection, histamine (100 ^ig./kg./hr.) is infused for 90 minutes with a Harvard Infusion Pump in a volume of 6 ml./hr. At this time 30 BL-5641, cimetidine (solubilized with one equivalent of HC1 and brought a proper 30 volume with normal saline) or normal saline is injected rapidly (within 30 seconds) in a volume of 0.1 ml/kg. and then infusion of histamine continues for an additional 150 minutes (total time of infusion is 4 hours). Each 15 minute sample of gastric juice is measured to the nearest 0.5 ml. and titratable acidity against 0.02N NaOH 35 (endpoint pH 7.0) is measured with an Autoburet and pH meter (radiometer). The 35

percent inhibition of acid output is calculated as described in the pylorus ligated rat procedure.

Equimolar doses of BL-5641 and cimetidine were administered to five different dogs and the results obtained are presented in Table 3.

40 Both BL-5641 and cimetidine produced an immediate inhibitory effect on 40

gastric acid output. However, the degree of inhibition at equimolar doses was consistently greater and of longer duration with BL-5641 than with cimetidine.

These results indicate that as an inhibitor of histamine-induced gastric acid output in the dog, BL-5641 is more potent and/or longer acting than cimetidine. 45 The invention is illustrated but in no way limited by the following Examples. 45

The temperatures given therein are in degrees Centrigrade.

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TABLE 3

Effect of BL-5641 and Cimetidine on Gastric Acid Output in Conscious Gastric Fistula Dogs

Drug & Dose

% Inhibition Acid Output (N=l)

(juM/kg. iv)

Dog No.

15

30

45

60

75

90

105

120 min.

BL-5641 (12)

24136

66

99

99

99

99

93

91

73

Cimetidine (12)

24136

63

99

89

76

54

48

41

14

BL 5641 (6)

22619

82

99

99

95

78

76

52

53

Cimetidine (6)

22619

84

96

73

67

65

54

40

32

BL-5641 (3)

23606

60

59

36

34

32

42

24

0

Cimetidine (3)

23606

43

27

15

0

17

38

8

0

BL-5641 (1.5)

24895

82

72

53

49

33

7

0

0

Cimetidine (1.5)

24895

73

57

60

29

0

18

0

0

BL-5641 (0.75)

23553

51

38

28

28

31

43

42

46

Cimetidine (0.75)

23553

50

10

24

17

35

21

25

19

10

15

Example 1

N-Cyano-N'-{2-[(4-methyl-5-imidazolyI)methylthio]ethyl}-N"-propargylguanidine

.ch,

i! il k hcn

1!

ch2schck2k:-*c-sch3

jlTCHgC i=c:-

20

V

20

ncjj

I!

CH2SCK2CH2NHCMHCH,C=;CH

25

30

A mixture of N - cyano - N' - (2 - [(4 - methyl - 5 -imidazolyl)methylthio]ethyl] - S - methyl - isothiourea (3.00 g, 0.0111 mole) and propargylamine (2.50 g, 0.045 mole) in acetonitrile (60 ml) was stirred at reflux for 65 hours, and then was heated in a stainless steel pressure vessel at 120—130° for 38 hours. The reaction mixture was cooled, decanted from a tar, and then evaporated to leave a gum (3.57 g). This material was placed on silica gel (100—200 mesh) and eluted with a mixture of methylene chloride (97 parts) and methanol (3 parts). The product obtained from a middle fraction was crystallized by trituration under acetonitrile, and then was recrystallized from acetonitrile to yield the title compound (0.236 g; 7.7%) mp 146—149.5°.

25

30

Anal. Calc'd for C12HiaN6S: Found:

C, 52.15; C, 51.86;

H, 5.83; N, 30.41. H, 5.81; N, 30.70.

BNSDOCID: <GB 1598628A_L>

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Example 2

N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine

(CH3S)2C=NCN + HjNHCjCsCH

I

NCN

II

CH3SCNHCH2CsCE

A

5 a. N-Cyano-N'-propargyl-S-methyl-isothiourea (A). 3

A solution of dimethyl cyanodithioiminocarbonate (16.00 g, 0.109 mole) and propargylamine (6.03 g, 0.109 mole) in acetonitrile (320 ml) was stirred at reflux for 4 hours, and then at 25° for 12 hours. Workup gave the title compound A (13.58 g, 81%), mp 160—164°.

10 b. N-cyano-N'-(2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"- 10

propargylguanidine

A solution of A (11.71 g, 0.0765 mole) and 2-[(4-methyl-5-imidazolyl)methylthio]ethylamine (13.10 g, 0.0765 mole) in methanol (250 ml) was heated at reflux for 64 hours. The solvent was removed by evaporation, the residue 15 placed on silica gel (100—200 mesh) and chromatographed by gradient elution 15 using methylene chlorine/methanol; the latter fractions yielded 4.0 g of the title compound. Recrystallization from acetonitrile gave purified product mp 150— 152.5° identical (ir, nmr, tic) with the product prepared in Example 1.

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14 1,598,628

Example 3

N-Cyano-N,-{2-[(4-methyl-5-imidazolyl)methy!th iol ethyl 1-N"-(2-butyn-I-yl)guanidine

(ch3s)2c=ncn + k2nch2c=cch3

p ch3scnhch2c=cch3

B

20

ncn ch2 schjch 2nhh;nhch 2cscch 2

5 a. N-(2-Butyn-l-yl)-N'-cyano-S-methylisothiourea (B) 5

A solution of dimethyl cyanodithioiminocarbonate (10.00 g, 0.0684 mole) and 2-butyn-l-ylamine (4.73 g, 0.0684 mole) in acetonitrile (200 ml) was stirred at 25° for 0.5 hour, and then at reflux for 2.5 hours. The mixture was cooled, then filtered to yield the title compound B, mp 180—183°.

10 b. N-Cyano-N'-|2-[(4-methyl-5-imidazolyl)methylthio]ethyll-N"- io

(2-butyn-1 -yl)guanidine A solution of B (6.82 g, 0.0407 mole) and 2 - [(4 - methyl - 5 -imidazo!yl)methylthio]ethylamine (6.98 g, 0.0407 mole) in methanol (140 ml) was heated at reflux for 40 hours. Workup and chromatography as described above for

15 Example 2 yielded the title compound. When the title compound was prepared 15 according to the general procedure of Example 1, it melted at 128—130°.

Example 4

N-Cyano-N'-(2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(3-butyn-1 -yl)guanidine The general procedure of Example 1 is repeated except that the 20 propargylamine utilized therein is replaced by an equimolar amount of 3-butyn-l-ylamine, and the title product is thereby produced.

Example 5

N-Cyano-N'-[2-[(4-methyl-5-imidazolyl)methyithio]ethyl)-N"-25 (4-pentyn-l-yI)guanidine 25

The general procedure of Example 1 is repeated except that the propargylamine utilized therein is replaced by an equimolar amount of 4-pentyn-l-ylamine, and the title product is thereby produced; m.p. 99—103°.

BNSDOCID: <GB 1598628A_L>

15 1,598,628 ; 15

Example 6

N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-methyl-3-butyn-2-yI)guanidine The general procedure of Example 3 is repeated except that the 2-butyn-l-5 ylamine utilized therein is replaced by an equimolar amount of 1,1- 5

dimethylpropargylamine, and the title product is thereby produced.

Example 7

N-Cyano-N'-{2-[(4-methyl-5-imidazoly[)methylthio] sthyl)-N"-.« (3-butyn-2-yl)guanidine

The general procedure of Example 3 is repeated except that the 2-butyn-l- 10

ylamine utilized therein is replaced by an equimolar amount of 1-methylpropargylamine, and the title product is thereby produced.

Example 8

N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-15 (2-butyn-l-yl)guanidine 15

A mixture of N - cyano - N' - (2 - [(4 - methyl - 5 -imidazolyl)methylthio]ethyl| - S - methylisothiourea (3.00 g. 0.0111 mole) and 2-butyn-1-ylamine (3.07 g., 0.0445 mole) in 60 ml. of propionitrile was stirred at reflux for 40 hours. TLC assay of an aliquot of the reaction mixture showed a trace of the 20 isothiourea starting material, so the mixture was refluxed for an additional 6 hours 20

and then stirred at room temperature for 64 hours. The solvent (along with excess amine) was removed at reduced pressure and the residual gum was placed on silica gel (100—200 mesh) and eluted with a mixture of methylene chloride (97 parts) and methanol (3 parts). The middle fractions were combined and evaporated to give 25 1.81 g. of yellow gum. The gum was dissolved in 20 ml. of ethyl acetate and 25

crystallized at —15°C. The resulting pale yellow solid (1.2 g.) was dissolved in 11 ml. of hot acetonitrile and recrystallized at —15°C; yield 1.072 g., m.p. 128—

130°C.

Anal. Calc'd for C13H18N6S:

30 C, 53.77; H, 6.25; N, 28.94; S, 11.08 30

Found: C, 53.72; H, 6.29; N, 29.62; S, 11.34

Example 9

N-Cy ano-N'-l 2-l(4-methyl-5-imidazolyl)methylthio] ethyl} -N"-(3-butyn-1 -yl)guanidine

35 A mixture of N - cyano - N' - (2 - [(4 - methyl - 5 - 35

imidazolyl)methylthio]ethyl}-S - methylisothiourea (3.00 g., 0.0111 mole) and 3-butyn - 1 - ylamine (3.13 g., 0.0453 mole) in 60 ml. of propionitrile was stirred at reflux for 40 hours. The solvent was evaporated to give 5.40 g. of a syrup which was placed on 70 g. of 100—200 mesh silica gel and chromatographed by gradient 40 elution using methylene chloride/methanol. 40

Fraction Eluant Volume Weight

1 99 CHjCI/1 MeOH 100 ml. —

2 „ 70 ml. —

3 „ 50 ml. 0.117 g.

45 4 „ 30 ml. — 45

5 „ 75 ml. 0.067 g.

6 „ 150 ml. 0.080 g.

7 „ 325 ml. 0.168 g.

8 98 CH2C1j/2 MeOH 50 ml. —

50 9 „ 150 ml. 0.125 g. 50

10 „ 250 ml. 0.811 g.

11 „ 250 ml. 0.72 g.

12 97 CHjCl/3 MeOH 175 ml. 0.125 g.

13 „ 225 ml. 0.133 g.

55 14 „ — 0.027 g. 55

!« jooiSi:) 0002

17 95 CH2Cl2/5 MeOH 250 ml. 0.035 g.

18 „ 250 ml. 0.236 g.

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TLC (silica gel, 90 CH2C12/10 MeOH) indicated fractions 9—12 were pure and should be combined. Fractions 1—8 showed fast moving impurities. Fractions 13 and 14 showed some trailing impurities. Fractions 9—12 were combined and evaporated to 1.72 g. of a yellow gum. The gum was dissolved in 1! ml. of 5 nitromethane, crystallized at — 15°C (pale yellow solid, 1.18 g.), and recrystallized from 9 ml. of nitromethane to give 0.987 gm.; m.p. 86—89°C (softens at 85°C). Infrared and NMR (100 MHZ) were clean ana consistent with the desired structure. NMR showed that the product was solvated with approximately 0.08 mole of nitromethane.

10 Anal. Calc'd for C,3H18NBS • 0.08 (CH3NOz):

C, 53.21; H, 6.22; N, 28.84; S, 10.86 Found: C 52.68, 52.87; H, 6.28, 6.02, N, 29.39, 29.50; S, 11.22

Example 10

N-Cyano-Nf-{2-[(4-methyl-5-imidazolyl)methylthio]ethyll-15 N"-(4-pentyn-l-yl)guanidine

A mixture of N - cyano - N' - {2-[(4 - methyl - 5 -imidazolyl)methylthio]ethyl) -S - methylisothiourea (3.00 g., 0.0111 mole) and 4 -pentyn - 1 - ylamine (3.69 g„ 0.0445 mole) in 60 ml. of acetonitrile was stirred at reflux for 24 hours, and then allowed to stand at room temperature for 96 hours. 20 The solvent and excess amine were removed under reduced pressure and the residual yellow gum was purified by chromatography on 50 g. of 100—200 mesh silica gel, using gradient elution with methylene chloride/methanol (99:1—96:4). The middle fractions indicated by TLC to be pure were combined and evaporated to give 1.91 g. of yellow gum which was crystallized at — 15°C from 18 ml. of ethyl 25 acetate. The resulting white solid (1.25 g.) was recrystallized at —15°C from 10 ml. of acetonitrile to give 1.063 g. of product; m.p. 99—103°C.

Anal. Calc'd for C14H20N6S:

C, 55.24; H, 6.52, N, 27.61; S, 10.53 Found: C, 55.43; H, 6.58, N, 28.26; S, 10.97

30 Example 11

N-Cyano-N'-( 2-[(4-methyI-5-imidazoly l)methylthio] ethyl) -N"-propargylguanidine

The mixture of N - cyano - N' - {2 - [(4 - methyl - 5 -imidazolyl)methylthio]ethyl| - S - methylisothiourea (10.0 g; 0.0371 mole) and 35 distilled propargylamine (20 ml; 0.325 mole) in methanol (50 ml) was stirred at reflux, under a positive pressure nitrogen atomosphere (nitrogen sweep), for 20.5 hours. The solvent and excess amine were then removed by evaporation to leave a yellow-brown oil that readily crystallized. Trituration of the crude product under isopropanol (30 ml) gave the title compound as an off-white, friable solid (8.11 g, 40 79%); m.p. 146—148.5°.

Example 12

N-Cyano-N'-|2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine A mixture of N - cyano - N' - [2-[(4 - methyl - 5 -45 imidazolyl)methylthio]ethyl} - S - methylisothiourea (100 g; 0.371 mole) and distilled propargylamine (150 ml; 2.44 moles) in methanol (500 ml) was stirred at reflux under a positive pressure nitrogen atmosphere (nitrogen sweep) for 22 hours. The reaction mixture was cooled, and the solvent and excess amine were removed by evaporation to leave an amber oil that readily crystallized. The crude product 50 was triturated under isopropanol (250 ml), cooled at 0° for 2 hours and collected by filtration. The filter cake was washed with cold isopropanol and dried in vacuo over P205 for 16 hours. The dried title product was a near-white dense solid; yield 73.5 gm. (71.7%) m.p. 147—149°.

Example 13

55 Recrystallization of N-Cyano-N'-[2-[(4-methyi-5-imidazolyl)-

methylthio]ethyl]-N"-propargylguanidine The final products obtained in Examples 11 ana 12 were combined (total 81.3 g.), dissolved in hot isopropanol (1000 ml.), filtered through "Super-Cel" (Registered Trade Mark) and allowed to cool at room temperature for ca. 68 hours.

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1,598,628

The resulting crystalline product was recovered by filtration, washed with cold isopropanol, pulverized and dried in a heated desiccator under high vacuum for ca. 45 hours. Yield 72.4 g. (89% recovery); m.p. 149—151°. HPLC assay showed the purity to be ca. 99.5%. The NMR (100 MHz) spectrum was clean and consistent.

Anal. Calc'd for C12H16NeS: C, 52.15; H, 5.83; N, 30.41; S, 11.60 Found: C, 52.42; H, 5.94; N, 30.51; S, 11.35

Example 14

N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-propargylguanidine

A. N-Cyano-N'-propargyl-S-methylisothiourea

A solution of dimethyl cyanodithioiminocarbonate (16.00 g, 0.109 mole) and propargylamine (6.03 g, 0.109 mole) in acetonitrile (320 ml) was stirred at reflux for 4 hours, and then at 25° for 12 hours. The mixture was cooled and filtered to yield the title compound (13.58 g, 81%), m.p. 160—164°.

B. N-Cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine

A mixture of 1.136 g. (10 m moles) of cysteamine hydrochloride, 1.53 g. (10 m moles) of the product of step A, above, and 0.055 g. of hydroquinone in 10 ml. DMF was slightly warmed to dissolve the compounds. To this solution was added 10 ml. of IN aqueous sodium hydroxide and nitrogen was bubbled through the solution. After standing at room temperature for 17 hours, the reaction mixture was evaporated to dryness to give a mixture of the title product and sodium chloride. The title product was extracted from this mixture with 10 ml. of ethanol and the ethanolic solution was used in step C, below.

C. N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl)-

N"-propargylguanidine The ethanol solution of the product of step B, above, (about 10 m moles) was added to a solution of 0.46 g sodium (0.02 g-atoms) in 10 ml ethanol at 4°C under nitrogen. After 5 minutes, a solution of 1.67 g. (10 m moles) of 4-methyl-5-chloromethylimidazole • HC1 in 14 ml. ethanol was added and the mixture was stirred at room temperature under nitrogen for 70 minutes. The reaction mixture was filtered through a bed of Celite (Registered Trade Mark) filter aid to remove the inorganic salts and the Celite was washed with ethanol. The filtrate was evaporated to dryness and the product was purified by chromatography on a silica gel column (20 g silica, 3.2x4.5 cm bed) with ethanol-chloroform mixtures as the solvent. The ethanol content was gradually increased from 2 to 15%. The eluant was evaporated to dryness to give 1.906 g of crystalline product. Recrystallization from 2-propanol gave 1.49 g. (54%) of the title product, m.p. 144—145°C.

Example 15

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

A. N-Cyano-N'-(2-butyn-l-yl)-S-methylisothiourea

A solution of dimethyl cyanodithioiminocarbonate (10.00 g., 0.0684 mole) and 2-butyn-l-ylamine (4.73 g., 0.0684 mole) in acetonitrile (200 ml.) was stirred at 25° for 0.5 hour, and then at reflux for 2.5 hours. The mixture was cooled, then filtered to yield the title compound, m.p. 180—183°.

B. N-Cyano-N'-(2-butyn-1 -yl)-N"-(2-mercaptoethyI)guanidine

The general procedure of Example 14B is repeated except that the N -cyano - N' - propargyl - S - methylisothiourea utilized therein is replaced by an equimolar amount of N - cyano -N' -(2 - butyn -1 -yl) -S - methylisothiourea, and the title product is thereby produced.

C. N-Cyano-N'-{ 2- [(4-methyl-5-imidazolyl)methylthio] ethyl}-N"-

(2-buty n-1 -yl)guanidine The general procedure of Example 14C is repeated except that the N -cyano - N' - propargyl - N" - (2 - mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N - cyano - N' - (2 - butyn - 1 - yl) - N" -(2 - mercaptoethyl)guanidine, and the title product is thereby produced.

Claims (32)

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Example 16

N-Cyano-N'-|2-[(4-methyl-5-imidazolyl)methylthio]ethyl|-N"-(3-butyn-1 -yl)guanidi ne

A. N-Cyano-N'-(3-butyn-l-yl)-N''-(2-mercaptoethyl)guanidine

5 The general procedures of Example 14 steps A and B, are repeated except that the propargylamine utilized in step A thereof is replaced by an equimolar amount of 3 - butyn - 1 - ylamine, and the title product is thereby produced.

B. N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyI)-N"-

(3-butyn-1 -yl)guanidine 10 The general procedure of Example 14C is repeated except that the N -

cyano - N' - propargyl - N" - (2 - mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N - cyano - N' - (3 - butyn - 1 - yl) - N" -(2 - mercaptoethyl)guanidine, and the title product is thereby produced.

Example 17

15 N-Cyano-N'-|2-[(4-methyl-5-imidazolyl)methylthio]ethyI}-N"-

(4-pentyr-1 -yl)guanidine

A. N-Cyano-N'-(4-pentyn-l-yl)-N''-(2-mercaptoethyl)guanidine

The general procedures of Example 14, steps A and 8, are repeated except that the propargylamine utilized in step A thereof is replaced by an equimolar 20 amount of 4 - pentyn - 1 - ylamine, and the title product is thereby produced.

B. N-Cyano-N'-i2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-

(4-penty n-1 -y l)guanidine The general procedure of Example 14C is repeated except that the N -cyano - N' - propargyl - N" - (2 - mercaptoethyl)guandine utilized therein is 25 replaced by an equimolar amount of N - cyano - N' - (4 - pentyn - 1 - yl) - N" -(2 - mercaptoethyl)guanidine, and the title product is thereby produced.

Example 18

N-Cyano-N'-{2-[(4-methyl-5-imidazolyI)methylthio]ethyl|-N"-(2-methyl-3-butyn-2-yl)guanidine 30 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 except that the propargylamine utilized in step A thereof is replaced by an equimolar amount of 1,1-dimethylpropargylamine, and the title product is thereby produced.

B. N-Cyano-N'-(2-[(4-methyl-5-imidazolyl)methylthio]-ethyl }-35 N"-(2-methyl-3-butyn-2-yl)guanidine

The general procedure of Example 14C is repeated except that the N -cyano - N' - propargyl - N" - (2 - mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount ofN - cyano -N' -(2 -methyl -3 - butyn -2 -yl) - N* - (2 - mercaptoethyl)guanidine, and the title product is thereby produced.

40 Example 19

N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methyIthio]ethyl}-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 except 45 that the propargylamine utilized in step A thereof is replaced by an equimolar amount of 1-methyl-propargylamine, and the title product is thereby produced.

B. N-Cyano-N'-(2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-

N"-(3-butyn-2-yl)guanidine The general procedure of Example 14C is repeated except that the N -50 cyano - N' - propargyl - N" - (2 - mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N - cyano - N' - (3 - butyn - 2 - yl) - N" -(2 - mercaptoethyl)guanidine, and the title product is thereby produced.

WHAT WE CLAIM IS:—

1. A compound of the general formula:

5

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1,598,628

19

10

ncn unh-i

CH2sch2CH2N»

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive.

2. A compound as claimed in claim I wherein R1 is

—CHC=CR4

I

ch3

wherein R4 is H or CH3.

3. A compound as claimed in claim 1 wherein R1 is:

—(CH^C^CR"

wherein R4 is H or CH3 and n is an integer of from 1 to 6.

4. A compound as claimed in claim 1 wherein R1 is:

CH3

CH,

:=cr4

10

15

20

25

30

35

wherein R4 is H or CH3.

5. A compound as claimed in claim 3, wherein n is 1 or 2.

6. A compound as claimed in any one of claims 2 to 5 wherein R4 is H.

7. A compound as claimed in any one of claims 2 to 5 wherein R4 is —CH3. 15

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

9. N - Cyano -N' -{2 - [(4 - methyl -5 - imidazolyl)methylthio] ethyl} -N" -(3 - butyn - 1 - yl)guanidine.

10. N - Cyano - N' - (2 - [(4 - methyl - 5 - imidazolyl)methylthio] ethyl} - 20 N" - (4 - pentyn - 1 - yl)guanidine.

11. N - Cyano - N' - {2 - [(4 - methyl - 5 - imidazoiyl)methylthio]ethyl} -N" - (2 - methyl - 3 - butyn - 2 - yl)guanidine.

12. N - Cyano - N' - {2 - [(4 - methyl - 5 - imidazolyl)methylthio]ethyl} -

N" - (3 - butyn - 2 - yl)guanidine. 25

13. N - Cyano - N' - (2 - [(4 - methyl - 5 - imidazolyl)methylthio]ethyl} -N" - propargyl - guanidine.

14. A non-toxic pharmaceuticaily acceptable acid addition salt of a compound as claimed in any one of the preceding claims.

15. A non-toxic pharmaceuticaily acceptable acid addition salt as claimed in 30 claim 14 which is a salt with hydrochloric, hydrobomic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, 1,2-ethanedisulfonic, benzenesulfonic, acetic, propionic, tartaric, citric or d-camphorsulfonic acid.

16. A process for the preparation of a compound of the formula: 35

40

ncn ch2sch2ch2nhi

Unh-r1

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, or a non-toxic pharmaceuticaily acceptable acid addition salt thereof which process comprises reacting in a non-reactive solvent at a temperature above ambient temperature a compound of the formula

40

BNSDOCID: <GB 1S98628A_L>

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15

II

ch2sch2ch2nhr5

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

RaNHR1 III

wherein R1 is as defined above and one of R5 and R6 is H and the other is the group

NCN

il

—C—SR

where —SR is a leaving group, and, if desired, converting the resulting compound of formula I basic form or an acid addition salt thereof to the corresponding nontoxic pharmaceuticaily acceptable acid addition salt or free base form.

17. A process as claimed in claim 16 wherein equimolar quantities of the compounds of formulae II and III are used.

18. A process as claimed in claim 11 or claim 12 wherein R is a (lower)alkyl, aryl, substituted aryl, aralkyl, —CH2CN, or —CH2COOR" group wherein R" is hydrogen or a C,_a alkyl group.

19. A process for the preparation of a compound having the formula ncn

CH2SCH2CH2NHI

Unh-r1

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, or a non-toxic pharmaceuticaily acceptable acid addition salt thereof which comprises reacting a compound of the formula

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h

CH2sch2CH2NH2

with a compound of the formula

S=C=NR1

wherein R1 is as defined above, to produce the compound ch„

ir ch2sh2ch2nhcnhr

VI

which is then reacted with methyl iodide and cyanamide to produce compound I in basic form and, if desired, converting the product to the corresponding non-toxic pharmaceuticaily acceptable acid addition salt.

20. A process for the preparation of a compound of the formula

20

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BNSDOCID: cGB 1598628A„L>

21

1,598,628

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ncn

CI^SCI^CHjNHBNH-R1

wherein R1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, or a non-toxic pharmaceuticaily acceptable acid addition salt thereof which comprises reacting in an inert organic solvent a compound of the formula vii or an acid addition salt thereof in which X is hydroxy or a leaving group with a compound of the formula ncn li hsch2ch2nhcnh—r1 viii

10 wherein R1 is as defined above and, if desired, converting the resulting compound 10 of formula i in basic form or an acid addition salt thereof to the corresponding nontoxic pharmaceuticaily acceptable acid addition salt or free base form.

21. A process as claimed in claim 20 wherein X is fluoro, chloro, bromo, iodo,

—OgSR2 wherein R2 is (lower)alkyl, —03SR3 wherein R3 is aryl or substituted aryl,

15 —03sf, acetoxy or 2,4-dinitrophenoxy. 15

22. A process as claimed in claim 20 or claim 21 wherein equimolar quantities of the compounds of formulae vii and viii are reacted in the presence of a base.

23. A process as claimed in any one of claims 16 to 22 wherein R1 is:

—chcscr4

i ch3

20

20 wherein r4 is h or ch3.

24. A process as claimed in any one of claims 16 to 22 wherein r1 is

—(ch2)no=cr4

wherein r4 is h or ch3 and n is an integer of from 1 to 6.

25. A process as claimed in any one of claims 16 to 22 wherein r1 is ch3

I

25 —c—cscr4 25

I

ch3

wherein r4 is h or ch3.

26. A process as claimed in any one of claims 16 to 22 wherein r4 is h.

27. A process as claimed in any one of claims 16 to 22 wherein r4 is ch3.

28. A process as claimed in claim 16, claim 19 or claim 20 substantially as

30 hereinbefore described with reference to the Examples. 30

29. A compound as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 16 to 28.

30. A pharmaceutical composition for inhibiting gastric acid secretion comprising a compound as claimed in any one of claims 1 to 15, or claim 29

35 together with a pharmaceuticaily acceptable carrier or diluent. 35

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31. A composition as claimed in claim 30 which is adapted for oral administration.

32. A composition as claimed in claim 30 which is adapted for parental administration.

BOULT, WADE & TENNANT,

Chartered Patent Agents,

34 Cursitor Street,

London, EC4A 1PQ

Printed for Her Majesty's Stationery Office, by the Courier Press. LeamiriEton Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.

BNSDOCID: <GB 1598628A_L>