GB2149406A

GB2149406A - Substituted ethane diimidamides

Info

Publication number: GB2149406A
Application number: GB08432809A
Authority: GB
Inventors: Ronnie Ray Crenshaw; Aldo Antonio Algieri
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1982-03-29
Filing date: 1984-12-31
Publication date: 1985-06-12
Also published as: OA07356A; SU1419518A3; IL68259A0; DD219768A5; SE8704689L; DE3311281A1; GR78524B; PT76459B; FR2597867A1; MY8700942A; AT386599B; HU188742B; GB2117769A; HU196386B; YU74483A; ZW7683A1; NO163055B; AU1290783A; JPH0568472B2; YU44849B

Abstract

Substituted ethanediimidamides of the formula <IMAGE> wherein m is 0-2, n is 2-5, Z is O, S or methylene, R<1> is H or alkyl and A is exemplified as piperidino - or pyrrolidino - methylphenyl, dimethylaminomethyl-furyl or thienyl, or piperidinomethyl- thienyl or - pyridyl are used as intermediates to prepare histamine H2-receptor antagonists of the formula <IMAGE> as disclosed in parent specification No. 2117769.

Description

1 GB 2 149 406A 1

SPECIFICATION

Substituted diamino-thiadiazole intermediates The present Application has been divided out of our Application No. 83. 08518 (referred to below as our -primary- Application).

As disclosed in our primary Application, certain 3-(amino or substituted amino)-4-(substituted amino)- 1, 2,5-thiad iazoles having the formula 10 A-WH2)mZ(CH2),NH NHR1 N N \ S,-/ 15 wherein A, m, Z, n and RI are as defined below, and their nontoxic pharmaceutically acceptable salts, hydrates and solvates, are potent histamine 1-12-receptor antagonists which inhibit gastric acid secretion and are useful in the treatment of peptic ulcers and other pathological hypersecretory conditions. The compounds are prepared by ring closure of the correspondingly substituted ethanediimidamide of the formula A-W112)m Z (CH2)nNH-C - C-1,1HR1 HN N1i 11 Background and Prior Art Our published United Kingdom Patent Application No. 2,067,987 discloses 3,4-disubstituted1,2,5-thiadiazole 1 -oxides and 1,1 -dioxides having the formula

35 A-(CH2)MZ(CH2)r;H >-- R1 N \ S/ N 40 (0)p and processes for their preparation, wherein the variables A, m, Z, n and R' are similar to the corresponding substituents of the compounds disclosed and claimed herein. However, the compounds disclosed therein are 1 -oxides or 1,1 -dioxides (p is 1 or 2), and the compounds of the present invention cannot be prepared by any of the processes described therein for the preparation of the prior art compounds.

Published European Patent Application No. 40,696 discloses inter alia 3,4disubstituted50 11,2,5-thiadiazole 1 -oxides and 1,1 -dioxides having the formula R1 R-G-(CH2),X-(CH2)MNH N / k-- \ R2 N N 11\ S / (0)p 60 and processes for their preparation, wherein the variables R, 8 n, X, m, R' and R 2 are similar to the corresponding substituents of the compounds disclosed and claimed herein. However, the compounds disclosed therein also are 1-oxides or 1,14oxides (p is 1 or 2) and the compounds65 2 GB 2 149 406A 2 of the present invention cannot be prepared by any of the processes described therein for the preparation of the prior art compounds.

In the two publications cited above, each of the processes described for preparation of the prior art compounds involves the use (as a starting material or intermediate) of a 1,2,5thiadiazole 1 -oxide or 1,1 -dioxide having either amino groups or suitable -leaving groups- on the 3- and 4positions. The desired substituents on the 3- and 4-positions are then obtained by substitution on the amino groups or by replacement of the leaving groups---. We have made extensive attempts to prepare the compounds of the present invention by similar procedures, i.e. by utilizing 1,2,5-thiadiazole having amino groups or suitable -leaving groups- on the 3- and 4- positions as starting materials or intermediates. Although numerous variations were tried, along 10 with varying reaction conditions, we were not able to isolate the compounds of this invention by that route.

We have now found that the compounds of the present invention may be prepared by ring closure of the correspondingly substituted ethanediimidamide of the formula A- (CH2)m Z (CH2]nbH-C - CA ': H R1 P \\ H N NH Intermediate 11, itself, may be prepared by various procedures.

Complete Description

This invention relates to histamine H,-receptor antagonists of the formula A-(CH2)MZ(CH2)nbJH NHR1 N N N \ S 1,11 1 wherein R' is hydrogen, (lower)aikyi, 2-fluoroethyl, 2,2,2-trifluoroethyi, allyl, propargy], R2 R3'2=- (CH2) p - or R4 -ON - (CH2) p - in which p is 1 or 2, R 2 and R 3 each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when R 2 is hydrogen, R' also may be trifl uoro methyl, or R 2 and R 3, taken together, may be methylenedioxy, and R 4 is hydrogen, (lower)aikyl or (lower)alkoxy; m is an integer of from 0 to 2 inclusive; 50 n is an integer of from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and A is 3 GB 2 149 406A 3 R7 R5 R7 R5 \ N(CH2)q N(CH2)q RO 0 R6 S 1.0 10 R5 R7 \ N(CH21q- R6/ R7 R5 or \ N(CH2) q N R6 in which R' is hydrogen, (lower)alkyl or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and R 6 and R 7 each are independently (lower)alkyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl(lower)alkyl, and, when R 6 is hydrogen, R 7 also may be cyclo(lower)alkyl, or R 6 and R 7 taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperi dino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, hep tamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yi or 3pyrrolino; and non toxic, pharmaceutically acceptable salts, hydrates and solvates thereof.

This invention also relates to processes for the preparation of the compounds of Formula I and to the intermediate compounds of Formula 11.

The present invention includes within its scope all possible tautomeric forms, diastereoisom eric forms and optically active isomers of the compounds of Formula I as well as mixtures thereof. As used herein and in the claims, the term "(lower)-alkyl" means a straight or branched 35 chain alkyl group containing from 1 to 6 carbon atoms. The term "(Iower)alkoxy" means a straight or branched chain alkoxy group containing from 1 to 4 carbon atoms. "Cyclo(lower)al koxy- means a cycloalkyl group containing from 3 to 6 carbon atoms. The term "nontoxic pharmaceutically acceptable salts" means acid addition salts formed with acids such as hydrochloric, hydrobromic, nitric, sulfuric, acetic, propionic, fumaric, methanesulfonic, maleic, 40 tartaric, citric, levulinic, benzoic, succinic and the like.

In the compounds of Formula 1, R1 preferably is hydrogen or (lower)alkyl, more preferably is hydrogen or methyl and most preferably in hydrogen. Substituent A preferably is the substituted phenyl moiety, substituted furyl moiety or substituted thienyl moiety shown above, and most preferably is the substituted phenyl moiety. Substituent Z preferably is sulfur or oxygen and, when A is the substituted phenyl moiety, Z preferably is oxygen. It is preferred that m is zero or 1 and n is 2 or 3, and that, when A is the substituted phenyl moiety, m is zero and n is 3. R5 preferably is hydrogen or methyl and most preferably is hydrogen. It is preferred that q is 1. R 6 and R 7 preferably are (lower)alkyl or, taken together with the nitrogen atom to which they are attached, are pyrrolidino or piperidino.

The compounds of Formula I may be prepared by reaction of a compound of Formula 11 with sulfur monochloride (S2CI2)1 sulfur dichloride (SC12) or chemical equivalents thereof, as follows:

4 GB 2 149 406A 4 A-(CH2)n.Z(CH2)nNH-C-C,-NHR' 11 52C12 or SC12 A-(CH2rnZ(CHJnNH NHO 1 10 15 wherein A, m, Z, n and R' are as defined above. At least about 1 mole of S2C12 or SCI, should be used per mole of Compound 11; it is preferred to use an excess of S2C12 or SC12, e.g. from about 2 to about 3 moles of SP2 or SC12 for mole of Compound 11. It has been found that SC12 20 often gives a cruder product and lower yield of purified product, and we usually prefer to use SP2 for the reaction. The reaction temperature is not critical; we prefer to conduct the reaction at a temperature of from about OC to about 5WC, and it is most convenient to conduct the reaction at ambient temperature. The reaction time is not critical and is dependent on temperature. We normally utilize a reaction time of from about 30 minutes to about 6 hours. At ambient temperature, reaction times of from about 1 1 /2 to 4 hours usually are preferred. The reaction may be conducted in an inert organic solvent, preferably a mixture of an inert organic solvent and dimethylformamide. Most preferably the reaction is conducted in dimethylformam ide.

In a preferred embodiment of the invention, the compounds of Formula 1 have the structure 30 A-(CH2)MZ(CH2),JH NHR1 35 N \ S,/ N wherein RI is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen or sulfur and A is 40 R7 R5 7 R5 NCH2 Y7 R \NCH2 45 R6/ J S 50 R7 R5 R7 R5 N CH2 or NCH2 55 R 6 -c R6 N 60 in which R5 is hydrogen or methyl, and R 6 and R 7 each are independently methyl or ethyl, or when taken together with the nitrogen to which they are attached, RI and R 7 represent a pyrrolidino or piperidino ring; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In a more preferred embodiment, the compounds of Formula I have the structure GB 2 149 406A 5 R7 -\., "/ NCH2 -cl R6 7 R5 /NCH2-ACH2SCH2CH2NH NHR1 C lb N "\S.1-1 N wherein R' and R5 each are independently hydrogen or methyl, and R6 and R' each are independently methyl or ethyl; or a nontoxic pharmaceutical ly acceptable salt, hydrate or solvate 35 thereof.

In another more preferred embodiment, the compounds of Formula 1 have the structure R7 RS CH2SCH2CH2NH NHO R6 / NN \ S.'.

lc wherein RI and R5 each are independently hydrogen or methyl, and R 6 and R 7 each are independently methyl or ethyl; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate 50 thereof.

OCH2CH2CH2NH NHR1 N-N \S/ la wherein R' is hydrogen or methyl, and R6 and R' each are methyl or, when taken together with 15 the nitrogen atom to which they are attached, R 6 and R' represent a pyrrolidino or piperidino ring; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. In another more preferred embodiment, the compounds of Formula 1 have the structure In another more preferred embodiment, the compounds of Formula 1 have the structure RS 55 R7 N CH2 --- OCH CH CH2NH NHR1 2 2 Id R6 N >- N \"/ N 60 wherein R' and R5 each are independently hydrogen or methyl, and R 6 and R7 each are independently methyl or ethyl, or, when taken together with the nitrogen to which they are 65 6 GB 2 149 406A 6 attached, R6 and R 7 represent piperidino; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

As presently envisaged, the most preferred compounds of Formula I are 1) 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole, 2) 3-amino-4-(2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylaminol-1, 2,5-th iadiazole; 5 3) 3-amino-4-t2-[(5-dimethylaminomethyl-4-methyl-2thienyl)methylthio]ethylamin o)-1,2,5- thiadiazole, 4) 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5- thiadiazole, 5) 3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5thiadiazole, 6) 3-benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5thiadiazole, 7) 3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino)1,2,5-t hiadiazole, 8) 3-amino-4-t2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylaminol-1,2, 5-thi adiazole, 9) 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5thiadiazole and 10) 3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5thiadiazole; and their nontoxic, pharmaceutically acceptable salts, hydrates and solvates.

The intermediates of Formula 11 used in the preparation of the compounds of Formula I may themselves be prepared by various procedures. In one procedure, the corresponding 3-(amino or substituted amino)-4(substituted amino)- 1, 2,5-thiadiazole 1-oxide of Formula III is treated with a strong mineral acid (preferably HCI) to produce the compound of Formula 11.

20 25 A-WH2)j(CH2)n NH)7 NHO 25 N N S 30 I-IC1 A-(CH2)rnZ(C5NH NHR1 35 HN NH 40 The reaction may be conducted in an inert solvent and preferably is conducted in methanol. Reaction temperature is not critical; it most conveniently is conducted at room temperature. The compounds of Formula Ill are known or may readily be prepared by the procedures described in 45 our published United Kingdom Patent Application No. 2,067,987.

In an alternate procedure, the compounds of Formula 11 may be prepared by the following reaction scheme. The A(CH2)mZCH2)nNH2 + CH30 \ / 0C113 50 / C-C HN NH 55 IV v 7 GB 2 149 406A 7 A-WH2)mZ(C112)nNH OCH3 c -c \\ V1 5 1 HN NH 10. 1 R' N112 10 15, A- (CH2)mZ(CH2)n NH \ C-C / NHR1 VII 15 1 HN NH 20 reaction may be conducted in an inert solvent and preferably is conducted in methanol. The starting materials of Formula IV are known or may be readily prepared by known procedures, e.g. as by procedures described in our published United Kingdom Patent Application No. 25 2,067,987.

In another aspect, this invention relates to novel intermediates of the formula A-(CE!2)MZ(C1[2)nNHI NHA 30 J71M wherein R' is hydrogen, (lower)alky], 2-fluoroethyl, 2,2,2-trifluoroethyi, allyl, propargy], R2 4C - 0 (CH2) p R3 or R4 -ON - (CH2 1 p in which p is 1 or 2, R 2 and R 3 each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when R2 is hydrogen, R3 also may be trifluoromethyl, or R 2 and R 3, taken together, may be methylenedioxy, and R 4 is hydrogen, (lower)alkyl or (lower)alkoxy; m is an integer of from 0 to 2 inclusive; 50 n is an integer of from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and A is 8 GB 2 149 406A 8 R7 R5 R7 R5 N (CH2)q N(CH2)q 5 RO 0 R6 S 10 R7 \ R7 R 15 N(C1-12)q- o r \N(CH2)q R6 R6 N 20 in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and R 6 and R' each are independently (lower)alkyl, (lower)aikoxy(lower)aikyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl(lower)alkyl, and, when R6 is hydrogen, R 7 also may be cyclo(lower)alkyl, or R6 and R 7, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrroli dino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpi peridino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or a salt, hydrate or solvate thereof.

In a preferred embodiment, the intermediates of Formula 11 have the structure H A- (CH2) J (C11 2 N 35 wherein RI is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen or sulfur and A is 40 RS R5 7 R7\ 45 \NCH2 -o NCH2 S R6/ 50 R7 R5 R7 RS \ NCH2 - or NCH2 - 55 R6 R6 N 60 in which R 5 is hydrogen or methyl, and R 6 and RI each are independently methyl or ethyl, or when taken together with the nitrogen to which they are attached, R 6 and R 7 represent a pyrrolindo or piperidino ring; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula 11 have the structure 9 GB 2 149 406A 9 R7 CH2 5 / -C, R6 OCH2CH2CH2NH NHR1 Ila HN NH wherein R' is hydrogen or methyl, and R 6 and R 7 each are methyl or, when taken together with the nitrogen atom to which they are attached, R 6 and R' represent a pyrrolidino or piperidino ring; or a salt; hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula 11 have the structure R7 PS /NCH2-7/17-CH2SCH2CH2NH NHR R6 lib HN NH wherein R' and R' each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl, or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula 11 have the structure R7 R5 NCH2--7pCH2SCH2CH2NH NHR1 6 lie R HN NH 35 wherein R' and R5 each are independently hydrogen or methyl, and R6 and R 7 each are 40 independently methyl or ethyl; or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula 11 have the structure RS R7 45 \ NCH2 OCH2CH2CH NH NHR1 R 6 6N_ 2 lid HN NH 50 wherein R' and R5 each are independently hydrogen or methyl, and R6 and R 7 each are independently methyl or ethyl, or, when taken together with the nitrogen to which they are 55 attached, R 6 and R 7 represent piperidino; or a salt, hydrate or solvate thereof.

As presently envisaged, the most preferred intermediates of Formula 11 are 1) N-[3-(3-piperidinomethylphenoxy)propyi]ethanediimidamide, 2) N{2-[(5-d i methyl am i nomethyl-2-fu ryl)rnethylth io]ethyl} etha ned i i m ida m ide, 3) W{2-[(5-d i methyl am i nomethyl-4-m ethyl-2-th ie nyl)rnethylth io]ethyi}ethanediimidamide, 60 4) N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamide, 5) N2-[(5-dimethylaminomethyi-3- thienyi)methylthiolethyi}ethanediimidamide, 6) N- 2-[(5-p i perid i nomethyl-3-th ienyi) methylth iolethyi} etha need i i m ida m i d e, 7) N-[3-(6-piperidinomethyi-2-pyridyloxy)propyl]ethandeiimidamide and 8) N-[3-(4-piperidinomethyi-2-pyridyloxy)propyl]ethanediimidamide; GB 2 149 406A 10 or a salt, hydrate or solvate thereof.

For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in its basic form or in the form of a nontoxic pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable 5 carrier.

The pharmaceutical compositions may be administered orally, parenterally or by rectal suppository. A wide variety of pharmaceutical forms may be employed. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. If a liquid carrier is employed, the preparation may 10 be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injection, or an aqueous or non-aqueous liquid suspension. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation.

The dosage of the compounds of this invention will depend not only on such factors as the weight of the patient, but also on the degree of gastric acid inhibition desired and the potency of the particular compound being utilized. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of the specific patient. With the preferred compounds of this invention, each oral dosage unit will contain the active ingredient in an amount of from about 2 mg to about 300 mg, and most preferably from about 4 mg to about 100 mg. The active ingredient will preferably be administered in equal doses from one to four times a day.

Histamine 1-12-receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and man, Brimblecome et al., J. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the histamine 1-12-receptor antagonist cimetidine has shown it to be an effective therapeutic agent in the treatment of peptic ulcer disease, Gray et al., Lancet, 1, 8001 (1977).

Some of the preferred compounds of this invention have been compared with cimetidine in various tests and have been found to be more potent than cimetidine both as an histamine H2_ receptor antagonist in isolated guinea pig right atria and as an inhibitor of gastric acid secretion in rats and dogs.

Determination of Gastric Antisecretory Activity in the Gastric Fistula Rat Male Long Evans rats weighing about 240-260 grams at the time of cannular implantation are used. The design and implantation of the stainless steel cannula into the anterior wall of the fore-stomach are carried out essentially as described by Pare et al. [Laboratory Animal Science, 35 27, 244 (1977)]. The fistula components are designed and the operative procedure is carried out exactly as described in the above reference. Post operatively the animals are individually housed in solid bottom cages with sawdust and are allowed food and water ad libitum throughout the entire recovery period. Animals are not used for test purposes for at least 15 days after the operative procedure.

The animals are fasted but allowed water ad libitum for 20 hours before the testing procedure is to begin. Immediately prior to collection, the cannula is opened and the stomach washed gently with 30-40 mL of warm saline or distilled water to remove any residual contents. The catheter is then screwed into the cannula in place of the plugging screw and the rat is placed in a clear plastic rectangular cage measuring 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage has a slit approximately 1.5 cm wide and 25 cm long running down the center to accommodate the catheter which hangs through it. In this way the rat is not restricted and can move freely about the cage during collection periods. The remainder of the assay is carried out as described by Ridley et al. [Research Comm. Chem. Path. Pharm., 17, 365 (1977)].

Gastric secretions collected during the first hour after washing the stomach are discarded as they may be contaminated. For oral evaluation, the catheter is then removed from the cannula and replaced with the plugging screw. Water (2 mL/kg) is administered orally via gastric intubation and the animal is returned to the cage for 45 minutes. After this time the plugging screw is removed and replaced with a catheter to which a small plastic via[ has been attached to 55 collect the gastric secretions. A two-hour sample is collected (this represents the control secretion), the catheter is removed and replaced with the plugging screw. The test drug is now administered orally in a volume of 2 mL/kg via gastric intubation. Forty- five minutes later the plugging screw is again removed, replaced with the catheter attached to a small plastic vial and another 2-hour sample is collected. The secretions in the second sample are compared to those 60 of the control sample in order to determine the effects of the test drug.

When test compounds are to be evaluated parenterally, the animal is injected ip or sc with the test compound vehicle in a volume of 2 mL/kg immediately after discarding the initial 60 minute collection. A two-hour sample is collected (control secretion) and the animals are injected either ip or sc with the test compound in a volume of 2 mL/kg. An additional two-hour sample 65 GB 2 149 406A 11 is collected and its secretions are compared to those of the control period to determine drug effects.

The samples are centrifuged and placed in a graduated centrifuge tube for volume determination. Titratable acidity is measured by titrating a onemL sample to pH 7.0 with 0.2N NaOH, using an Autoburet and an electrometric pH meter (Radiometer). Titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in milliequivalents per liter.

Results are expressed as percent inhibition relative to control readings. Dose response curves are constructed and ED,O values are calculated by regression analyses. At least three rats are used at each dosage level and a minimum of three dosage levels are utilized for determination of 10 a dose response curve.

Table 1

Gastric Antisecretory Activity in the Gastric Fistula Rat ED so sc Potency Ratio Compc=d umoles/kg (cimetidine - 1.0) cimetidine 3.48 1.0 (1. 68-5.75) 1 1 i Example 1 0.094 (0.043-0.20) 37 Ex a,,np 1 e 2 0.77 (0.45-1.4) 4.5 Example 3 1.0.5 1 %7 Example 4 j 0.18 (0.13-0.36) 95% confidence limits Histamine H,-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 H,-receptors when they reported the properties of burimamide, a competitive antagonist of these receptors. Subsequent investiga55 tions 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 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 60 comparative studies were carried out using a modification of the procedure reported by Reinhardt et al., Agents and Actions, 4, 217 (1974).

Male Hartly strain guinea pigs (360-450 gm) were sacrificed by a blow on the head. The heart was excised and placed in a Petri dish of oxygenated (95% 0, 5% C02) modified Krebs solution (g/liter: NaCl 6.6, KC1 0.35, MgSO,-7H20 0.295, KH2PO4 0.162, CaC12 0.238, 65 GB 2 149 406A 12 12 NaHC03 2.1 and dextrose 2.09). The spontaneously beating right atrium was dissected free from other tissues and a silk thread (4-0) attached to each end. The atrium was suspended in a 20 mi muscle chamber containing oxygenated modified Kirebs 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 Dynograph.

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

The dissociation constants (K,) were derived from Schild plots by the method of Arunlakshana, 0. and Schild, H. 0. [Br. J. Pharmacol. 14, 48 (1959)] using at least three dose levels. Parallel shifts in doseresponse curves were obtained without depressing the maximal response at the antagonist concentrations utilized, and the results are shown in Table 2.

able 2 Activity in Isolated Guinea Pig Right Atria 25 Potency Ratio compound N KB (11M0 le 5 (cimetidine-1.0) cimetidine 20 0.41 (.21-.64) 1.0 Example 1 12 0.003 (.001-.004) 137 Example 4 11 0.004 (.001-.010) 102 A 1 1 1 95% confidence limits As described in U.S. Patent Application Serial No. (SY-1 75 1), filed (concurrently) by our colleague Thomas A. Montzka, the compounds of Formula I also may be prepared by ring closure of a compound of Formula 11 with N,N'- thiobisphthalimide having the formula 0 ([:::4)N S 0 2 so The use of N, W-thiobisphthalimide instead of S2C12 or SC12 or SC12 for the ring closure reaction results in both purer and higher crude yields of the compounds of Formula 1. The crude products of Formula 1 thereby produced normally are pure enough to form crystalline salts directly without prior chromatographic purification.

In this process, the starting diimidamide of Formula 11 is reacted with about an equimolar amount of N,N'-thiobisphthalimide in an inert organic solvent such as CH2C12. Preferably the starting diimidamide is used in the form of its trihydrochloride salt, in which case three molar equivalents of an amine, such as triethylamine, are added to the. reaction mixture to neutralize the trihydrochloride salt. The reaction may be conducted by stirring at room temperature for 65 13 GB 2 149 406A about an hour to insure completeness of the reaction. The phthalimide which precipitates from the reaction mixture is then extracted with a strong base (e.g. 10-20% aqueous KOH), and the organic solvent layer is dried, filtered and concentrated to yield the crude compound of Formula 1. The N,N'-thiobisphthalimide used in the reaction is a known compound which may be prepared as described in the Canadian Journal of Chemistry, 44, 2111 2113 (1966), or as described below in Preparation No. 1.

Preparation No. 1 N,N'Thiobisphthalimide A cooled (O'C) solution ofphthalimide (14.7 g, 0. 1 mole) in 80 mi of dimethylformamide (DIVIF) was treated dropwise with sulfur dichloride (5.15 g, 0.05 mole). After the addition, the mixture was allowed to warm to 2WC with stirring over four hours. The solid was collected and dried to give 12.5 g of the title compound as a DIVIF solvate, mp 301-31 WC. Both ir and nmr spectra are consistant for structure.

Anal. CaWd. for C,H81\1204SC3H7NO: C, 57.42; H, 3.80; N, 10.57; S, 8.07 Found:C, 57.50; H, 3.80; N, 10.29; S, 8.57 The DIVIF solvate can be removed by recrystallization of the above material from chloroform; mp of the DIVIF-free product was 320-325'C. The nmr spectrum shows that the DMF has been 20 removed.

Anal. Calc'd. for C,^3N,0,S: C, 59.25; H, 2.49; N, 8.64; S, 9.89 Found: C, 59.21; H, 2.21; N, 8.91; S, 10.14 Example 1 3-Amino-4-[3-(3-piperidinomethylphenoxy)propylaminol- 1, 2,5- thiadiazole A. N-[3-(3-Piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride A suspension of 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2, 5-thiadiazole 130 oxide (17.1 g; 47.0 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 450 mL of methanol was treated with 38 mL of concentrated HCL The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave colorless crystals.

These were suspended in 200 mL of absolute ethanol, filtered and dried under vacuum to give 16.6 g (82.6%) of the title compound, m.p. 205-222'C (dec.). Recrystallization from 50% methanolethyl acetate gave an analytical sample, m.p. 206-21 WC (dec.).

Anal. Calc'd for C,^^0.3HCl: C, 47.84; H, 7.08; N, 16.41 Found: C, 47.56; H, 7.18; N, 16.75 B. 3-Amino-4-[3-(3-piperidinomethylphenoxy)propylaminol-1,2,5-thiadiazote A stirred suspension of N-[3-(3piperidinomethylphenoxy)propyi]ethanediimidamide trihydro- chloride (2.13 g, 5.0 mmoles) [prepared in Step A] in 20 mi- of dimethylformamide (DMF) was treated with sulfur monochloride (2.02 9, 15.0 mmoles) and stirred for 4 hours. The resultant 45 mixture was poured cautiously into 200 mi- of water and made basic with K, CO, This was extracted with 3 X 50 mL portions of methylene chloride and, after drying over MgSO, and concentration, 2.1 9 of a dark gum containing the product was obtained. The product was purified by preparative high pressure liquid chromatography on silica using CH2C12 (100):2 propanol (10):NH,OH(O.5) as the mobile phase. The appropriate fractions yielded 0.89 9 of the 50 title compound which gave, with fumaric acid in n-propanol, 0.76 g (21. 4%) of the title compound as a crystalline fumarate salt, m.p. 187-1 87.WC. HPLC indicated a purity of >99%.

Anal. Calc'd for (C,,H2,N,OS)2.C,H,O,: C, 56.27; H, 6.71; N, 17.27; S, 7. 90 Found: C, 56.09; H, 6.36; N, 16.98; S, 8.08 A portion of the fumarate was suspended in water, neutralized with K2C03 and extracted with CH2C12. The CH2C12 WaS concentrated and the free base of the title compound crystallized out; m.p. 43-47'C. A portion of the free base was converted to the hydrochloride salt, m.p. 60 1 38-140'C.

Anal. CaWd for C17H2.,N, OS.HCI: C, 53.18; H, 6.83; N, 18.24; S, 8.35 Found:C, 53.14; H, 6.88; N, 18.49; S, 8.74 14 GB 2 149 406A 14 Example 2 3-Amino-4-(2-[(5-dimethylaminomethyl-2furyl)methytthiollethylamino)-1,2,5-t hiadiazole A. N-(2-[(5-Dimethylaminomethyl-2- furyi)methylthio]ethyl)ethanediimidamide trihydrochloride 5 hydrate A suspension of 3-amino-4-(2-[(5-dimethylaminomethyl-2furyl)methylthio]ethylamino)-1,2,5thiadiazole 1-oxide (6.59 g; 20.0 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 200 mL of methanol was warmed slightly to achieve complete solution, then treated with 13.3 mL of concentrated HCL After stirring at ambient temperature for 2.5 hours, the solution was concentrated and the residue was triturated with 7010 mL of absolute ethanol. The crystals were collected by filtration and dried under vacuum to give 4.3 g (52%) of the title compounds, m.p. 166- 169'C (dec.).

Anal. Calc'd for C12H,^OS-31-ICIffl,O: C, 35.08; H, 6.38; N, 17.05; S, 7. 80 Found: C, 34.85; H, 6.24; N, 17.45; S, 7.97 B. 3-Amino-4-(2-[(5-dimethylaminomethyl-2-furyl)methylthiolethylamino)-1, 2,5-th iadiazole To a stirred suspension of N- {2[(5-di methyl a minomethyl-24 uryl)rnethylth io]ethyl} ethaned Hmi damide trihydrochloride hydrate (12.3 g; 30.0 mmoles) [prepared in Step A] in 150 mi- of DIVIF was added 7.2 mi- of sulfur monochloride (12.1 g; 90 mmoles). After stirring for 4 hours at 20 ambient temperature, approximately half of the DIVIF was removed at reduced pressure. The remaining black solution was poured into 1 liter of water, made basic with K2CO, and extracted first with ethyl acetate and then with chloroform. After drying over MgSO, filtration and concentration, 9.0 9 of a black gum containing the product was obtained. This was purified by preparative high pressure liquid chromatography on silica using ethyl acetate (100): 2-propanol 25 (10): NI-1,0H (0.5) as the mobile phase. The appropriate fractions yielded 1.24 g of the title compound as a gum.

Treatment of part of this product with an equivalent amount of 2N HCl in methanol yielded the hydrochloride salt of the title compound.

Anal. Calc'd for C12H1,N.SA-HCL C, 41.18; H, 5.76; N, 20.02; S, 18.33 Found (corr. for 1.65% H20): C, 40.54; H, 5.70; N, 19.39; S, 18.44 Treatment of the product with an equivalent amount of cyclohexyisulfamic acid in acetone yielded the cyclo hexyisu Ifa mate salt of the title compound, m.p. 93- 95T.

Anal. Cale'd for C12H,9N5S20-C,H,,N03S: C, 43.88; H, 6.55; N, 17.06; S, 19.53 Found: C, 43.77; H, 6.17; N, 17.21; S, 19.58 Example 3 3-Amino-4-(2-[(5-dimethylaminomethyl-4-methyl-2thienyl)methylthiolethylamin o)-1,2,5-thiadiazole A. N-(2-[(5-Dimethylaminomethyl-4-methyl-2thienyi)methylthio]ethyl)ethanediimi damide trihy drochloride A stirred solution of 3-amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2thienyl)methylthioje- thylaminol-1,2,5-thiadiazole 1-oxide (17.9 g, 50.0 mmoles) [prepared according to the general procedure described in published United Kingdom Patent Application No. 2, 067,987] in 500 mL of methanol was treated with 33.3 mL of concentrated HCL After stirring for 3 hours, the reaction mixture was concentrated and excess water was removed by azeotropic concentration 50 with absolute ethanol to give an almost colorless crystalline residue. The residue was triturated with 200 mL of absolute ethanol at O'C, filtered and dried to give 16.9 g (80%) of the title compound, m.p. 206-220C (dec.). Recrystallization from 50% methanolethyl acetate gave a product having m.p. 210-221'C (dec.).

Anal. Calc'd for C,^.N.S2.3HO: C, 36.92; H, 6.20; N, 16.56; S, 15.17 Found:C, 36.76; H, 6.33; N, 16.97; S, 15.54 B. 3-Amino-4-(2-[(5-dimethylaminomethyl-4-methyl-2thienyl)methytthio]ethylamin o)-1,2,5-thi60 adiazole To a stirred suspension of N-(2-[(5-dimethylaminomethyi-4-methyi-2thienyi)methyithio]ehy- 1}ethanediimidamide trihydrochloride (6.34 9; 15.0 mmoles) [prepared in Step A] in 60 mIL of DIVIF was added 6.1 9 (45.0 mmoles) of sulfur monochloride. After stirring for 4 hours at ambient temperature, the reaction mixture was poured into 800 mi- of water, made basic with K2C03, and extracted several times with 100 mL-portions of methylene chloride. The extracts 65 GB 2 149 406A 15 were dried over M9S04, filtered, and concentrated to give 3.4 9 of a black gum containing the product. The product was purified by preparative high pressure liquid chromatography on silica using CH2C12 (100): 2- propanol (10): N H40 H (0. 5) as the mobile phase. Further purif ication was achieved by an additional preparative high pressure liquid chromatography on silica using CH2C12 (100): CH30H (2.5): NH40H (0.5) as the mobile phase. The appropriate fractions yielded the title compound (purity -98%). Treatment of the product with an equivalent amount of 2N HCl gave the hydrochloride salt of the title compound.

Anal. CaWd for C13HA.S3MC1: C, 41.09; H, 5.84; N, 18.43; S, 25.32 Found (corr. for 0.51% H20): C, 40.78; H, 5.63; N, 18.31; S, 25.44 Example 4 3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]- 1, 2,5- thiadiazole A. N-[3-(3-Pyrrolidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride A suspension of 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2, 5-thiadiazole 1- oxide (13.4 g; 38.3 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 350 mL of methanol was treated with 25.5 mL of concentrated HCL The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave the product. The 20 crystalline residue was triturated with 150 mL of absolute ethanol, filtered and dried to give 10.8 g of the title compound, m.p. 195-203'C (dec.).

Anal. CaWd for C,6H2.N.O.31-ICI: C, 46.55; H, 6.84; N, 16.97 Found: C, 46.55; H, 6.93; N, 16.93 B. 3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5- thiadiazole A stirred suspension of N-[3-(3pyrrolidinomethylphenoxy)propyi]ethanediimidamide trihydro- chloride (8.25 g; 20.0 mmoles) [prepared in Step A] in 80 mi- of DIVIF was treated with sulfur monochloride (5.4 g; 40.0 mmoles) and stirred under a nitrogen atmosphere for 3 hours. Concentration of the reaction mixture gave a dark gum which was suspended in 500 mi- of water, made basic with K2C03 and extracted with 3 X 100 mL of methylene chloride. The extracts were dried over MgSO, filtered and concentrated to give 7.5 9 of a dark gum containing the product. The product was purified by preparative high pressure liquid chromato35 graphy on silica using CH2C12 (100): 2-propanol (5): NH,OH (0. 5) as the mobile phase. Fractions 35 containing the desired product were combined and concentrated to give 1.64 g (24.6%) of the purified title product. Treatment of the product in absolute ethanol with an equivalent amount of 2N HCI gave the hydrochloride salt of the title compound (1. 13 g); m.p. 138-1 4WC.

Anal. Calc'd for Cl,H23N,OS-HCI: C, 51.95; H, 6.54; N, 18.93; S, 8.67 Found:Q 51.97; H, 6.36; N, 18.63; S, 8.76 Example 5

The general procedure of Example 1, Steps A and B, is repeated except that the 3-amino-4-[3(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide utilized therein is replaced by an equimolar amount of (a) 3-a m i no-4-[3-(3-d i methyl am i nomethyl phen oxy)propyla m in o]- 1, 2,5-th iad iazole 1-oxide, (b) 3-amino-4-[3-(3-diethylaminomethylphenoxy)propylamino]-1,2,5thiadiazoie 1-oxide, (C) 3-amino-4-{3-[3-(2-methylpyrrolidino)methylphenoxy]propylamino)-1,2,5thiadi azole 1-oxide, (d) 3-amino-4-{3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino}-1,2,5thiadi azole 1-oxide, (e) 3-a m i no-4- {3-[3-(4-methyl p iperid i no) methyl p henoxy]propyla m in o} - 1 2,5-th iad iazo le 1-oxide, (f) 3-a m i no-4-[3-(3-morp ho 1 i no methyl phe noxy)propyla m i no]- 1, 2,5-th iad iazol e 1-oxide, (g) 3-amino-4-{3-[3-(N-methylpiperazino)methylphenoxy]propylamino}-1,2,5thiadia zole 1-oxide, 55 (h) 3-amino-4-[3-(3-diallytaminomethylphenoxy)propylaminol-1,2,5- thiadiazoie 1-oxide, (i) 3-amino-4-[3-(3-hexamethyleneiminomethylphenoxy)propylaminol-1,2,5thiadiazo le 1-oxide, (j) 3-amino-4-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]-1,2,5thiadiaz ole 1-oxide, (k) 3-a m i no-4- (3-[3-(3-aza bicyclo[3.2.2]no n-3-y1)m ethyl ph enoxy]pro pyl am i no} - 1, 2, 5-th i ad i azole 1 -oxide and (1) 3-amino-4-{3-[3-(3-pyrrolino)methylphenoxy]propylamino}-1,2,5- thiadiazole 1-oxide, respec tively, and there is thereby produced (a) 3-amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1,2,5thiadiazole, (b) 3-amino-4-[3-(3-diethylaminomethylphenoxy)propylamino]-1,2,5thiadiazoie, 16 GB 2 149 406A 16 (c) 3-amino-4-(3-[3-(2-methylpyrrolidino)methylphenoxy]propylaminol-1,2,5thiadi azole, (d) 3-amino-4-{3-[3-(3methylpyrrolidino)methylphenoxy]propylamino}-1,2,5-thiadi azole, (e) 3amino-4-{3-[3-(4-methylpiperidino)methylphenoxy]propylamino}-1,2,5thiadia zole, (f) 3-a m ino-4-[3-(3-morphol i no methyl phenoxy)pro pyla m i no]- 1, 2,5,-th iad iazol e, (g) 3-amino-4-{3-[3-(Nmethyipiperazino)methylphenoxy]propylamino}-1,2,5-thiadia zole, (h) 3amino-4-[3-(3-diallylaminomethylphenoxy)propylaminoll,2,5-thiadiazole, (i) 3-a m ino-4-[3-(3-hexa m ethylenei m i nomethyl p hen oxy)propyl am in o] 1, 2,5-th iad iazol e, (j) 3-a m i no-4-[3-(3-hepta methyl enei m inomethyl phenoxy)propyla m i no] 1, 2, 5-th iad iazo le, (k) 3-amino-4{3-[3-(3-azabicyclo[3.2.2.]non-3-yl)methylphenoxy]propylamino}-1,2,5thiadiazole 10 and (1) 3-a m i no-4- {3-[3-(3-pyrrol id in o) methyl phen oxy]propyla m i no} - 1, 2,5-th iad iazole, respectively.

Example 6

3-Amino-4-[3-(3-piperidinomethylphenoxy)propylaminol- 1, 2,5-thiadiazole This is a variation of Example 1, Step B, utilizing less sulfur monochloride and a shorter 15 reaction time.

To a stirred suspension of W[3-(3-pi perid i nom ethyl p henoxy)propyl]etha ned i i m ida m i de trihy drochloride (12.08 g; 28.3 mmoles) in 120 mi- of DIVIF was added suffur monochloride (7.64 9; 56.6 mmoles) and the mixture was stirred under an N2 atmosphere for 3 hours. The DIVIF was removed at reduced pressure to leave a black gum which was suspended in water, made 20 basic with K2CO, and extracted with 3 X 100 mL portions of CH2C12. The combined extracts were dried over MgSO, filtered and concentrated to a black gum. This gum was purified by preparative high pressure liquid chromatography on silica using CH2C12 (100): 2-propanol(5):

NH,OH (0.5) as the mobile phase. The appropriate fractions yielded 3.1 g of the title product as a dark oil which gave, with fumaric acid in n-propanol, 2.66 g (23.2%) of the title compound as 25 a crystalline fumarate salt, m.p. 186-1 86.5'C. HPLC indicated a purity of 99%.

Anal. Calc'd. for (C,,H2,N,OS)2CH,O,: C, 56.27; H, 6.71; N, 17.27; S, 7. 90 Found: C, 56.27; H, 6.96; N, 17.31; S, 7.98 Example 7

3-Amino-4-[3-(3-piperidinomethylphenoxy)propylaminol- 1,2,5-thiadiazole This is a variation of Example 1, Step B, utilizing sulfur dichloride instead of sulfur monochloride.

To a stirred suspension of N-[3-(3piperidinomethylphenoxy)propyl]ethanediimidamide trihy- 35 drochloride (854 mg; 2 mmoles) in 6 mL of DMF under N2 in an ice bath was added SC12 (206 mg; 2 mmoles) in 2 mL of DMF. The reaction mixture was stirred at ambient temperature and the title compound was produced.

Example 8 3-Methylamino-4-[3-(3-piperidinomethylphenoxy)propylaminol- 1,2, 5-thiadiazole A. N-Methyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride A suspension of 3-methylamino-4-[3-(3piperidinomethylphenoxy)propylamino]-1,2,5-thiadia- zole 1-oxide (4.13 g; 10.9 mmoles) [prepared according to published United Kingdom Patent 45 Application No 2,067,987] in 95 ml of methanol was treated with 7.2 ml of concentrated HCL After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue was triturated with acetone, filtered and dried to give 4.35 g (90.4%) of product. A sample was recrystallized from aqueous isopropyl alcohol to give the title compound, mp 207-225C (dec.).

Anal. CaWd. for C,,H2,N50-3HCI: C, 49.03; H, 7.33; N, 15.89 Found (corr. for 0.94% H20): C, 49.37; H, 7.35; N, 15.71 B. 3-Methylamino4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5thiadiazole A mixture of N-methyl-N'-[3-(3piperidinomethylphenoxy)propyi]ethanediimidamidetrihydro- 55 chloride (3.74 g; 8.47 mmoles) [prepared in Step A], 34 mi of CH2C12 and 3.5 mi of triethylamine was treated with N,W-thiobisphthalimide (DMF solvate) (3.36 g; 8.46 mmoles) and stirred for one hour. The mixture was washed with 30 m[ of 10% KOH, dried (M9S04), filtered, diluted with toluene and concentrated to give 3.6 g of the product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate methanol (95:5) as the eluent to give 1.9 9 (62%) of the title compound. Treatment of the product with an equivalent amount of aqueous HQ in 1-propanol gave the hydrochloride salt of the title compound, mp 163.3-164.5'C.

17 GB 2 149 406A 17 Anal. CaVd. for C,^^OS.HCl: C, 54.32; H, 7.04; N, 17.60; S, 8.06; Cl, 8. 91 Found: C, 54.35; H, 7.07; N, 17.64; S, 8.36; Cl, 8.86 Example 9

3-Benzylamino-4-[3-(3-piperidinomethylphenoxy)propylaminol- 1, 2,5thiadiazole A. N-Benzyl-N,-[3-(3-piperidinomethylphenoxy)propyllethanediimidamide trihydrochloride A suspension of 3-benzyiamino-4-[3-(3piperidinomethylphenoxy)propylamino]-1,2,5-thiadia- 10 zole 1 -oxide (5.14 9; 11.3 mmoles) [prepared according to published United Kingdom Patent Application No. 2,06 7,9 8 7] in 100 mi of methanol was treated with 7.5 5 mi of concentrated HCL After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue was triturated with acetone, filtered and dried to give 5.16 9 (88%) of the title compound, mp 187-20WC (dec.).

Anal. Cale'd for CUHA50.3HCL C, 55.75; H, 7.03; N, 13.55; Cl, 20.57 Found: C, 54.88; H, 6.75; N, 13.33; Cl, 20.20 B. 3-Benzyiamino-4-[3-(3piperidinomethylphenoxy)propylamino]-1,2,5thiadiazole A mixture of N-benzyi-N'-[3-(3-pi peri d i no methyl phenoxy)p ro pyi]etha ned i i m ida m i de tri hyd rochloride (4.73 9; 9. 16 mmoles) [prepared in Step A], 45 mi of CH2C12 and 3,8 m] of triethylamine was treated with N,W-thiobisphthalimide (DIVIF solvate) (3.64 g; 9.16 mmoles) and stirred for one hour. The mixture was washed with 44 mi of 10% KOH, dried (MgSO,), filtered, diluted with toluene and concentrated. The residue was chromatographed by flash chromatography on 110 g of silica gel (230-400 mesh) using ethyl acetate as the eluent to give 3.1 g (77%) of the title compound. Treatment of the product with an equivalent amount of aqueous HCI in 2-propanol gave the hydrochloride salt of the title compound, mp 138-141 C.

Anal. Calc'cl. for C2^^OS.HCL C, 60.80; H, 6.80; N, 14.77; S, 6.76; Cl, 7. 48 Found:C, 60.53; H, 6.64; N, 14.99; S, 6.91; Cl, 7.47 Example 10

3-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]- 1, 2,5-thiadiazole This is a variation of Example 1, Step B, utilizing N,N'thiobisphthalamide instead of sulfur 35 monochloride.

A mixture of N-[3-(3piperidinomethylphenoxy)propyl]ethanediimidamidetrihydrochloride (27.3 g; 64.0 mmoles) [prepared in Example 1, Step A], 250 ml of CH2C12 and 26.6 ml (192.0 mmoles) of triethylamine was treated portionwise with N,N'thiobisphthalimide (DMF solvate) (25.4 g; 64.0 mmoles). After stirring at ambient temperature for one hour, the mixture was 40 washed with 120 ml of 20% KOH, dried (MgSOJ, filtered and concentrated, then taken up in ml of toluene and reconcentrated. The product was taken up in 250 ml of 1 -propanol and 10.7 ml of 6N HCI, treated with decolorizing carbon and filtered through Celite. This solution was concentrated in 100 ml volume, diluted with 17 5 ml of dry 1 - propanol and stored at OC to give 20.2 g (82.1 %) of crystalline hydrochloride salt of the title compound, mp 137-1 38C. 45 Anal. Calc'd. for C,,H2,N,OS.HCI: C, 53.18; H, 6.83; N, 18.24; S, 8.35 Found: C, 52.78; H, 6.74; N, 18.52; S, 8.66 Example 11 3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylaminol- 1, 2,5- thiadiazole This is a variation of Example 4, Step B, utilizing NX-thiobisphthalimide instead of sulfur monochloride.

A mixture of N-[3-(3pyrrolidinomethylphenoxy)propyi]ethanediimidamidetrihydrochloride (22.0 g; 53.0 mmoles) [prepared in Example 4, Step A], 200 mi of CH2C12 and 22 mi of triethylamine was treated with N,W-thiobisphthalimide (DIVIF solvate) (21.2 g; 53.0 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 100 mi of 20% KOH, dried (MgSOJ, filtered, diluted with 100 mi of toluene and concentrated. The product was treated with one equivalent of aqueous HCI in 1-propanol to give 13.2 g (67%) of the hydrochloride salt of the title compound, mp 135-1 37'C.

Anal. Calc'd. for Cl,H23N,OS.HCI: C, 51.95; H, 6.54; N, 18.93; S, 8.67 Found: C, 51.92; H, 6.55; N, 19.30; S, 9.06 6 5 Example 12 18 GB 2 149 406A 18 3-Amino-4(2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylaminoj -1, 2,5-thiadiazole A. N-(2-[(5-dimethylaminomethyl-3thienyl)methylthio]ethyl)ethanediimidamide trihydrochlo ride A suspension of 3-amino-4-12-[(5-dimethylaminomethyl-3- thienyl)methylthio]ethylaminol5 1,2,5-thiadiazole 1 -oxide (7.8 g; 22.6 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 150 ml of methanol was treated with 15.0 ml of concentrated HCL After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 1-propanol, filtered and dried to give 7.38 g (80%) of product. A sample was recrystallized from methanol-acetone to give the title compound, mp 10 190-205'C (dec.).

Anal. Calc'cl. for C12NN.S2-3HCl: C, 35.25; H, 5.92; N, 17.13 Found:C, 35.03; H, 5.93; N, 17.39 B. 3-Amino-4-(2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino)1,2,5-t hiadiazole A mixture of N-{2-[(5-dimethylaminomethyi-3thienyi)methylthio]ethyl}ethanediimidamide trihydrochloride (6.13 g; 15.0 mmoles) [prepared in Step A], 60 m] of CH2C12 and 6.3 mi of triethylamine was treated with NX-thiobisphthalimide (DMF solvate) (5.96 g; 15.0 mmoles) and stirred for one hour. The mixture was washed with 100 m[ of 10% KOH, dried (MgSO,), 20 filtered, diluted with toluene and concentrated to give 5.1 g of product. Treatment of the product with 0. 5 molar equivalent of fumaric acid in 1 -propanol gave the fumaric acid salt of the compound, mp 141-143'C. The nmr spectrum in DIVISO-d, shows the presence of approximately 0. 12 moles of 1 -propanol.

Anal. CaWd. for (C12H,,N5S3)2C4H404'0'1 2C3H,O: C, 43.68; H, 5.6 1X 17.75; S, 24.38 Found: C, 43.41; H, 5.53;N, 17.54; S, 24.24 Example 13 30 3-Amino-4-(2-[(5-piperidinomethyl-3thienyl)methytthiolethylamino)-1,2,5-thi adiazole A. N(2-[(5-piperdinomethyl-3-thienyl)methylthio]ethyl) ethanediimidamide trihydrochloride A suspension of 3-amino-4- (2-[(5-piperidinomethyl-3thienyl)methylthio]ethylamino)-1,2,5-thi- adiazole 1 -oxide (6.1 g; 15.8 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 80 ml of methanol was treated with 10.5 ml of concentrated 35 HCL After stirring at ambient temperature for 3 hours, the solution was concentrated and the residue triturated with 50 ml of 1-propanol, filtered and dried to give 5. 86 g (83%) of product.

A sample was recrystallized from methanol-acetone to give the title compound, mp 201-214C (dec.).

Anal. Calc'd. for C,^,NsS,.3HCL C, 40.13; H, 6.29; N, 15.60; S, 14.29 Found:C, 39.97; H, 6.47; N, 15.28; S, 14.63 B. 3-Amino4-(2-[(5-piperidinomethyl-3-thienyl)methylthiolethylamino)-1,2, 5-thi adiazole A mixture of N-{2-[(5-piperidinomethyi-3thienyi)methyithio]ethyi}ethanediimidamidetrihyd ro- 45 chloride (5.17 g; 11. 5 mmoles) [prepared in Step A], 48 m] of CH2C12 and 4.8 mi of triethylamine was treated with N,W-thiobisphthalimide (DIVIF solvate) (4. 57 g; 11.5 mmoles) and stirred for one hour. The mixture was washed with 90 mi of 10% KOH, dried (M9S04), filtered, diluted with toluene and concentrated to give 4.5 g of product. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in methanol gave the cyclohexyl 50 sulfamate salt of the title compound, mp 142-143'C.

Anal. Cale'd. for C,,H23N5S3CM3NO3S: C, 45.96; H, 6.61; N, 15.31; S, 23. 38 Found: C, 45.61; H, 6.41; N, 15.46; S, 23.48 Example 14 The general procedures of Example 1, Step A, and then either Example 1, Step B, or Example 10 is repeated except that the 3-amino-4-[3(3-piperidinomethylphenoxy)propylamino]-1,2,5thiadiazole 1 -oxide utilized therein is replaced by an equimolar amount of (a) 3-ethylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5thiadiazole 1-oxide, (b) 3-al lyla m i no-4-[3-(3-p iperid ino methyl phenoxy)propyla m i no]- 1, 2,5-th iad iazo le 1-oxide, (c) 3-(2propynyi)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-t.iiadiazo ie 1-oxide, (d) 3-(3-pyridyimethylamino)-4-[3-(3piperidinomethylphenoxy)propylamino]-1,2,5-t hiadiazole oxide, (e) 3-(6-methyi-3-pyridyi)methylamino-4-[3-(3piperidinomethylphenoxy)propylamin o]-1,2,5-thia- 65 19 GB 2 149 406A 19 diazole 1-oxide and (f) 3-(3,4-methylened ioxybenzy[am i no)-4-[3-(3-pi perid i no methyl p henoxy)p ropyla m in o]- 1, 2,5-th iadiazole 1-oxide, respectively, and there is thereby produced (a) 3-ethyla m i no-4-[3-(3-p iperid i no methyl phenoxy)propyla m i no]- 1, 2,5-th iad iazo le, (b) 3-allylamino-4-[3-(3piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole, (c) 3-(2propynyi)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazol e, (d) 3-(3-pyridyimethylamino)-4-[3-(3piperidinomethylphenoxy)propylamino]-1,2,5-t hiadiazole, (e) 3-(6-methyi3-pyridyi)methyla m i no-4-[3-(3-p i perid in om ethyl ph enoxy)pro pyla m i no]- 1, 2,5-th ia- diazole and (f) 3-(3,4-methylened ioxybenzyla m i no)-4-[3-(3-pi perid i no methyl p henoxy)propyla m i no]- 1, 2,5-th iadiazole, respectively.

Example 15 15 3-Amino-4-[3-(6-piperidinomethyl-2-pyridyfoxy)propylaminol1,2,5-thiadiazole A. 3-Amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5thiadiazole 1-oxide A solution of 3-(6-piperidinomethyl-2-pyridyloxy)propylamine (4.65 g; 18. 6 mmoles) [pre pared according to published United Kingdom Patent Application No. 2,098, 988] in 50 ml of methanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2. 74 g; 18.6 mmoles) 20 according to the general procedure described in United Kingdom Patent Application No.

2,067,987 to give a solution containing 3-amino-4-[3-(6-piperidinomethyl2-pyridyloxy)propy- laminoj-1,2,5-thiadiazole 1-oxide. A purified sample melted at 145-147'C.

B. N-[3-(6-Piperidinamethyl-2-pyridyfoxy)propyllethanediimidamide trihydrochloride A methanolic solution of the product prepared in Step A was diluted to 100 m] and 12.4 mi of concentrated HCI was added. The solution was stirred at ambient temperature for 18 hours, concentrated, and the residue was dissolved in 80 mi of water and extracted twice with CH2C12. The aqueous layer was concentrated, treated with n-propanol and concentrated under high vacuum to give the title compound as a foam.

C. 3-Amino-4-[3-(6-piperidinomethyl-2-pyridyfoxy)propylaminol-1,2,5thiadiazole A mixture of the crude product prepared in Step B in 80 mi of CH2C1, and containing 7.69 mi of triethylamine was treated with N,N'-thiobisphthalimide (DIVIF solvate) (7.35 9; 18.5 mmoles).

After stirring at ambient temperature for one hour, the mixture was washed with 50 mi of 4N 35 NaOH, water, saturated aqueous NaCI solution, dried (Na2S04), filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 100 9 of silica gel (230-400 mesh) using ethyl acetate-methanol (95:5) as the eluent to give 3.63 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate salt of the title compound, 40 mp 125.5-131 'C.

Anal. CaWd. for C,,H24N6OS C61-113NO3S: C, 50.07; H, 7.07; N, 18.58; S, 12.15 Found: C, 50.02; H, 7.03; N, 18.54; S, 12.14 Example 16 3-Amino-4-[3-(6-dimethylaminomethyl-2-pyridyloxy)propylaminol- 1, 2,5-thiadiazole When a methanolic solution of 3-(6 -d i methyl am i no methyl-2- pyridyloxy)pro pyla m i ne [prepared according to published United Kingdom Patent Application No. 2,098,988] is reacted with 3amino-4-methoxy-1,2,5-thiadiazole 1-oxide according to the general procedure described in United Kingdom Patent Application No. 2,067,987 and the resulting 3-amino-4-[3-(6-piperidinomethyi-2pyridyloxy)propylamino]-1,2,5-thiadiazole 1-oxide is successively reacted by the general procedure described in Example 1, Step A, and then by either Example 1, Step B, or Example 10, the title compound is thereby produced.

Example 17

3-Amino-4- (2[(6-dimethylaminomethyl-2-pyridyl)methytthiolethylamino) - 1, 2,5-thiadiazole When a suspension of 3-a m in o-4- {2-[(6-d i methyl am i no methy 1-2- pyridyl)methyith iolethyla m ino}-1,2,5-thiadiazole 1-oxide [prepared according to published United Kingdom Patent Applica tion No. 2,067,987] is successively reacted according to the procedures of Example1, Step A, 60 and then by either Example 1, Step B, or Example 10, the title compound is thereby produced.

Example 18 3-Amino-4- (2-[(6-piperidinomethyl-2pyridyl)methylthiolethylamino) - 1, 2,5-thiadiazole When a suspension of 3-amino-4-{2-[(6-piperidinomethyi-2- pyridyi)methyithio]ethylamino}- 65 GB 2 149 406A 20 1,2,5-thiadiazole 1-oxide [prepared according to published United Kingdom Patent Application No. 2,067,9871 is successively reacted according to the procedures of Example 1, Step A, and then by either Example 1, Step B, or Example 10, the title compound is thereby produced.

Example 19

The general procedure of Example 1, Step A, and then either Example 1, Step B, or Example is repeated except that the 3-amino-4-[3-(3piperidinomethylphenoxy)propylamino]-1,2,5- thiadiazole 1-oxide utilized therein is replaced by an equimolar amount of (a) 3-amino-4-[3-(3-piperidinomethyithiophenoxy)propylamino]-1,2,5thiadiazole 1-oxide, (b) 3-amino-4-[3-(3-dimethylaminomethyithiophenoxy)propylamino]-1,2,5thiadiazol e 1-oxide, (c) 3-amino-4-[3-(3-pyrrolidinomethyithiophenoxy)propylamino]-1,2,5thiadiazole 1-oxide, (d) 3-amino-4-[3-(4-dimethylaminomethyl-2-pyridyloxy)propylamino]-1,2,5thiadiaz oie 1-oxide, (e) 3-amino-4-[3-(5-dimethylaminoethyi-3-thienyloxy)propylamino]-1,2,5thiadiazo le 1-oxide, (f) 3-amino-4[3-(5-piperidinomethyl-3-thienyloxy)propylaminol-1,2,5thiadiazole 1-oxide, (g) 3-a m in o-4- {2-[(4-cl i methyl am i noethyl-2-pyridyl)methyith io]ethyl am i no} - 1, 2,5-th iad iazo le 1 oxide and (h) 3-amino-4-{2-[(4-piperidinomethyi-2-pyridyl)methyithio]ethylamino}-1, 2,5-thi adiazole 1-ox ide, respectively, and there is thereby produced (a) 3-amino-4-[3-(3-piperidinomethyithiophenoxy)propylamino]-1,2,5thiadiazole, (b) 3-amino-4-[3-(3-dimethylaminomethy[thiophenoxy)propylamino]-1,2,5thiadiazol e, (c) 3-amino4-[3-(3-pyrrolidinomethyithiophenoxy)propylamino]-1,2,5thiadiazole, (d) 3-amino-4-[3-(4-dimethylaminomethy]-2-pyridyloxy)-propylamino]-1,2,5thiadia zole, (e) 3-amino-4-[3-(5-dimethylaminomethy]-3-thienyloxy)propylamino]-1,2,5thiadiaz ole, (f) 3-amino-4-[3-(5-piperidinomethyl-3-thienyloxy)propylamino]-1,2,5thiadiazole, (g) 3-amino-4-{2-[(4-dimethylaminomethyi-2-pyridyi)methy[thio]ethylamino}1,2,5-t hiadiazole and (h) 3-amino-4-{2-[(4-piperidinomethyl-2-pyridyi)methylthio]ethylamino)-1, 2,5-thi adiazole, respec tively.

The above starting materials are prepared according to the general procedures described in 30 published U.K. Patent Application No. 2,067,987. The precursors of the starting materials are prepared by the procedures and analogous general procedures described in U.K. Patent Application Nos. 2,067,987, 2,098,988, 2,063,875 and published European Patent Applica tion No. 49,173.

Example 20 3-Amino-4-[3-(4-piperidinomethyl-2-pyridyfoxy)propylaminol- 1, 2,5-thiadiazole A. 3-(4-Piperidinomethyl-2-pyridyfoxy)propylamine When the general procedure for the preparation of 3-(6-p iperid i nom ethyl-2-pyridyl oxy) p ropy 40 lamine described in U.K. Patent Application No. 2,098,988 was followed except that the 2ch loro-6 -methyl pyrid i ne utilized therein was replaced by 2-bromo-4-methylpyridine, then the title compound was produced as an oil.

Anal. Calc'd. for C14H23N30, C, 67.44; H, 9.30; N, 16.85 Found: C, 67.54; H, 8.98; N, 16.55 B. 3-Amino-4-[3-(4-piperidinomethyl-2-pyridyfoxy)propylaminol-1,2,5thiadiazoie 1-oxide A solution of the product of Step A (6.5 g; 26.0 mmoles) in 90 mi of methanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1 -oxide (3.84 g; 26.0 mmoles) according to the general procedures described in U.K. Patent Application 2,067,987 to give 6.33 g of product.

Recrystallization from methanolacetonitrile yielded the title compound, mp 1 54-158"C.

Anal. Calc'd. for C,,H24N,OS: C, 52.73; H, 6.64; N, 23.06; S, 8.80 Found: C, 52.72; H, 6.30; N, 23.32; S, 8.74 C. N-[3-(4-Piperidinomethyl2-pyridyfoxy)propyllethanediimidamide trihydrochloride The product of Step B (5.0 g; 13.7 mmoles) was dissolved in 80 mi of methanol and treated with 9. 1 mi of concentrated HCL After stirring at ambient temperature for 4.5 hours, the solution was evaporated to dryness under reduced pressure to give the title compound.

D. 3-Amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylaminol-1,2,5thiadiazole A mixture of the product prepared in Step C in 50 mi of CH,CI, and 5.7 m[ of triethylamine was treated with N,N'-thiobisphthalimide (DIVIF solvate) (5.44 g; 13.7 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 40 mi of 4N NaOH, water, 65 GB 2 149 406A 21 saturated aqueous NaCI solution, dried (Na,S0j, filtered and evaporated under reduced pressure to give the crude product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (96:4) as the eluent to give 3.44 g of the title compound as a viscous oil. Treatment of the product with one equivalent of cyclohexyl sulfamic acid in acetone gave the cyclohexyl sulfamate of the title compound, mp 5 124.5-1 2WC.

R2 Anal. CaWd. for C161-124N60S.C.1---113NO3S: C, 50.07; H, 7.07; N, 18.58; S, 12.15 Found: C, 50.47; H, 7.12; N, 18.33; S, 11.87 Example 21 3-Amino-4- (3-[3-[1,2,3,6-tetrahydro-lpyridyl)methylphenoxylpropylamino)-1,2,5-thiadia zole The general procedure of Example 15 was repeated, except that the 3-(6piperidinomethyi-2pyridyloxy)propylamine utilized therein was replaced by an equivalent amount of 3-[3-(1,2,3,6- tetrahydro-l -pyridyl) methyl phenoxy)p ro pyla m i ne, to give 2.31 g of product, Crystallization from 15 toluene yielded the title compound, mp 99.5-104'C.

Anal. Calc'cl. for Cl,N2MOS: C, 59.10; H, 6.7 1; N, 20.27; S, 9.28 Found (corr. for 2.19% H20): C, 58.78; H, 6.71; N, 19.90; S, 9.26

Claims

1. A compound of the formula 1 A- (C13- 2)MZ(CH2)aNH, I" J-1n 11 wherein R' is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, R & (CH2) p - or R4 -ON - (CH2) p - in which p is 1 or 2, R 2 and R 3 each are independently hydrogen, (lower)aikyi, (lower)alkoxy or halogen, and, when R 2 is hydrogen, R 3 also may be trifluoromethyl, or R 2 and R 3, taken together, may be methylenedioxy, and R 4 is hydrogen, (lower)aikyl or (lower)aikoxy; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and A is 22 GB 2 149 406A 22 R7 RS R7 R5 5 N(CH2)q N(CH2)q RO 0 R6 S 10 R7 R5 or R7 RS 15 N(CH2)q- \N(CH2)q R6 R6 N 20 25 in which R5 is hydrogen, (lower)alkyi or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and R6 and R 7 each are independently (lower)alkyl, (lower)aikoxy(lower)aikyl in which the (lower)alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl(lower)alkyl, and, when R6 is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R 7 taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methyl pyrrol id i no, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, Nmethylpiperazino, 1,2,3,6-tetrahydropyridyi, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2]non-3-yi or 3pyrrolino; or a salt, hydrate or solvate thereof.

2. A compound of Claim 1 having the formula A- (CP-2) MZ (CE2) nNH,, 40 wherein RI is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or 3, Z is hydrogen or sulfur and A is R5 R5 R7 R7\ \NCH2 - NCH2 0 R6/ OY7 R S 50 R 5 55 R7 7 \ N CH2 _c \ NCH2 - or b 60R6 R6 N 60 in which R5 is hydrogen or methyl, and R6 and R 7 each are independently methyl or ethyl, or when taken together with the nitrogen to which they are attached, R6 and R 7 represent a 65 pyrrolidino or piperidino ring; or a salt; hydrate or solvate thereof.

23 GB 2 149 406A 23

3. A compound of Claim 1 having the formula R7 5 / CH. 2 R6 OCH2CH2CH2NH NHR1 Ila HN NH 10 wherein R' is hydrogen or methyl, and R 6 and R 7 each are methyl or, when taken together with the nitrogen atom to which they are attached, R 6 and R' represent a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

4. A compound of Claim 1 having the formula R7\\ NCH2 _ RS CH2SCH2CH2 NH NHO R6 0 lib HN NH wherein R' and R5 each are independently hydrogen or methyl, and R6 and R 7 each are independently methyl or ethyl; or a salt, hydrate or solvate thereof.

5. A compound of Claim 1 having the formula R7 \ NCH2 RS CH2SCH2CH2NH NHR1 6 R lic HN NH wherein R' and R5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl; or a salt, hydrate or solvate thereof.

6. A compound of Claim 1 having the formula R 6 R7 RS NCH2- OCH2CH2CH2NH NHR1 lid HN NH wherein R' and R5 each are independently hydrogen or methyl, and R 6 and R' each are 55 independently methyl or ethyl, or, when taken together with the nitrogen to which they are attached, R 6 and R 7 represent piperidino; or a salt, hydrate or solvate thereof.

7. The compound of Claim 1 which is W[3-(3-pi peri d i no methyl ph en oxy)propyl]etha ned i i m i damide, or a salt, hydrate or solvate thereof.

8. The compound of Claim 1 which is N-{2-[(5-dimethylaminomethyi-2furyl)methylthio]ethy- 60 1}ethanediimidamide, or a salt, hydrate or solvate thereof.

9. The compound of Claim 1 which is N-{2-[(5-dimethylaminomethyi-4-methyi2-thienyi)me- thyithio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof.

10. The compound of Claim 1 which is N-[3-(3pyrrolidinomethylphenoxy)propyi]ethanediim- idamide, or a salt, hydrate or solvate thereof.

24 GB 2 149 406A

11. The compound of Claim 1 which is N-{2-[(5-dimethylaminomethyi-3- thienyl)methyithio]ethyl} ethanediimidamide, or a salt, hydrate or solvate thereof.

12. The compound of Claim 1 which is N-{2-[(5-piperidinomethyl-3thienyl)methylthio]ethy1} ethanediimidamide, or a salt, hydrate or solvate thereof.

13. The compound of Claim 1 which is N-[3-(6-piperidinomethyi-2pyridyloxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof.

14. The compound of Claim 1 which is W[3-(4-p i pe rid i no methyl-2pyridyloxy)propyi]eth an ediimidamide, or a salt, hydrate or solvate thereof.

15. The compound of Claim 1 which is N- {3-[3-(1,2,3,6-tetrahydro-1 pyridyl) methyl phen ox10 y]propyl} ethanediimidamide, or a salt, hydrate or solvate thereof.

16. Process for preparing a compound of the formula 11 according to claim 1, comprising reacting, preferably in an inert solvent and at room temperature, a compound of formula A- (CH 2)mZ(CH2)nNH NHR' ill with a strong mineral acid, preferably hydrochloric acid, or reacting a compound of formula A-(CHAZ(CI-1201-12 IV with a compound of formula CH 3 0 \ -ACH 3 c -C ENII' \NH v to produce a compound of formula A-(W!,J Z(CE) NR\ OCH 2 n 3 V1 then reacting said compound of formula VI with a compound of formula WNI- 1, Printed in the United Kingdom for Her Majesty's Stationery Office. Dd 8818935, 1985, 4235Published at The Patent Office, 25 Southampton Buildings, London, WC2A l AY, from which copies may be obtained-