CA1209919A - Pharmaceutical methods and compositions - Google Patents

Abstract

Abstract Enhanced antiulcer activity is obtained in warm-blooded animals by the concomitant administration of the pepsin complexing agent, pepstatin, and an histamine H2-receptor antagonist of the formula

Description

~2~9~19 PE~R~CEUTICAL MEr~ODS AND COMPOSITIONS

Summary~ In~en-tion ~ n the treatment of peptic ulcers in warm-blooded animals, the concomitan~ administra~ion of the pepsin-complexing agent, pepstatin, and an histamine H2-re~ep~or antagonist of the formula (o) /s~
N N

A-(CH2)mz~cH2~n Rl wherein A, m, z, n, p and Rl are as defined below, provides enha~ced antiulcer activity, reduces the amount of ~he compound of Formula I necessary for effective treatment and thereby .-reduces the Siae efect ~iability of the compound of Formula I.
This invention relates to the method of treating peptic ulcers in wanm blooded animals by the concomitant adminis~ration sf pepstat~n and at least one compound of Formula I, and to phasmaceutical compositions conta~ning pepstatin and at least one compound of Formula I .

: Back~round of the Invention ~ . ~

Th~ precise cause of peptic ulce~tion in man is unknown although gastric acid is considered to be one of the essential factors in the etiology of thîs disease. It.recently was discovered that gastric acid secretion is mediated, at least in part, by histæmine H2-receptors located on parietal cells in the ~as~ric mucosa and that gas~ric acid output induced by - ~0~919 all secretagogues could be an~agonized by specific antagonists of these receptors [Blac~, J. W. et al., Nature, 236, 385-390 (1972); Brimblecombe, R. W. et al., J. Int. Med. Res., 3, 86-92 ~1975)]. The first successful commercial histamine H2-receptor antagonist, cimetidine (II), ~CN
N--~CH2St::H2CH2NH~NHCH3 H

is now in widespread use as an antiulcer agen~. A more recently introduced histamine H2-receptor antagonist, ranitidine (III), H~N ~ CH2SC~2CH2~NHc~3 III

is now being sold and used in several countries of the world~

The role of the proteolytic e~zyme, pepsin, in the etiology of ulc~ration is not completely understood. Pepsin has been shown to play a major role in the development of experimentally induced ulcer~ in animals, but this may be due to lesion enlaxgement by means of pepsin digestion of necrotic tissue rather than by causing the initial damage. It i~ also possible that pepsin is entirely responsible for the erosions and that the acid produces ~ain and retards healing~
De3~ _n of the Prior Art 1) Umëzawa, H. et al., in J. Antibiotics, 23, 259-262 (1970), disclose the pentapeptide, pepstatin, which has the structure 1~9 3 ~ / 3 ~ / 3 CH CH~ /CH3 CH~ ~CH3 lH ~H
fH2 ~x fH H2 IH CH3 IH2 ~H
CO_NH--1H--CO~ CH--C~NH--~H--CH-~H2-CO--~H-I~H-CO-NH-~H~H-CH;~-COOH
~L) tL) (L) and which is a specific complexing agent for the enzyme pepsin.
Pepstatin was found to prevent the formation of stomach ulcers in the pylorus ligated ~Shay) rat.

2) Miyawaki, et al.~ Ln Nagano-ken Noygo Sogo Shikenjo Chikus~n Shikenjo Kenkyu Hokoku, 14; 14-25 (1977) [as reported in Chemical Abstracts, 90, 34373X (1979)] report that the addition of pepstatin to the feed at >50 ppm inhibited pepsin activity in the gastric juice of swine and preYented the occurrence of ulcers.

3) Bonnevie, O. e~ al., in ~ut, 20, 624-628 (1979), report the results of a double-bl~nd randomized clinical trial of pepstatin versus placebo in patients having duodenal ulcers.
Pepstatin was administered in 100 mg doses~ given seven-times a day, this dosage being sufficient to inhibit the peptic aotivity of gastric juice for 18 hours a day. They found no significant difference between pepstatin and placebo in the healing or symptomatology of duodenal ulcer.

4) Svendsen, L. B. et al I in Scand. J. GastroentO, 14, 929-932 (lg7~ r report the results of a double blind randomized clinical trial of pepstatin vexsus placebo in patients having gastric ulcer. ~epstatin wa~ administered in 100 mg doses seven times a day. They were not able to detect any influence of pepstatin either on the healing or on the symptomatology of gastric ulcerO

5) StraussO ~. J. et al., in Surg. Forumr 28, 361-363 (1977), disclose that~ in stress ulceration tests in rats, two or more days of pretreatment with either cimet~dine or carbe~oxolone significantly decreased ulcer formation. When the two agents were given together, significant ulcer reduction l~ossJ 9 was found after only one-half day of predosing. Carbenoxolone is not an antisecretory or anti~pepsin agent, but acts by stimulating gastric mucus synthesis.

6) Dajani, E. Z. et al., in J. Pharmacol. Exp. Th~r., 210, 373-377 (1979), disclose that, ~n stress ulceration tests in rats, a combination of cimetidine and propantheline bromide produced synergisti~ antiulcer activity and that a combination of cimetidine and thiopropazate hydrochloride produced additive antiulcer actiYi~y. Propantheline bromide (an anticholLnergic agent~ and thiopropazate h~drochloride (a tranquilizer) each act by inhibiting gastric secretion.

7) Bri~ish ~edical Journal, 95-96 ~1980) re~ie~s the results obtained in a large number of studies wîth various new antiulcer agents. With regard to pepsin antagonists, it states:

"The results of using pepsin antagonistQ have been uniformly disappointing. Amylope~tin showed no signif icant beneit in patients with duodenal ulcer, and sucralfate showed none in those with gastric ulcer. Even pepstatin, the mo~t potent in-vitro and in-vi~o pepsin antagonist, was ineffective in a formal controlied trial in healing duodenal ulcer and in preventing recurrent bleeding in patients admitted with haematemesis and melaena~

&~ U.S. 4,101,650 discloses long-acting pepstatin floating minicapsules comprising center particles of sodium bicar~onate coated with a water-soluble film-coating agent, which are further coated with pepstatin and a water-soluble film coating agent. Because of the release of carbon dioxide in gastric j~ice, these minicapsules float in the stomach and provid~ pepsin suppression for 3-5 hours as compared with about 1 hour for plain pepstatin.

. _ .

~9 ~

9) Published United Kingdom Patent Application No.
2,067,987 discloses a large number of the histamine H2-receptor antagonists of Formula I herein which are utilized in the methods and compositions disclosed and claimed in the present invention.
However, it doe~ not disclose that such compounds may be administered concomitantly with pepstatin and thereby provide enhanced antiulcer activity.

Complete ~isclosure This invention relates to antiulcer therapy. In one aspect it relates to a pharmaceutical composition comprising a mixture of the pepsin-inhibi~ing agen~, pepsta~in, and at least one histamine H2-receptor antagonist of the formula (S)~

A-(C~2)mZ(CH2)nN ~ 1 wherein p is 1 or 2;
Rl is hydroxy or NR R ;
R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)al~;ynyl, cyclo(lower~alkylllower)al~yl, hyaroxy(lower~alkyl, (lower)alkoxy(lower)alkyl, (lower)-alkylthio(lower)al~yl, 2-fluoroethyl, 2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R2 is hydrogen, R3 may also be cyclo~lower)alkyl, amino(lower)alkyl, (lower~alkylamino~lower)-alkyl, di(lower)alkylamino(lower~alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino~lower~-alkyl, pyridvl(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower~alkyl, [lower)alkoxy, hydroxy~ amino and halo~en, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)~
alkoxy, 2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidinot A'-(CH2)m,Z'(C~2~n,-, phenyl, phenyl(lower)alXyl, substi~uted phenyl or substituted phenyltlower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower~alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di~lower)alkylamino; or R2 and R3, taken together, may be -CX2CH2X(~H2)r ;
r is an integer of from 1 to 3, inclusive;
X is methylene, sulfur, oxygen or N-R4, provided that, when r is 1, X is methylene;
R4 is hydrogen, (lower)alkyl, tlower)alkenyl, (lower)-alkynyl, (lower)alkanoyl or benzoyl;
m and m' each are independently an integer of ~rom zero to 2, inclusive;
n and n' each are independently an integer of from 2 to 4, inclusive;
Z and Z' each are independen~ly sulfur, oY~ygen or methylene;
A and A' each are independently phenyl, imidazolyl, thiazolyl, isothiazolyl~ oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from ~lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, NHR
-(C~ ) N-C / and -(CH2) NR5R , and the second subs~i~uent being selec~ed from ~lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy;
q is an integer of from O to 6, inclusive; R14 and X15 independen~ly are hydrogen or (lower)alkyl, or, if R14 is hydroaen, R15 also may be (lower)al~.anoyl or benzoyl, or R14 and R15, taken together, may be ethyl~ne; and ~ 5 and ~6 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, [lower)alkynyl~ ~lower)alkoxy(lower)al~yl, cyclo(lower~alkyl, phenyl or phenyl~lower~alkyl, provided that R5 aAd R6 may not both be cyclo(lower)alky~ or phenyl; or R5 and R6, taken together with the nitrogen atom to which they are . ., .

~20~g~9 attached, may be pyrrolidino, methylpyrrolidino, dimethyl-pyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, homopiperidino, hep~amethyleneimino or octame~hyleneimino;
or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.
In another aspect, this invention relates to the method of trea~ing peptic ulcers Ln a warm-blooded animal in need o such treatment which comprises concomitantly administering to said animal a peptic activi~y-inhibiting amount of pepstatin and an effec~i~e antiulcerogenic amount of at least one compound of Formula I, or a pharmaceutically acceptabie acid addition salt, hydrate or solvate ~hereof. In still another aspect~ this invention relates to the improvement in the treabment of peptic ulcers in a warm-blooded animal by the administration to said animal of an effective an~iulcerogenic amount of at least one compound of Formula I, or a pharmaceutically acceptable acid addition salt, hydrate or solvate thereof, which improvement comprises reducing the amount of the compound of For~ula I
necessary or effective treatment by concomitantly administering to said animal a peptic activity-inhibiting amount of pepstatin.

The compounds of Formula I are not themselves our invention~ but are the invention of our colleagues, Aldo A.
Algieri and Ronnie R. Crenshaw~

The compounds of Foxm~la I are relatively nontoxic substances, as demonstrated by pharmacological studies in an~mals of some of the compounds. These studies showed a toxicity profile substantially the same as that of the commercial H2-antagonist cimetidîne. Although widespread human usage of cimetidine has demonstra~ed it to be a relatiYely safe drug with a low incidence of side-effect~, it would, of course, be desirable to even further reduce the side-effect liability of such a drug. Some of the preferred compounds of Formula I have been shown by various animal studies to be up to about 400 t~mes ~8-as potent as cLmetidine as inhibitors of gastric secretion, depending on the animal model and route of administration. The preferred compounds of Examples 86 and 88 are about 30 and 15, respectively, times more potent than cimetidine by the oral route.
Based on this potency difference, the oral dosage of the compounds of Examples 86 and 88 would be about 1/30 and 1/1~ r respectively, that of cimetidine, thus reducing the expected incidence of side effects. The usual oral dosage of cimettdine is 300 mg, given four times a day, while the usual dosage of the compounds of Examples 86 and ~8 i5 about 10 mg and 20 mg, respectively, given four times a day~ It was an object of this invention to further reduce the necessary dosage of the compounds of Formula I by the concomitant administration of a peptic activity-Lnhibitory amount of pepstatin. As will be shown below, such concomitant adminis-tration pro~ides about a two- to ~hree-fold increase in potency compared with the administration of an equal amount of the compound of Formula I alone, thus permitting a further tw~- to three-fold reduction in ~he dosage of the compound of Formula I.

Pepstatin has also been shown by pharmacological studies in animals to be a relatively nontoxic substance; its ~D50 exceeded 3000 mg/kg in all animal species studied ~Svendsen, L. B. et al~, Scand. J. GastroentO, 11, 459-463 ~1976)]. It is essentially unabsorbed upon oral administration; no side effects were observed in human patients with ulcer dyspepsia recei~ing daily oral doses of 700 mg of papstatin for up to three months ~Svendsen, L. B. et al. (1976~ supra]. Pepstatin does not inhibit the production of pepsin but inhibits peptic activity by forming a 1:1 pepsin-pepst2tin complex which is devoid of proteolytic activity~

In patients with ulcer dyspepsia, it has been demon-strated ~hat pepstati~ inhibits gastric peptic activity, but has na effect on the gastric acid ty [Svendse~, L. B. et al., Scan. J. Gastroent., 11, 459-463 (1976)]. I~ contrast, the histamine ~2-receptor antagonist cimetidine has b~en shown to antagonize both basal a~d stimulated gastric acid secre~ion in normal volunteers [Burland, W L. ~t al~, Brit. J. Cl~n.
Pharmacol., 2, 481 486 (1975)~ a~d in patients with duodenal ~0~919 , ulcer tLongs~reth, G. F. et al., New England J. Med., 294, 801-804 (1976)~, but its effect on pepsin secre~ion is less marked [Binder, H. J. and Donaldson Jx., R. M., Gastroenterology, 74, 371-375 (1978)]. The resul~s of those studies indicate that pepstatin and cLmetidina act by dif~erent mechanisms. The inhibitory effect of the compounds of Formula I on gastri~ acid secretion is also significantly greater than on pepsin activity, and in this respect its pharmacological profile is sLmilar to that of cimetidine.
In the tests described below, gastric erosions produced i~ rats by the oral instillation of 1.0 mL of 0.75N HCl were com-pared with those in rats which had been pxetreated with the most preferred compound of Formula I (of Exampl~ ~) or with tha~
compound and pepstatin. Comparison tests utilizing pretreatment with the newer commercial product, r nitidine, and with rani~idine and pepstatin, are also shown. Ranitidine is about 4 and 6 times as potent as cime~idine as an ~nhibitor of gastric secretion, by the oral route, in the rat and dog, respectively.
~perimental Methods ~ modification of the method of Robert et al., lGastroenterology, 77, 433-443 (1979)] was employed to produce gastric erosions. Adult male, Long Evans rats weighing 280-30Q y (Blue Spruce Farms, Alton, New York) were used. The animals were individually caged znd food and water were removed 24 and 18 hours, respectively, prior to testing. On the following day, the test compound was administered orally to the animals 30 minutes before 1.0 mL of 0.75N HCl was ins~illed into the stomach by gavage. Animals treated with the combination of the test compound and pepstatin received the test compound 30 minutes before, and a fixed amount of pepstatin ~20 mg/kg po) 10 minu~es before, the hydrochloric acid was administered. Previous studies i~ our laboratories had shown that this dose of pepstatin ~20 mg/kg po) completely inhibited pepsin activity and antagonized ulcer ormation in the 18 hour pylorus ligated rat. One hour after receiving the HCl solution, the ~nimals were sacri~iced with an intraperitoneal injection of 0.2 mL of T-61~; a euthanasia solution (Na~ional La~oratories Corp.).

The stomachs were removed fxom the animals, cut along the greater curvature, opened, rinsed with saline and pinned out flat in a standard position for macroscopic examination and scoring of erosions. The stomachs were photographed with a Polaroi ~ Close Up camera tPolaroid Corporation) and scoring was determined rom the photographs. For scoring purposes, only those erosions with a minimum length of 1 mm were considered.
The se~exity of gastric ulceration was defined for each animal as the sum of the maxim~m continuous leng~hs (in mm3 of the erosionC satisfying the above criteria. Percent inhibition of lesion formation was defined as (mm erosion, vehicle control) - (mm erosion, test agent) X 100 ~mm erosion, vehicle control) Data were analyzed using the t test for unpaired data and ED50 values were calculated from the dose response data using probit analysis [Finney, Probit Analysis, 3rd ed., University Press, Cambridge, England (1971)].

The compound of Example 1 and ranitidine ~synthesized by the Medicinal Chemistry Research Department of Bri~tol Laboratories, Division of Bristol-Myers Company) were dissolved in one equival-ent of HCl and the pH adjusted to 5.5 with Na~H. A suspension of pepstatin (Banyu Pharmaceutical Co. $td.) in water was made by homogenizing ~he compound with a few drops of Tween-80~ (Atlas Chemical Industries). Each of these compounds were administered orally by gavage in a volume of 2 mL/kg.

Test Results . The i~stillation of HCl to untreated rats caused extensive gastric erosions consis~ing of elongated bands 1-10 mm long by 1-3 mm wide. These erosions were located primarily in the corpus (portion of the stomach which secretes acid and pepsin), while the antrum was not as severely affected and no lesions were~observed in the fores~omach (the non-secreto~y portion)~ These findings are similar to those reported by ~obert et al.~ in their initial description of this procedure.

~ ~, - ~099~9 Pretreatment of the rats with 25, 50 or 75 mg/kg of the compound of Example 86 prior to ins~illation of the HCl decreased the formation of gastric erosions in a dose-related manner. Pretreatment of the rats with the above amounts of the compound of Example 86 plus 20 mg/kg of pepstatin significantly enhanced the inhibitory effect of the compound of Example 86 when the latter was given at 25 mg~kg. An enhancement was also seen at 50 mg/kg, but the significance level was between .05 and .10. A small, non-~ignificant enhancement was observed at 75 mg/kg. Figure 1 shows, in graphic form, the percent of reductio~ in gas~ric erosions over that of the control rats (no pr~treatment) which was obtained at each of the dosage levels of the compound of Example 86 alone and with pepstatin. When the data shown in Fi~ure 1 were a~alyzed by probit analysis according to Finney, it was shown that the response to the compound of Example 86 was linear with respect to the log of the dose administered and that ~he addition of pepstatin shifted the dose response to the lef~ in a parallel manner. These data are shown in Figure 2. It may be seen from Figure 2 that the ED50 values for the compound of Example 86 alone and with pepstatin were found to be 82 and 46 mg/kg, respectively, thus showing that the combination had approximately twice the potenGy of the compound of Example 86 alone.

Pretreat~ent of the rats with a 25, 50, 100 or 200 mg/kg dose of the compound of Exampl~ 88 prior to instillation of the HCl also decreased the formation of gastric erosions in a dose-related manner. Pretreatment of rats with the above amounts of the compound of Example 88 plus 20 mg/kg of pepstatin significantly enhanced the inhibitory effect of the compound of Example 88 when the latter was dosed at 25 or 50 mg/kg. No further enhancement of the inhibitory effect over that of the compound of ~xa~ple 88 alone occurred when pepstatin and 100 mg/kg or 200 mg~kg of the compound of Example 88 were used for pretreatment. Figur¢ 3 shows, in graphic form, the percent of reduc~ion in gastric erosions over that of the control r~ts (no pretreatment) which was obtained at each of the dosage le~els of the compound of Example 88 alone and with pepstatin. When ~he ~L~

data shown in ~igure 3 were analyzed by probit analysis according to Fi~ney, it was shown that the response to the compound of Example 88 was linear with respect to the log of the dose administered. Furthermore, with concomitant administration of pepstatin, the response was also linear with respect to the log dose of the conpound of Example 88, but the two lines were not parallel. These data are shown in Figure 4. It may be seen from Figure 4 that the ED50 values for the compound of Example 88 alone and with pepstatin were found to be 63 and 25 mg/kg, respectively. At the ED50 level, the combination was 2.5 tLmes as potent as ~he ~ompound of Example 88 alone.

Pretreatment of rats with a 25, 50, 75 or 100 mgjkg dose of ranitidine pr~or to instillation of the ~Cl similarly decreased the formation of gastric ero~ion~ in a dose-related mannex. No enhancement of ~ha inhibitory effect over that of ranitidine alone occurred when pepstatin was given along with ranitidine. Figure 5 shows, in graphic form, the percent reduction in gastric erosions over that of the control rats ~no pretreatment), which was ob~ained at each of the dosage levels of ranitidine alone and ranitidine plus pepstatin. When the data shown in Figure5 were analyzed by probit analysis according to Finney, it was shown that the response to ranitidine was linear with respect to the log dose of the compound and that the addition of pepstatin shifted the dos~ response to the lef~ in a parallel manner~ These data are shown in Figure 6. It may be seen from Figure 6 that the ED50 ~alues for ranitidine alone and the ranitidine-pepstatin combination were found to be 123 and 104 mg/kg, respectivel~.
The ratio of potencies of the combination to ranitidine alone was 1.18, which wa3 not statistically different from unity.

The data fro~ these tests are summarized in Table 1.
It may be seen that the ED50's or the compounds of Examples 86 a~d 88, give~ alone, were about 1.5 and 2 tLmes, respectively, more potent than ranitidine given alone. When each of these compounds were administered wi~h pepstatin, the compounds of Examples 86 and 88 were about 2.3 and 4.2 times, respectively, ~a~0~919 more potent than ranitidine plus pepsta~in.

Table 1 CQmparison of the Compound of Exam~le 1 and_Ra~itidine in Inhibit-in HCl-Induce~ Formation of ~astric Lesions Alone or in Combina-tion with Pepstatin . . ~
. ED50 (mg!kg) for Inhibition of Ulcer Formation . _ . _ _ Compound . . Alone . with Pepstatin Potency Ratio _ _ _ _ _ _ Compound of Example 88 63 25 2.5 Compound of Example 86 82 46 1~8 Ranitidine 123 104 1.18 .~ _, aRatio of potency (cpd. alone) to pote~cy of combination (cpd.
plus pepstatin).
bDefi~ed as ratio of ED50 (cpd. of Example 88 alone~ to ED50 (cpd. of Example 88 plus pepstatin~; dose-response lines were nonparallel.

Antagonism o~ H2-receptors and the subsequent anti-secretory e~fect probably is not ~he mechanism of the antiulcer ef~ect in this test~ since exogenous HCl ~s beLng supplied.
P~.pstatin i~ only poorly absorbed following oral a~ministration as animal studie~ have shown that more than 90 percent o~ the compo~nd is excreted in ~he feces within 72 hour3. Therefore, the inhibition of proteolytlc activity following oral adminis-tratlon of pepstatin is due primarily to a local effect of this compound.

I~ oxder to obtain the maximum benefit of the present invention, it is desirable ~hat the dosage of pepstatin be such that there is substantially complete inhibition of gastric pepsin activity for as long a per~od of the day as practical. When ~2099~9 pepstatin was administered to ulcer patients in 100 mg doses seven ~imes a day ~with meals, two hours after mea~s and at bedtime~ pepsin acti~ity was inhibited for 18 ho~rs a day.

In one preferred embodiment o~ this invention, pepstatin i5 adminis~ered in dosages o~ about 100 mg seven times a day. In another preferred embodimen~ of this invention, pepstatLn is administered in dosages of abou~ 175 mg four times a day. In a more preferred embodiment of ~his inven~ion the pepstatin is administered ln the form of floa~ing minicapsules as described in U.S. Patent 4,101,6500 The pepsta~in floating minicapsules provide pepsin suppression for about 3-5 t~mes as long as plain pepstatin and, in ~hls form, may be administered? for example, four times a day in a dosage of f loating mInicapsules containing about 100 mg of pepstatin.

The dosage of the compou~ds of Formula I to be adminis-tered conco~itantly with pepstatin will depend not only on s~ch factors as the weight of the patie~t, but also on ~he degree of gastric acid inhibition desired and ~he potency of the particular compound being utilized. The decision as to ~he particular dosage to be employed is within the di~cretion o~ the physician.
In the Heidenhain Pouch Dog test described below, c~metidine has an oral EDSg of approximately 3.3 ~moles/kg. The usual human adult oral dose of cimetidine is 30G mg, given four time~ a day~
The usual human adult start~ng oral dosages of the compounds of Formula I Cwithout pepstatin) are readily determined from their oral ED50 in this same te~t. Thus, if the oral D50 ~ a particular compound of Formula I is 0~33 ~moles/kg, the usual st~rting dosage (without pepstatin) would be approximately 30 mg, given four times a day, etc~ When administered concomitantly with pepstatin, the usual starting dose would be approx~mately 15 mg, gi~en four times a day~ Similar calculations may be made for parenteral dosages. These starting dosages (and the number of times administered per day) may, of course, be varied by titration of the dosage to the particular circumstanc~3 of the specific patient.

~, ~0~

It will be appreciated by those skilled in the art that,-to obtain the benefits o~ the present invention, it is not neces-sary ~o physioally combine the compound of Formula-I and .
pepstatin in a single unitary dosage form. Not only may ~he two active ingredients be ta~en separately, but they may even be given by different routes of adm~nistration. Although pepstatLn provides its effects by local action in the stomach and must be given orally, the compound of Formula I may ~e given orally or parenterally. For convenience, however, it usually i5 preferred to administer it orally.

The present invention pro~ides a method for the treat-ment of peptic ulcers in a warm-blooded animal in need of such treatmen~ which compxises concomitantly administering ~o said animal a peptic activity-inhibiting amount of pepstatin and an effective antiulcerogenic amount of at least one compound of Formula I, or a pharmaceutically acceptable acid addition salt r hydrate or solvate thereof. In man, the usual dosage of the preferred compounds of Formula I is from about ~ to about 100 mg ~and most preferably from about 4 to about 50 mg), gi~en three or four times (and most preferably four times) a day~ With particularly preferred compounds of Formula I, the usual dosage is f_om abou~ 2 to about 50 mg, and preferably from about 4 to about 25 mg. The preferred dosage of pepstatin in man is from about 100 mg when administered about seven times a day, to about 175 mg when administered about ~our time a day. However, in a more prefexred embodLment of this invention, when the pepstatin i~ in the form of pepstatin floating mLnicapsules, the preferred dosage is ~hat amount of minicapsules containing about 100 mg of pepstatin, administered about four times a day.

The present invention also provides an improvement in the method o~ treatment of peptic ulcers in a warm-blooded animal by administering to said animal an effective antiulcero-genic amount of at least one compound of Formula I or a pharma-ceutic~lly acceptable acid addition salt, hydrate or sol~ate thereof, which improvement comprises reduc~ng the amount of the compound of ~ormula I necessary for effect~ve treatmPnt by ., 1~099~

concomitantly administering a peptic activity-Lnhibiting amount of pepstatin. The preferred dosage of pepsta~Ln and of pepstatin floating minicapsules in man is as described in the preceding paragraph.

There is also provided by the present invention a pharmaceutical composition useful ~n the treatment of peptic ulcers, in unit dosage form, which comprises a peptic activity-~nhibiting amount of pepstatin and an effective antiulcerogenic amount of at least one ~ompound of Formula I, or a pharmaceutically acceptable acid addition salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier. In a preferred embodiment the unitary dosage form contains from about 2 to about 100 mg (and mos~ preferably from about 4 to a~out 50 mg) of one o~ the preferred compound~ of Formula I and from about 100 to about 175 mg of pepstatin. In particularly preferred embodiments, the composition con~ains from about 2 to about 50 (and most preferably from about 4 to about 25) mg of the compound of Example 1, plus from about 100 to about 17S mg of pepstatin.

As used herein, reference to a pharmaceutically accept-able acid addition salt of a compound of Formula I means ~he mono-or disalt with a nontoxic pharmaceutically acceptable organic or inorganic acid. Such acids are well known and include hydrochloric, hydrobromic ~ sulfuric, sulf amic, phosphoric, nitric, maleic, fumarie, succinic, oxalic, benzoic, methane-sulfonic, ethanedisulfonic, benzenesulfonic, acetic, propionic, tartaric, ci~ric, camphorsulfonic, levulinic and the like. The salts are made by ~ethods known in the art.

~ he present inventio~ incl~des within its scope the use of all possible tautomeric forms, geometric isomers, optical i~omers and zwitterionic forms of the compounds of Formula I~ as well as mixtures ~hereof. As used herein and in the claims, the terms "(lower)alkyl,n n ~lower)alkenyl,n n (lower)alkynyl,~ U(lower)-alkoxy" and "(lower)al~ylthio" mean, in their broadest sense, ~2099~

straight or branched chain alkyl, alkenyl, alkynyl, alkoxy ~nd alkylthio groups containing from 1 to 12 carbon atoms. Prefer-ably, these groups contain from 1 to 8 carbon atoms and, most preferably, from 1 ~o 6 carbon atoms.

In practicing the present invention, a ~ide variety of pharmaceutical forms may be employed for the ad~inistration of the compound of Formula I and pepstatin, or the pharmaceutical composition containing both entities~ Thus, if a solid carrier is used, the preparations 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 liqu~d carrier is used, the prepara-tions may be in the ~orm o~ a soft gelatin capsule, syrup, emulsion, aqueous or non-aqueous susp~nsion or, in the case of the compounds of Formula I, a sterile solution or suspension for Lnjection. These pharmaceutical dosage forms are prepared by conventional techniqueæ.

In ~ preferred embodiment of the invention the compounds of For~ula I have the structure (O) p ~ Id \\ Y
A-(CH2)~(CH2)nN ~ R R
herein p is 1 or 2;
R2 and R3 each are indepen~ently hydrogen, (lower)alkyl, (lower)al~enyl, ~lower)alkynyl or cyclo~lower)al~yl(lower~al~yl~
or, when R2 i5 hydrogen, R3 also may ~e pyridyl(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituen~ selected from (lower~alXyl, (lowPr)alXoxy, hydroxy, amino and halogen, A '-(C~2~m'Z'(CH2)n'~, phenyl(lower)-alkyl or 3, 4-methylenedioxybenzyl;
m and m' each are independently zero or l;
n and n ' each are independently 2 or 3;
Z and Z' each are independently sulfur, oxygen or methylene;

~Z~)9919 A a~d A' each are independently phenyl, Lmidazolyl, thiazolyl, furyl~ thienyl or pyridyl; prvvided that ~ and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, NHR
-N=C \ 15 and -CH2NR R6, NHR

and the second substituent being selected from (lower)alkyl;
R14 and R15 independentl~ are hydrogen or ~lower)alkylO
or R14 and R15, taken together, may be ethylene; and R5 and R6 each are independen~ly hydrogen or (lower)~
alkyl; or ~5 and R6, taken tcgether with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dime hylpyrrolidino, morpholino, thiomorpholino, piperidino, me~nylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino~ homopiperidino, heptamethyleneimino or oct methyleneImino;
or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

In a~other preferred embodLment of tbe invention the compounds of Formula I have the s~ructure /s)~
~ 3 - NC~ ~ C~2Z~2c~2N ~ R2R3 Ie wherein p is 1 or 2; Z is sulfur or methylene; R~ and R3 each are independently hydrogen or tlower)alkyl, or, when R i~
hydrogen, ~3 also may be (lower)alkenyl, (lower)alkynyl,-phenyl(lower)alkyl, cyclo(lower)alkyl~lower)alkyl, pyridylme~hyl or ~JL9 -C~2CH2~C~2 ~ R

R16 ;s methyl and R13 is hydro~en or methyl, or R16 and R13, taken together with the nitrogen atom to which they are attached, may be piperidino; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment of the invention the compound~ of Formula I have the str~c~ure (O)p RlSN / ~ ~ CX2ZCH2CH2N ~ ~ R2~3 wherein p is 1 or 2; Z is sulfur or methylene;,~14 and R15 i~dependently are hydrogen or methyl, or, R14 and R15, taken together~ may be ethylene; and R2 and R3 each are independently hydrosen or ~lower)al~yl, or, when R is hydrogen, R also may.
be (lower)al~enyl, tlowerJal~ynyl, pyridylmethyl, H

~ ~ = ~ or -C~2C 2 2 or a nontoxic pharmaceut~cally acceptable salt, hydrate or solvate thereof.

In another preferred embodiment of the invention the compounds of Formula I have the structure ~20~3~9 ~13 (O)p NCH2 ~ ~ N~ S \ N

~2ZcH2cH2~7~ NR R
wherein p is 1 or 2, Z is sul~ur or methylene; R2 and R3 eaeh are independently hydrogen or ~lower)alkyl, or when R is hydrogen, R3 also may be ~lower)alkenyl, (lower)-alkynyl or ~ ~ C~ N ~

--CH2C~2SCH2 and R13 is hydrogen or me~hyl; or a n~ntoxic phanmaceutically acceptable salt, hydrate or solvate thereof.

IA another preferred embodi~e~,t of the invention the compounds of Formula I have the structure ~ ~N Ih - NCH ~ ~ CH2ZC~z 2 NR2R3 wherein p is 1 or 2; Z is sulfur or me~hylene; R2 and R3 . each are independen~ly hydrogen or (lower~alkyl, or, when R2 is hydrogen, R3 also may be (lower)alk~nyl, tlower~
alkynyl, phenyl~lower)al~yl~ pyridylmethyl, 3,4-methylenedioxybenzyl or ~2C)99~9 -C~2CH2SCH2 ~ C~2N/
c~3 and R13 is hydrogen or methyl; or a no~toxic pharmaceutically acceptable sal~, hydrate or solvate thereof.

In another preferred ~bodiment of the invention the compounds of Formula I have the structure ~ (O) C~zSc~zc~2N~ NR R3 Ii wherein p is 1 or 2; and R2 and R3 each are independently hydrogen or (lower)alkyl, or, when ~2 is hydrogen, R3 als~ may be (lower~alkenyl, (lower)alkynyl or ~ N

CH2C~25C~

or a n~ntoxic phanmaceutically acceptable salt, hydrate, or solvate thereof.

In another preferred embod~ment of the invention the compounds of Formula I have the structure ~20~

S ,~
~ N N
R6~ 2~LCH;2ZCH2CH2N~R2R3 Ij wherein p is 1 or 2; Z is Qulfur or me~ylene; ~2 and R3 each are independently hydrogen or (lower)alXyl, or, when R2 is hydrogen, R also may be ~lower)alkenyl, tlower)alkynyl or ~ H2CH2ZCH2¢~L ~R6 and ~5 and R~ each are independently hydrogen or (lower)a~kyl, or~ ~5 and R6, taken together with the nitrogen ato~ ~o which they are attached, may be piperidino; or a nontoxiç, pharma-ceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment of the invention the c~mpounds of Formula I have the structure ~O) p ~6 / 2 ~ CR2CH2C~2N ~ NR2R3 Ik wherein p is 1 or 2; ~ is oxygen or sulfur, R2 and ~3 each are independently hyarogen or tlower~alkYl, or, when R is hy~rogen, R3 als~ may be tlower)alkenyl, tlower)al~ynyl, pyridylmethyl or ~2~99~9 -CH2c~2cH2z ~ \ R

and RS and R6 each are indep~ndently hydrogen or (lower)alkyl, or, when RS is hydrogen, ~6 also may be (lower)alkenyl or (lower)alkynyl; or R5 and R~, ta~en together with the nitrogen to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, me~hylpiperidino, d~methylpiperidino, homopiperidino or heptame~hyleneimino;
or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment of th~ invention the compounds of Formula I have the structur~
~S)P

2 ~ C=N ~ ZCH2CH2CH2 ~ N~2R3 Il wherein p is 1 or 2; Z is oxygen or sulfur; R2 and R3 each are independently hydrogen or (lower)alkyl, or, when R is hydrogen, R3 may be ~lower)alkenyl, (lower)al~ynyl, pyridylmethyl or --CH2CH2CH2Z~L \

or a nontoxic pharmaceutically acceptable -~alt, hydrate or s~lvate thereof.

As presently envisaged, the particularly preferred compound~ of Formula I utilized in this invention are i ~9~9 a) 3-{2-[(5-Dimethylaminomethyl-2-furyl)-me~hylthio~ethylamino}-4-methyl~ino-1,2~5-thiadiazole l,l-dioxide, b) 3-{Z-t(5-Dime~hylaminomethyl-2 furyl)-methylthiolethylamino} 4-methylamino-1,2,5-thiadiazole l-oxide, c) 3-{2-[(S-Dimethylaminomethyl-2-furyl)-methylthio~e~hylamino}-4-cthylamino-1,2,5-thiadi~zo7e l-l-dioxide, d) 3-{2-[(S-~Lmethylaminomethyl-2-furyl)-methylthio]e~hylamino}-4-(n-propyl)amino-1,2,5-~hiadiazole l,l-dioxide, e) 3-Allylamino-4-{2-~(5-dimethylaminomethyl-2-furyl~methylthio~ethylamino~-1,2 t S-thiadiazole l,l-dioxide, ~ ) 3-{2- E (S-Dimethylzminomethyl-2-fury~)methyl-thio]ethylamino~-4-(2-propynyl)amino-1,2,5-thiadiazole .l,l-dioxide, g) 3-{2-[(5-Dimethylaminomethyl-2-furyl)me~hyl-thio]ethylamino}-4-amino-1,2,5-thiadiazole 1,l-dioxide, h) 3-{2-t~5-Dimethylaminomethyl;2-furyl)methyl-~hioJethyla~ino~-4-amino-1,2,5-thiadiazole l-cxide, ~ 3-Amino-4-t3-~3-pyrrolidinomethylphenoxy)-propylamino]-1,2,5 thiadiazole l,l-dioxide, j~ 3-~4~5-Dimethylamino-2-furyl)butylamLno}-4-methylamino-1,2,5-thiadiazole l,l-dioxide, ~20~9~.9 k~ 3-Methylamino-4-[3-(3-pyrrolidinomethylphenoxy)-propylamino3 1,2,5-thiadiazole 1,l-dioxide, 1) 3-{2-[(2-Guanidino~hiazol-4-yl)methylthio~-ethylamino}-4-methylamino-1,2,5-thiadiazole l,l-dioxide, m) 3-{2-[(2-Guanidinothiazol-4-yl)methylthio]-ethylamino}-4-~2-propynyl)amino-1,2,5-thiadiazole l,l-dioxide, n) 3-Amino 4-t3 (3-pyrrolidinomethylphenoxy)-propylamino3-1,2,5-thiadiazole l-oxide, o~ 3-{2-~2-Guanidinothiazol-4-yl)methylthio]-ethylamino}-4-amino-1,2, S-thiadiazole l,l-dioxide, p) 3-{2-1(2-Dimethylaminomethyl~4-thiazolyl)-methylthio]ethylamino}-4-methylamino-1,2,5-thîadiazole l,l-dioxide, , .

q) 3-{2-t~5-Dimethylaminomethyl-2-thienyl)-methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole dioxide, r) 3-{2-t(5-Dimethylaminomethyl-2-furyl~-methylthio~ethylamino}-4-ethylamino-1,2,5-thiadiazole l-oxide~

s) 3-Amino-4-{3-t3-(4-methylpîperidinomethyl)-phenoxylpropylamino}-1,2,5-thiadiazole l,l-dioxida, t) 3-Amino-4-~2-[(2-guanidinothiaZol-4-yl)methyithiOl~
ethylamino~-1,2,5-thiadi~zole 1 oxide, u) 3-8enzylamino-4-{2-[~5-dimethylaminomethyl-2~
uryl)methylthiolethylamino}-1 t 2,5-thiadiazole l,l-dioxide, ~ ) 3-{2~(3-~imethylaminomethyl}phenyl)methylthio]-ethylamino}-4-methylamino-1,2,S-~hiadiazole 1 r l-dioxide, g w) 3-Amino-4~¦2-~(3-{dimethylaminomethyl}phenyl)-methylthio~ethylamino}-1,2,5-thiadiazole l-oxide r xj 3-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]-ethylamino} 4-methyl~mino-1~2,5-thiadiazole l-oxide, y) 3-Amino-4-t4-(5-dimethylaminomethyl-2-furyl)-butylamino}-1,2,5-thiadiazole l,l-dioxide, z) 3-Amino-4-{2-~t2-dimethylaminomethyl-4-thiazolyl)methylthio~ethyIamino~}-1,2,5-thiadiazole 1,1-dioxide, . aaS 3-Butylamino-4-{2-~(5-dimethylaminomethyl-2-furyl)methylthio~ethylamino}-1,Z,5-thiadiazole 1,l-dioxide, bb) 3~CyclopropylmethylamLno-4-{2-[(5-dime~hylamino-methyl-2-fu~yl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide, cc) 3-{2-t(5-Dimethylaminomethyl-2-furyl)methylthiol~
ethylamino}-4-tt2-pyri~yl~methylamino~-1,2,5-thiadiazole l,l-dioxid~, dd~ 3-Amino-4-{3-~3-~4-methylpiperidinomethyl)-phenoxy3propylamino}-1,2,5-thiadiazole l-oxide, ee) 4-{2-[(5-DimethylamInomethyl-2-thienyl)-methylthio~ethylamino}-3-(1-propylamino)-1,2,5-thiadiazole l,l-dioxide, ff) 3-{2-~(2-Guanidinothiazol-4-yl)methylthiol-ethylamino}-4-methylamino-1,2,5-thiadiazole l-oxide, g~ 3-{ 3- I3- (hexamethyleneiminomethyl)phenoxyJ-propyl~mino~-4-methylamino-1,2,5-thiadiazole l,1-dioxide, ~ . ,, ~09~9 hh) 3-[3-(3-dimethylaminomethylphenoxy)propylamino~-4-methylamino-1,2,$-~hiadiazole 1,l-dioxide, ii) 3-Amino-4-~3 [3-~hexamethyleneiminomethyl)-phenoxy~propylamino}-1,2,5-thiadiazole l-oxîde, ~ ;) 4-{2-t(5-Dimethylaminomethyl-2-thienyl)-methylthio~ethylamino}-3-(3-pyridyl)methylamino-1,2,5-thiadiazole l,l-dioxide, kk) 3-Amino-4-t3-(3-morpholinome~hylphenoxy)-propylaminoJ-1,2,5-thiadiazole l~l-dioxide, 11) 3-Methylamino-4-[3-(3-morpholinomethylphenoxy)-propylamino]-1,2,5 thiadiazole 1,l-dioxide, mm) 3-Amino-4-t3-t3-dime~hyl~minomethylphenoxy)-propylamino]~1,2,5-thiadiazole l-oxide, nn~ 3-Amino-4-t3-[3-(heptamethyleneLminomethyl~-phenoxy]propyl~mino}-1,2,5-thiadiazol~ l-oxide, oo) 3-~(3-Pyridyl)me~hylamino]-4-t3-(3~piperidino-methylphenoxy)propy~aminol-1,2,5-thiadiazole l-oxide, pp) 3-Amino-4-{2-1(2-~2-methylguanidino}thiazol-4 yl)methylthio~ethylamino~-1,2,5-thiadiazol~ l-oxide, qq) 3-MethylamLno-4-[3-(3-piperidinomethylphenoxy)-propylamino]~ ,5-thiadiazole l,l-dioxide, rr) 3-Amino-4-t3-~3-piperidinomethy~phenoxy) propylamino~-1,2,5-thiadiazole l-oxide, ss) 3-{2-[(5-Dimethylaminomethyl-2-thienyl)-methylthio~ethylamino3-4-ethylamino-1,2,5-thiadiazole 1,1-dioxide, ~2Q~3L9 tt) 3-Amino-4-[3-~3-piperidinomethylphenoxy)-propylamino]-1,2,5-thiadiazole l,l-dioxide, uu) 3-~mino-4-t3-(3-guanidinophenoxy)propylamino~-1,2,5-thiadiazole l-oxide !

His'amLne H2-receptor antagonists have been shown to be effec~ive inhibitors of gastric secretion L~ animals, including man, Brim~lecombe et al , J Int. ~ed. ~es., 3, 86 (1975).
Clinical evalua~ion of the histamine H2-receptor antagonist cimetidine has shown it to be an effectiYe ~herapeutic agent i~
the treatment of peptic ulcer disease, Gray et al., Lancet, 1, 8001 (1977~. Two of the standard an~mal models for de~ermining gastr~c antisecretory actiYity o~ histamine H2-antagonists are ~he Gastric Fistula Ra~ and the Heidenhain Pouch Dog. The ED50is for some of the compounds of Formula I in these two animal models are giYen in Tables 2 and 3, below~

Determination of Gastric Antisecre~orY
_ Activit in the Gastric Fistula Rat Y, ._ _ Male Long Evans rats w~ighing about 240-260 grams at the t~me of cannula implan~ation are used. The design and implantation of the stainless steel cannula into the anterior wall o the fore-stomach are carried out essentially as described by Pare et al. ~Laboratory Animal 5cience, 27, 244 (1977)].
The fistula components are designed and the operati~e procedu~e is carried sut exactly as described in the aboYe referenceO Post operatively the animals ~re individually housed in so}id bott~m cages with sawdust and are allowed food and water ad libitum throughout the entire recovery period. An~mals are not used for test purposes for at least 15 days after the operative procedure.

The animals are fasted but allowed water ad lib1tum for 20 hours before the testing procedure is to begin. ~mmed-iately prior to collection, the cannula is spened and the stomach washed gently with 30-40 mL o~ w~r~ saline or distilled ~ ,, ~2Qg~19 water to remove any residual contents. ThP catheter is then screwed into the cannula in place o 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 ce~er to accommodate ~he catheter which hangs through i~. In this way ~he rat is not re tricted 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)3.

Gast~ic secretions collected during the first hour after washing ~he stomach are discarded as they may be contam-inated. For oral evalua~ion, the catheter is then removed fr~m the cannula and replaced with the plugging screw. Water (2 mh/kg) is a~ministered orally via gastric intubation and the animal i~
returned to the cage ~or 45 minutes. After this time the plug-ging screw is removed and replaced with a catheter to which a small plastic vial has been attached to col~ect the gastric secretions. A two hour sample is collected (this represents the control secretion~, the catheter removed and replaced with the plugging screw. ~he test drug i~ now adminis~ered 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 aktached to a small plastic vial and another 2 hour sample is collected. The secretions in the second sample are compared ~o those of the cc~trol sample ~n order to determine the ef ects of the tPst drug.

~ hen test compounds are to be evaluated paxenterally, the animal is injected ip or sc with the test compound vehicle in a volume of 2 mL/kg ~mmediately af ter discarding the initial 60 minute collection. A two hour sample is collected ~control secretion) and the animals are injected e~ther ip or sc with the test compound in a volume of 2 mL/~g. An additional two hour sample is collected and it~ secretions are compared to those of the control period to determing drug effects.

~209~

The samples are centrifuged in a graduated tube for volume determination. Titratable acidity is measured by titrating a one mL sample to pH 7.0 wi~h 0.02N NaOH0 using an Autoburet and an electrometric pH meter (Radiome~er). Titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in milli~
equivalents per liter.

Results are expressed as percent inhibition relative to control re2dings. Dose response curves are cons~ructed and E~50 values are calculated by regression analyses~ At least three rats are used at each dosage level and a minim~m of three dosage levels are utilized for determination of a dose response curve.

Determination of Gastr~c Antisecretor~
Actitity in the Heid_nhain Pouch Dog Prior to surgery, hematology and blood chemistry pro-files are obtained and an assessment made as to the genera~
health of selected female dogs. Dogs are vaccinated with Tissue Vax 5 (DHLP - Pitman-Moore) and housed in general animal quarters for four weeks' obser~ation so incipient diseases ~ay become apparent. Dogs are fasted w~th water ad libit~m 24 hours prior to surgery.

Anesthesia is induced with Sodium Pentothal (Abbott) 25-30 mgjkg iv. Subsequent anesthe~ia ~s maintai~ed with methoxy-flura~e (Pitman-Moore~. A mid-line linea alba incision from xiphoid to umbilicus provides good exposure and ease of closure.
The stomach i5 pulled up into the operative field, the greater curvature stretched out at multiple points and clamps placed along the selected line of incision. The pouch is made from the corpus of the stomach 50 that true parietal cell juice is obtained. About 30~ of the corpu~ volume is resected. The cannula is made of light-weight, biologically-inert material such as nylon or Delrin with dimensions and attachments after De~ito and Harkins [J. Appl. Physiol., 14, 138 ~1959)~. Post operatively, ~209~

dogs are medicated with antibiotics and an analgesic~ They are allowed 2-3 months for recovery. Experiments are carried out in the following way: Dogs are fasted overnigh~ ~18 hours~ with water ad _bitum prior to each expeximent. The dogs are placed Ln a sling and a saphenous vein cannulated for drug administra~ion.
Histamine as the base (100 ~g/kg/hr) and chlorpheniramine maleate (0.25 mg/kg/hx) are in~used continuously (in a ~olume of 6 mL/hr) with a Harvard infusion pump.

Ninety minu~es' infusion are allowed for the dogs to reach a steady state of acid output. At this time the drug or normal saline ~control) is administered concomitantly with the secretagogue in a volume of 0.S mL/kg over a 30 second period.
When oral studies are to be carxied out, the drug is adminis~ered via gastric gavage in a volume of 5 mL/kg. Infusion of the secretagogue i~ continued and 15 minute samples of the gastr;c juice are taken for 4.5 hours. Each sample is measured to the nearest 0.5 mL and titratable acidity is determined by titrating a 1 mL 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 concen~xation in milliequivalents per liter.

Results are expressed as percent inhib~tion relative to control readings. Dose response curves are constructed and ED50 values are calculated by regression analyses. From 3 to 5 dogs a~e used at each dose le~el and a min~mum of three dosage levels are utilized for determination of a dose response curve.

Table 2 Effect of Compounds of ~ormula I on Gastric Acid Output in the Two-Hour Pylorus Li~ated Rat _ _ _. _ _ _ . _ _ Compound of Route of ED50 *
Example No. Admi~istration ~moles/kg . . . ~
1 i.p. 12.5 (4.90-33,0) 2 s.c. ~100 3 i.p. 0.46 (0c26-0.74) 7 i. p. 3101 (11.1-82.8) 11 B i.p. 0O69 tOo31~1~33) 11 C s.c. 0.~0 (0.03-2.~) 12 i.p. 0.28 -(0.11-0.69) 13 s~c. 0.46 (0.02-3.1) 14 s.c. ~25 17 5,c. 33 ~8.7-141) 18 s.c. 0~38 (0.02-5.33) 19 s.c. 0.34 (0.15-0.81) 20 A s.c. 1.15 (0.32-3.7) 21 s.c. 0.30 (0.09-1.0) 28 s.c. . 1.39 l0.39-4.91) 31 ~ i.p. 0.41 ~0.19-0.81) 32 i.p. 0.08 ~.03-0.15) 33 s.c- 0O57 (0-16-1.84) s.c. 0.08 (0.02-C.22) 36 s.c. 1.59 (0.48-6.46 51 ~.c. 55 (8.8-g30 52 ~.~. ~350 s.c. 0.07 (0.0~-0.32) 84 8.~. 0.15 (0.02-0.53) ~.c~ 0.14 (0.05-0.41) 86 s.c. 0.04 ~0.015-0.12 87 s.cO 0.02 (0.006-0.04 88 s.c. 0.08 (0.04-0.22) 8g s.~. 0.25 (0.07-0.84 _. _ . .

Table 2 (cont. ) . . _ . _ _ 90- s~c~ 0~86 (0~2402~69) 91 s.c. 1.3 ~0~36-3~9) 92 s.c. 0~24 (0.09-0.71) 93 s~c~ 0~14 ~0~07-~o32) 94 s.c. ~44 (0~08~1~93 src~ ~15 96 s~c~ ~15 97 s~c~ ~3 98 s~c~ 0~5~ (0~08-2~33) 99 s~c~ , 32 (5~7-20~) 100 s~c~ 1.6 ~0~38-5~5) 101 s.~. 6~ (10-750) 102 s~c~ ~15 103 s.c. 0~54 (0.21-1.4) 104 ~oc~ 0.61 ~0.15-1.88~
105 ~c~ 1~65 (0~4~;4~45) 106 s~c~ ~0 107 ~c~ 23 ~5O1-110) 108 s~ 2~2 (0~54-8~9) 109 g~c~ 1~4 (0~51-3~9) 110 s~c~ 0~05 ~0~3-0~14) 111 ~co 0~64 (0.17-2.5) 112 s~ 1~2 (0~47-2~9) 113 s~c~ 0~07 (0~03-0~14) 114 s~c~ ~15 115 s~c~ ~57 (0.20-1.6) 116 s.~. >10 117 ~c~ ~0~5 118 s~c~ 0~066 (0~018-0~19) 119 s.c. ~10 120 s~c~ ~5 121 s~c~ 0~19 ~0~055-0~56) 122 s~c~ ~10~0 123 s.c. ~10 124 s~c~ ~10 _ _~

,, ~ . .

:~2~9~1~9 Table 2 (cont.) . _ . . ~
1 125 s.c. ~10 1 127 s.~. ~10 128 s.~. ~10 129 s.c. ~1 130 s.c. 2.3 (0.79-14) 131 s.c. ~0O5 132 s.c. 0.025 (C.007-0.069) 133 s.c. 0.061 (0.019-0.24) 134 ~.c. 0.024 (0.011-0.050) 135 sOc. 0.57 ~0.29-1.~2) 144 a s.c. 0.095 (0.033-0.30) 144 b s.c~ 0.025 (0.0087-0.065) 144 c s.c. 0.14 (0.034-0.44) 144 d s.c. 0.91 (0.36-3.2) 145 a ~.c~ 0.056 (0.021-0.181 145 b s.c. ~0.06 145 c s~c. 0.025 (0.0098-0.057) 145 d s.c. 3.05 (0.005-0.2) 146 a s.c. 0.023 (0.0091-0.046) 146 d s.c. 0.28 ~0.066-1.21) j 149 s.c. ~0.08 151 s.c. 0.9 (0.15-3.5) ,, ,_ ~
*Numbers in parentheses are the 95~ confidence limits.

~09~

Table 3 -Oral Gastric Antisecretory Activi~y Or Cc~unds of Formula I in the Heidenhain Pouch Dog __ _ Compound Potency Ratio o~ Example . . (cimetidine = 1.0 11 ~ 11 87 ~30 118 1~
133 ~10 145 ~ 8 146 a ~20 AS u~ed herein and i~ the claims, the terms "(lower)-a~kyl" and ~(lower~alkoxy" mean straight or branched chain alkyl or alkoxy groups containLng fr~m 1 to 6 carbon atoms. Pre~erably these groups contain from 1 to 4 carbon atoms and, most prefer-ably, they contain i or 2 carbon atoms~ The term "cyclo(lower)-alkyl~, as used herein and in the claims, means a cycloalkyl ring con~aining from 3 to 7 car~on atoms and preferably from 3 to 6 ~Z09~19 carbon atoms.

Celite is a registered trademark of the Johns-Manville Products CorporatiGn for diatomaeeous ear~h~

In ~he following examples, all temperatures are given in degrees Centigrade.

l~V99~9 Exam~le 1 3-r2-[(5-Methyl-~-imidazol-4-~13methyl~hio~ethylamino}-4-t2-~roDvnYl)amino-1,2,5-thiadiazole l!l-dioxide A. 3-{2-[(S-Methyl-lH-imidazol-4~yl)meth~lthio]
ethylamino~-4-methoxy-1,2,5-~hiadiazole l,l-diox~de To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide ~2.0 g; 11.2 mmoles) ~prepared according to the procedure described in J. _rg. Chem., 40, 2743 tl975)] in 200 ml of methanol at ambient temperature was added ~ solution of 2-t(5-methyl lH-imidazol-4-yl)-methylthio~ethylamine (from the dihydrochloride, 2.73 g;
11.2 ~moles) tPrePared according to Belgian Patent 779,775 in 25 ml o methanol. After st~rring for 30 ~inutes~ a methanolic so~ution of the title compound was produced.
The TLC (Silica/CH2C12:CEI30~I (90:10)] gave Rf = Q.44.

B. 3-{2-~(5-r.lethyl-lH-Lmidazo1-4-vl)meth~lthiol -ethylam -4-(2-~ro~y~yl)amino-1,2,5-thiadiazole 1,1-dioxide ~ o ~he methanolic solution of the product o Ste~ A was added 7 ml of 2-propynylamine. A~ter s~irring at ambient temperature for 20 minutes, the reaction mixture was evaporated under reduced pressure, and the residual oil was placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. The a,opropriat~
fractions were com~ined to yield 2.74 g of the title compound as an oil.

An additional purification was achieved by com-bining the above material with that obtained in an identical second experiment and the mixture placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. The appropriate fractions were combined with methanol and evaporated under reduced pressure to yield the title compound (2.93 g) as a friable solid, mp 82-103°;
the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of 1/3 mole of methanol.
Anal. Calcd for C12H16N6O2S2.1/3CH3OH: C, 42.19; H, 4.97;
N, 23.95; S, 18.27.
Found: C, 42.05; H, 5.05;
N, 24.01; S, 18.45.

Example 2 3-(2-[(5-Methyl-1H-imidazol-4-yl)methylthio)ethylamino)-4-methylamino-1,2,5-thiadiazole 1,1-dioxide To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.5 g; 14.0 mmoles) in 250 ml of dry methanol that had been cooled to 2° in an ice-water bath was added dropwise over a period of 25 minutes a solution of 2-[(5-methyl-1H-imidazol-4-yl)methyl-thio]ethylamine (from the dihydrochloride, 3.42 g; 14.0 mmoles) in 25 ml of methanol. After stirring at 2° for 20 minutes, anhydrous methylamine was bubbled into the solution for 6 minutes and stirring was continued at ambient tempera-ture for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on 50 g of silica gel and chromatographed by gradient elution using methylene chloride-methanol. The appropriate fractions 1209~19 were combined to give 3~2 g OL the title compound. Addi-tional-purification of the product using column chroma tography gave an analytical sample of the title com~ound as an amorphous solid, mp 98-110. The NMR spectrum (100 ~Hz) in d6 dime~hyl sulfoxide gave the following resonances ~: 7.46 ~s, lH~, 3.70 (s, 2H); 2.53 (t, 2H);
2.86 (s, 3H~; 2.72 (t, 2H~; 2.15 (s, 3H~.
Anal. Calcd f~r CloHl6N6Q2s2 S, ~0.27.
Found tcorr. for 1.60% H20): C, 37.79; H, 5.16; ~J, 26.52;
S, 2~.24.

ExamDle 3 3-{2-[(2-Guanidinothiazol-4-yl)methylthio~ethYla~ino}-4-{2-[(5-methvl-lH ~midazol-4-Yl~methYlthio]ethylamino}-1,2,5-thia~iazole l,l-dioxide To a well stirred solution at -10 of 3-{2-[(5-methyl-l~-imidazol-4-yl)methylthio]ethylamino}~4-methoxy-1,2,5-thiadiazole l,l-dioxide lPrePared from the dihydro-chloride of 2-{(5-methyl-l~-imida201-4-yl)methylthio}ethyl-amine (2.73 g~o 11.2 mmole) ~y the procedure of ctep A of ~xample lJ was rapidly added ~ solution of 2-[(2-guanidino-thi~zol-4-yl)me~hyl~hio~ethylamine (from the dihyd~ochloride, 3.41 g; 11.2 mmoles) Iprepared according to the procedure described in South African Patent 78/2129] in 35 ml o~
methanol. After stirring at -10 ~or 30 minutes, the solution wa~ allowed to warm to ambient temperature. ~he reaction mixture was evaporated under reduced pressure and the residue was placed on 45 g of silica gel and chromato-graphed using 1 liter of methylene chloride-methanol (4:1).

~2~9~9 --~o--The appropr~ate frac~ions were combined and evaporated, and ~he residue (S.82 g) was placed on 80 g of aluminum oxide and chromatographed using a gradient elu~ion of ethyl aceta~e-methanol~, The appropriate fractions were combined, filtered through Celite and evaporated under -hi~h vacuum to yield the title compound t2.5 g) as an amorphous solid containing approximately 2/3 mole o~
ethyl acetat~, as ascertai~ed by the NMR spectrum ~100 M~z~
in d6 dimethyl sulfoxide.
Cl6~24Nloo254-2/3c~Hgo2: C, 38-96; ~ 5 14 N, 24.34; S, 22.29.
Found: ~, 39.08; H, 4.96;
N, 24~48; S, 22.26.

Example 4 3 {2- r _5-Methyl-lH-imidazol-4-yl)met~ io]et~ylamino}-4-meth~lamino-1,2,5-th~adiazole_l-oxiae A. 3,4-Dimethoxy-1,2,$-thiadiazole l-oxide A solution of 3,4-d~methoxy-1,2,5-~iadiazole (35.2 g; 24.1 mmoles) lPrePared a~cording to the procedure described in J. ~. Chem., 40, 2749 (1915~ in 100 ml of chloroform was added over a period of 3 minutes to a stirred solution of m-chloroperbenzoic acid ~50.7 g; 25.0 mmoles; 85% assay) in 900 ml of chloroform at 20, using a cooling ~ath to keep the exothermic rea~tion from rising above 32. After stirring for 3 hours at ambien~ tempera-ture, ~he excess peracid was reacted with an additional-2.0 g of 3,4-dimethoxy-1,2,5-thiadiazole and stirred for 1 hour.

~Z~39919 The organic solution ~Jas extxacted with two-300 ml portions of a 1% solution of NaHCO3, washed with 250 ml of water, dried and evaparated under reduced pressure to gi~e 47.0 g of prod~ct. ~ecrystallization from isopropyl alcohol gave the title compound ~34.0 g). An additional recrystalliza~ion fxom isopropyl alcohol gaYe an analytical sample, mp 135-137.
AnalO Calcd for C4H6~203S: C, 29.63; H, 3.72; N, 1.7.27;
S, 1~.77.
Found: C, 29.~3; H, 3.75; N, 17a26;
S, lg.B3.

B. 3-{2-~(5-~ethy~-lH-imida2o1-4-Yl)methylthio]-ethylamino}-4-methvlamino-1,2,5-thiadiazole l-oxide A solution of. 3, 4-dimethoxy-1, 2, 5-thiadiazole l-oxide obtained from the above Step A is reacted wi~h an e~uimolar amount of 2-~5-methyl-lH-imidazol-4-yl~methyl-thio] ethylamine and the resulting 3-{ 2- ~ (5-methyl-lH-Lmidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thia-diazole l-oxide is treated with an excess of methylamine, and the title compound is thereby produced.

ExamPle 5 _ 3-{2Ot(5-~drox~ ethy~-lH-imidazol-4-Yl~methylthio~ethy~
amino}-4 methylamino-1,2,5-thiadiazole 1 r l-dioxide 2-[(5-Hydroxymethyl-lH-imidazol-4-yl ~ methylthio 1 -ethylamine tprePared according to ~h~ procedure described in Belgian Patent 843,840] is reacted with 3,4-d~methoxy-1,2,5-thiadiazole l,l-dioxide and the resultant 3-{2-[(5-hydroxy-methyl lH~i~idazol-4-yl)meth~lthio~ethylamino~-4-methoxy-.

~2099~9 1,2,5-thiadiazole l,l-dioxide is treated with excess methyl-amine ac~ording to the general procedure described in Example 2, and the ti~le compound is ther~by produced.

ExamDle 6 .

The general procedure o' Exam~le 5 ic repeated except that the 2-[(5-hydroxymethyl-lH imidazol-4-yl)-methylthio~ethylamtne utilized therein is replaced by an équimolar amount of 2-~(5-bromo-1~-imidazol-4 yl)me~hylthiolethylamine, 2-timidazol 4-ylme~hyl~hio~ethylami~e, 2-[imidazol-2-ylmethylthio]ethylamine, 2-t(l-methyl-imidazol-2-yl)methylthio~ethylzmine, 2-[(2-methyl-lH-imidazol-4-yl)methy}thio3ethylamine, 2-[~ methyl-imidazol-4-yl)me.hylthio~ethylamine f 2-t(l,S-dimethyl-imidazol-4-yl)methylthio~ethylamine, 2-[(5-chloro-1-methyl-imidazol-4-yl)methylthio~ethylami~e, 2-~5-trifluoromethyl-lH-imidaæol-4-yl)methyl~io]ethylamine, 2-t(5-ethyl-lH-imidazol-4-yl)methylthio~ethylamine and 2-[(2-ami~o-lH-imidazol-4-yl)methylthio~ethylami~e, respectively, [each prepa~ed by the general procedures described in Belgian Patent 779,775J and there is there~y produced 3-{2-~(5-bromo-l~-imidazol-4-yl)methylthio]ethyl2mino~-4-methylamino-1,2,5-thiadiazole l,l-dioxide, 3-{2-timidazol-4-ylmethylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole l,l-dioxide, 3-~2-[imida~ol-2-ylmethylthio]ethylamino~-4-methylamino-1,2,5-thiadiazole l,l-dioxide, . .

~209~9 3-{2-[~l~methyl-1midaxol-2-yl~methylthioJethylamino~-4-methylamino-1~2,5-thiadiazole l,l-dioxide, 3-~2-~(2-methyl lH imidazol-4-yl~methyl~hio3ethylamino}-4-methylamino-1,2,5-thiadiazole 1,l-dioxide, 3-~2~ methyl-imidazol 4-yl)methylthio3ethylamino~-4-methylamino-1,2,5 ~hiadiazole 1,l-dioxide, 3-{2-~(1,5-dimethyl-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2j5-thiadiazole 1,l-dioxide, 3-{2-t(5-chloro-1-methyl-imidazol-4-yl)methylthio~ethyl-amino}-4-methylamino-1,2,5-~hiadiazole l,l-dioxide, 3-{2-~t5 trifluoromethyl-lH-imidazol-4-yl)methylthiol-ethylamino~-4-methylamino-1,2,5-thiadiazole 1,1 dioxide, 3-{2-[(5-ethyl-1~-imidazol-4-yl)methylthio]ethylamino}-4-metnylamino-1,2,5-~hiadiazole 1,l-dioxide and 3-{2-[~2-amino-lH-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1,l-dioxide, respecti~ely.
, Exam~le 7 3-H~roxy-4-{2-t(5-meth~l- ~ h ~thio]-ethylamino}-1,2,5-th adiazole l,1-dioxide ~ hen a methanolic solution of 3-{2-[~5-methyl-lH-imidazol-4-yl)methylthio~ethylamino}-4-methoxy-1,2~5-thiadiazole 1,l-dioxide tprepared by the procedure of Step A of Example 11 is treated with a solution or sodium hydroxide in methanol by the general procedure of Example 17, Step 8, the title compound is produced, mp 263-265 (dec).

12~9~:19 A.nal. Calcd CgH13N5S203 C, 35.64; H, 4.32; N, 23.09;
S, 21.13.
Found: C, 35.56; H, 4.38; N, 23.01;
S, 21.,13.

Exallsple 8 3 t 4~ ~ (2-Guanidino-lH-imidazol-4-yl~ butvlamino}-4-methY
amino-1,2,~-thiadiazole l,l-dioxide - A me~hanolic suspension of 3,4-dime~hoxy-1,2,5-thiadiaz~le 1,lodioxide is successively reacted with an equimolar a~ount o~ 4-t2-guanidino-lH-imidazol-4-yl~-butylamine tprepared according to Belgia~ Patent 866,1~6]
and excess methylamine according to the general procedure of Example 2, and the t~tl~ compound is thereby produced.

Example g 3-{2-1~5-'~ethYl-l~-imidazol-4-yl~metllYlthio~ethvlamino}-4-(2-~ropynyl)am o-1,2,5-thiadiazol~ 1,1 dioxide Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide with one equi~alent of 2-propynylamine and treating the resultant 3-methoxv-4-propynylamino-l, 2, 5-thiadiazole 1, l-dioxide with one equiva lent of 2-~ (5-methyl~ -iMidazol-4-yl)methylthioJethylamine yields the title compound; iden~ical to the produrt o~
Exampl~ 1.
_ample 10 3-~2-~(5-~ethvl-lH-~midazol~4-v~)m.ethylthio~ethylamino}-4-methylami..o-l, 2, 5-thiadiazole 1, l-dio~cide , .

~209!~J19 -~5-When a solutio~ of 3 methylamino-4~(2-merca~to-ethyl)-1,2,5-thiadiazole l,l-dioxide (prepared in ~xample 25, Step ~) i5 reacted with 4-chloromethyl-5-methyli~idazole hydrochloride and a strong base, the title compound is thereby ~roduced; identical to the product of Exam~le 2.

Example 11 3-{2-~(5-DimethYlaminomethvl-2-fury~)methvl~lioJethYlamino}-4-me~h lamino-1,2,S-thiadiazole 1,l-dioxide and 3,4-bis-Y , , ~
{2-~(5-dimethylaminomPthyl-2-f~yl)methYlthio]eth,vlamino}-1, 2, 5-~hiadiazole 1, l-dioxide R. 3-{2-[(5-Dimethvlaminomethyl-2-furyl)methyl-thio~thylamino}-4-methoxy-1,2,5 thiadiazole l,l-dioxide A solution of 2- 1 (5-dLmethylaminomethyl-2-furyl~-me~hylthio~ ethylamine ~2 . 41 g; 11. 2 mmoles) tprepared according to the procedure described in Belgian Pa~ent 857,3883 in 20 ml of dry methanol was added all at once to a well s~irred, ~old t8) suspension of 3,4-dimethoxy-1,2~5-thiadiazole 1 r l~dioxide (2.0 g; 11.2 mmoles) in 200 ml of methanol . After stirring at 8-10 for 15 minutes, a methanolic ~olution of the title compound is produced.

B.
thio]ethyl~mino}-4-methylamino-1,2,5-~h _diazole 1,1-dioxide ~ nhydrous methylamine was bubbled into the cooled (1) methanolic solution of the product of Step A for 6 minutes. Stirring was continued for 10 minutes and the mix~ure w as evaporated under reduced pressure. The residue , ~2~99~

was pla~ed on 45 g of silica gel and chromatographed using a gradient elution of methyl~ne chloride-methanol. The appropriate fractions, u5i~g methylene chloride-~ethanol ~95 :5) were combined in methanol, filtered through Celite, and then concentsated under reduced pressure to si~e product. Recrystallization from methanol yielded the title com~ound (1.76 g), mp 82-90~; the N~lR spectrum (100 .~Hz~ in d6 dimethyl sulfoxide showed the presence of 2/3 mole of methano7.
Anal. C~lcd for C13H21I`J~03S2~2~3CH30~: C, 43.10; ~, 6.26;
N, 18.38; 5, 16.83.
Found (corr. for 1.72% ~2): C~ 43.30; H, 6.12;
- N, ~8.57; S, 16.96.

C. 3,4-Bis-{2-1(5-dimethYlaminomethYl-2-~uryl)-meth lthio]eth lamino}-1,2,5-thiadia2O1e 1,l-dioxide Y Y _ _ The slower eluting ~omponent using methylene chloride-methanol 19:1) from the chromatoyraphy in Step B
was placed on 45 g of aluminum oxide and ~hromatographed usi~g a gradient elution of ethyl acetate-methanol. The appropriate fraction was evapor~t2d and the residue triturated under ether-acetonitrile to give a colorless solld which was collected by filtration to yield th~ ti~le compound (428 mg) as a monohydrate, mp 92.5-96.
na1. Calcd for ~2~H~4N6534~I~2 C, 47O12; H~ 6.47;
N, 14.99; S, 17.15.
Found: C, 47.28; ~, 5.48;
~, 15.09; S, 17.39.
C~lcd for H2O ~ 3.21%;
Pound H2O = 3.32 * trade mark.

~;~Q~9 Example12 3-{2~[(~-DimethvlAminometh 1-2-fur l)methvlthio~ethvl ~ Y ,,"
amino}-4-ethylamino-1,2,5-thiadiazole 1,1-dioxide ~ solution of 2-~(S-dimethylaminomethyl-2-furyl)-me~hylthio~ethylamine t2.41 g; 1102 mmoles) in 20 ml of drv methanol was added all a~ once to a well stirred cold (1~ suspens ion o~ 3,~-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2~0 g; 11.2 mmoles) in 200 m~ of methanol. Af~er stirring for 15 minutes at 1-5, ethylamine ~4.0 ~1~ was added and stirring was continued at approximately 5 for 29 minutes.- ~he reaction mixture was evaporated under reduced pressure and the residue was placed on 46 g of silica gel and chromatographed using a gradient elution of ~ethylene chloride-methanol. ~e appropriate fractions were combined, evaporated and the gelatinous residua triturated ~nder ether and filtered to giva the product as a coloxless solid t2.81 g). Two recrystallizations from methanol and drying o~er P205 at ambient tempera~ure ~or 17 hours yielded ~he title compound, mp 155-160 with ~ariable sintering at 94-96; ~he ~R spectrum (100 ~1~z) in d6 dimethyl sulfoxide showed tha presence o~ apprcxi-mately 0~8 moles OJ methanol.
Anal. Calcd for C14~23N503S2 - 3 ~, 17.55; S, 16.07.
Found: C, 44.35; H, 6.58;
M, 17.44; S, 16.1~.

3~2Q9~9 -4~-Example 13 3-{2-[(5-Dime~hYlaminomethvl-2-furt~l)met v~thio3ethyl-amin ~ ropYnyl)amino-1,2,5-thiadiazole 1,1-dioxide A solutisn of 2-[(5-dimethylaminomethyl-2-furyl)-me~hyl~hio~ethylamine (2.41 g; 11.2 mmoles) in 20 ml o~ dry methanol was added dropwise over a period of 25 minutes to a well stirred cold (1) suspension o 3,4-dimethoxy-1,2,5-khiadiazole l,l-dioxide (2.0 g; 11.2 mmoles) in 200 ml o~ methanol, A ter stirring at 1-2 for 15 minutes, a solution of 2-propynylamine t4.0 ml) ~n lg ml of dry methanol was added all at once, and stirrIng was then ~ontinued at ambien~ temperature fsr 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was placed on ~0 ~ of silica gel and chromatographQd using a gsadient elution of methylene chlori~e-methanol.
The appropriate frac~ions were com~ined, evaporated and crystallized from metha~ol to gi~e 4.0 g o~ product.
~ecrystallization from methanol and then from isopropyl alcohol yielded ~he title compound (2.gO g)~ mp 92-100, the NMR spectrum (109 ~z) in d6 dimethyl sul~oxide showed the product to be solvated with 1 mole o~ methanol.
~nal. Calcd for Cls~2lN5o3s2-cH3oH: C, 46.~5; H, 6-06;
N, 16.85~ S, 15.43.
Found: C, 46.36; ~, 6.22;
N, 16.95; S, 15.73.

12~9919 Exa~le 14 3-~ethylamino-4-{2-[(S-{~N-methyl N-(2-~ropynvl)amino]~
me'hyl}-2-furyl)met~ylth oleth~lamino~-1,2,5-th~adîazole l,l~dioxide , A. 5-{~N-methyl-N-32-pxopvnYl~aminolmethyl~-2-uranmethanol To fururyl alcohol (2.49 g; 25.4 mmoles) which was cooled i~ an ice-water bath to 5 was added N-methyl-propargylamine hydrochloride t4.0 g; 37.9 ~unoles) and 40%
formalin (3.13 ml; 41.7 mmoles~, and the mixture stirred while allowed ~o reach ambient t2mperature. After 1 hour of stirring the solution was allowed to stand a~ ambient temp~rature for 4-1/2 days. The reactio~ mixture was poured into ice water, made strongly basic with 40% aqueous ~aOH and extracted with five portions of methylene chloride The combined organic phase was dried, filtered and evap-orated under reduced pressure to give the product as an oil tqua~titati~e yield). Vacuum distillation yielded ~he title compound, bp 102-106/0.3 mm Hg.
Anal. Calcd for Cl~H13NO2 ~ ;
Found: C, 66.80, H, 7.44: N, 1.93 B. 2-~(5-{tN- ~ l-N-t2-pro~y~vl)amino~-methyl}-2-furyL)m ~ lthiolethylamine A solution of 5-{~ methyl-N-t2-propynyl)amin methyl~-2Ofuranmethanol ~40.0 ~; 223 mmoles) ~prepared in ~Z~9~9 so-Step A] in 100 ml of ice-cold concentrated HCl was added to a cold t5) stirred solution of cys~eamine hydrochloride (27 . 9 g; 24 . 6 mmoles ) in 12 5 ~1 of concentrated hydrochloric acid. The solution was allowed to stand at 0 for 2-1/2 days, and then at ambient temperature for 7 hours to complete the reaction. The reaction mixture was cooled in an ice-water bath, diluted with 20a ml of water, made strongly alkaline with 4 0 % aqueous NaOH~ and then extracted with three portions of ~ethylene chlorideO The oombined organic phase was dried, filtered, and evap~rated under reduced pressure to gi~e the product as a thick oil (46.4 g)~ A
rapid vacuum distillation of the oil yielded the title compound, bp 136-140~0.2 ~m Hg.
Anal. Calcd for C12H18N2OS: C, 60.47; H, 7.61; N, 11.76;
S, 13.46.
Found: C, 59.82; H, 7.68; N, 11.61;
S, 13.27.

C. 3-MethYlamino-4-{2-[(5-~[~-methyl~ 2-ro~ n l)amino~methvl-2-~urYl)methYlthio~ethylamino}-1,2,5-P Y Y ~
thiadiazole l,l-dioxide .

To a stirred cold (3) suspension of 304-dimethoxy-1,2,5-~hiadiazole l,l-dioxide t2.0 g; 11.2 mmoles) in 200 ml of dry methanol was added a solution of 2-E(5-{tN
methyl-N-(2-propynyl)amino~methyl~-2-furvl)methyl~hio~-ethylamine (2.68 g; 11.2 mmoles) [prepared in Step Bl.
After stirring at 3 7 for 15 minutes, methylamine was bu~bled int3 the solution ~or 16 minutes. ~he reaction mixture was e~aporated under reduced pressure and the oily residue was placed on 100 g of silica gel and chromatographed u~ing a gradient of acetonitrile-met~anol. T~e aporopriate fraotions were combined and rechromatographed on 100 g o~ ~ilica gel using a gradient of methylene c~.loride-i ~2~919 methanol. The appropriate fracltions was dissolved in methyl~ne chloride and extracted with 1% aqueous NaOH.
m e aqueous phase was brou~ht to pH 9 with 5 % aqueous HCl and the separated oil was extracted with three portions of methylene chloride. The combined extracts were dried t fil~red ~nd evaporated under reduced pressure to give product as a foam. Recrystallization fro~
isopropyl alcohol yielded the title compound, mp 50-51, clear m~lt 54-56; the NMR spectrum ~100 MHz) in D6 dimethyl sul~oxide showed the presence o~ approximateiy 1~4 mole of isopropyl alcohQl.
Anal. Calcd ~or C15~21~5352 1/ 3 ~
N~ 17.57; S, 16.09.
Found: Cr 47.51; H, 6.~1, N, 16.40; S, 15.97.

Example 15-3-{2-[(5-Dime~h~la~ yl-3-meth~1-2-fur~l)methvlthio]-ethylamino}-4-methylamino-1,2,5-thiadiazole l,l-dioxide A. 5 DimethylaminomethYl-3-methY1 2 furanmethanol A mixture containing 3-methyl-2-furfuryl alcohol ~11.2 g; 0.1 mole ~pxepared acc~rding to the ~rocedure descrihed in ~. Am~ Chem. 50c., 72, 2195 (1950)], dimethyl-amine hydrochloride (12.23 g; 0.15 mole~ and 37% aqueous ormaldehyde (12 ml7 O.lS mole) was stirred for 2.5 hours at approximately S, and then at ambient temperature ov2rnight.
The solution was heated for 10 minutes on a steam bath~
diluted with 12 ml of water and basified with sodium oar-honate. The mixture was e~tracted with ethyl acetate, and ~Z~3919 the organic ~hase dried, ~iltered and evaporated under reduced pressure to yield the title compound, hp 88-96~0.05-0.08 mm Hg.

B. 2-[(5-Dimethyl2minometh~1-3-methyl-2-furyl) methylthio]et~y~amine To a solution of 2-aminoethanethiol hydrochloride ~2.27 g; 20.0 mmole ) in 20 ml of concentrated HCl that was cooled ~n an ice-salt bath to -10 was added dropwise S-d~ethylaminomethyl-3-methyl-2-furanmethanol (3.38 g;
20 . 0 mmoles) ~prepared in Step Al, and ~he mix~ure stirred for lS minutes then allowed to stand in the cold (0 ) overnight. Aftex 17 hours the cold solution was made strongly basic with aqueous ~H solution and then extracted with i~e portions of methylene chloride. The combined organic phase was dried~ filtered and evaporated under-~educed pressure to yield the title co~pound (4.16 g~, bp 110-120~
O .1 mm Hg O

C r 3~{2-[( ~ aminomethyl-3-~urvl)met~ thio~ethylzmino}-4-methYlamino-1,2,5-thia-diazole l,l-dioxide When a methanol suspension o~ 3,4-di~ethoxy-1,2,5-thiadiazole l,l-dioxide is reacted with an equimolar amount o~ 2-l(S. dimethyl2minomethyl-3 methyl-2-furyl)methyl-thio]ethylamin~ lprepared in Step Bl and the resultant 3-{2-C(5-dL~ethylaminomethyl~3-methyl-2-furyl) methylthio~ -ethy}amino}-4-methoxy-1,2,5-thiadi~zole 1,l-dioxide is treated witl~ an excess o m~thylamine, the title compound is thereby produced.

~2g)9~

xample 16 3-{2-~(5-Dimethvlaminometh 1-4 methvl-2-furvl)methylthio~-ethvlamino}-4-methylamino-1,2,5-thiadiazole 1,l-di~xide A. 2-Dimethylaminomethyl-3-methy~f~ran A stirred solution o~ 3-methyl-2-furfuryl alcohol (25.2 g; 22.5 mmoles3 and triethyla~in~ (27.3 g; 27.0 mmoles) in 200 ml of methylene chloride was cooled to -15 in an ice-salt bath and a solution of thionyl chloride ~18.0 ml, 24.8 mmoles) in 30 ml o~ methylene chloride was added dropwise, keeping the temperature between -10 to -15.
After 15 minutes, ~he mixture was poured into ice-water and the organic layer was separated. The methylene chloride phase containing 3-methyl-2-chlorome~ylfuran w~s added to a stirred solution, at 0, o~ dimethylamine (137.0 g;
3.04 mo7es~ in 400 ml of absolute ethanol and the resultin~
solution was stirred at ambient temperature for 17 hours.
T~e re~ction mixture was evaporated under reduced pressure and ~he residue was mixed with 4 00 ml of water, made strongly basic with 40% a~ueous NaOH ~nd ex~racted with fi~e portions of methylene chloride. The combinsd extracts were dried, ~iltered and evaporated under reduced pressure to yield 26.0 g of th~ title compo~nd, bp 64-70/20 mm Hg. .
A TI,C ~Silica/CHC13:C~30H (85:15~] ga~re Rf -- 0.500 B. 2-Chlor~yl S-dimethYlaminomethYl-3-methylfuran To a solution of 2-dimethylaminomethyl-3-methyl-fur~n (6.5 g; 37.0 mmoles) tprepared in Step ~.~ in 250 ml .,, ~ . , ~o~ ~

of chloroform was added paraformaldehyde (1.67 g; 55.7 mmoles~ and ~inc chloride (31~ mg), and a slow stream of HCl gas was bubbled ~hrough while stirring a~ ambient temperature for 15 minutes. Stirring was continued for 2 hours, then ~Cl gas was bu~bled through for 15 minutes and the mixture stirred for 1 hour. At this time addi-tional paraformaldehyde (1.67 g; 55.7 mmoles) was added to ~he reaction mixture and a slow strea~ of HCl gas was passed through for 15 minutes. A ter stirring at ambient temperature for 18 hours, the reaction mixture was ~iltered thsough Celite and the filtrate evaporated under reduced pressure to yield the title.compound (4.97 g) which crystallized upon standing and was used without further purification in Step C.

The ~MR spectrum (60 ~z) in CDC13 gave the ~ollowing resonances ~: 6.33 (s, lH); 4.55 (s, 2~);
4.30 (d, 2H~; 2.83 ~d, 6H); 2.13 (s, 3H) C. 2-~(5-Dimethylaminometh~1~4-methyl-2-~urvl)-methylthio~ethylamine To a solution of 2-chloromethyl-5-dimethylam~no-methyl-3-methylfuran (773 mg, 3.45 mmoles) tprepared in Step B] in 20 ml of concen~rated hydrochloric a~id that was cooled in an ice-water bath was added 2-aminoethanethiol hydrochloride (392 mg, 3.4; mmoles), and the mixture was stirred for 30 minutes. The solution was allowed to stand at 0 for 3 davs, then made strongly ~asic with 50~
aqueous KOH, diluted with water and extracted with five portions o~ methylene chloride. The combined extract was dried, filtered and evaporated under reduced pressure .o ~2~99'1 ~9 yield the title compound as an oil.

Th2 product was dissolved in absolute ethanol, treated with anhydrous hydrogen chloride and evaporated under reduced pressure. The residue was dissolved in hot isopropyl alcohol, treated with charcoal, filtered and co~centrated to crystallize the hydrochloride salt.
Recrys~allizztion from isopropyl alcohol yielded ~he title comDound as the dihydrochloride salt, mp 185 190 (dec).

D. 3-{2-[(5-Dimethvl ~minomethvl-4-methyl-2-furvl)meth~lthio3ethYlamino}-4-meth~lamlno-1,2,5-thiadiazole l,l-dioxid_ When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1, l-dioxiae i5 reac~ed with an e~uimolar amount o~ 2-~t5-dimethylaminomethyl-4-methyl-2-furyl)methyl-.
thio~ e~hylamine ~prepared in Step C] and the resultant 3-~2-1(5-dimethylaminomethyl-4-methyl-2-furyl~methylthio}-ethylamino}-4-methoxy-1,2,5-thiadiazole 1,l-dioxi~e is treated with an excess of methylamine, the title compound is produc~d.

Example 17 3-~2-[(5-D methy~aminomethvl-2-furYl~ethy~thio3ethYla~ino~-4-hydroxy-1,2,5Othiadiazole l,l-dioxide A. 3~{2-[tS-DimethYlaminomethyl-2-furyl)meth thio]ethylamino}-4-methoxy-1,2,5-thiadiazole l,l dioxide A solution of 2-~(5-dimethylaminomethyl-2-furyl-,, ~2~

methylthio]ethylamine (2.14 g; 10.0 mmoles) in 25 ml of dry methan~l was added dropwise over 3~ minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1~?8 g; lOoO mmoles) in 180 ml of dry methanol that had been cooled to 1 în an ice-water bathO After 15 minutes at 0, a me~hanol solution of the title compound is prsducedO
A TLC ~silica/C~2C12.:CX30H (9:1)] gave Rf = 0.48~

A 2.0 ml aliquot of the so~ ution was made acidic with 6.ON HC1 and evaporated under reduced pressure without heating to yield the title compound as the hydroch~oride salt. The ~.~R spectrum (100 MHz) in D20 gave the following resonances ~: 6.45 (d, lH); 6~19 (d, lH); 4.14 (s, 2H);
4.0 (s, 3H); 3.64 (s, ~H); 3.37 (t, 2E3); 2.65 ~s, 6~);
2.61 (t, 2~).

B. 3-~2-t(5-Dimethylaminomethyl-2_fur~1)methylo thio~ethylamino}-4-hydroxy-1,2, 5-thiadiazole 1, l-dioxide , To the methanolic solution of the product o~ S~ep A, cooled to 0 in an ice~wat~r b~th, was added a solution of sodium hydroxide pellets (2.10 g; 52.5 mmoles) in 25 ml of dry metha~ol~ After stirring at 0 for 2 hours and at a~bient temperature for 68 hours, the reactisn mixture was neutralized with 8.75 ml C52.5 mmoles~ of aqueous 6.0N HCl and after 10 minutes o~ ~tirring was evaporatea under reduced pressure. The residue was crystallized u~der 95%
EtOH to give crude product which was ~i~solved in methanol, filtered to remoYe sodi~m chloride, placed on 60 g of silica gel and chromatographed usin~ a gradient elution of methylene chloride-methanol. The approprsate fractions were ~209~19 combined and evaporated under reduced pressure to give 3.19 g of ~roduct~ Recrystalli~ation from aqueous methanol yielded the title com~oundJ mp 109-122.
C~2~18N404S2: C~ 41-61; H, 5.24; N, 16 17 S, 18.51.
Found (corr. for 1.15% H20): C, 41.59; ~, 5.32; ~, 16.33;
S, ~8.810 Example 18 3-{ 2-1 ~S-DimethylamirlomethYl-2-f~r~l )methylthiol ethylamino~-4 methylamino-1,2~5-thiadiazole l-oxide , A. 3-{2-~(5-?imethylaminomethYl-2-furyl)metnyl-thio] ethylamino ? -4-methoxY-1,2,5-thiadiazole l-oxide A solution of 2- [ (5-dimethylaminomethyl-2-furyl)-me~hylthio~ethylamine ~3.30 g; 15.4 mmoles~ in 25 ml of methanol was ~dded dropwise over a period o~ 14 minutes to a well st;rred suspension of 3,4-dimethoxy-1,2,5-thia-diazole l-oxide (2.50 g; 15.4 mmoles) [prepared ~ccording to the proc~dure in Example 4, Step Al that was cooled to 12-15 in an ice-water ~ath. The solution was stirred at ambient temperature for 1.5 hours to yield a met~anolic solution of the title compound.

B. 3-{2-~(S-D~methvlaminometh~1-2-fur~l)methJl-thioleth~lamino}-4~methylam~no~1,2,5-~hiadiazole l oxide To ~he methanolic solution of the product of Step A that was coo~ed to 5 in an ice-water bath was added ,............................ .

~209~19 anhydrous methylamine for 8 minutes. The reaction mixture was s~.irred at ambien~ temperature for 17 hours, then evaporated under reduced pressure to gi~e the ~roduct as a yellow oil ~hat was placed on ~5 g of silica gel and chromatogra~hed using a gradie~t elution of methylene chloride-methanolO The appropriate fraction was evaporated, dissolved in methanol and diluted with diethyl etner to yield the title compound t2 . 32 g) as a solid that . was dried in vacuo at ambient temperature over P205 for .
3 hours, mp 86-92.
Anal- Calcd ~or C13H21N52S2 ~' S, 18.67.
Found: C, 45.24; H, 6.24; N, 20.41;
S, 18.90.

Exam~le 19 3-Allylamino-4-{2-[(5-dimethylaminomethYl-2-fur~l)methyl-th~o]ethylamino}-1,2,5-th diazole 1,l-dio~ide To a paxtial suspension of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide (2.08 g; 11.7 mmoles) in 20~ ml of methanol that had been cooled to 0 in an ice-water hath was added dropwise o~er a period of 45 mi~utes a solution o 2-tt5-dimethylaminome~hyl-2-furyl)methyl~hio~ethylamine in 30 ml of methanolO t~hen the addition was coF~pleted, 10. 5 ml of allylamine was added and the solution was allowed to st~r at a~bient temperature for 1~ hours. The reaction mixture was evaporated under reduced pressure and the residue was placed on 120 g of silica qel and chromatographed using a gradient elution of methylene chloride-methanol.

~he appropriate fractions were combined, evaporated under reduced pressure and the residue crystallized with isopropyl alcohol to gîve the title compound, mp 83-86; the ~nsR
spe::trum (100 ~Hz) in d6 dimethyl sulfoxide sh~wed the presence of approximately 0.9 moles of isopropyl alcohol.
Anal. Calcd ~or C15B23N503S2 3 8 N, 15.93; S, 14.59.
Found: C, 48.46; H, 6.96;
N, 16.13; S, 14.58.

Example 20 3-Meth 12nino-4-{2-t(5-methvlaminomethYl-2-fur l)methvlthio~-__ Y ~ ___ _ Y ,, ethylamino}-1,2,5-thiadiazole l,l-dioxide and 3,4-bis-{2-[~5-methylaminomethyl-2-furvl)methylthio~eth~clamino}-1,2,5-thiadiazole l,1-dioxide A. 3-Meth~laminQ-4-{2-t(5-me~hvlaminomethyl-2-furyl~methylthio3ethylamino}-1,2,5-thiadia201e~ dioxide To a partial suspension of 3,4~dimethoxy-1,2,5-thiadiazole ~1.89 g; lO.S mmoles) in 210 ml of methanol that was cooled to 8 was added all at once a solution of 2-t(5-methylaminomethyl-2-furyl)me~hylthio]ethylamine (O.7 g; 3.51 mmoles) ~prepared according to the procedure described in Belgian Patent 857~388] in 21 ml of methanol.
The mixture was stirred for lS minutes and cooled to 1 in an ice-water bath, and anhydrous methylamine then was bu~bled into the solution for 6 minutes. After stirrin~
for lS minutes the reaction mixture was e~aporated under reduced pressure and t~e residue placed on 110 g of silica gel using a gradient el~tion from a~etonitrile to aceton-itrile-methanol-glacial acetic acid (50:50:0.5). mhe ~ , .

~209~19 appropriate fractions containing the first eluting component ~7ith Rf = 0.50 ~TLC-silica/C~13CN:CH3OH:CH3COOH (50:50:1)]
were combined and evaporated under reduced pressure to yield the title compound as a foam, mp 59-56.

The NM~ spectrum (100 ~Hz~ in d6 dimethyl sul-foxide ~ave the following resonances C: 6.20 tm, 2~);
3.80 (s, 28); 3,62 (s, 2~); 3.50 (t, 2~); 2.90 ~c; 3H);
2.70 (t, 2H); 2.28 (s, 3H); it also showed the presence of approximately 0 . 2 mole o methanol.
r C12Hl9N53S2'-2 ~30H: C, 41.65; ~ s 65;
~ 1, 13.96; S, 18.28.
Found (corr. for 1.42% H~O): C, 41.S8; H, 5.69;
N, 19.54; S, 18.54.

B. 3~4-~is-{2-~5-methylaminomethyl-2-furvl)-methylthio~eth a ~ 1, 2, S-thiadiazole l,l-diox-de The fractions containing the slower eluting component from the chromatography in Step A with Rf = 0.07 ETLC-silica/CH3CN:CH3OH~C~3COOH ~50:50:1)3 were eombined, evaporated and the residue partitioned between 2.5N ~aO~
and ethyl acetate. The aqueous phase was extracted with several portions o~ e~hyl ace~ate and the combined or~ nic layer was dried and evaporated under reduced pressure to give ~he title compound as a~ oil.

The NMR spectrum (100 MIIz) in d6 di~ethyl sulfoxide gav~ the following resonances ~: 6.22 (m, 4H); 3.82 (s, 4H)i 3.6~ (s, 4H~; 3.50 tt, 4H); 2.72 ~t, 4~); 2.30 (s, 6H)o ~2~ 19 Example 21 3-{4-~5-Dime~hyl~minometh~1-2-fuxyl)butYlamin_}-~
thYlamino-l, 2 ! 5 thiadiazole 1,l-di x~de A s~lutio~ of 4-~5-d~methylaminomethyl-2-furyl)-butylamine (1.5 g; 7.64 mmoles) ~prepared according to the proced~re de~cribed in U.S. Patent 4,128,6~81 in 40 ml of dry methanol was added dropwise o~er ~ period of 45 minutes to a stirred solution of 3,4-dime~hoxy-1,2,5-thiadiazole l,l-dioxide (1.36 g; 7.64 mmoles) ~n 200 ml o~ dry methanol that had been cooled to 3 in an ice-water bath . A ter lS minutes at 3, anhydrous methylamine was bubbled into the cooled solution for 10 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 60 g of silica gel and chroma-tographed using a gradient elution of ac~tonitril~ meth~nol..
The appropriate fractions were combined to give 2.16 g of -.
product. Recrystallization from acetonitrile yielded the title compound, mp 152-153.
Anal. Calcd for C14H~3N~03S: C, 49.25; El, 6.79; N, 20.51;
-S, g.39.
Found: C, 49.41; ~, 6.87; N, 20.61;
S, 9.28 .

~209~:~ 9 Exam~le ~2 3-{2-t(5-Dimethylaminomethyl-2-furyl)methoxvJethylamino}-4 methylamino-1,2,5-thiadiazole l,l-dioxide When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole ~ dioxide is reacted with one equivalent of 2-t~S-dimethylaminomethyl 2-furyl)~ethoxy3-ethylamine ~prepared according to U.S. Patent 4,128,6581 and then with exces~ methylamine, the title ~ompound i5 th~reby produced.

Example 23 3-{2-[(5-DimethylaminomethYl-2-furYl)methylthio~ethylamino}-4-ethylamino-1,2,5-thiadiazole l,l-dioxide Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide wi~h one equivalent of ethylamine and treatment of the xesultant 3-methoxy-4-ethylamino-1,2,~-~hiadi~zole 1,l-dioxide with one equivalent o 2-~(5-d~methylaminomethyl-2-furyl)~ethylthio~ethylamine yields the t~tle com~ound, which is identical to the product prepared in Example 12.

Exam~le 24 -3-{2-~(5-Dimeth ~ 1~2-furyl)meth~lthio~ethYlamino}-4-methylamln -1,2,5-thiadiazole l-oxide Reaction of a meth~nolic solution of 3,4-dLmethoxy-1,2,5-thiadiazole l-oxide ~prepared in Exam~le 4, Step ~

1209~L9 -~3-wi~h one equiYalent of methylamine and txeabment of th~
result~nt 3 methoxy-4-methylamino-1,2,5-thiadiazole l-oxide with one e~uivalent of 2- [ ( S-dimethylaminomethyl-2-furyl3methylthio~ethylamine yields ~he ti~le compound, which is identical to ~he product prep~r~d in Example 18.

Example 25 3-{2-t(5-Dimethy am _omethyl-2-furyl)methYlthio~eth~lamino}_ 4-meth lamino-1,2,5-thiadiazole l,l-dioxide y _ _ --A, 3-Me~hylamino-4-(2-meroaPtoethvl~ 1,2,5-thiadiazole l,l-dioxide A solution of 2-aminoethanethiol (from the hydro-chloride 1. 91 g; 16. 8 mmoles) in 20 ml of methanol was added drop~Jise over a period of 15 minutes to a tt211 stirred suspension of 3,4-dim~thoxy-1,2, S-thiadiazole 1, l-dioxide (3.0 g; 16.8 mmol~s) in 250 ml of methanol that had b~en cooled to 1 in an ice-water ba~h. After 10 minu~es at 2-4, methylamine was bubbled into the cooled solution for 6 minutes and stirr~ng was contlnued for an additional 30 minutes at ambient temperature. The rea~tion ~ixture was evaporated under reduced pressure and the residue placed on 45 g o~ silica gel and chromatographed using a.
gradient elution of methylene chloride-methanol. The appropriate ~ractions were combined and evaporated, and the product (2.43 g) uas crystallized from absolute ethanol.
Recrystallizataon from absolute ethanol yielded the title compound, ~p 259-260 (dec).

1%~9~9 -6~-Anal. Calcd for C5H10~4O2S2: C, 27.03; H, 4.54; N, 25.20.
. Found: C, 27.13; H, 4.55; N, 24.86.

B. 3-{2-~(5-~imethylaminomethyl-2-furYl)methyl thio]ethvlamino~-4-mèthylamino-1,2, 5-thiadia ZQl e 1,1-dioxide ... . _ A mixture containing 3-methyl amino-4- (2-mercap- -toethyl-l, 2, 5-thiadiazole 1, l-dioxide (1. 0 g; 4 . 5 mmoles ) [prepared in Step A~ and 5-dimethylaminomethyl-2-fura~-methanol (0.82 g; 4.5 mmoles) lprepared according to the procedure in J. Chem. oc., 4728 (1958)] in 20 ~1 of concentrated hydrochloric acid was stirred in a~ ice-water bath for 2 hours and then allowed to stand at 0 for 64 hours. The reaction mixture was stirred at ambient tempera-~ure for 23 hours, evaporated without heating under reduccd pressure and the residu@ parti$ioned between water and methylene chloxide. ~he aqueous phase was made ba~ic wi~h sodium bicarbonate and ext~acted with methylene chlo~ide. The combined organi~ phase was washed with saturated brine solution, dried and evaporated under red~ced pressure. The residue wa~ placed on 25 g of silica gel and chromatographed using a gxadient elution of methylene chlorid~methanol. The appxopriate fraction was e~aporated and ~he product crystallizéd from methanol.
Recrys~alli~ation from mekhanol yielded the title compound, mp 92-g6.

. ~

~9~19 Example 2 6 3={ 2~1 (5-Dimeth~tlaminomethYl-2-furvl~methYlthio] ethvlamino} -4-methvlamino 1, 2, 5-thiadiazole 1-oxîde . _ .

A. 3-Meth~lamino-4-~2-mercap~oethyl)-1,2,5-thiadiazole l~oxide .

A solution of 2-aminoethanethiol (fro~ the hydrochloride, 2~04 g; 18.0 ~oles) in 25 ml of methanol was added dropwise over a period of 30 minutes to a well stirred suspension of 3,4-d~methoxy-1,2,5-thiadia201e l-dioxide ~2.92 g; 18.0 mmoles) tprepared ~ Example 4, Step A3 in 150 ml of met~anol that had been cooled to 3 in an ice-water bath. After 10 minutes, anhydrous methylamine was ~ubbled into the solution for 6 minutes and stirring was continued at ambient temperature for an additional 20 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 45 g of sil~ca gel and chromatographed using a gradient .
elution of methylene chloride-methanol. The appropriat2 fractions were ~om~ined and e~aporated to give 2 r 74 g of product. Recrystallization from methanol and then 95 eth~nol yie~ded the title compound, mp 191-193.

B. 3-{2-[~5-DimethYlaminomethYl-Z-furYl)methyl-thio~ethylamino}-4-m ~ 1no-1,2,5-thiadiazole l-oxide When 3-methylamino-4-(2-mercaptoethyl3-1,2,S-thiadiazole l-oxide tPrePared in Step A] is treated with about one equivalent of 5-dimethylaminomethyl-2 furan-methanol in concentrated hydrochloric acid according ~o the procedure described in Example 25, Step B, the title compound is thereby produced; identic~l to the product of Exam~le 18.
.. ,.. i .

~;209~9 ~xample_27 3-~3O[~S-Dimethylamino~eth~1~2-furYl~meth~lthio~ro~v~-a~ino}-4-ethvlamino 1,2,5-thiadiazole 1,l-dioxide ~ en l-phthalimido-3-t(5-dimethylaminomethyl-2-furyl)methythio~propane lprepared ac~ording to the pro-ced~re described in Belgian Patent 857,388] is tr.eated with hydrazi~e, and the resulting substituted propvlamine i5 reacted ~ccording to the general procedure of Example 12, ~he title product is these~y produced.

Example_28 3-~2-1(5-Dimethy_aminomethyl-2-fur~l)me~hYlthio~ethvl-amino}-4 dimethvlamino-1,2,5-thiadiazole 1,l-dioxide To a cooled ~6) partial suspension of 3,4-dimethoxy-l,Z,5-thiadiazole 1,1-dioxidP (2.08 g5 11.7 mmoles) in 200 ml of methanol wAs added dro~ise over a period of 45 minutes a solution of 2-~(5-dimethylamino-methyl-2-furyl~mathylthio~ethylamine (2.$ g; 11.7 mmoles) in S0 ml of methanol. ~hen the addition was completed, anhydrous dimethylamine was bubbled înto the solution for 10 minutes while maintaining the temperature at 6. After stirring at ambient temperature for 18 ~ours, the reaction mixture was evaporated under reduced pressure and the residue placed on 200 g of silica and cnromatographed using a gradient elution of methylene chloride-methanol.
The appropriate fractions were combined and evaporated and the residue was rechromatographed on 7~ g o aluminum oxide using a sradient elution of methylene chloride-.

.

~209~L9 methanol. The appropriate fractions were combined and evaporated under reduced pressure to give the ~itle compound, ~p 139-142~
Anal- Calcd ~r Cl9H24Ns352: C, 44.~0; H, 6.46; N, 18.70; .
S, 17.12.
Found ~corr. for 0.51% H20): C, 44077; H, 6.25; N, 18.89;
S, 17.42.

Exa~ple 29 The general procedure of Example 28 is repeated, except that the dimethy~amine utilized therein i5 replaced ~Y
thiomorpholi~e, piperazine, N-ace~ylpiperaz~e, N-methylpiperazine, hexamethylerieimine ar~d homopiperazine, res~ecti~ely, and thexe is thereby produced 3-{2-t(5-dimethylaminome~hyl-2-furyl)methy~thiolethylamino}-4-(4-thiomorpholinyl)-1,2,5-thiadiazole 1,l-dioxide, 3-~2-~(50dimethylaminomethyl-2-furyl~methylthiolethylamino}-4-(l-piperazinyl~ 2,5-thi~diazole l,l-dioxide, 3-{2- t (5-dimethylaminomethyl-2-furyl)methylthio] ethylamino~-4-(4 acetyl-l-piperazinyl) -1, 2, 5-thiadiazole 1, l-dioxide, 3-{2-t(5-d~methylaminomethyl-2-furyl)methyl~io]ethylamino}-4-(4-methyl 1-piperazinyl)-1,2,5-thiadiazole l,l-dioxlde, 3-~2 t(5-d~methylaminomethyl-2-furyl)methylthio]ethylamino}-4-(l-hexamethyleneimino)-1,2,5-thiadiazole 1,l-dioxide and 3-{2-[~5-dimethylami~omethyl-2-furyl)methylthio~ethylamino}-4-(l-homopiperazinyl);1,2,5-thiadiazole l,l-dioxide, respectively.

~ 9~

Example 30 The general pxocedure of ~xample 13 is repeated,.
except that the 2-propynylamine utilized therein is replaoed by an equLmolar amount of cy~lobu~ylamine, aminomethylcyclobutane, e~hanolamine, 2-methylthioethylamin~, - 2,2,2-trifluoroethylamine, 2-1uoroethylamine, ethylenediam~ne, 2-methylaminoethylamine, 2-dimethylaminoethylamine, l,1-dimethylhydrazine, cyanamide, 3-aminopropionitrile, guanidine and-methylguanidine, respectively, and there i~ thereby produced 3-(cyclobutyl~mino1o4-{2-tt5-dLme~hyiaminomethyl-2-furyl)-methylthiolethylamino~l,2,5-thiadi~zole 1,l-dioxide~
3-~(cyclobutyl)methylamino]-4 ~2-1(5-dimethylaminomethyl 2-furyl)methylthio~ethylamino}-1,2,5-thiadiazole 1,l-dioxide, 3-~2-1(5-dimethylaminomethyl-2-furyl)methylthio]ethylzmino~-4-(2-hydroxyethylamino)-1,2,5 thi diazole 1,l-dioxide, 3-{2-~5-dimethylaminomethyl-2-furyl)methylthio]e~hylamino~-- 4-t2-methylthioethylamino)-1,2,5-thiad~azole 1,l-dioxide, 3-~2-[(5-dimethy~aminomethyl-2-~u~yl)methylthio]ethylamino~-4-(2,2,2-trifluoroethylamino)-1,2,5-~hiadi2zole 1,1-dioxide, 3-{2-tt5-dimethylaminomethyl-2 furyl)me~hylthio]ethylamino}-4-(2-fluoroethylamino)-1,2,5-thiadiazole l,l-dioxide, .

~2099~L9 3-~2-aminoethylamino)-4-{2-~(5-dimethylaminomethyl-2-furyl)-methylthio~ethylamLno}-1,2,5-thiadiazole 1,l-dioxide, 3-~2-t(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino~-4-(2-methylaminoethylamino) 1,2,5-thiadiazole 1,l-dioxide.
3-t2-~(5-dimethylaminomethyl-2-furyl~methylthiolethylamino}~
4-(2-dimethylam~noe~hylamino)-1,2,5~thiadiazole l,l-dioxide, 3-{2-1(5-dimethylaminomethyl-2-furyl)methylthio3ethylamino}-4-(2,2-dime~hylhydrazino)-1,2,5~thiadiazQle l,l-dioxide, 3-cyanoamino-4~{2-[(5-dimethylaminomethyl-2-fu~yl)methyl-thiolethylamino}-1,2,5 thiadia~ole l,l-dioxi~e, 3-~3-cyanopropylamino)-4-t2-[(5-dimethylaminomethyl 2-furyl~-me~hylthio]e~hylamino}-1,2,5-thiadiazole 1,l-dioxide, 3-{2-[(5-dimethylaminomethyl-2-furyl~methylthiolethylamino}-aanidino-l, 2, S-thiadiazole 1, l-dioxide, 3-{2-[tS-dimethylaminomethyl-2-furyl)methylthio3e~hylamino~-4-(N'-methyl)guanidino-1,2,5-thiadiazole 1, l-dioxide.

~ 31 3-{2-t(2-Guanid~nothiazol-4-Yl)methYlthio~eth~lamino}-4-met~ylamino-1,2,5-thiadiazole 1,l-dioxide A solution o~ 20 t~2-guanidinothiazol-4-Yl)methYl-thio~ethyl min (from the dihydrochloride, 4.27 g; 1~.0 mmoles) t n 30 ml o~ methanol was added to a well stirred suspension of 3,4-d~methoxy-1,2,5-thiadiazole 1,l-dioxide ~2.50 g; 14.0 mmoles) in 250 ml of methanol at 10. ~fter 15 minutes at 10, the solution was cooled to 1 in a cooling bath and anhydrous methylamine was bubbled into the solution for 10 minutes. The reaction mixture was evapo-r~ted under reduced pressure and the residue placed on 60 g of silica gel.and chxomatographed ~sing a gradient elution of met~ylene chloride-methanol. The appropri~te fraction 12099~.9 containing 4.53 g of product was placeZ on 80 g of alumin~;
oxide and rechroma~ographed using a gradient elution of ethyl acetate-methanol. The appropriate fractions were combined and evaporated to gi~e a foam which crystallized fro~. ~ethanol to yield (2.38 g) of the title compound, mp 196-l~nC (dec).
Anal. Calcd for CloH16N8O2S3 ~, 25.5~
Found: C, 31.85; ~, 4.24; ri, 29.79;
S, 25.45.

l~xample 3 ~

3-{2-~2-~uanidinothiazol-4-yl)methylthio~ethvlamino}-4-(2-~rooynyl)amino-1,2,5-thiadiazole l,l-dioxide A solution Or 2-~(2-guanidinothiazol-4-yl)methyl-thio~ethylamine (from the dihy~rochloride, 3.42 q; 11.2 mmoles) in 2; ml of methanol was added to a well stirred rold (8~ suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,l-dioxide ~2.0 g; 11.2 mmoles) in 200 ml of me~hanol.
After 15 minutes at 8-10, the solution was cooled to 1 in a~ ice-bath and a solution of 6.0 ml 2-propynylamine in 15 ml of methanol was added. The ice-bath was remo~ed and stirring was continued for 15 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 50 g of siiica gel and chromatographed using a yradient elution of methylene chloride-methanol.
I~o o~ the fractions yielded crystalline product (1.74 g) from methanol. The product was dissol~ed in hot methanol, filtered ~hrough Celite, cooled an~ filtered to yiald the title compound~ mp 176 178.

.

12~9~19 C12H16N8O253: C, 35,99; H, 4.03; N 27 980 S, 24~02.
Founa C, 35.82; H, 4.12; N, 28.41;
s, 24.28.

.

3-~2-[(2-Dimethyl~minomethyl-4-thiazslvl)methvlthio~ethyl-amino}-4-meth~lamino-1,2,5-thiad~azole l,l-dioxide A. ~-Carbo~henoxv-N-methylaminoacetonitrile To a suspension of methylamin~acetonitrile hydrochloride ~100 g; 0.94 mole~ in 1 liter of methylene chloride tcooled in a~ ice-water bath) was added triethyl-amine ~260 ml, 1.88 moles3 and a solution of phenyl chloroformat~ ~155.0 g, 0.99 mole) in 500 ml of ~ethylene chloride. The reaction mixture was heated at reflux temperature for 18 hours, then evaporated under reduced pressure to give a semi-~olid which was triturated with 1 liter of diethyl ether and filtered. The filtsate was evaporated under reduced pressure and the residual o~l was ~acuum.distilled to yield ~he title compound (123 g), bp 111-113~0.25 mm Hg; the ~R s~ectrum (60 M~z) in CDC13 gaYe the follo~Jing resonances ô: 7.23 ~m~ 5~
4.30 (s, 2H); 3.13 ~s, 3~).

B. (y-~a~ b~L~ meth~lami-olthioacetamide A solution of N-carbopheno~y-N-methylaminoace-tonitrile ~131~0 g; O.Ç9 mole) lPrepared in Step Al and thioacetamide (57.1 g; 0.71 mole) in 917 ml of dry D.
was ~reated wi~h BCl gas until an exothermic reaction too~
place, and then heated on a steam bath for 20 minute~.

- ~20979219 The reaction mixture was partially e~aporated under reduced pressure to remove some of the solvent, then made basic with sa~urated aqueous WaHCO3 solution and partitioned between ether and water. The aqueous phase was extracted with ethex and the combined ether phase ~Jas washed with water, saturated aqueous `.~aCl solution and dried. Filtra-tion and evaporation of the solvent gave an oil which was triturated with methylcyclohexane to gi~e the ~roduct as a solid. Recrystallization from isopropyl a~cohol yielded the ~itle compound, mp 101-103.
~nal, Calcd CloH12N202S 5~ 53.55; ~, 5-40; N, 12-49;
S, 14.30.
Found: C, 53.65; H, 5.51; ~,J, 12.69;
S, 14.41.

C. 4-Chlo om thyl-2-(N-carbo henoxv-N-methvl amino)methylthiazole To a caoled solution of (N-carbophenoxy-N-methylamino~thioacetamide (1.0 g; ~.46 ~moles~ and dry pyridine ~0.36 ml, 4.46 mmoles~ in 6 ml of absolute ethanol wa~ added a solution o~ 1~3-dichloropropanona ~0.57 g; 4.49 mmoles) in 3 ml of absolute ethanol. The mixture was heated at reflux temperature ~or 1.5 hours, ~hen evaporated under reduced pressure and the oil residue partitioned between ether and water. The aqueous layer was extracted with ether and the combined ether phase was ~ashed with water t saturated aqueous sodium chloride solution and dried. Filtration and evaporation yielded 1.02 g of the title compound as a viscous oil; TLC lSilica/
CH2C12CH3CN (85:15)~ gav~ ~f ~ 0.82, The NMR spectrum (60 M}l~) in CDC13 gave the following resonance5 ~: 7.16 (~, 6H); 4. 7? (broad s, 2~I);.4.60 (s, 2~); 3.07 (broad s, 3H).

~20g~19 ~ . 2~{[2-~N-Carbophenoxy-N-methvlamino)meth~
thiaz~lyl]methylthio}ethylamine To a solution cf sodium methoxide (26.1 g 0.48 mole) in 290 ml of a~solute e~anol at 0 under a nitro~en atmosphere was added cysteamine hy~rochloride (27.6 g;
0.24 mole) and an additional 218 ml of absolute ethanol~
Af ter ~tirring at 0 for 1 hour a solution of 4-chloro-methyl-2-(N-car~ophenoxy-N-methylamino)methylthiazole (72.5 g; 0.24 mole) in 218 ml of absolute ethanol was added o~rer a 15 minute period~ The reaction mixture was stirred at ambient te~perature for 18 hours, filtered and e~aporated under reduced pressure to give an oil which was partitioned between methyler~e chloride and water.
The aqueous phase was extracted with methylene chloride and the combined organic phase was washed ~Jith water, dried, filtered and evapo~ated under reduced pressure to gi~e the product ~68.5 g) as an oil which was treated with fumaric acid ~23.6 g) in n-propanol to gi~e the salt (47.0 g). Recrystalii~ation from absolute ethanol yielded the title compound as the fumarate salt, mp 145-146.
~nal. Calcd for C15~19~3252 4 4 4 ~, 9.27t S,_14.14.
Found: C, 50.32; H, 5.16;
~I, 9.47; S, 14.22.

E . 2- ~ t2-Di~methylaminometh~ thiazolvl ) -methy ~ l~ine To a solution of 2-~t2-(N-Carbophenoxy-N-methyl-amino)methyl-4-thiazolyl~methylthio}ethylamine ~0~50 g;

~2~9919 1.48 mmoles) ~prepared in Step D] in 10 ml of dry tetra-hydrofuran under a nitroge~ atmosphere was added lithium aluminum hydride (0.17 g; ~.48 mmoles) and the mixture was heated at reflux temperature for 0.5 hour. ~n additional 10 ml of tetrahydrofuran was added and neating was continued for 3 hours. ~he reaction mixture was trea~ed with 0.17 ml of H20, 0.17 ml of 15~ a~ueous ~laOH and Q.51 ml of H20, and filtered through Celite and dried. The filtrate was ~iltered and e~aporated under redu~ed pressure to giYe an oil which was dissolved in absolute ethanol, diluted with diethyl e~her and acidified with dry HCl.
The hydroscop~e hydrochloride salt of the title compound was collected and partition~d between aqueous 2.5N NaOH
and me~hylene chloride. The organic phase was washed with water, dried and filtered. The filtrate was evaporated und er reduced pressure to gi~e the free base of the title compound as an oil (0.22 g; 0.95 mmole) which was com~ine~
with anhydrous oxalic acid (0.24 g; 1.90 mmole) in 30 ml of hot acetonitrile~ The mixture was e~aposated from hot absolute ethanol to yield the title compound the bis-oxalate, mp 168-171.
9 17N34S2-2C2H2~4 C~ 37.95; H~ 5 lS;
N, lQ.21; $, 15.59.
Found: C, 37.95: H, 5.04;
N, 9.81; S, 15027.

~ . 3-~2-~2-DimethvlzminomethYl-4-thiazolvl)-methvlthio]ethyiamino}-4-m t~ylamino-1,2,5-thiadiazole l,l-dioxide .

To a cooled (6) suspension of 3,4-dimethoxy-1,2,S-thiadiazole l,l-dioxide (0.74 g; 4.17 mmoles~ in 80 ml of methanol was added dropwise o~er a period of 45 minutes ~ solution of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio~ethylamine (0.~6 g; 4.17 mmoles~
~prepared in Step E~ to give 3-{2-[(2-dLmethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxv-1,2,5-thiadiazole l,l-dioxide, ~ - 0c64 ~Silica~C~2C12:CH30H (9:1)]. m e temperature was maintained at 6 and anhydro~s methylamine was bubbled into ~he solution for 8 minutes. The reaction mixture was evaporated under reduced pressure and the r~sidue pl~ced on 80 g of silica gel and.~hromatographed using a gradient elution of mekhylene chloride-methanol.
m e appropriate fractions were ~ombined and ~he residue was rechromatographed on 25 g o~ aluminum oxide using a gradient elution of methylene chloride-methanol to give O.52 g of product. Recrystalliza~ion from isopropyl alconol/ether yielded the title compound, mp 144-148 ~oaming).
r C12H20N62S3: C~ 38~28; H, 5.35; ~ 22 32;
S, 2~.55.
Found: C, 37.8g, H, 5.43; W, 22.1~;
S, 2S.40.

3-t2-~2-DlmethylaminomethYlo4-thi-azolyl)methylthio~eth amino~-4-methylam ~

A. N-Carbethoxy~ meth~laminoacetonitrile ~riethylamine (5.2 ml; 37.6 mmoles) was added to a ~2~99~19 suspension of methylaminoacetonitrile hydrochloride (2.0 g;
i8 . 8 mmole~ in 20 ml of methylene chloride. The resulting suspension was coo~ed in an ice-bath and a solution o ethyl chloroformate (2.14 g; 19.8 mmoles) in 10 ml of methylene chloride was added over a 0.5 hour period, and the mixture was then heated at reflux te~perature fsr 13 hours. The reaction mixture was ~vaporated under reduced pressure to give a semi-solid residue which was triturated with diethyl ether and filtered, and the filtrate was evaporated under reduced pressure to yield the titl2 compound as an oil (2.2 g), b~ 96-98/~.2 mm Hg.

B~ (~-Carbethoxy-N-methylamino~thioacetamide A solution of N-carbethoxy-N-methylaminoace-tonitrile (9.8 g; 6.9 mmoles) ~prepared in Step Al, and thioacetamide (10.35 g; 13.8 mmoles) in 175 ml of dry D.
wa~ treated with hydrogen chloride gas until a vigorous exothermic reaction took place, ana ~en was heated on a steam bath for 15 minutesu The reaction mixture was made basic with saturat~d NaHC03 solution, and then extracted with ether, washed with water and dried. The ethexal phase was evaporated under reduced pressure to give a solid residue which was dissolved in methylene chloride and washed with water. The organic phase was dxied, filtered and e~aporated under reduced pressur2 to give product (2.$ g~. Recrystallization from ethyl acetate-hexane yielded the title compound, mp 91-93.

~209~

AnalO Calcd for C6H12~2O25: C, 40.89; H, 6.87; ~ 36;
S, 18.92.
Found: C, 40.73; ~, 6.85; N, 16.13;
S, 18.8~.

C. 2-(N-CarbethoxY-N-meth~lamino~methyl-4-carbethoxvthiazole .

To a solution of (N-carbe~hoxv-~-methylamino)-thioacetamide (30.7 g; 0.17 mole) ~prepared in Step Bl in 180 ml of absolute ethar.ol was added a solution of ethyl bromoDyruvate (25.0 ml; 0.20 mole) in l3q ml of absolute ethanol. The reaction mixture was heated at re~lux temperature for 17 hours and then evaporated under reduced prPssure~ and the residue was partitioned ~etween ether and water. The organic layer was washed with water and saturated sodium chloride solution, dried, filtered and evaporated under reduced pressure to give an oil which was plac¢d on siii~a gel and ohromatographed using diethyl ether as the eluting sol~ent. The appropriate fractions yielded ~he title compound as an oil; mLC ~Sil ica/C~2C12:CH3-CN (85:15)3 gave Rf - 0.50. The ~R spectrum (60 '~z) in d6 dimethyl sulfoxide ga~e the following resonances ~: 8.49 (s, lH); 4.79 ~s, 2H); 4.23 (m, 4}~); 3~00 (~, 3~);
1.30 (~, 6H~.

; D. 2-Dimet~y~ __nomethvl-4-h~droxvm~ thiazole To a cooled suspension of lithlum aluminum hydride ~8.4 g; 0.~2 mole~ in 80 ml of dry tetrahydrofuran was added a solution of 2-~W-~ar~ethoxy-~-met~ylamino)methyl-4-carbet~oxythiazole ~20.0 g; 0.07 mole~ ~repared in Step C~

~2099~L9 -7~-i~ 160 ml of dry tetrahydrofuran over a 1 hour period.
The reaction mixture was heated at reflux temperature for 8 hours, ~hen cooled and decomposed with ~a2S04 and 40~ aqueous potassium hydroxide. The mixture was ~iltered, dried and evaporated under reduced pressure to giv~ 4.2 g of the ti~le com~ound as an oll; ~LC
(aluminum oxide/CH3CN) gave ~F - 0.45. The ~-IR spec~r~m (60 ~IHz) in CDC13 gave the following resonances ~.: 7.17 (s, lH); 4.73 (d, 2H); 3.43 (s, 2H); 3.35 ts, 6H).

E. 2-t~2-Dimethylaminomethvl-4-thia201vl)me~hyl-hio]~ ylamine Whsen 2-dimethylaminomethyl-4-hydroxymethylthiazole ~prepared in Step D] is reacted with thionyl ~hloride and the resultant 2-dimethylaminomethyl-4-chloxomethylthiazole is reacted with an equimolar amount o~ cyste~mine hydro-chloride and two equi~alen~s of base according to the general procedure of Example 33, Step D, the title co~pound is there~y produced.

F. 3-t2-[(2-Oime~hylaminomethyl-4-thiazolYl)-m t~ylthio}eth~_amino}-4-m~ylamino-1,2, 5-thiadiazole l-oxi~e When a methanol suspension of 3,4-di~sethoxy-1,2,5-thiadia~ole l-oxide tprePared in Example 4, Step A]
is reac~ed with an equimolar amount of 2- ~ t2-dimethylas~ino-methyl-4-thiazolyl)methylt~sio3ethylamine tPrepared in Example 33, Step E] and the resulting 3-{2-t(2-d~ethylam~so-met~syl-4- thiazolyl)methylthio~ ethyiamins~-4-methoxy-1, 2, 5-t~iadiazole l-oxide is treated with methylamine, ~he :~2~:)9~19 ~79-title compound is therehy produced.

Example 35 3-~ino-4-{2-[t2-~uanidinothiazol-4-Yl)methylthio]ethyl-amino}-l,2,5-~hiadiazole l,l-dioxide A solution of 2-[(2-guanidino~hiazol-4-~l)me~hyl-thio~ethylamine ~2.75 g; 11.9 mmoles) ~obt~ined by ne,utra-lization of 2- E ~2-guanidinothiazol-4-yl)me~iylthioJethyl-amine dihydrochloride (4.0 g; 13.0 mmoles) with 2.5N
aqueous sodium hydroxide and extraction with ethyl acetate~ in 30 ml of methanol was added over a 1 hour period to a well stirred, cold (0) suspensio~ o. 3,4--dLmethoxy-1,2,5-~hiadiazole l,l-dioxide (2 rl2 g; 11~9 mmoles) in 220 ml o~ methanol. ~ile maintaining the temperature at O , anhydrous ammonia was bubl~led into the solution for 6 minutes and stirring was continued at ambient te~perature or 0.5 hour. The reaction mixture was evaporated under reduced pressure and the residue place~ on 120 g of siliça gel and chromatographed usin~ a gradient e~utlon of methylene chloride-methanol. The appropriate fractions were co~bined and evaporated, and the residue wa~ rechromatographed on 40 g of silic~ gel using a gradient elution of methylene chloride-methanol. The ;ap~ropriate fractions were co~hined, concentrated under vacuum, filtered and dried under ~igh ~acuum to yield the title compound, mp 134-149 (foaming); the ~lR spectrum ~lO0 '~z) in d6 dimethyl sulfoxide~2O~DCl gave the follot~ing resonances ~: 7.1B ~5 , lH?; 3 . 84 (s ~ 2H~; 3.52 :' (t, 2H); 2.75 ~t, 2H); and showed the presence of approx-imately 1.~ moles of methanol.

1~0~

Anal. Calcn for C~H14N802S3 1. 3 N, 27.95; 5, 23.99.
~ound (corr. for 1.31% H20): C, 30.19; H, 4.32;
N, 27.91; S, 24.71.

Example 36 3-{2-~2-Guanidino~hiazol-4-~l)methYlthio~ethvl~m1no~-4-(2-hy~roxvethvlamino3-1,2~5-thiadiazole l,l-dioxide To a well stirred suspension of 3,4-dI~ethoxy-},2,5-thiadiazole l,l-dioxid~ (2.05 g; lt.S ~moles) in 200 ml of dry methanol at 3 was added, dropwis~ over 30 minutes, a solukion of 2-[(2-guanidino~liazol-4-yl)-methyl~hio~ethylamine (~rom the dihydrochlori~e; 3.5 g;
11.5 mmoles~ in 40 ml of dry methanol. After 15 minu~es at:~, a solution of ethanolamine -(1003 ml, 17.3 mmoles) in 10 ml o~ methanol was rapidly added dro~ise and stirred for 15 minutes. The reaction mixture was evaporated under reduced pressure to give the produe~ as a friable foam that crystallized from methanol. Two recrystalliza-tions from methanol y~elded the title compound, mp = slowly resiniied starting at 115, deco~posed starting at 175~.
CllH18NsO3S3: C~ 32.50; H, 4.46; 1~ 27 57;
S, 23.66~
Found (corr. for 3.85% ~2) C, 32077; X, 4.21: ~, 27.90;
S, Z4.39.

....
-~ ~2099~.9 Example 37 3-(2,3-~ih~droxypropYlamino)-4-t2-[(2-quanidino~iazol-4-yl)methylthlo]ethylamino}-1,2,5-~ia_iazole l,l-d~oxide When a methanolic solution of 2-~2-guanidino-thiazol-4-yl)methylthio3ethylamine i5 reacted with 3,4-dimethoxv-1,2,5-thiadiazole 1,l-dioxide by the procedure of Example 31 and the resultant 3-methoxy-4-{2-~(2-guani-dinot~iazol-4-yl)me~hylthio3ethylamino~-1,2,5-thiadia~ole l,l-dioxide i5 treated with 3-amino-1,2-propanediol, t~G
title compound is there~y produced. ~

Example 38 3-~1ethvlamino-4-t2-[(th~azo~-2-vl)methylthio]etllylamino}-1,2,5-thiadiazole l,l-dioxide When a methanolic solution of 2-[(thiazol-2-yl)-methylthio]ethylamine tprepared according to the proc-dure described in U.S~ Patent 3,950,333~ is reacted ~ith 3,4-dimethoxy-1,2,5-thiadia201e 1,l-dioxide and the resultant 3-methoxy-4-C2-~(thiazol-2-yl)methylthio~ethylamino~-1,2,5-thiadiazole 1 t l-dioxide trea~ed with methylamine according to th~ general procedu~e described in Example 3i, e title compound is thereby produced.

. ~YamDle 39 When 2-chlorome~hyl-4-methylthiazole [prepared by the reaction of thionyl chloride and 2 hydroxymethyl-4-~ethylthiazole, which itself is pre~ared accordin~ to the , ~ .

9gl9

-8~-procedure of J. Chem. Soc., (Suppl. Issue ~oO 1), S106-111 (1966~. or Acta Chem. Scand., 20, 2649 (19&6)~ is reacted with cys~eamine hydrochloride and about two equivalents o~ a stsong base such as sodium me~hoxide, and the resultant amine is ~reated with 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide, ~here is produced 3-methoxy-4-{2-~(4-methyl-thiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole l,l-dtoxide. When th~ latter compound is reacted wi~h methylamine according to the general proceduxe of Example 31, there is produced 3-methylamino-4-{2-~ (4-methyltlliazol-2-yl)methylthio~ethylamir.o}-1,2,5-thiadiazole 1,l-dioxide.

When the above procedure is repeated, exce?t .that the 2-chloromethyl-4-me~hylthiazole utilized therein is xeplaced by an equimolar a~ount 9f the chloromethyl-thiazoles prepared by reacting thionyl chloride with 2-amino-4-hydroxymethylthiazolel, 2-hydroxym~thyl-4,5-dimethylthiazol~2, 4-hydroxymethyl-2-methyl~hiazole3, 4-hydroxymekhyl-2 ~hlorothiazole4, 5-hydroxy~ethyl-2-methylthiazole5, S-hydroxymethyl-4-methyl ~ iazole6, 4-hydroxymethylthiazole7 and 4 dimethylaminomethyl-2-hydroxyme~lylthiazole8, respecti~ly, there is thereby produced 3-~2-~2-aminothiazol-4-yl)methylthiolethyl~mino~-4-methylamino-1,2,5-thiadia 20 le l,l-dioxide t 3-{2-[~4,5-dimethylthiazol-2-yl)methvlthio3ethyla~ino}-4-methylamino-1,2,5-thiadiazole 1,l-dioxide, 3-{2-t(2-methylthiazol-4-yl)methylthio3ethylam~no~-4-methylamino-1,2,50thiadiazo~e l,l-aioxide, ~Z0~919 3-{2-[(2-chlorothiazol-4-yl)methylthio~ethylamino}-4-methylamino-1,2,5-thiadiazole l,l-dioxide, 3-{2-~2-methylthiazol-5 yl)methylthio~ethylamino}-4-methylamino-1,2,5-thiadaazole 1,l-dioxide, 3-{2-C(4-methylthiazol-5-yl~methylthio]e~hylaml~o~-4-methylamino-1,2,5-thiadiazole l,l-d ioxide, 3-{2-t(~hiazol-4-yl)methy~thio]ethylamino}-4-me~hylamino-1,2,5-thiadiazole 1,l-dioxide and 3-{2 t~4-dimethylaminomethylthiazol-2-yl~methylthioJ-ethylamino~-4-methylamino-1,2,5-thiadiazole 1,l-dioxide, respectively.

The above starting materials are prepared according to the procedures described in the following pu~licatio~:
(1) J. ~m. Chem~ Soc., 68, 2155 tl946~;
~2) Hel~. Chim. Acta, 31, 652 (1948);
(3) and (5) ~. Obshch. Khim., 32, 570 (1962) ~C. A., 58, 2~25b (1963)~;
(4) Rev. Roumaine ChimO, 10, 897 (1965) ~C. ~., 64, 8164b (1~66)];
Am. ~ . Soc., 67, 400 (7945);
~7) 2h. Obshch. ~im., 27, 726 (1957) [C. A., 51, 16436h ~1957)~;
(8) An ethanol solution of dimethylamine is reacted with 2-bromo-4-chloromethylthiazole, prepared according to reference ~4) above, and the resultant 2-bromo~4-dimethylaminomethylthiazole is treated with a strong base and formaldehyde according to the general procedur~
described in Acta Chem. Scand., 20, 2649 (1966), to give the desired 4-dLmethylaminomethyl-2-hydroxymethyl-thiazole, ~99.~9 ~xample 40 3- r 3-~2-Dim~thvlaminomethyl-4-thiazo 1Y1 )methy_th~o~pro~Yl-amino~-4-meth lamino-l 2 5-thiadiazole l,l-dioxide When 2-dLmethylaminomethyl-4-hydroxymethylthiazole [prep~red in ~xampl~ 34, Step Dl is reacted with 3-mercapto-propylamine hydrochloride ~prepared according to the pro-cedure described in J. Orq. Chem., 27, 2846 ~1962)1 in aqueous hydrobromic acid (48%), and the resultant amine is successively treated with 3,4-d~methoxy-1,2,5-thiadiazole 1,l-dioxide and excess methylamine as in.the general procedure of Example 31, the title compound is produced.

Exam~le 41 .
3-{2-t(2-Guanidinothiazol-4-~l)methvlthiol~ro~ lamino}-4-amino-l,2,5-~hiadiazole l~oxide .
When a methanolic ~olution of 2-ttguanidinothiazol-4-yl)methylthiolpropyla~ine is reacted with 3,4-dimethoxy-1,2,5-thiadiazole l-oxide t~repared Ln Example 4, Step A~, and the resultant 3-t2-tt2-guanidinothiazol-4-yl)methyl-thio~propylamino~ 4-m~thoxy-1,2,5-thiadiazole l-oxide is trea~ed with excess ammonia by the procedure in Example 35, the title compound is thereby pro~uced.

Example 42 3-{2-t(2 Guanidino~hiazol-4-~l)methylthio~ethylamino~-4-methylamino-1,2,5-thiad~a~ole l!l-dioxide 1209919 .

Reaction of a methanolic suspensisn of 3,4-dimethoxy-1,2,5-~hiadiazole 1,l-dioxide with one e~ui~a-lent of methylamine and treatment of ~he resultant 3-methoxy-4-methylamino 1,2,5-thiadi zole 1,l-~ioxide with one e~uivalent of 2-t(2-guanidinothi~zolo4-yl)methyl-th~o~ethylamine yields the title compound, which is identieal to ~he product obtained in Example 31.

Example 43 3-{2-[(~-~uanid~'nothiazol-4-~l)meth~lthio~ethYlamino}-4-methvlamino-1,2,5-thiadiazole l,l-dioxide .
. When a solutio~ of 3-methylamino-4-(2-mercapto-ethyl)-1,2,5-thiadiazole l,l-dioxide [prepared in Exa~ple 25, Step Al is reacted with 4-chloromethyl-2-gua~idino-thiazole hydrochloride and a strong b~s2, the title compound is thereby produced, which is ide~tical to the product o~tained in Example 31.

Example 44 3-{2-[(Z~Gu~nidinothiazol-4-yl)~ethylthio~ ethy~amino}-4-hydroxy-1,2~5-thiadiazole l!l-dioxide When 3,4 dimethoxy-1,2,5-thiadiazole l,l-dioxide is reac~ed with one equivalent of 2-[(2-guanidino~hiazol-4 yl)methylthio~ethylamine and tha resultant 3-{2-~2-guani-di~o~hiazol-4-yl)methylthio]ethylamino~-4-methoxy-1,2,5-thiadiazole l,i-dioxide is reacted with sodium hydroxide according to the procedure descr~bed in Example 17, Step B~ the title ompound is produced.

-8~-Example 45 3-{2-tt2-Dimeth laminomethvl-4~thiazolYl)meth~thio~-eth~lamino~-4-methylamino-1,2,5-~hiadiazole 1,l-dioxide Reac~ion of a me~hanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide with one equivalent o~ methylamine and treatment of ~he resul~ant 3-m~hoxy-4-methyl~mino-1,2,5-thiadiazole l~l-dioxide with one equivalent of 2-~(2-dimethylaminomethyl-4-thiazolyl)methylthio~ethyl-amine ~prepared in Example 33, S~ep E], produces the title compound which is identical to the produc~ prepared in Example 33.

3-t2-t~-Dimethylaminome~hyl-4-thiazolYl)methYl~hio~e~hYl-amino~-4-methylæ~ino-1,2,5-thiadia20l~ dlox~d~

Reaction o~ 3-mPthylamino-4-(2-mercaptoethyl)-1,2,5-~hiadia~ole l,l-dioxide [prépared in Example 25, Step AJ with about one equivalent of 2-d ~ ethylaminomethyl-4-hydroxymethylthiazole ~prepared in Example 34, Step D~ in concentra~ed hydrochloric acid, and then made basic and worked up, produces the title compound which is identica$
to the product prepared in Example 33.

i; .
Example 47 3-~2-[~2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethyl-amino}-4-hydroxy-1,2,5-thiadiazole 1,l-dioxide 9g~

When a solution of 3-{2-[t2-dimethylaminomethyl-4-thiazolyl)methylthio] ethylamino}-4 -methoxy-1,2,5-thiadiazole 1 ,l-dioxide [prepared accoxdir~s to the procedure desrribed irl Example 33, Step F~ is reacted with sodium hydroxide according to ~he procedure descri~ed in Example 17, Step B, the title compound is produced.

Example 48 3-Amino-4-{2-~(2-dimethYlaminomethYl-4-thiazolyl)methyl-_io]e~hylamino}-1,2,5-thiadiazole l-oxide When a methanolic solution of 3-{2-t(2-dimethyl-aminomethyl-4-thiazolyl)methylthio~ ethylamino~-4-methoxy-1, 2, 5-thiadiazole l-oxide [prepared from 3, 4-d~methoxy-1,2,5-thiadiazole 1-oxide ~y the general proredure described Ln Example 34, Step F] is reacted with anhyarous ammonia according to the general procedure ~escribed i~ Example 35, the title compound is thereby produced~

Example 49 3-{?- t (2-~i~et~th azolyl)methylthio~ e~yl-amino}-4-meth~lamino-1,2, S-thiadiazole l-oxide ~ eaction o~ 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole l-oxide tprepared by reacting 3,4-dimethoxy 1, 2, S-thiad~ azole l-oxide with ~-aminoethanethiol and m~thylamine a~cording to the procedure described in Example 25, Step Al with abo~t one equi~alent of 2-dimethyl-aminomethyl-4-hydroxymethylthiazole ~prepared in Example 34, Step D], produces the title compound.

12~ 9 -8~-Example 50 3-Amino-4-~4-(2-quanidinothiaz~ -yl3bu~ylam.ino~-1,2,5-thiadiazole l-oxide When a methano~ic solution of 3,4~dimethoxy-1,2,5-thiadiazole l-oxide is successively treated with 4-~2-guanidinothia~ol-4-yl)butylamine [prepared according to the procedure described in U.S. Patent 4,165,377] and excess anhydrous ammonia according to the general procedure desoribed in Example 35, the title compound is hereby produced.

Example 51 3-~2-l~5-DimethylaminomethYl-2-furYl)methvlthio]eth ~amina}-4-hvdrazino 1,2,5-thiadiazole l,l-dioxide A solutio~ of 2-t~5-dimethylaminomethyl-2-'uryl)-methylthio]ethylamine (2.41 g; 11.2 mmoles) in 30 ml of dry methanol was added dropwise over a period of 45 mi~ute~ to a well stirrea cold (ice-water bath) suspension of 3,4-dimethoxy~1,2,5-thiadia~ole l,l-dioxide ~2.0 g 11.2 mmoles) in 250 ml of methanol. After st~rring at 0 for 15 minutes, a solution o~ anhydrous hydrazine (1~8 g;
56.13 mmole ) i~ 30 ml of dry methanol was added all at once, and stirring was continued for 30 minutes. The reaction mixture was evaporated under reduced pressure and the solid residue wa~ treated with chloroform and filterad to give 3.28 ~ of the title compound, mp 17.0 (dec.) r 099~'9 ~89-_xample 52 3-MethYl~m no-4-{2-t(2-pyridyl?methylthio~eth~lamino}-1~2~5-~hiadiazole l,l-dioxide A solution of 2-~2-pyridyl)methylthio]ethylamine (from the dihydrobromide, 3.5 g; 10.6 mmoles) tprepared according t~ the procedure described in Belgian Pa~ent 779,775] in 25 ml of dry methanol was added dropwise over 30 min~tes to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide in 20~ ml of dry methanol that was cooled to 0-5 in an ice-water bath. After stirri~g the cold so~ution for 15 minutes, anhydrous methylamine was bubbled into the s~lution for 15 minutes.
The reaction mixture was stirred at ambient temperature for 4 5 minutes, evaporated under reduced pressure and the residue crys~allized with methanoL. Two recrystallizations from methanol yielded the title compound, mp 168-171.
252 C~ 42.15; H, 4.8~; N, 22 35;
S, ~0.46.
Found: C, 42.07; ~, 4.75; N, 22.28;
S, 20.73.

Example 53 3-~2- E ~3-Chloro-2-pyridYl)methYlthao] eth~.lamino}-4-meth~l-amin~-1,2,5~thiadiaz ~

~ hen a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazol~ l,lo~ioxide is successively treated with 2-t(3-chloro-2-pyridyl)me~hylthio~ethylamane tprepared according -so-to the.procedure described in U.S. Pa~ent 4,024,2601 and~
methylamine according to the general procedure of Example 52, the title co~pound is thereby produced.

Example 54 3-{2-[~6-Dimethvlam~ ~ .y~ y~idYl)methYlthiolethYl-~mino}-4~meth~1amino-1,2 ! 5-thiadiazole 1,l-dioxide ~ en a methanolic solu~ion of 3,.4-dLmethoxy 1,2,5-thiadiazole l,l-dioxide is successively treated with an equimolar amount o~ 2-[~6-dlmethylzminomethyl-2-pyridyl)methylthio~ethylamine [prepared in Example 136, Step Cl and excass methylamine, the title compound is thereby produced.

Example 55 The general procedure of Example 52 is repeated except that the 2-~(2-pyridyl)methylthio]ethyl~mine utilized ~herein is replaced by an equ~molar amount of 2- t (3-~romo-2 pyridyl)methylt}liolethylamine, 2-t(3-cyano-2-pyridyl)m~thylthio~e~hy7.amine, 2- [(3-hydroxy-2-pyridyl~methylthio]ethylamine, 2-[(3 methoxy-2-pyridyl)methyl~hio]ethylam~ne, 2-[~30ethoxy-2-pyridyl~methylthio]ethylamine, 2-[(3-methyl-2-pyridyl)methylthio~ethylamine a~d 2-~ (3-amino-2-pyridyl)methylthio~ eehyla~ine, respectively, ~2O~1L9 [prepared according to the general ~rocedures described in Belgian Patents 779,775, 804,144 and 844,504] and these is thereby produced 3~2-E~3-bromo-2-pyridyl)~ethylthio]ethylamlno~-4-methylamino-1,2,5-thiadiazole l,l-dioxide, 3-t2-~3-cyano-2-pyridyl)methylthioJethy~amino}-4-methyl~m~no-1,2,5-thiadiazole ~,l-dioxide, 3-{2-tt3-hydroxy-2-pyridyl)methylthio]ethylamino}-4-~ethylamino-1,2,5-thiadiazole }, l-di~xide, 3-{2-~(3-methoxy-2-pyridyl)methylthio]ethyla~ino3-4 methylamino-1,2,5-thiadiazole 1,l-dioxide, 3-{2-t(3-ethoxy--2-pyridyl)methylthio~ethy~mino}-4- -methylamsno-1,2,5-thiadiazole 1,l-dioxide, 3-{2-~3-methyl-2-pyridy~methylthiol~thylamino~-4-me~hylamino-1,2~5-thiadiazole l,l~dioxide and 3-{2-~3-amino-2-pyridy.l)methylthio]ethyla~ino~-4-~ethylæmino-1,2,5-~hiadiazole l,l-dioxide, respectively.

Example 56 3 ~2 [(3 Chloro-2- rid l)meth lthio]eth iamino}-4-~2-[(5-py y y y dLmethylaminomethyl-2-~urvl)m~thvlthioJethYlamino}-1,2,5-thiadiazole l,l-dioxide .

Wh~ a methanolic solution of 3,4-dLmethoxyol,2,5-thiadiazole 1,l-dioxide is successi~ely treated with 2-~5-dimethylaminom~thyl 2-furyl)methylthio]ethylamine a~d 2-~(3-chloEo-2-pyridyl)methylthio3ethylamine, ~he title compound is thereby produced.

~ z~99~9 ExamPle s?

3-{2-tl6-Dimeth~laminomethY1-2-DvridYl)methvlthio~ethvl-amino~-4-methylamino-1,2,5-~hiadiazole l-oxide When a me~hanolic solution of 3,4-dimethoxy~1,2,5-thiadiazole 1-oxid~ tobtained from Example 4, Step Al is successivel.y ~reated with an equ~molar amount of 2.-1~6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine ~prepared in Example 136, Step C~ and an excess of methyl-am~e, the title compound is thereby produced.

Exzmple 58 3-{2-tt4 Methyl-1,2,5-oxadiazol-3~vl)m~thYlthio3ethvl~mino~-4-methylamino-1,?,S-~hiadiazole l,l-dioxid~

A. 3-Hydroxymethyl-4-meth~lfurazan .

To a stirred solution of 3-methylo4-furazancar-~oxylic acid ~27~0 g; 0.21 mole) in 180 ml of tetrahydro-furan (that ~as cooled in an ice-water bath) under a nitrogen abmosphere was added dropwise a 1.02 solution of borane in tetrahydrofuran (825 ml; 0.84 mole). When the addition was completed, th~ mixtur~ was stirred at ambient tzm~erature ov~rnight. After 20 hour~, 6~ HCl was added dropwise until the evolution of hydrogen ceased and the reaction m~xture was e~aporated under reduced pressure. The residue was partitioned ~etwee~ methylene chloride and water, made basic with potassium carbonate and th~ combined methylene chloride ~2099~9 extract was dried and evaporated under reduced pressure to give 21. O g of produc~. Vacuum di~tillation yielded the title compound, bp 99 /1 Irun Hgr B. 2-~(4-MethYl-1,2,5-oxadi~zol-3-yl~met~rlthio~-ethylam- ne A solution of 3-hydroxymethyl-4-methylfurazan ~2 . 49 g; 21. 8 mmoles) ~prepared in Step A] and 2-amino-ethanethiol hydrochloride (2.48 g; 21.8 mmoles) in 60 ml of 4 8 % aqueous hydrobromic acid was stirred and heated at reflux temperature for 23 hours and then at ambient temperature for 40 hours. T~e excess hydrobromic acid was removed under reduced pressure, and the oil residu~
was dissolved in isoprc)pyl alcohol, filtered through Celite and the product was cry$tallized from the filtrate.
~ecrystallization from isopropyl alcohol yielded the title compound as the hydrobromide salt, mp 142-143.
.

C. 3-{2-1(4-Methyl-1,2,5-oxadiazol 3-Yl)methYl-thio]ethylamino~-4-methYlamino-1,2,~-thiadiazole l,l-dioxide When a methanolic suspension o~ 3, 4-dimethoxy-1,2,5-thiad~azole l~l-dioxide i5 successively treated with an equLmolar amount o~ 2-t(4-methyl-1,2,5-oxadiazol-3-yl~
methylthiolethylamine lprepared in Step B; and excess methylamine by the general procedure o~ Example 2, the title compound is ther~by produced.

~2099~g Example 59 3-{2- E (5-Dim th laminomethvl-2-furYl)methYlthioJethylamino}-4-{2 t(4-m~thyl-1,2,_5-oxadiazol-3-Yl~methylthio~ethy~amino}-1,2,5-thiadiazole 1,l-dioxide When a methanolic solution o~ 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide i~ treated with 2-t(4-methyl-1,2,5-oxadiazol-3-yl)methylthiolethylamine tPxepared in Example 58, 5tep Bl and 2-tt5-dimethylaminomethyl-2-furyl)methylo ~hio~ethylamine, the title compound is thereby produced.

ExamDle 60 3-{2~ Methyl-_,2,4-oxadiazol-3-Yl)methYlthio]e~ylamino}
4-meth lamino-~. 2,5-thiadiazole l,l-dioxide =_ A. 2-~t5-Met~yl-1,2,4-oxadiazol-3-Yl)methYlthio3-ethylamine Cysteamine hydrochloride (3.03 g; 26.7 mmoles) was added in several portions over a period of 1~ minutes to a stirred solution of sodium methylate ~2.89 g; 53.4 m~oles) in 50 ml of methanol at O. After stirring for 70 minutes at 0~, a solution of 3-chloromethyl-S-methyl-1,2,4-oxadiazole (3.54 g; 26.7 mmoles~ in lS ml of methanol was added drop-wise over a period of lS minutes, and the reaction mixture was allowed to stir at ambient temperature ~or 16 hours.
The mixture was filtered, evaporated and redissolved in ~L209~1~

isopropyl alcohol, then filtered and evaporated under re-duced ~ressure to gi~e the title compound (5.54 g) as a yellow oil. The NMR spectrum (60 MHz) in CDC13 gave the followiny resonances ~: 3.77 (s, 2H~; 2.77 (ml 4~);
2.63 (s, 3H~.

B. 3-{2-~(5-Methyl-1 ! 2,4-oxadia201-3-yl)-me~hylthio~ethylamino}-4-methYlamino 1,2,5-~hiadiazole 1, l-dioxide When a methanolic suspension of 3,4-dimethoxy-1,2,~-~h~adia~ole l,l-dioxide is treated ~uccessively with 2- [ (5-methyl-1,2, 4-oxadiazol-3-yl~methylthio~ ethylamine [prepared in Step A] and m~thylamine, by the general procedure of Example 2, the title compound is there~y produced.

Example 61 ~ -5-Yl)meth~lthio~ethylamino}-4-met ~ 2,5-thiadiazole l,l-dioxide A. 2-[t2-Methyl-1,3,4-oxadiazol-5~1)methyl~hio3-ethylamine Cysteamine hydsochloride (1.13 g7 0.01 mole) wa~added to a st rred solution of sodium methylate (1.08 g;
0.02 mole) in 20.ml of me~hanol at 0~ und~r an argon a mos-phere. The mixture was stirred for 1 hour at 0 a~ the 1209~9 resultant suspension was added dropwise over a period of 25 minutes to a stirred solution of 2-me~hyl-5-chloromethyl-1,3,4-oxadiazole ~1.32 g; 0.01 mole) tpre~ared by the procedure described in Xel. Chim. Acta, 55, 1979 tl972)~
in 15 ml of methanol at 0. The reaction mixture was stirred a~ ambient temperature for 45 minutes, concentrated to near dryness, and then diluted with methylene chloride, filtered and evaporatea ~nder reduced pressuxe to.give the title compound (1.92 g) as a yellow oil. The ~R
spectrum (60 MHz) in CDC13 gave the following resonances ~: 3.87 (s, 2H); 2.8 (m, 4H); 2.53 (s, 3~).

B. 3-{2-~(2~Methyl-1,3~4-oxadiazol-5-~l~me~hyl-thio~ethylamino}-4-methYlamino-1,2,5-thiadiazole 1,l-dioxide When a suspension of 3,4 dimethoxy-1,2,5-thia-diazole l,l-dioxide is treated with an equimolar amount of 2-t(2-methyl-1,3,4-oxadiazol-5-yl~mDthylthiolethylamine tprepared in Step A] and an excess of methylamine by the ge~eral procedure descr~bed in Example ~ t the title compound is thereby produced.

Examl~le 62 3-{2-1(2-Dimethylamino-1,3,4-oxad~azol-5-Yl?methylthio~-ethYi~nino}-4-methy~2m~no-1,2,5-thiadiazole l,l-dioxide When 2-dLmethylamino-5-ethoxycar~onyl-1,3,4-oxadiazole tprepared according to the procedure described in ~ Ma~n. Resonancet 6, 144 (1974)J is hydrolyzed and reduced with borane as described in Example 58, Step A, 120991'~

and then is reacted with cysteamine according f o the pro-cedure described in Example 60, Step A, there is produced 2-t(2-dLmekhylamino-1,3,4-oxadiazol-5-yl)methylthio]-ethylamine.

~ hen ~he above amine is reacted with an equ~molar amount of 3,4-dimethoxy-1,2,5-~hiadiazole 1,l-dioxide, and the resultant 3-{2-~(2-dimethylamino-1,3,4-oxadia2O1-5-yl)-me~hylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,l-dioxid2 is treated with an excess of me~hylamine, ~he title compound is ~herPby produced.

Example 63 3-{2 E(3-{DLmethylaminomethYl}~henYl~methylthio~ethyl .

amino~-4-~mino-1,2,5-thiadiazole 1,1-dioxide , When a methanolie suspens~on of 3,4-dimethoxy-1, 2, 5-thiadiazole 1, l-dioxide is successiYely treated with an equimolar amount of 2-t(3-{dimethylaminomethyl~phenyl)~
m~thylthio]e~hylzmine tprepared according to the procedure described i~ Belgian Patent 867,106~ and excess zmm~nia by the general procedure described i~ Examp1~ 35, th~ title compound is thereby produoed.

Example b4 3-{3-l3-(DimethYlaminomet ~ lamino~-4-amino-1,2,5-th~adiazole l,l-dioxide lZ09~ 9 When a methanolic suspension of 3,4-dlme~hoxy-1,2,5-~hiadiazole l,l-dioxide is successi~ely treated with an equ~molar amount of 3OE~o(dImethylaminomethyl)phenoxy~-propylamine ~prepared accord~ng to the.procedure described in Belgian Patent 867,106] and excess ammonia by the general procedure described in Example 35, the title compound is thereby produeed.

Example 65 3-{2-~(5-Dimethyl~minomethYl-2~thienYl)methYlthio]ethy~
amino}-4-methylamino-1,2,5-thiadiazole l,I-dioxide , .
A solution of 2-~(5-dLme~hylaminomethyl-2-thienyl) me~hyl~hio~ethylamine (1.0 g; 4O34 mmoles) ~psepared accord-ing to the procedure described in Belgian Patent 867,1051 in 25 ml of dry methanol was added dropwise o~er a period of 35 minutes to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide ~0.77 g; 4.34 mmoles~ in 150 ml o~ dry methanol that had been cooled to 0-3~ in an ice-water bath. After the addition was comple~ed, anhydrous methylami~e was bubb~ed into the solution for 10 mi~utes and stirring was continued for 15 minutes. The reaction mixture was evaporated unde~ reduced pressure and th~ residue placed on 50 g o~ silica gel and chromatographed using a gradient elution of acetonitrile-methanol. The appropriate fractions were combi~ed to give 1.0 g of product. Recry-stallization from methanol yi~lded the title compound, mp 60.5-66~

lZ099~9 Exam~le 66 3-{2-~t5-DimethYlaminomethyl-2-thienyl~meth~lthio~eth~
amino~-4-ethylamino-1,2,5-thiadiazole l-oxide When a solution of 3,4-dimethoxy-1,2,5-thiadiazole l-oxide ~prepared i~ Example 4, Step Al is su~cessively reacted with an e~uimolax amount of 2-t(5-dimethyl.amino methyl-2-thienyl)m thylthio]e~hylamine and excess ethylamine according to ~he procedure described in Example 18, the title compound is thereby producea.

Exam~le 57 3-{2-l(5~ 3~ yL~___ methvl-2-thienyl~g5~___o~ethvl-am~no}-4-{2-1(4-methvl-1,2 l~hiol-ethyl2~ino}-l,2,5~thiadiazole 1 r l-dioxid When a suspension of 3,4-d~methoxy-1,2,5-thiadia-zole 1,l-dioxide i3 reacted with an e~uimolar amount of 2-[~5-dimethylaminomethyl-2-thienyl)methyl~hio]ethylamine and t~e resultant 3-{2-1(5-dimethylaminomethyl-2-thienyl)-methylthio~ethylamino~-4-me~hoxy-1,2,5-thiadiazole 1,1-dioxide is ~reated with 2-E(40methyl-1,2,~-oxadiazol-3-yl) me~hylthio]ethylamine lprepared in Example 58, Step Bl, the title compound is ther~by produced.

- 12Q99Ig 10~-Exam~le _6 8 3_{4- ~ (2-Guanidino-4-oxazolYl]b~t~lamino}-4-meth~la;nino-1, 2, S-thiadia zol e 1, l-dioxide When a suspens ior~ of 3, 4-dimethoxy 1, 2, 5-thiadiazole l,l-dioxide is reacted with an e~uimolax amount of 4-t(Z guanidino-4-oxazolyl~butylzmine [prepared aceording to the procedure described in Belgian Patenk 866,1551 and the resultant 3-{4-~(2-guanidino-~-oxazoiyl]-butylamino~ ~4-methoxy-1,2,5-thiadiazole 1,l-dioxide is treated with excess methylamine, the title compound is thereby produced.

Example 69 3-{2-~2-~2-Amino-5-oxa ~ thio~ethYlamlno~-4-methylamino-1,2,5~thiadiazole l,l-diox de .
Reac~ing an equimolar amount of 3,4-dimethoxy-1 t ~ t 5-thiadiazole l~l-dioxide and 2-12-~2-amino-5-oxazolyl3ethylthio~ethylamine [prepared according to U.S. Patent 3,950,3531 and treatment of the resultant 3-~2-[2-(2-amino-5-oxazolyl)ethylthio]ethylamino}-4-methoxy-1,2,5 thiadiazole l,l-dioxide with excess methylamine gives the title compound.

-lQl-Exam~le 70 _{2-E3-Isoxazolvlmeth~rtthio~ethYlamino}-4-methylamino-1,2,5-thiadiazsl2 l~l~dioxide Re ction of a methanolic suspension o~ 3,4-dimethoxy-1,2,5-~hiadi~zole 1,l-dioxide with one equi~alent of 2-t3-isoxa201ylmethylthio~ethylamine [prepared according to ~he procedure described Ln U.S. Patent 3,950,353]
and treabment of the resultant 3-{2- [3-isoxazolylmethyl-thio]e~hylamino}-4-methoxy-1,2,5-~hiadiazole 1,1-dioxlde with an exces~ of me~hylamine9 produced t~e title compound.

Example 71 The genera~ procedure of Exasnple 70 .i3 re~eated except ~hat the 2-[3-isoxazolylmethylthio]ethylæmine utilized therein is replaced by an equimolar amount of 2-t(5-methyl-3-isoxazolyl)methylthio]ethylami~e, 2-[(3~5-di~ethyl 4-isoxazolyl)methylthio~ethylamine and 2-~2-(5-methyl-4-isoxazolyl)ethylthio]ethyla~i~e, respect vely, teach prepared ~y the general prscedure described in U.S. Patent 3 ,950,353] and the~re is the~eby produced 3-t2- { tS-methyl-3-isoxazolyl)methylthiol ethylamir~o}-4-methylamino-l,2,5-thiadiazole 1,1-dioxide, 3-{2- t ~3 ,S-dimethyl-4-isoxazolyl)methylthio}-4-methyl-amino-l ,, 2, 5-thiadiazole 1, l-dioxide and 3-{2-t2-(5~methyl-4-i oxazolyl)ethylthio~ethyl~mino}-4-me~hyiamino-l, 2 ~ 5-thiadiazole 1,1-dioxide, respecti~ely.

, .

~2099~9 ~xam~le 72 3-{2-t(5-Dimethylaminomethvl-2-furyl)methYlthiolethvl-methy~th o]ethylamLno}-l,2,5-thiadiazole l,l-dioxide ~ hen a methanolic suspe~sion of 3,4-dimethoxy 1,2,5,thiadiazole 1,l-dioxide is reacted with ona equ~a-lent of 2-~(S-dimethylaminomethyl-2-furyl)methylthio~ethyl-amine according to the procedùre d~scribed in Exam~le 17, Step Ar and the resultant product is treated with one equivalen~ of 2-t(3-~soxazolylmethylthio~ethylamine, the title compound i~ there~y produoed.

Example 73 3-{2-~3-Isothia~ylmethYlth~o]ethylamino}-4-methvlamino-1~2,5-~hiadiazo e l,l-dioxide R~action of a methanol suspension of 3,4-dimethoxy-1/2,5-thiadiazole l,l-dioxide wi~h on~ equivalent of 2-t3-isothiazolylmethylth~o]ethylamine ~prPpare~ accord~ng to the procedure described in U.S. Patent 3,~50,353J and treatment of the resultant 3-{2-~3-isot~iazolylmethyl~hio]-ethylamino}-4-me~hoxy-1,2,5-thiadiazole l,l-dioxide with an excess of methylamine, produces ~he title compo~nd.

n L~

~19 Exam~le 74 The general procedure of Example 73 is repeated except that the 2~[3-isothiazolylmethylthio~ethylamine utilized therein is replaced by an equimolar amount of 2-t(3-methyl-4-isothiazolyl)methylthio]ethylamine;
2-~t4-bromo-3-methyl-5-isothiazolyl)methylthiole~hylami~e and 2-~t3-methyl-S-isothiazolyl )me~hylthio; ethylamine, respecti~ely, tprepared by the general proceduxes described in U.S. Paten~ 3,450,353 and ~. Chem~ Soc., 2032 (1963)] and there is thereby produced 3-{2-t(3-methyl-4-isothiazolyl)methylthio~et~ylam~no}-4-methylamino-1,2,5-thladiazole 1,l-dioxide, 3-{2-~4-bromo-3-methyl-5-isothiazolyl~methylthio~e~hyl-amino~o4-methylamino-1,2,~-thiadiazole 1,l~dioxide and 3 {2-t(3-methyl-S-iso~hiazolyl~methyl~hio~ethylam~n~}-4-methylamino~2,5-th~ad~azole l,l-diox~de, respectively.

Example 75 3-~2-[~5-Dimethvlam~nome~hvl-2-~u ~l)methy~thiolethylæmino}-4-{2-~3-isothia~olYlmeth~lthio]eth~lamino}ol~2,5-~hiadiazole l,l-dio_ide When a methanol suspension of 3,4-dimethoxy-1,2,5-~hiadiazole l,l-dioxide is reacted wi~h on equivalent of 2-tt~-dimethylaminomethyl-2-furyl)methylthio]e~hylamine accQrd~nq to the procedure described in Example 17, Step A, `` 12~9919 and th~ resultant 3-{2-~(5-dLmethylaminomethyl-2-furyl~-methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with one e~uivale~t of 2-~3-isothiazolyl-~ethylthio]ethylamine, the tit~e compound ss produced.

Example 75 3-{2-~(2-~mino-1 3 4-thiadiazol-5- l)meth lthio~eth 1-Y ~ . Y
amino~-4-meth 1amino-l,2,5-thiadiazole 1,l-dioxide Y~

~ eaction of 3,4-dimethoxy-1,Z,5-thiadiazole 1,1-dioxide with one equivalent of 2-t(2-amino-1,3,4-thiadiazol-5-yl~methyl~hiolethylamine ~prepared according to the .procedure describe~ in U.~. Pate~t 3,950,3531 and tr~atment of ~he resultant 3-t2-t(2-amino-1,3,4-thiadiazol 5-yl)-methylthio~ethylamino~-4-methoxy-1,2,5-thiadiazole 1,1-dioxide with methylamLne, produc~d the title compound.

Exam~le 77 Tha general procedur~ o~ Example 76 is repeated except that th~ 2-lt2-amino-l~3~4-thiadiazol-5-yl)meth thio]ethylamine utilized ~her~in is replaced by an equimolar ~moun~ of 3-11,2,4-thiadiazol-3-Y~thiolpropYlamine, 2-{(1,2~3 thiadiaz~l-4-yl)m~thylthio]e~hyla~ine, 2-[t3-hydroxy-1,2,5-thiaaiazol-4-yl)methyl'chiolethylamine and 2~ ~ ( 3-aminG-~,2,50thiadiazol-4-yl)methylthio~ethylamine, respectiYely, lprepared by ~he general procedure~ described in U.S. Patent 3,950,353, J. Am. Chem. 50co r 86~ 2861 (1964) and J. ~. Chem., 28, 1491 ~1963)] and there is ~hereby produced ..... ,.. ~ .

~0~9'19 3-{3-tl,2,4-~hiadiazol-3-ylthio3propylamino}-4-methyl-~mino-1~2,5-thiadiazole 1,l-dioxide, 3-~2-t(1,2,3-thiadiazol-4-~l)methylthioJethylamino}-4-~ethylamino-1,2,5-thiadiazole 1,l-dioxide, 3-~2-t~3-hydroxy-1,2,5-thiadiazol-4-yl~ methylthio~ ethyl-amino}-4-methylamino~ ,5-thiadiazole 1,1-dioxide and 3-t2-1(3-amino-1,2,5-thiadiazol-4-yl)methylthio~ethyl-amino}-4-methylamino 1,2,5-thiadiazo le 1, l-dioxide, respecti~ely.

Exam~le ?8 3-{2-[~S-~imethylaminomethyl-2-~uryl)methylthio~ethyl-2mino~-4-{2-l(3-h~droxv-1,2, 5-thiadiazol-4-Yl ~ methYlthio~ -ath lamino}-1,2,5-thiadiazole ~,l-dioxide _ Y , . .

~ hen a methanol suspension of 3,4-dLmethoxy-1,2,5-thiadiazole l,l dioxide is reacted with - an equ~molar amount of 2-~(S-dimethylaminomethyl-2-furyl)methylthiolethylamine according to the procedure described in Example 17, Step A, and an equimclar amou~t of 2 ~3-hydroxy-1,2,5-thiadiazol-4-yl~methylthio3ethylamine, the title compound is th~reby ~roduced.

Example 79 3-{2~ Am no~ c~ L~L=____ methYlthiD~ethvlamlno~-4-methYlamino-l,2,5-thiadiazole 1,l-dioxide Reaction of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with one equi~alent o~ 2-t~2-amino-l~2~4-triazol-5 yl)methylthio~ethylamine [prep~red according to general procedures described in U.S. Patent 3,950,3531 and an excess of methyl~mine by the general procedure described in Examole 2, ~roduoes the title com?ound.
B
!

~ %~9 Exam~le 80 The general procedur. of Example 79 is repeated except that the 2-t(2-amino-1,2,4 -tri2201-5-yl ~methylthio]-e~hylamine u~ilized thereLn is replaced ~y an e~uimolar amount o~
2-lt4-methyl-1,2,4-triazol-3-yl)methylthioJethylzmlne, 2-~tS-methyl-1,2,3-~riazol-4-yl)methyl~hio]ethyla~ine and 2-tl,2,4-triazol-3-yl)methylthiolethylamine, respectively, ~each prepared ~y th~ general procedures described ~n U.S.
Patent 3,950,3531 and therP is there~y produced 3-{2-l~4-methyl-1,2,4-triazol-3-yl~met~ylthio]e~hylamino~-4-methylzmino~l,2,5-thiadiazole l,l-dioxiae, 3-{2-t(5-methyl-1,2,3-tria201-4-yl)methylthioJethylamino}-4-methylamino-1,2,5-thiadiazole l~l-dioxide and 3-m~thylamino-4-{2-~1 r 2;4-triazol~3-ylmethylthiole~hyl-amino? -1 t 2,5-~h~adiazole l,l-dioxiae, respectively.

Example 81 3-~2-1~5 DimethYla~inome~hYl-2-furvl)methYlthio]ethYlamino}
4-{2-t ~s-methy~ -1,2,3-triazol-4-y~)methylth~o] ethYlamino?-l, 2 ~ S-thiadi~zole 1, l-dioxide When a me'chanolic suspension of 3,4-dimethoxy-lr2,5-thiadiazole l,l-dioxide i3 reas:ted with an e~uimolar amount of 2- t t5-dimethylaminomethyl-2-furyl)methylthiol ~-ethylsmine according to 'che procedure described is~ Example 17, Step A, and an equimolar amount of 2-t(5-methyl-1,2,3-tr~azol-4-yl)~ethylthio] ethylamine, the title compound is produced.

B

~%099~9 Exam~le 82 3-~2-~(2-DimethylaminomethYl-4-thiazolyl)methylthio~ethyl-amino}-4-dimethylamino--1,2,5-thiadiazole 1 oxide ~he~ a solution of 3,4-dimethoxy-1,2,5-thiadiazole .l-oxide lprepared in Example 4, Step A] is reacted with one equi~alent of 2-[~2~dime~5ylaminomethyl-4-thiazo~vl)methyl-thio~et~ylamine tPrepared in Exampl~ 33, Step El and the Eesultant 3-{2-[(2-dLmethylaminomethyl-4-thiazolyl~me~hyl-thi~ethylamino};4-~ethoxy-1,2,5-thiadia201e l-oxide is treated with an excess of dimethylamine according to the procedure described in Example 28, ~Se titl~ compound is ther~by produced.

: Example 83 The general proceaure of Example 82 is repeated, .
except that the d~methylamine utilized there1n i~ xe~laced by pyrrolidine, piperidine, mo~pholine, thiomorpholine, piperazine, N-acetylpiperazin~, N-methylpiperaz ine, hexamet.Sylene~mine and homopiperazine, respectively, , ~ ~

~Z~9!~9 and there ic thereby produced 3-{2-[.(2-d~methylaminomethyl-4-thia~olyl)methylthio~ethyl-amino}-4~ pyrrolidinyl~-1,2,5-thiadiazQle l-oxide, 3-{2-[t2-dimethylaminomethyl-4-thiazolyl)methylthio~ethyl-amino}-4-(1-piperidinyl)-1,2,5-thiadiazole l-oxide, ~-{2-~(2-dimethylaminomethyl-4-thiazolyl)methyl~hio~thyl-amino~-4-(morpholinyl)-1,2,5-thiadiazole l-oxide, 3-C2-~(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylo amino~-4-(4-thiomorpholinyl)-1,2,5-thiadiazole l-oxide, 3-{2-t~2-dimethylaminomethyl-4-thiazolyl)methylthio]ethyl-amino} 4-(1-piperazinyl)-1,2,5-thiadiazole l-oxide, 3-{2-[~2-dimethylaminomethyl-4-thiazolyl)~ethylthio]ethyl-amino}-4-(4 acetyl-1-piperazinyl)-1,2,5-thiadiazole l-oxide, 3~{2~t~2-dimethylaminomethyl-4-thiazolyl~methylthio~ethyl-amino~-4-~4-methyl-1-piperazinyl)-1,2,5-thiadiazole l-oxide, 3-{2-t[2-dlmethylaminom~thyl-4-thiazolyl)methylthio]ethyl-amino}-4-~1-hexamethyleneLmino)-1,2,5-thiadiazole l-oxide and 3-{2-t(2-dimet~ylaminomethyl-4 ~hiazolyl)methyl~hiojethyl-amino~-4-(1-homopiperazinyl)-1,2,5-thiad~azole l-oxide, respe~tively, Example 84 3-{2- ~ (5-Dimethylaminc~ furYl)methYlthioJ ethvlamino~-4-eth~lamino-l, 2, ~-th adlazole l-oxide A solution of 2- [ ( 5-dimethylaminomethyl-2-furyl) -methylthio~ethylamine (2,64 g; 12.3 rnmoles) ir~ 25 ml of dry rs .
D

~%~

methanol was added dropwise over a period of 30 minutes to a well stisred solution of 3,4-dLmethoxy-1,2,5-thiadiazole l-oxide (2.0 g; 12.3 mmoles3 i~ 75 ml of dry methanol that had been cooled to 8 in an ice-water bath. After lS
minutes, 4.0 ml of ethylamine was added and the mixture stirred at ambient temperature for 1 hour. The reaction mixture was e~aporated under reduced pressure and ~he residue placed on 55 g of silica gel and chromato~raphed using a gxadient elution of methylene chloride-methanol.
The appropriate fractions were combined, e~aporated under reduced pressure and the residue troated with ether and decanted. The residue was treated with ~resh ether to qive 1.5 g o~ ~he title compound, mp 68-74.
Anal. Calcd. f9r ~14R23Ns252: C~
S~ 17.94.
Found (corr. for 1.24% ~2) C, 46.54; ~, 6.33; N, 19.37;
S, 17.96.

Example 85 3-{2-t(5-Dimethylaminomethyl-2--furYl)me~hvlthio]ethylami~o}-4-propylamino~iad-iazole 1, l-dioxide A solution o 2~t(5-dimethylaminomethyl-2-furyl) methylthio~ethylami~Q (2.41 g; 11.2 ~moles) in 25 ml of dry methanol was addea dropwis~ over a period of 30 minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5~thiadia-zole l,l-dioxiae (2.0 g; 11.2 mmoles) in 20~ ml of dry methanol that had been cooled to 2 in an ice-water bath.
After 15 minutes, 4.0 ml of n-propylamine was added all at once and ~he mixture stirred at a~bient temperature for 30 minutes. The reaction mixture was evaporated under n ,, .

~)9~L9 --llo--reduced pressure and the residue placed on 5; g of silica gel and chromatographed using a gradient Plution o~
methylene chloride-methAnol. The appropriate fractions wese combined, evaporated under reduced pressure and the syrup crystallized with ether to give 3.7 g of the ti~le compound, mp 164-166; the ~lR spectrum ~100 rlHz) in d6 aimethyl sulfoxide showed the presence of approximately 0.9 moles of methanol.
Anal. ~alcd for C15H25N5O3s2-Q-9cH4~ C~ 45-86; H~ 6.92;
Nr ~6.82; S, 15.40 Fou~d: C, 45.60; ~, 6.93;
~, 17.03; S, 15.47.

ExamPle 86 3-~mino-4-{2-[~S-dimethy~aminomethyl-2-furyl)methY-lthio]
ethylamino~-1,2,5-thiadiazole l-oxid~

A ~olutio~ of 2-l(S-di~ethylam~nomethyl-2-furyl~
methylthio]ethylæmine (3.3 gs 15.4 mmoles) i~ 25 ml~ o~
~ethanol was added dropwise over a period of 30 minute~
to a well stirred solution o~ 3,4-dimethoxyol,2,5-thiadiazole l-oxide (2.5 g; 15~4 mmoles) in 75 ml of methanol that had been cooled to 8- in an ice-water ba~h~ Ater loS hours, anhydrous anmlonia was ~ubbled into the solutiorl ~or 8 minutes and ~he mixture stirred at ambien~ temperat~re for 30 minutes. Th~ reaction mixture was e~aporated under redueed pressure and the residue placed on 60 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined and evaporated, and the product: w~s crystallized from .

.

12~

acetonitxile. Recrystallization from isopropyl alcohol yielded 2.59 g of the tit~e compound, mp 139-142.
Ar.al. Calcd for C12H19N502S2 C, 43.7S; ~, 5-81; ~, 21-26;
S, 19.46.
~ound: C, 43.71; ~, 6.05; N, 21.32;
S, 19.51.

Exam~le 87 3-Am no-4-{2~t~5-dLmethylaminomethYl-2-fury~l)methylthi eth l~mino}-1,2,5-thiadiazole 1,l-dioxide Y _ _ A solution of 2-t~5-dimethylamino~ethyl-2-furyl)~ethyl-~hiolethylamine (2.5 ~; 11.7 mmoles) in 50 ml. of dry methanol was added dropwise over 45 minutes to a well stirred suspen-sio~ of ~,4-dimethoxy-1,2,5-thiadiazole 1, l-dioxiae S2 . 08 g;
11.8 mmoles) in 200 ml. o~ dry methanol that had been coole~-to 5 in aA Lce-water bath. Afte~ 30 minutes, anhydrous ammo~ia was bubbled ~nto the solution for 10 minute~ and th2 mixture stirred at ambient temperature for 8 hours. Th~
reaction ~ixture w~s e~aporated under reducea pressur~ and the resiaue placed on 200 g of -~ilica gel and chromatographed us~ng a gradient elution of ;l~ethylene chloride-methanol .
The appropriat~ fractions were combined and evaporated to gi~e 3.6 g of product. Recrystallization fxom methanol-~ther yielded ~he t~tle compound, mp 1560158-.
_. ~or C12HlgN5O3S2 C~ 41.72; H, 5.54; N, 20.28;
: S, 18.56.
~ou~d: Cr 41.5C; H, 5.52; N, 20.33;
5, 18.?4.

B

~ ~Qg~

Example 88 3-Amino-4-{2-t(2-~uanidin~thiazol-4-yl)methylthio~ethYlamino}-1,2,5-thiadiazole l-oxide A solution of 2-t~guanidinothia2Ol-4-yl)methyl~hio~-ethylamine ~from ~he dihydrochloride, 6.08 g; 20.0 mmolesl in 50 ml of methanol was added dropwise, oYer 45 minutes, to a cold ~5) w~ll stirred solution of 3,4-dimethoxy-1,2,5-thiadiazol~ l-oxide (3.24 g; 20.Q mmoles) in 150 ml of methanol. After stirring at 5-10 for l.S hours, anhydrous ammonia was bub~led into the solution for 10 minutes and stirring wa~ continued at ambient tempQrature for 13 hours. T~e reaction mixture was evaporated under reduced pressure and the residu2 placed on 65 g of silica gel and chromatographed using a gradient elution of methylene chloride-me~hanol. The appropriate fxactions were combined an~ evaporated to give 4.16 g of product from methanol. Recrystallization from me~hanol yielded the title compound, mp 167-~7Q tdec).
Anal. Cal~d for Cg~l4N8OS3 C, 31.20; H, 4.07; ~, 32-35;
S, 27.76.
Found (corr. for 0.48% H2O): C~ 30.39; Ho 3.97; N, 32.25;
S, 2?.91.

Recrystallization of the crude product from 95%
e~hanol yielded th~ title compound as a monohydrate, mp 136-138 (dec).
Anal. Calcd for C9~14M80S3 H20 S, ~6.39.
Found: C, 29.92; ~, 4.42; N, 30.84;
S, 2Ç.58.

A s~mple of tLhe product as the free ~a~e was ~20~19 suspended in 95% ethanol~ treated with one equivalent of aqueous 6.0N hydrochloric acid and filtexed to yield the hydrochloride salt, mp 200-2û1C (dec. ) Anal. Calcd for CgH15ClN80S3: C~ 28.23; H, 3.95;
N, 29.26; Cl, 9.26 Founa (corx. for 1.02~ H20): C, 28.26; ~, 3.83;
N, 29.41; Cl, 9.53 Exam~le 8g 3-Benz la~ino-4-{2-[t5-d~methvlaminomethvl-2-fur~13-meth~lthio~ethylamino}-1,2,5 thiadia 201e ~ dioxide A solution of 2-t~5~dimethylaminomethvl-2-furyl)me'chylthio~eth~lamirle (204 g; 11.2 mmoles) in 30 ml of dr~ methanol was added dropwise over a period of 35 J minutes to a stirred solution of 3,4-dimethoxv-1,2,5-thiadiazole l,l-dioxide (2.0 g; 11.2 mmoles) in 200 ml of dry methanol ~hat had been cooled to 1-3~ in an ice water bath. After 15 mlnute~ at 1-3, benzylamine ~1.8 g, 1.83 ml; 16. a mmoles) was added and the solution stirred at ~mbient temperature for 1 hour. The reaction m~xture was evaporated under reduced pressure and the residue placed on SO ~ of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined to gi~e 4.1 g of productO Recrystallization from aqueous methanol and then methanol yielded the ti~le compound, mp 152~ tdec);
the ~R spectrum (100 .~z~ in d6 dLmethyl sulfoxide showed the presence of approximately 1.0 mole of methanol.
~nal. Calcd for ClgH25N503S2-CH40: C, 51.37; H, 6025;
~, 14.g8.
Found: C, 51.51; H, 6.05;
~ ' .
~ ~, 14.~8.

L9 ..

Example 90 -3 {2 ~(3 {Dime~h laminometh 1} hen l)methvlthio]eth lamino}--- y y P Y_ ~
4-meth lamino-l 2,5-~hiadiazole l,l-d~oxide A solution of 2-t(3-~dimethylaminomethyl~phenyl)-methylthio]ethylamine (2.51 g; 11.2 mmoles) tprepared according to the procedure described in Belgian Patent 867,106I in 25 ml of dry methanol was ad~ed dropwise over 30 minutes to a well stirred suspension of 3, 4-dLmethoxy-1,2,5-thladiazole l,l-dioxide (2.0 g; 11.2 mmoles) in 200 ml o~ dry methanol that had been ~ooled to 2 in an ice-water bath. After 15 minutes at 2-5, anhydrous methylamine was b~bbled into the solution for 10 minutes and t~e solution was then stirred at a~bient temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 60 g of silica gel æna chromatographed using a gradient elution of me~yl~ae chloride~ethanol. The appropriate fractions were comb~ned to gi~e 2.96 g of product.
~e~rystallization from acetonitrile and then from m~thanol yieldea ~he titl~ c~mpc~nd, mp 152-158; the ~IR spectrum (100 mHz) in d6 dîmethyl sulfoxide showed the presence of approximately 0.6 mole of methanol.
Anal. Calcd for C15H23N5O2S2oO.6 CH40: C, 48.20; E~, 6.59;
tJ~ 18.02; S, 16.A9 Found: C, 41.99; H, 6.78;
PJ, 17.81: S, 16~09.

Ex?mple 9 1 ~-A~ino-4-~2-[53 ~im~ hylaminom th~phenvl)methvlthio~-ethylamino}-1,2 5-thiadiazole l-oxi~.e 12(~9~19 i A sol~tion of 2-[~3-{dimethylaminomethvl}phenyl)-methylthio]ethylamine (2.77 ~; 12.3 mmolesl in ~5 ~1 of dry ~ethanol was added dropwise o~er 45 minutes to a wel}
stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole l-oxide .
52.Q g; 12.3 mmoles~ in 100 ml of dry methanol that had been cooled to 5 in an ice-water bath. When the addition was completed, the solution was stirred at ambient temper-ature for 1.5 hours and then cooled to 5 and anhydrous ammonia was bubbled into the solution for 8 minutes. After stirring 16 hours at ambient temperature, the reaction mixtur~ was evaporated under reduced pressur~ and the residue placed on 55 g of sil~ca gel and chromatographed using a gradient elution of methylene chloride-me~anol.
The appropria~e ~ractions were co~bined to give 3.0 g of product from a~etonit~ile. Recrystallizatio~ from ace~one yielded the title compound, mp 122-125.
Anal. Calcd for C14I~21N5OS2: , S, 18.89.
~ound: C, 49.18; ~, 6.08; N, 20.93;
5, 19~25.

Exam~le 92 ~ .~ _ 3-{2-t(5 Dimeth laminomethYl-2-~hien l)methylth~ol-. _ Y _ Y _ _ , eth~lamino}-4-methYlamino~ 5 thiad~azole l-ox~d~
~ . ~ r A solution of 2- t (5-dimethylaminomethyl-2-thienyl)methylthio~ ethylamine (1. 5 g; 6.5 mmoles) in 25 ml of dry methanol was ahded dropwise ovex a period of 4 5 minutes to a stirred solution of 3, 4-dimethoxy-1, 2, S-thiadiazole ~-oxide (1. 06 g; 6. 5 mmo}es~ in 150 ml of dry methanol that had been coo~ ed to 3 in an ice-t~ater bath. After 15 m~nutes at 3, anhydrous methylamine was ~ubbled into the solution for 5 minutes and the solution ~. . .

~ %09~9 was stirred for lS minutes. The reaction mixture, after standing o~ernighk at ambient temperature, was evaporated under reduced pressure and the residue placed on 75 g of silica gel and chromatographed using a ~radient elution of acetonitrile-methanol. The appropriate fractions were combined to give ~rystalline product from acetoni~rile.
Recrystallization from acetonitrile yielded the title compoundt mp 98.5-102.
~na~- ~alcd for C13H21N5S3 C~ 43-42; H~ 5-89; N~ 19-48;
5, 26.?6.
Found: C, 43170; H, 5.58; N, 19.71;
S, 26.79.

EX~mD1~ 9 3 3-Amino-4-{4-(5-dimethylaminomethyl-2-fur~l)butylamino}-1, 2, 5-thiadiazole 1,1 ~dioxide .

A solutio~ of 4-(5 dime~hylaminome~hyl-2-~uryl)-butyl~mine ~1.61 g; 8.2 mmoles) in 25 ml of dry methanol w~s added dropwise over a period of 35 minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5-th~adiazole l,lodioxide (1.46 g; 802 mmoles) i~ 150 ml of dry meth~nol that had been cooled to 0-3 in an ice-water bath. After 15 ~inute5, anhydrous ammon~a w3~ bubbled ~nto the solution for 5 minutes and the solution was stirr d for 30 minutes. The reaction mixture was evaporated unde~
reduced pressure and ~he residue placed on 60 g of silica gel and chromatographed using a g~adient elution of acetonitrile-methanol. The appropriate gractions were combined and evaporated to give 1.68 g of produc~.
Crysta~lizatio~ from acetonitrile yielded th~ title compound, mp L54-15~ ~dec).
r~
D

- ~zo~

Anal Calcd for C13H21N503S: C, 47.69; H, 6-47; N, 21-39;
__ S, 9.80.
Found: C, 47.73; ~, 6.28; N, 21.43;
S, 9.84.

Example g4 3 Amino-4 {2-t(2~dimethylaminomethyl-4-thia201 l?methvlthioJ-ethylamino~-1,2!5-thîadiazole 1,l-dioxide A solu~ion of 2-~2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine ~0~,9 g; 3.89 m~oles) in 20 ml of dry methanol was added dropwise over 40 minutes to a well stirred suspension of 3,4-d~methoxy-1,2,5-thiadi~zole 1,1-dioxide (0.69 g; 3.89 mmoles) in 70 ml of methanol that had been cooled to 8~; anhydrous ammonia was bubbled into the solutio~ for 8 ~inutes and then the solution was allowed to stir at ambient t~mperature for 18 hours. Th~ reaction mixture was evaporated under reduced pressure and the residu~ placed o~ 150 g of silica gel and chromatographed using ~ gradient elution o~ ac~tonitrile-methanol. The approprsate frac~ons were c~mbined and ~aporated to give 0.66 g o~ ~he produot, Th~ foam was dissolved in 2-prop~nsl and evaparated to dryness to gi~ the title compound, mp 60-65; the I~MR
~pec~rum (100 ~Hz) in d6 dime~hyl sulfoxide showed the presence of approxLmately 0.15 mole o 2-propanol.
Anal. Calcd for ~llH18N6S32 - 3 8 l~ 22.62; S, 25089.
Found (corx. for 2.79~ H20) : C~ 36.75; H, 5.13;
~ , 21.75; S, 25.03.

lZ~)9~19 Example 9S

3-{2-[(i-Guanidinothiazol-5-yl?me~lylthio]etnylamino}-4-meth lamino-1,2,5-thiadiazoie 1,l-dioxide Y . ~

(A) thyl 2-~uanidino-5-thiazolecarboxYlate Hydrochloride A solution of amidinothiourea (117 g; 0.99 mole) and e~hyl chloro-~-formylacetate (150 g; 1.0 mole) in 3.~
liters of absolute ethanol was s~irred at ambient temper-ature fox 18 hours and then heated at refl.ux t~perature for 1 hour. At this time additional ethyl chloro-~-formylacetate (20.0 g; 0.13 mole) was added and 1 hour lat2~ another 20.O g of ethyl chloro-G-forntylacetate was added. Af'er 2 hours of additional heating at reflux temperature, the reaction mixture was evaporated under reduced pressure and the residue triturated with 1.5 liters of acetone and filtered to give 103 g of psoduct.
Recrystallization from 2-propanol yielded ~he ti~le compound, mp 204-206~. -Anal~ Calcd for ~7~11ClN4025 C~ 33-53; ~ 4-43; ~, 22-35;
Cl, 14.14; S, 12.79.
Found: C, 33.38; H, 4.40; N, 22.54;
Cl, 13.97; S, 12.92.

(~S 2-Guan _ o-S-hvdroxymeth~lthiazole Ethyl 2-gua~idino-5-thiazolecarboxylate hydro-chloride (1.0 g; 3~99 mmoles) Iprepared in Step Al was added to a cooted (ice water bath) st~spension of lithium aluminum hydride (0.46 g; 12.1 mmoles) in 25 ml of tetra-hydrofuran. The reaction mixture was then heated at reflux temperature for 2 hours, cooled, decom~osed with 0.46 ml . ~'`` i ~20~19 ~2~ 0.46 ml of 15% NaOH and 1.38 ml H~O and filtered.
The filtrate was dried and e~aporated under reduced pressure to give 0.61 g of product. Recrystallization from acetonitrile yielded ~he title compcund, mp 168-170.
Anal. Calcd for C5H8N40S: C, 34.87; H, 4.68; N, 32.54;
S, 18.62.
Found: C, 34.55; H, 4.52; N, 32.63;
S, 18.54.

(C) 2-l~2-Guanidinothiazol-S-yl)meth~lthio~_ e~hYlasnine _ _ _ Cystea~ine hydrochloride (10.6 g, 9.3 mmoles) and 2-guanidino-S-hydroxymethvlthiazole (16.0 g; 9.3 mmoles) ~prepared in Step B] .were dissolved Ln 80 ml o~
concentrated hydrochloric acid and the solution stirred at ambient t~mperature for 1 hour and then heated at reflux temperature for 3 hours. The reaction mixture was cooled, made basic (p~ 11) with 40% aqueous NaO~ and filtered to give 15 g of product. Recrystallization from acetoni~rile yield~d ~he title compound, mp 150-153.
Anal- Calcd for C7~13N5S2 C~ 36034; H, 5.66; N, ~0.27;
S, 27O72~
Found: C, 36.2g; ~, S.70; N, 30.40;
S, 27.64.

(D) 3-{2-~2-Guanidinothiazol-S-vl)m~thy~thio3-}-4-methylamino-1,2,5-thiadiazole l~l-dioxide A solution of 2-~(2-guanidinoth~azol-5-yl)-methyl~hio~ethylami~e (2.0 g; 8.64 mmoles~ lprepared in Step Cl in 60 ml o~ m~thanol was added dropwise over 40 minutes to a well stirred suspension of 3,4-di~ethoxy-T2 1,2,5-thiadiazole l,l-dioxide ~1.54 g; 3.64 mmoles) in L~

9~Z09~19 -12~-160 ml of methanol that had been cooled to 8 in an ice-water bath. While maintaining the temperature at 8, anhydrous methylamine was bubble~ into the solution for 8 minutesO After stirring a~ ambient temperature for 18 hours, the reaction mixture was evaporated under reduced pressure and the residue placed on 175 g of silica gel and chromatographed using a gradient elution of acetonitrile-methanol. Th~ appropriate fractions were combined to give 1.3 g of product. ~ecrystalli~ation from met~anol yielded the title compound, mp 225-226 (de~).
r C10~16N8O253: C, 31.90; H, 4.28; t~ 29 76;
S, 25.55.
Found: C, 32.0~; ~, 4.14; N, 29.91;
S, 25.60.

Example 96 . , 3-lUnh~o- 4 - ~ 2- l ~ 2-~uanid inothiazol- S-Yl ) methy l thio~
eth lamino~-1,2,5-thiadiazole l-oxide Y

A solution of 2 t~2-guanidinothiazol-;-Yl)-methylthi~lethyla~inQ ~3.0 g; 13.0 mmoles) [preparea in Exampl~ 95, Step Cl in ~0 ml of methanol was added dropwise over 40 minutes to a well ~tirred solution of 3,4-dimethoxy-1,~,5-thiadiazole l-oxide t2.1 g; 13.0 mmole ) in 200 ml of methanol t~at had been cooled to 8, and anhydrous ammonia was then bubbled into the solution ~or 8 minutes.
~fter stirring at ambient temperature for 18 hour~, the reaction mixture wa~ evaporated under reduced pressurs and the resiaue placed on ~25 ~ of ~ilica gel and chromatographed using a gradie~t elution of acetonitrile-methanol. The B appropriate fractions were co~bined to give 3 . 6 g of the title compound~ mp 85-132; the t~SR spectrum (lOO :SHz) in d6 dimethyl ~ulfoxide showed the presence of approxLmately 0.3 mole of acetoni~rite.
Anal- Calcd for CgHl4N8Os3~o-3c2H3N C~ 32-24; ~ 4-22;
N, 32.41; S, 26.71.
Fo~nd (corr. for 1.84% H2O) : C, 32.63, H, 4.33;
N, 32.55; S, 26.62.

Example 97 3 1 lamino-4-{2-~(S-dimet laminomethvl-2-fur 1)--Cyc_opropy hY y _ meth lthio~eth lamino}-1,2,5-thiadiazole 1,l-dioxide Y _ . _ Y _ _ _ _ _ The g~neral procedure of Example 13 was repeated, except that the 2-propynylamine utilized therein was repla~ed by an equimolar amount of cyclopropyl~mine~ and t~e product was crystallized fro~ ~ethanol. Recrys~allization from isopropyl alcohol yielded 3.5 g of the tit~e compound, mp 194-195~ (de~ he NMR spectrum (100 ~ z) in d6 dimethyl ~ulfoXide and showed the presence of approx~mate~y 1.0 mole o~ isopropyl alcohol.
AnalO Calcd for ClsH23l~so3s2-c3H8o C~ 48-52; H~ 7-01;
~I, 15.72.
Found: e, 48.36; H, 6.95;
N, 14.87.

Exampte 98 vclopropYlmethylamino-4-{2-[(5-dimeth~laminomethyl-2 furyl)methvlthio~ethy~amino}-1,2,5-thiadiazole l,l-dioxide The general procedure of Example 13 ~as repeated, æo9~

except that the 2-propynyl~mine utilized therein was r -placed by an e~uimolar amount o cyclopropylmethyamine, and the product was crystallized from methanol. Recrys~al-lization from methanol yielded 1.6 g of the title compound, mp 86-89 (decO); the ~iR spectrum (100 ~Hz) in d6 dimethyl sulfoxide showed the presence o~ approxLmately 1.25 moles of meth~nol.
Anal- Calcd for C16H25N503S2~1-25 CH40. C, 47.13, H, 6.8~;
N, 15.93.
Found (corrO for 0~68% H20): Cr 47.40; H, 6.49;
N, 15.77.

Example 99 3-{2-[(5 Dimethylaminomethyl-2-furyl)m~thylthio]ethylamino}-4-mor holino-1,2,5~thiadiazole l,l-dioxide ~, P . _ . .

The general procedure o~ Example 28 was repeated, ex~ept that the dimethylamine utilized therein was replaced by an equimolar amount of morpholine. After column chroma-tography, the product was crystallized fxom isopropyl ~lcohol. The mixture was di~uted with S~llysolve B and Xiltered to yield the title compound, mp 122-127.
~nal- Calcd for C16~z5NsO4S2: C, 46.24; ~, 6.06; N, 16.86.

Found (corr. for 0.61% H2O) C ~ 45.8Z; H, 6.06; N, 16.62., Example 100 -3-~2-~5-Dimeth~_am namethyl-2-~ury~l)methylthio]ethylamino}-4-(2-methoxyethylamino)-1,2,5-th adiazole l,1-dioxide The general procedure of Example 13 was repeated, except that ~he 2-propynylamine utilized therein was B

~2~19 replaced by an equimolar a~ount of 2-methoxyethylamine.
After cQlumn chromatographyt the residue was treated with isopropyl alcohol, evaporated to near dryness and cooled to give 3 r 79 g of product. Recrystallization from isopropyl alcohol yielded the title compound, mp 56-58; the spectrum (10~ ~z) in d6 dimethyl sulfoxide showed the presence of approximately 0.6 moles of isopropyl alcohol.
Calcd fo~ C15H25N5O4S2-0-6 C3H8 C, 45.90; H, 6.83;
N, 15~93.
Found (corr. for 0-74% H2O) C, 45.50; H, 6.72;
t~, 15.63.

Example 101 .~
3-{2- ~ SS-Dimeth laminomethvl-2-furYl~ethYlthio~e~hylamino~-Y . .
4-o rrolidino-l, 2, S-thiadiazole 1, l-dioxide . Y

The general pro~edure of Example 28 wa~ repeated, except ~hat the dimethylamine utilized thereLn wa~ replace~
by an e~u~molar amount of pyrrolidine. ThQ crude reaction mixture w~ evaporated under reduced pressure, treated with isopropyl alcohol and filtered to yield 3.9 g of the title compound, mp 151-152~.
: C, 48.09; H, 6.31; N, 17 53 Found: C, 48.00; H, 6.10; N, 17.71.

Example 102 3-{2-[(5-DimethylaminomethYl-2-fur~l~methvlthio~-ethylamino}-4-pi~eridino~ L -thiadiazole 1,1 dioxide The general procedure of Example 28 was repeated, ~~ e~ept that the dimethylamine ~tilized therein was replaced L~

- ~O9~L9 by an equimolar amount of piperidine~ Chr~matography yielded 3.8 g of product. Recrystallization from hot aqueous ethanol yielded the title compound, mp 106-108.
Anal. Calcd~ for Clg~27N5O3S2 Found ~corr. for 0.2~ H2O3: C, 49.17; H, 6.52; N, 17.14.

3-Bu~ylamino-4- { 2- [ ( 5-dimethy~inomethyl-2-furyl) methylthio] -eth lami~o}-1,2,5-thiadiazole l,l-dioxide The general procedure o~ Example 13 was repeated, ex~ept that the 2 propynylamine utilized therein was replaced by an equimolar amount of butylamine. ~he crude product wa~
chromatographed three times and dried with heating under high vacuum for 3.5 hours to yield 1.81 g of the title compound as a somewhat gummy ~oam.
Anal. Calcd fo~ C16H27N503S2 C, 47-86; H~ 6-78; N~ 17044-Found ~corr. for 1.34% H2O): C, 47.60; ~, 6.81; N, 17.81.

Example 104 3-{2-ttS-Dimethylaminomethy~-2-furYl)methYlthio]et~y~mino}-4-~ pyridyl)meth~lam mo] 1,2,5-thiadiazole l,l-dioxide The general procedure of Example }3 was repeated, except that the 2-propynylamine u~ilized therein was replaced hy an equimolar amount of 2-aminomethylpyridine. The appropriate fractions from column chromatography were com~ined to give 3.9 g of product~ ~o recrystallizations from isopropyl alcohol yielded the title compound, mp 43-45. ~ sample was recry~tallized rom absolute ethanol and '~ ' , `i lZ09~
-12 ~

the solid was heated under vacuum at 60 for 5 hours to give a melt. The melt was dissolved in ho~ isopropyl alcohol, collected by filtration at amb~ent temperature and dried under high vacuum to yield the title compound, mp 45-47; the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of approximately 1.25 moles o~ isopropyl alcohol.
Ana~. Calcd for C18H24N603S2^1-~5 C3H8 N, 16.42.
Found ~corr. for 0 . 58 ~ H2O): C, 51. 08 ; H, 6. 32 ;
N, 16 . 03 .

Exasn~la 105 _ 3-{2-t(5-Dimethylami~omethyl 2-furyl)methylthio~ethyl2mino}o 4-hydroxylamino-1,2,5-thiadiazole l,l-dioxide The general procedur~ of Example 13 was repezted, except that t~e 2Opropynylamin~ utilized therein was replaced by an equ~molar amount of hydroxylamLneO me crude r~action mixture which had deposited the product as a~ oil was heated to reflux temperature until all the product cry~tallized, then filtered and dried to giv~ 2.59 g o~ the title compound, mp 203-205o Anal. Calcd for C E~lgN504S2 C, 39.87; H, 5.30; N, ~ 9.38;

S~ 1~o74~
Found (corr. ~or 1.18% H2O~: C, 39.53; ~, 5.04; N, 19.61;
S, 17 O 62 D

-~26-Example 106 3-{2-t(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino~-4-dodec lamino-1,2,5-thiadiazole l,l-dioxide Y _ _ A solution o~ 2-t(5-dimethylaminomethyl-2-furyl)-methylthio~ethylamine (2.~1 g; 11.2 mmoles~ in 25 ml of methanol was added dropwise to a well stirred cold suspension of 3,4-dimethoxy 1,2,5-thiadiazole 1,1 dioxide t2~0 g; 11~2 mmoles) in 200 ml of methanol. After stirring at 2-5 for 15 minute~, a so~ution of dodecylamine (4.15 g; 22.4 mmoles) i~ 25 ml of methanol was added all at once, and stirring was continued at ambient temperature for 18 hours. The rea~tion mixture was filtered and evaporated under reduced pressure, and the residue placed on 60 g of silica gel and chromatographed usins a ~radient elution of methylene chloride-methanol. ~he appropriate fraction~ were combined, evaporated and the residue was rechromatographed on 60 g of silica gel using a gradient elut~on of acetonitrile-~ethanol.
The appropriate fraction~ from the second chromatography were combined, concentrated under reduced pressure and the crystallized product wa~ collected by filtration and dried to give 2.13 g of the title compound~ mp 136-139~o Anal. Calcd for C24H45NSO3S2: -S, 12.43.
Found: C, 56.16; ~, 8.57; N, 13.38;
S, 12.61.

3-{2-t(5-Dimethyl~minometh~-2-furyl)me~hvlthio~ethylamino~-4-methoxy~mino-1,2,5-thiadiazole l,l~dioxide B The ~e~eral procedure of Example 13 was repeated, 1~09~

except that the 2-propynylamine utilized therein was replaced by an equimolar amoun~ of me~oxyamine. The reactior mixture was stirred a~ ambient temperature overnight, during which a crystalline precipitate ~ormed. The solution wa~ cooled and filtered, and the recovered solid was dried to yield 3.8 g of the title compound, mp 224-226 (dec.).

Anal. Calcd for C13H21N504S2 C~ 41-59; ~, 5-64; N~ 18-65;
S, 17.08~
Found ~corr. for 0.79% H20): C, 41.25; H, 5.54; N, 18.50;
S, 17.16.

Example 108 3-{2-~(5-Dimethylaminomethyl-2-thi~nyl)methyl~hio~ethylamino}
4-propylamino-1~2,5-thiadiazole l~l-dioxide The general procedure of Ex~mple 65 was repeated, except that the methylamine utili~ed therein was replaced by an equ~molar amount of propylamine. Chromatography gave 3.5 g of crys~alline product. Recrystallization from acetonitrile yielded the title compound, mp 194-196 ~dec.).
Anal. Calcd for C15H25N50253: C, 44.64; H, 6.24; N, 17035;
S, 23.84.
Found: C, 44.66; ~, 6.02; N, 17.88;
~, 23.87.

Exampl~ 109 3-Amino-4-{2-[~S-dimethylaminometh~1-2-thienyl)methYlthio]-ethyl~mino~-1,2,5-thiadiazole l-~xide ~ solution of 2-lt5-dimethylaminomethyl--2-thienyl) methylthio~ethylamine (2.84 g; 12~3 mmoles) in 25 ml o~
methanol was added dropwise over a period of 35 minute~ to a stirred solution of 3,4-d_methoxy-1,2,5-thiadiazole l-oxide `~ ~2~

-128~

(2.0 g; 12.3 m~oles) in 200 ml of methanol that had been cooled ~o 3 in an ice-water ~ath. After stirring for 15 minutes, anhydrous ammonia was bubbled into ~he solution for 5 minutes. The reaction mixture was evapoxated under reduced pressure, and the residue placed on 60 g of silica gel and chromatographed using a gradient elu~ion vf methylen~ chloride-methanol. Th~ appropriate fractions were combined to give 1.73 g of product. Recrystallization from acetonitrile yielded the title compound, mp 149-152 (dec.~.
.
Example 110 3-{2-~(5-Dimethylaminomethyl-2-thienyl)methylthiolethylamino}-4-1(3-pyridyl)methylamino~-1,2,5-thiadiazole l,l-dioxide Th~ general procedure of Exampl~ 65 was repeated, except that the methylamine ut~l~zed therein was replaced by an e~uimolar amount of 3-aminomethylpyridine. me appxopriate fractions fro~ column chromatography gave 3.10 g of the title compound as an oil. The product was dissolved in excesC 5~ HCl, evaporated and the~ ~riturate~ with isopropyl alcohol to give a ~olld product. Recrystallization from 95% a~ueous ethanol yielded the title compound as a dihydro hloride salt, mp 143-146.5~.
Anal. Calcd for C H2 C12~6O S3: C, 41.13; H, 4.99; N, 15.99;

59 18.30.
Eound (corr. for 2.04% ~2) C, 41.25; H, 4.90, N, 16.18;
S, 18.52.

' ` l~Q~g -12~-Ex~le 111 3-Amino 4-~2 ~(S-dimethvlaminometh~1-2-thienvl)me~hY~l~hio~-ethylamino}-1,2,5-thiadiazole l,l-dioxide A solution of 2-[(5-dimethylaminomethyl-2-thienyl)-methylthio~ethylamine (2~0 g; 8.68 mmoles) in 25 ml o methanol was added dropwise over a period of 35 minutes to a stixred solution of 3,4-dimethoxy-1,2,5 thiad~azole 1,1 dioxide (1.55 g; 8.68 mmoles) in 200 ml o~ methanol that had been cooled to 3 in an ice-water bath. After stirring for 15 minutes, anhydrous ammonia was bubbled through the solution for 10 minute~. The rea tion mixture was evapora-~ed under reduced pressure to gi~e 3.3 g of the title compound.

~ ne NMR spectrum (100 I~Hz) i~ d6 dimethyl sulfoxide gave the foll~wing resonances ~: 6.88 ~d, 1~); 6.78 ~d, lH);
4.03 ~ , 2H); 3.61 ts, 2H); 3.54 ~t, 2H); 2.74 (~, 2H);
2.22 (s, 6H) it also showed ~he presence of appxoximately 2/3 mole o~ methanol.

Example 112 3-BenzYlamino-4-{2-tt5-dimethvlaminomethYl-2-thienYl)-methylthio~e~hvlamino3-1,2,5-thiadiazole l,l-dioxide The general procedure o~ Example 65 wa~ repeated, except that the methylamine utilized therein was replaced by an equimolar zmount of benzylamine~ The reaction mixture was evaporated under reduced pressure to gi~e product.
~ecrystallization from methanol with charcoal trea ment yielded 2.63 ~ o~ the title com~ound~ mp 203-205.5 (dec.~.

` lZ09~l9 Anal. Calcd for ClgH25W5O2S3: C, 50.53; H, 5.58; M, 15.51;
S, 21.3~.
Found: C, 50.79; H, 5.34; N, 15.78;
S, 20~94.

Example 113 3 ~3-(3-Dimeth laminometh 1 henox )~rs Ylamino~-4-methylamino-y y~ y, p, _ .
1,2,5-thiadiazole l!l-dioxide A soLution of 3-t3-tdimethylaminomethyl)phenoxyl-propylamine ~2.73 g; 14.0 mmolesS tprepared according to the proc dure described in Belgian Patent 867,106] in 50 ml o~ methanol was added dropwiss over a period o~ 60 minute~
to a stirred su~pension of 3,4-dimethoxy ~,2,5-thiadiazole l,l-dioxide t2.5 g; 14.0 mmoles) in 250 ml of methanol that had been cooled to,4 in an ice-wa~er ~ath. ~fter stirring or 20 minutes, anhydrous methyla~ine was bubbled into th~
solution for 10 minutes. The reaction mixture was evapora-ted under reduced pressure and the residue placed on 75 g of silica gel and chromatographed using a gradient elutio~
of methylene chloride methanol~ The appropriate fractions w~re combined and evapoxated, and then dissolved in n-propanol and treated with on~ equivalent of HCl to gi~e the product as a hydrochloride sa}tO Recrystallization from aqueou ethanol yielded the title compo~nd as a hydrochloride salt, mp 140-145.
Anal. Calcd for C15H24ClN5O3 S, 8~22; Cl, 9.0~.
Found ~corr. for 3-79% H2O) C, 46.21; ~, 6~06, N, 18.24;
S, 8.38; Cl, g.~5.

~09~9 Example 114 3-{2~ -Dimeth~laminomethylthiazol-5-yl~methYlthio]~
ethylamino}-4 methylam~no-1,2!5-thiadiazole l,l-dioxide A. 5-Carbethox~o2-(1~-carbophenoxy-N-methylamino~-methylthiazole (N-Carbophenoxy-N-methylamino)thioacetamidë (46.7 g;
0.21 moles) was combined with ethyl ~-formylchloroacetate ~30.0 g; 0.20 moles) in 270 ml of 1,2-dichloroethane and heated to reflux temperature for 2 hours. ~n additional amount of ethyl ~-formylchloroacetate ~3.0 g; O.Q2 moles) was added and heating was continued for 1.5 hours. The reaction mixture waR extracted with two 300 ml poxtions of cold 5% aqueou~ sodium carbonate, then washed with two 300 ml portions of water and dried over Na2S04. Evaporation ga~e th~ product as a~ oil which slowly crystallized.
Recrystallization from 2-propanol yielded 26 g of the title compound, mp 81-83.
Anal. Calcd for C15~16N2O4S: C, 56.24; H, 5.03; ~1, 8.74;
S, 10 . 0~. , Found: C, 56~48; H, 4.97; N, 8,~4;
S, 10.17.

B. s-~droxy~ethyl-2-dimethylaminomethylthiazole 5~Carbethoxy-2-(~-carbophenoxy-~-methyl~mino~-methylthiazole ~19.8 g; 0.62 moles) [prepared in Step A]
~as added to a cold ~5~ stirred suspensicn of lithium aluminum hydride (~.12 g; 0.16 ~o~es) in 544 ~1 o~ dry tetrahydrofuran. The r~action mixture wa~ heated to reflux temperature for 0.5 hour and then cooled to a~ient temper~
ature and deco~posed, filtered thxough celite and evaporated D

~ Z09~1 9 13~-under reduced pressure. The residue was dissolved in 80 ml o~ 3N HCl an~ extracted with ether. ~he aqueous phase ~as adjusted to pH 8 and ~xtr~cted with methylene chloride.
me organic pha e was dried, filtered and e~aporated under vacuum to give 6.0 g of the ~itle compound as an oil. The ~.IR spectrum ~60 M~z) i~ CDC13 gave the following xesonances ~: 7.50 ~s, lH) î 4~85 ~5~ 2H) ~ 4~15 (s~
3.75 (s, 2~); 2.35 ~s, 6H).

C. 5-Chloxomethvl-2-dimethYlaminometh~lthiazole ~ . . . ~ . .
hydrochloride Thionyl chloride (27.4 g; 0.16 moles) ~ras added dropwise to a cooled ~ice-water bath) solu~ion of 5-hydroxymet~yl-2-dimethyl~minomethylthiazole ~3.9 g; 52~0 ~moles~ [prepared in Ste~ Bl in 300 ml of methylene chloride.
The mixture was heated at reflux temperature for 2 hours and then cooled and evaporated under reduced pressure to gi~e 12.3 g of product. Crystallization from acetonitrils yielded th~ title co~pou~d, mp 143-144.
Anal. Calcd for C7H12C12N2S: C, 37.01; ~, 5.32; N, 12-33;
Cl, 31.63.
Found (corr. for 0.91~ ~2) C, 36.88; ~, 5.11; N, 12.14;
- Cl, 31.6S.

D. 2- 1 t2-Dimethylam~ nomethylthiazol-5-yl) meth~rlthi~ ethYlamine Cys~eamine hydroch~oride (0.2 g; 1.76 ~moles) and 5-chloromethyl-2-dimethylaminom~thylthiazole hydrochloride (0.4 q; 1.76 mmoles~ [prepared in Step C~ were dissolved in 2. 5 ml of concentrated hydrochloric acid and the solution was heated at an oi~ bath temperature of 100.
~7 After 2 hours; the mixture was.eYaporated under reduced ~20~19 pressure and the residue made basic with 40% aqueous sodium hydroxide solution. The aqueous phase was extracted with methyl acetate and the organic phase was dried, filtered and evaporated to give 0.3 g of the title compound as an oil~ The ~R spec~rum (60 MHz) in CDC13 gave the following resonances ~: 7.50 (s, lH), 3.95 (s, 2H); 3~76 ~s, 2H);
2.85 (m, 4H); 2.40 (s, 6H), 1.85 (s, 2H).

E. 3-{2-[~2-Dimethylaminomethylthiazol-5-yl~-methylthio~ethyiamino}-4-methylamino-1,2~5-thiadiazole 1,1-dioxide -A solution of 2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamine ~1.55 g; 6.1 mmoles) [prepared in Step D] in 60 ml of methanol was added dropwise o~-er 40 minutes to a partial suspension of 3,4-dimethoxy-1,2,5~
thiadiazole l,l-dioxide (1,19 g; 6.7 mmoles) in 130 ~1 of methanol that had been cooled to 8. Upon completion of the addition, anhydrous methylamine was bubbled into the solution for 8 minutes, then stirred at ambien~ temperature o~ernight. The reaction mixture was evaporated under reduced pressure and the residue chromatographed on 150 g of 5il iC~ gel using a gradien~ elution of acetonitrile-methanol~ The appropriate fractions were combined to gi~e 1.05 g of product. Recrystallization from 2-propanol yielded the title compound, mp 170-172.
nal- Calcd for C12~20N62S3: C, 38.28; H~ 5.36; N, 22.33;
S, 25.56.
Found: C, 38.31; ~, 5.32; ~J, Z2.13;
S, 25.96.

09!9:19 Example 115 3-{2-~(2-Guanidinothiazol-4-vl)methylthio3ethYlamino}-4-methylamino-1,2,5-thiadiazole l-oxide The general procedure of Example 31 is repeated except ~hat ~he 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide utilized therein was replaced by an equimolar amoun~ of the corresponding l-oxide. The appropri~te fractions froan column chromatography were combined to give 4.5 g of produ~t~ Crystall~zation from absolute ethanol yielded 3.05 g of the title co~pound, mp 175-177. .
ClOH16NsOS3: C~ 33.32; H, 4.47; N 3i og;
S, 26.68.
~ound: C, 33rlO; H, 4.42; N, 31.00;
S, 26.51.

Example 116 3-{?~5 (2-~uanidinotlliazol-4-yl)methylthio] ethylamino}-4-~ydroxy-l, 2, S-thiadiazole l-oxide ~ solution of 2-~(2-guanidinothiazol-4-yl)methylthio~-ethylæmine (4.15 g; 17.9 mmolec) in 50 ml o~ methanol was added dropwiae ove~ a 30 minute period to a sslution of 3,4-dimethoxy-1,2,5-thiad~azole l-oxide t2.91 g; 17.9 mmoles) in 350 ml of methanol that had been cooled in an ice-water bathc The reaction mlxture was treated with a solution of sodium hydroxide pellets (3.58 g; 8~.5 mmoles) in methanol.
~fter stirri~g overnight at ambient temperature, t~.e mixture was neutralized with 14.3 ml (89.5 mmoles) of aqueous 6.0N
HCl and after 10 minutes was evaporated under reduced pressure. The solid residue was triturated for 2 hours ~ith 70 ml of water at ambient temperature and filtered to , .

~209~19 give product. Recrystallization from water yielded the title co.mpound, mp 148-151.
Anal~ Calcd for CgH13N702S3: C, 31~11; H, 3.77; N, 28.22;
S, 27.69.
Found ~corr. for 5.52% H~O): C, 30.95; H, 3.76; N, 28.27;
S, 28.11.

Example 11?

3-~mino-4-{2-t(2-t2-methylguanidino}thiazol-4-yl)methylthio]-ethylamino~-1,2,5-thiadiazole l-oxide A. 2-~ t2-(2-Methylguanidino)thiazol-4-yl]meth~lthio}
ethylamine Cysteamine hydrochloride (1.89 g; 16.6 mmoles) and 2-~2 methylguanidino)-4-chloromethylthiazole hydroohloride (4~0 g; 16.6 mmoles) tPrepared from (N-methylamidino)thiourea and 1,3-dichloxo-2-propanone~ were combined in 20 ml of concentrated hydrochloric acid and the solution was heated at an oil bath temperature of 100~ After 2 hours the mix-ture was evaporated under reduced pressure and the residue made ~asic with 40% aqueous NaOH solution. Th~ aqueous phase was extracted several times with methyl acetate and the organic phase was dried, filtered and evaporated to give 3.35 g of the title compound. The NMR spectrum (60 ~z) in D2O gave the following char~cteristic resonances ~:
6.52 (s, lH), 3.60 (s, 2~), 2.70 tm, 7H~.

B~ 3-Amino-4-{2-[~2-{2-methylquanidino}thiazol-4-yl)methylthio]ethy~amino}-1,2,5-thiadiazole 1 oxide A solution of 2-~(2-{2-methyl~uanidino}th~azol-4-yl)m~thylthio~-ethylamine (2~1 g; 8.56 mmoles) [prepared in 0~3~

Step A] in S0 ml of me~hanol was added dropwise over 30 minutes~to a solution of 3,4-dimethoxy-1,2,5-thiadiazole l-oxide (1.39 g; 8.56 mmoles? in 170 ml of methanol that had been cooled to 7. Anhydrous ammonia was bubbled into the solution for 7 minutes, then stirred at ambient temperature overnight. The reaction mixture was evaporated under reduced pressure and the residue chromatographed on 100 g of silica gel t230-400 mesh) by flash chromatography using a gradient elution of acetonitrile-methanal. The appropria~ fractions were combined, evaporated and the residue chromatographed on a Preparativ~ HPLC system using ~ porasil silica gel~ The appropriate fractions were combined, concentrated to a small volume and filtered to yield the title com~oun~, mp 86-91; the ~IR spectrum ~100 IIHz) in d6 dimethyl sulfoxide showed the presence of approxima~ely 0.8 moles of ethanol.
Anal. Calcd for ~loH16N80S3 0.8 C2H~O: C, 35.06; H, 5.28;
N, 28.20; S, 24.21.
Found ~corr. for 1.64% H2O): C, ~5~6~o H, 5.05;
N, 28O33; S, 23.96.

Ex~mple 118 3-Amino-4-~3-(3-dimethylaminomethYlph2-oxy)propylamino]-1,2,5 _ adiazole_l-oxide A solution of 3-C3-(dimethYlamino~ethYl~phenoxy]-propylamine (2.5 g; 12.9 mmoles) in 35 ml of methanol was added droprise over a period of 30 minutes to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole l-oxide in 200 ml of methanol that had been cooled to 2 in an ice-water bath. After stirring for 15 minutes, anhydrous a~monia was bubbled into the solution for 5 minutes~ The xeaction mixture was evaporated under r~duced pressure to give ~%

crystalline product. Two recrystallizations from methanol yielded the title compound, mp 165.5-166.5 5dec.).
Anal. Calcd for C H N O~S: C, Sl.g9; ~, 6,55; N, 21~66;

5, 9.9~.
Found: C~ 51.58; X, 6.49; N, 22.03;
S, 10.19.

Example 119 _Amino-4-{2-t(2-methyl~minothiazol-4-yl)methylthio~
ethylamino}-1,2,5-thiadiazole l-oxide A. 2-t(2-Meth~laminothiazol-4~yl)methylthio~-ethylamine Cysteamine hydrochloride ~2.8 g; 24.6 mmoles) and 2-methylamino-4-chloromethylthiazole (4.0 g; 24.6 mmoles) [prepared from N-methylthiourea and 1,3-dichloro-2-propaneJ were dissol~ed in 20 ml of concentrated hydro-chloxic acid and the solution was hea~ed at an oil bath temperature of 100. After 30 hours of heatingp the reaction mixture was evaporated under reduced pressure and the residue ~ade b~ic with 40% aqueous NaOH solution.
The aqueous phase was extracted with methyl acetate, dried, fil~ered and evaporated ~o give 1.75 g of the ~itle compsund as an oil which was used without further puri ica-tion in Step B.

1209~3119 B. 3-Amino-4-{2-[(2-methylaminothiazol~4-yl3-me~ylthio~ethylamino}-1j2,5-thiadiazole l-oxide The product of Step A, above, was reacted sequentially with 3,4-dimathoxy-1,2,5-thiadiazole l-oxide and anhydrous ammonia according to the general procedure of Example 117, Step B, and chromatograph~d as described therein. The appropriate fractions from flash chromatography were combined and evaporated to give 0.5 g of product as a foam.
Crys~allization from acetone yielded the title compound, mp 180-183 (dec.).
Anal Calcd for CgH141~60S3 : C, 33.94; ~, ~.43; N~ 26.39;
S, 30.21.
Found ~corr. for 1~41% H20~: C, 33.96; ~, 4.11; N, 26.27;
S, 30.44.

Example 120 3-~mino-4-{2-E(2-{Zf3-dimethy~guanidino}thiazol-4-Yl)-meth~thio]ethylamino}-1,2,5-thiadiazole l-oxide A~ 2-E(2-{2,3-Dimeth~lquanidino~thiazol-4-Yl)-methylthio~ ethylamine dihydrochloride Cystezmine hydroch~oride (2.25 g; 1906 mmoles) and 4-chloromethyl-2- (2 ,3-dimethylguanidino~ thiazole (5 g; 19.6 mmoles) tprepared from 1,3-dichloro-2-propanone and (~,N'-dimethylamidino)thiourea wllich is itself prepared from dime~hyl cyanodithioiminocarbonate and methyl~minel were dissolved in 17. 5 ml of conc:entra~ed hydrochloric acid and hèated at an oil ba~h ~perature of 1~0~ ~fter Z4 hours the reaction mixture was evaporated under reduced pressure lZ~9~9 -139~

and the residue crystallized from absolute ethanol to yield the title compound, mp 2 4 3 -2 4 5 .

B. 3-Amino-4-{2-[(2-~2,3-dimethYlquanidino}thiazol-4-yl)methylthio]e~hylamino~ 1,2,5-thiadiazole l-ox~de The product of Step A, above, was sequentially reacted with 3,4-dimethoxy-1,2,5-thiadiazole l-oxide and anhydrous ammonia by the general procedure of Example 117, Step B. The crude reaction mixture was evaporated unaer reduced pressure and the residue crystallized from methanol to give the title compound, mp 201-20~ tdec.).
Anal- Calcd for CllHlgNgS3: C, 35.28,o H, 4.84; N, 29.92;
S, 25.69~
Found tcorr. for 0.88% ~2) C, 34.93; H, 4.56; N, 30.27;
S, 25.92.

Example 121 3,4-Bis~{2-t(2-~uanLdinothiazol-4-yl)methylthioJethylamino}-l!~,S-thiadiazole l-oxide To a solution of sodium methoxide (~.16 g; 40.0 mmoles) in 1~0 ml of C~30H that was cooled to 0 in an ice-water bath was added 2-~(2-guanidinothiazol-4-yl)methylthio]ethylamine dihydrochloride (6~09 g; 20.0 mmoles) and, after 20 minutes of stirring, the solution was treated with 3,4-dimethoxy-1,2,5-thiadiazole l-oxide (1.62 g; 10 mmoles). The reaction mixture was stirred at ambient temperature for 65 hours and evaporated under reduced pressure. The residue was chromatographed `` 1~0~9~g .

on 100 g of sili~a gel (230-400 mesh) by ~lash chromatography using a gradient elution of acetonitrile-methanol. me appropriate fractions were combined, evaporated and the residue chromatographed on a Preparative HPLC system using ~-porasil silica gel~ The appropriate fractions were combined, and evaporated under reduced pressure to give the title compound as an amorphous solid; the NMR spectrum (190 MHz) in d6 dimethyl sulfoxide showed the presence of approximately 0.11 mcle of ethanol.
Anal. Calcd for C16~24N120S5 11~2~6 N, 29.71; S, 28.33.
Found ~corr. ~or 1~86% H2O): C,-34.95; ~, 4.41;
N, 29.04, S, 27.71.

Example 122 3-t2-[~2-Aminofhi~zol-4-yl)methylthioJethylamino} 4-methYlamino-l,2,5-thiadiazole 1,l-dioxide .. . . .

A~ 2-~2-Amino~hiazol-4-Yl)methYl~hio~ethylamine dihydrochloride Cysteamine hydrochloride (5.65 g, S0.0 mmoles) and 2-~mino-4-chloromethylthiazole hydrochloride (9.25 ~; 50.0 mmoles) were dis~olved in 70 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 105. After 64 hours of heating the mixture ~7as evaporated under reduc~d pressure and the residu~ triturated with acetone~ The collected product was re~triturated with ethanol, filtered and dried to yield the title compound, mp 170-200.

- ~2~99~9 Anal. Calcd for C6H1~C12N3S2. C, 27.48; H, 4.~0; N, 16.02;
S, 24.46; Cl, 27.04.
Found: C, 27.29; H, 5.07; N, 15.91;
S, 24.15; Cl, 27.24.

B. 3-{2~[(2-Aminothiazol-4-yl)methYlthio~ethY
amino}-4-meth lamino-l 2 S-thiadiazole 1 l-dioxide Y

A solution of 2-1~2-aminothiazol-4-yl)methylthio]-ethylamine (rom the dihydrochloride, 3.0 g; 11.4 mmoles) [prepared in Step ~3 in 25 ml of methanol was added dropwise over 1.5 hours to a cold t5), stirred, partis~

suspension of 3, 4-dimethoxy-1, 2,5-thiadiazole l,l-dioxide (2.03 g; 11.4 mmoles) in 55 ml of methanol. After 1.5 hours, anhydrous methylamine was bubbled into the solution for 30 minutes and stirred at 5u for 19 hours. ~he reaction mixture was evaporated under reduced pressure and the residue placed on 400 g of silica gei and chromatographed usi~g ace one-methylene chloride (7:3). The appropriate frac~ions were combined and evaporated to give productO

~ecrystallization from 95% ethanol yielded the title compound, mp 200-201.
Anal. Calcd for CgH14N602S3 C, 32.32; H, 4.32; N, 25.13;
-; S, 28.7~.
Found: C, 32.25; H, 4.20; N, 25.06;
S, 2~.14.

`` ~2~

Example 123 3-Amino-4-t2-1(2-dimethYlaminomethYlthiazol-5-Yl~methylthio]-ethylamino}-1,2,5-thiadiazole l-oxide A solution of 2-[(2-dimethylaminomethylthiazol-5-yl~methylthio]ethylamine (2.05 g; 8.~6 mmoles) [prepared in Example 114, Step D] in 70 ml of methanol was added dropwise to a cold (8~, stirred, solution of 3,4-dimethoxy-1,2,S-thiadiazole l-oxide ~1.44 g; 8.88 mmoles) in 770 ml of methanol. Anhydrous ammonia was bubbled into the solu-tion for 8 minute~ and then stirred at ambien~ temperature for 0.5 hour~. The reaction mi~ture was evaporated under reduced pressure and the residue triturated with acetonitrile to give 1.76 g of product. The product was purified by flash chromatography on 100 g of silica gel (230-403 mesh) using acetonitrile-methanol. he appropriate fractions were combined, e~aporated and the residue crystallized from a~etone to yield the title compound, mp 131-133.
nal- Calcd fox C11~17N6S3 C, 38.13; H, 5.24; N, 24.26;
5, 27.76.
Found (corr. for 0.49% H2O): C, 37.86; Ho 5.06; N, Z4.34;
S, 27.68.

Example 124 3-~mino-4-{2-~(2-~minothiazol-4-yl)methylthiolethYlamino~-1,2,5-thiadiazole l-oxide , , _ A solutiQn of 2-1(2-aminothiazol-4-yl)methylthio]-ethylamine (from the dihydrochloride, 2.62 g; 10.0 mmoles) ` ~20~9 [prepared in Example 122, Step A] in 20 ml of methanol was added dropwise over 30 minutes to a cold (5~ solution of 3,4-dLmethoxy-1,2,5-thiadiazole l-oxide (1.62 g; 10.0 mmoles) in 50 ml of methanol. After stirring for 1.5 hours~ anhydrous ammonia was bubbled into the solution for 30 minutes and the solution kept at 5 for 17 hours. ~he react~on mix~ure was evaporated under reduced pressure and the residue was chromatographed on a Preparative HPLC system using ~-~oxasil silica gel. m e appropriate fractions were combined and evaporated under reduced pressure to give -the title compound a~ an amorphous solid; th~ NMR spectrum ~100 M~z) in d6 dimethyl sulfoxide showed ~he presence of approximately 0.4 moles of ethanol.
Anal. Calcd for C8~12N60S3 0.4C2H6 N, 26.03; 5, 29,80.
Found (corr. for 1.39% H2O) C, 32.39; H, 4.28;
N, 28.39; S, 30.02.

Example 125 3-Methylamino-4-{2-E~2-{2,3-dimethYlguanidino}thiazol-4-~yl~-m thylthio?ethy ami 1,2,5-thiadiazole l,l-dioxide A solution of 2~t(2-{2,3-dimethylguanidino}thiazol-4-yl)methylthio]ethylamine (2.5 g; 9.64 mmoles) lprepared in Example 120, Step Al in methanol was added dropwise over a period o~ 40 minutes to a cold (8~, stirred suspension -of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide (1.72 g;
9.64 mmoles) in 270 ml of methanol. ~nhydrous methylamine was bubbled in~o the solution for 7 minutes a~d the solution then was e~apoxated under reduced pressure. The residue was chromatographed on 100 g of silica gel (230-4Q0 mesh) by flash chromatography and the appropria~e fractions ~ere combined and evaporated to give Z.5 g of product as a ~20~919 foam. Crystallizaticn from aqueous ethanol yielded the title ~ompound, mp 132-137~
~nal. Calcd for C12~20N8O253 S, 23.78.
Found (corr~ for 4.78g H2O): C, ~5.74; H, 5.04; N, 27.87;
S, 23.56.

Example 126 3-{2-~(2-DLmethylaminothiazol-4-yl~methylthio]ethylamino~-4-amino-1,2,5-thiadiazole l-oxide , A. 2-[(2-Dimethylaminothiazol-4-yl)methylthio~-ethylamine Cysteamine hydrochlorid~ ~5.24 g; 45.9 mmoles) and2-dImethyl~mino-4 chloromethylthiazole hydrochloride (9.8 g;
45.9 mmoles) ~prPpared from N,~-dimethyithiourea and 1,3-dichloro-2-propanone~ were dissolved in 45 ml of conc~n- .
trated hydrochloric acid and heated at an oil ~ath temperature of 100 for 96 hours. The ~ixture waC evaporated under reduced pressure and the residue made basic with 40% aqueous '.~aOH. ,he aoueous phase was extracted with methyl acetate, dried and evaporated to ~ive the title compound as an oil ~hich was used without further purification in Step 8.

The NMR spectrum (60 MI~z) in D20 gave the following resonances ~: 6 . 97 (s, lH); 3 . 94 (5, 2H); 3 . 67 (s, 3H);
3.15 (~;, 3H); 3.05 (m, 4H1.

B . 3-{ 2-1 ~2-D~ethylaminothiazol-4-yl)meth~lthio~
ethylam _o}=4-amino-1,2,5-thiadiazole l-oxide A solu~ion of 2-~2-dimethylamino~hiazol-4-yl)-o9~9-145-methylthio]ethylamine (3.5 g; 16.1 mmoles) [prepaxed inStep A] in 70 ml of methanol was added dropwise over a period of 30 minutes to a cold (7), stirred solution of 3,4-dimethoxy-1,2,S-thiadiazole l-oxide t2.61 g; 16.1 mmoles~ in 200 ml of methanol. Anhydrous ammonia was bubbled into the solution f or 8 minutes and after stirring for 30 minutes the mixture was evaporated under reduced pressure. The residue was triturated with i~opropyl alcohol then dissolved in methanol, filtered and e~aporated to give pxoduct. The product was purified by flash chroma-tography on 100 g o~ silica gel (230-400 mesh) using methylene chloride-methanol. The appropriate fractions were combined and re-chromatographed by ~PLC on a ~-porasil silica gel ~olumn. The appropriate fractions were comhined and evaporated under reduced pressure to yield the ~itle compound, mp 116-1~2; the NMR spectrum (100 MHz) in d6 dimethyl sulfoxid~ showed the presence of approxim tely 1/3 mole of ethanol.
~nal- Calcd for ClOH16N6S3 1/3 C2H6~
N, 24.15.
Found tcorr. for 11.92% H~O): C, 36.61; H, 4.06;
N, 24.22.

Example 127 3-{2-1(2-Dimeth ~ azol-4-vl)methYlthio~ethvlzm no~-4-methylam o-1,2,5-thiadiazole 1,l-~ioxide A solution of 2- t~2-dimethylaminothiazol-4-yl)-methylthio~ e~hylamine t2.5 g; 11.5 mmoles) [prepared in Example 126, Step A~ was added dropwise over a period of 30 minutes to a col~ (7), stirred suspension of 3,4-dimethoxy-1,2,5 thiadiazole l,l-dioxide ~2~05 g; 11.5 mmoles) in 200 ml of methanol. Anhydrous methylamine was bubbled 1~099 9 into the solution for 7 minutes and after stirring for 30 minutes, the m~xture was evaporated under reduced pressure.
The resiaue was crystallized from methanol to give 1.6 g of product. Two recrystallizations from 2-methoxyethanol yielded the title compound, mp 227-229.

Example 128 3-{2-tt2 {2-Imid~zolidiny7}iminothia ol-4-Yllmethyithio~-ethvlamino}-4-methYlamino-1,2,5-thiAdiazole l,l-dioxide A 2- 1 ~2-{ 2-Imidazolidi~l} iminothiazol-4-yl) -.

methylthio~ethylamine Cysteamine hydrochloride ~2.22 g; 19.5 mmoles) and 2~t(2-imidazolidinyl)im~no]-4-chloromethylthiazole hydrochloride ~4.94 g; 19.51 mmoles) ~prepared fxom 1,3-dichloro-2-propanone and N-~2-imidazolidin-2-yl)thiour~a which is i~self prepared from 2-(cyanimino)imidazolidinel were dissolvea in 20 ml of concentrated hydrochlori~ acid and heated at an oil bath temperature of 100 for 5.5 hours. The reaction mixture wa~ evaporated under reduced press~re and the residue made basic with 40% NaO~. The aqueous phase wa~ extracted with methyl acetate~ dried and evaporated to giYe 2.02 g of the title compound which was used in the next step without further purification.

B. 3-{2-t(Z-{2-Imidazolidin~l}~minothiazol-4-yl)methylthio~ethylami -4-m~ aminoDl,2,5-thiadiazole l,l-dioxide A solution of 2-t(2-{2-imidazolidinyl}im$nothiazol-4-yl3methylthiolethylamine ~2.02 g; 7.85 mmoles) ~prepared in Step Al in 85 ml of methanol was added dropwise over 40 9~9 minutes to a cold (8~, stirred suspension of 3,4-dimethoxy 1,2,5-thiadiazole l,l-dioxide (1.4 g; 7.85 mmoles) ~n 190 ml of methanol. Anhydxous methylamine was bub~:led i~to the solution for 7 minutes and~ after 30 minutes at ambien~
temperature, the mixtur~ was evaporated under reduced pressure to give 3.5 g of produc~. The.product was chroma tographed on a Preparati~e ~PLC system using ~-porasil Si1ica gel. ~he appropriate fractions were com~ined, evaporated and the residue crystallized from metha~ol to give the title compound, mp 229-231. ReGrystallization from aqueous ethanol gave the ti~l~ compound with mp 136 140 which resolidified with remelting a~ mp 219-224.
Cl2Hl8~8o2s3: C~ 35.Bl; H, 4.51; N, 27 84;
S~ 23.90.
Found ~corr. for 4.59% H~O): C, 35.51; H, 4.43; N, 27.98;
S, 23.S6.

Exampl~ 129 .

3 - { 2- t ~ S-Dimethylaminomethyl-2-thienyl ) methylthlo I e~
4- ~ (2-pyridyl~ ~1, 2, S-thiadiazole 1, l-dioxide The general procedure of Example 65 wa~ repeated except that the methylamine utilized thereLn was replaced by an equimolar amount of 2-aminomethylpyridine. Column chromatography of the crude solid yieldea 3.08 g of product.
Recrystallization from isopropyl alcohol y~elded the title compound, mp 162-164 (dec.).

~.2~

Anal. Calcd f~r C18~24N602S3 ~ound: C, 47.80; H, 5.32; N. 18.75.

3-{2-~S-Dimethylaminomethyl-2-~hien~l)methylthio]ethYlamino~-4-[(4-pyridyl)methylamino]-1,2,5-thiadiazole l,1-dioxide The general procedur~ of Example 65 was repeated except that the methylamin2 utilized therein was replaced by an e~uimolar amount of 4-aminomethylpyridine. After chromatography the crude product was dissolved in hot isopropyl alcohol, decanted from insoluble material and the solution treated with anhydrous HCl to give the titl~
compo~nd as the hydrochloride salt. This salt was dissolved in water and made alkaline with saturated aqueous sodi~m bicarbonate solution to give, after filtration, the title compound as a free base, mp 88-90.
Anal. Calcd for Cl~H24N6O2S3: C, 47.76, ~, 5O34; N, 18.57.
Found (corr. for 3.73% H2O): C, 47.54; H, 5.32; N, 19.09.

Example 131 3-{2-[(S-Dimethylaminomethyl-2-thienyl)methvlthio]ethvlamino}
4-ethylamino-1,2,5-thiadiazole l,l-dioxide The qeneral procedure o~ Example 65 was repeated except that the methylamine utilized therein was replac~d by an equimolar amount of ethylamine. The appropriate fractions from column chromatography were dissolved in warm isopropyl alcohol and saturat~d with anhydrous ~Cl. me crystalline solid was collected by filtration, washed with acetone and dried to give 2.9 g of the title compound as its hydrQchloride salt, mp 246-247C ~dec~).

12~19 --14~--Anal. Calcd for C14H24ClN52S3^ C~ 39.47; H~ 5-68; N~ 16-44;
. 3 2 .
Found: C, 39.81; H, 5.74; N, 16.62;
Cl, B.20.

Example 132 3 Methylasnino-4 ~3- (3-piperidinomethylphenoxY) propYlaminol -1, 2, 5-~hiadiazole 1, l-diox de A solution of 3-(3-piperidinomethylphenoxy3propylamine (2.35 g; 9.45 mmoles) lprepared according to published U.K.
patent application 2,023,1331 in 30 ml of methanol was added dropw~se over a period of 40 minutes to a stirred partial suspension of 3, 4-dimethoxy-1,2,5-thiadiazole l,l-dioxide ~1.68 g; 9.45 mmoles) that had been cooled to 1 in an ice-watcr bath. A~ter 15 m~nutes, anhydrous methylamine was bubbled into ~he solution for 5 minutes and the solution then wa~ stirred at ambient temperature or 30 minutes.
The reaction mixture was evaporated under reduced pressure and the residue chromatographed by flash chromatography on 100 g of silica gel ~230-400 mesh) using methanol-acetonitrile. The appropriate fr~ctions were combined and e~aporated to give 2.2 g of product. Recrystallization ~rom acetonitrile with charcoal treatment yielded the title compound, mp 182-184.
An81. Calcd ~or C18H27N503S: C, 54.94; H, 6-92; N~ 17-80;
S, 8015.
Found: C, 54.90; H, 7O07; N, 18.14;
S, 8.29~

`! 1~09!~19 ~xample 133 3-Amino-4-13-(3-pi~ridinomet~ylphenoxy)propylamino~-1,2,5-thiadiazole l-oxide ~ , . .

A solution of 3-(3-piperidinomethylphenoxy)pxopylamine (from th, dihydrochloride, 4.0 g; 12~4 mmoles) in 40 ml Qf methano~ was added dropwise over a period o 50 minute~ ~o a solution of 3,4-dimethoxy-1,2,5-thiadiazole l-oxide ~2.01 g; 12.4 mmoles3 in 20Q ml of me~hanol that had been cooled to 9 in an ice-water bath. After ~5 minutes, anhydxous ammonia was bubbled into the solution for S minutes and the solution then was stirred at ambient temperature for ~7 hours. The reaction mixtuxe was evaporated under reduced pressure and the residue chroma~ographed by flash chroma-tography on 100 g of silica gel (230-4~0 mesh) using methanoloacetonitrile. The appropriate fractions were com-bined and evaporated to give 4~18 g o product. Recrys~al-lization fro~'35% aqueous ethanol yielded the title compound, mp 155-157 ~dec.~.
Anal- Calcd for C17H25N52S C, 56-17; H~ 6-93; N~ 13-27;
S, 8.82.
Found: C, 55.97; H, 7.04; N, 19.~7;
S, 8.63.

xample 134 3-Amino-4-~3-(3-piperidinomethYlphenoxY)PropYlam1~o thiadiazole l,l-dioxide A solution of 3-(3-piperidinomethylphenoxy)-propylamine ~from the dihydrochloridet 4.0 g; 12.4 mmoles) in 35 ml of methanol was added dropwise over a period o~
65 minutes to a stixred partial suspension o~ 3,4-dimethoxy-~i-`? 1~C~99~9 1,2,5-thiadiazole l-oxide ~2.22 g; 12.4 mmoles~ in 200 ml o~ methanol ~hat had been cooled to 2 in an ice-water bath.
After 15 minutes anhydrous ammonia was bubbled into the solution or 5 minutes and the solution then was stirred at ambient temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 100 g of silica gel t230-400 mesh) and chromatographed by flash chromatography using methanol-acetonitrile. The appropriate ractions were combined and ~aporated to giYe 3.2 g of product. The NMR spectrum (100 MHz) in d6 dLme~hyl sulfoxide showed the following resonances ~: 7.2 (m, lH);
6.9 ~m, 3H); 4.1 ~t, 2H); 3~5 (t, 2H); 3.4 (s, 2H); 2.3 (m, 4~); 2 . 0 Im, 2H), 1.4 (~road s, 6H).

Example 13 5 3-{2-[(S-~imethylaminomet~yl-2-thienvl)methyl-thiolethylamino}
4- (3, 4-methvlenedioxvben zvlamino)-1,2,5-thiadiazole 1,1-dioxid~
___ A solution of 2-~t5-dimethylaminomethyl-2-thienyl)-methylthio]ethylamine (2.02 g; 8.8 mmoles) in 30 ml of methanol was added dropwise o~er a period of 40 miAutes to a stirred solution of 3,4-dime~hoxy-1,2,5-thiadiazole 1,1- !
dioxide ~1.5G g; 8.8 mmoles) in 200 ml of methanol that had been cooled to 0 in an i~e-water bath. After 20 miAute5 r piperonylamine (1.46 g; 9.~ mmoles) was added and the mix-ture stirred at zmbie~t temperatuse for 3 hours. The reaction mixture was evaporated to near dryness, ether was added, and the mixture was filtered to give 3.47 g of product. Recrystallization from methanol yielded the title compound, mp 180-~82~.

9~9 C20H25N5O4S3: C, 48.46; H, 5,08; N 14 13 Found (corr. for 0.38% H2O): C, 48.92; H, 4.88; N. 14.52.
.

Example 136 3-Amino-4-{2-1(6-dimethylaminomethy~1-2-pyridyl~methylthio~-ethylamino}-l,2,5-thiadiazole l-oxide A. 6-~N,N-dimeth~lcarbamyl~-2-carbomethoxyEyridine A solution of 6-carbomethoxy-2-pi~olinic acid (22.8 g; 0.13 mole) in 80 ml of thionyl chloride was heated at an oil bath temperature of 100 for 3 hours. The solut~on was evaporated under reduced pressure and the residue dissolve~ in 200 ml of dioxane which then was added drop wise ~o a solution of dLmethylamine (70 g) in dioxane. ~he reaction mixture was stirred for 2 hours and then allowed to stand at 4 overnight, filtered and evaporated under redu~ed pressuxe. The residue was dissolved in toluene, diluted with methylcyclohexane and filtered to give 20.7 g o~ the title compound, mp 90-92.
Anal. Calcd for C~oH12N203: C, 57.68; ~, 5.81; N~ 13.460 Found: C, 57.64; H, 5.85; N, 13.77.

B. 6-Dimethylaminomethyl~2-hydr~ymethYlE~yrldine A solution of 6r (N,~-dimethy~carbamyl-2-car~omethoxy-pyridine ~20.3 g; 97.S mmoles) lprepared in Step Al in 200 ml of tetrahydrofuran was added to a suspension of lithium aluminum hydride t9.6 g; 0.25 moles) in ~00 ml of tetra-hydrofuran~ The mixture was s~irred.and heated at reflux temperature under a nitrogen a~mosphere for 3 hours then left a~ ambient temperature o~ernight. ~he mixture was decomposed with a saturated aqueous solution of Na2SO4, 09~9 filtered, dried and evaporated under reduced pressure. The residue was placed on 275 g of aluminum oxide and eluted with methylene chloride. The appropriate fractions were combined and evaporated to gi~e 5.2 g of the title ~ompound.

The NMR spectrum ~60 MHz) in CDC13 gave the follow-ing resonances ~: 7.38 (m, 3H); 4.75 (s, 2H); 3.58 (s, 2H);
2.27 (s, 6~

C. 2-[(6-Dime~hylaminome~hyl-2-pyridyl)methylthio]-ethyla~ine Cysteamine hydrochloride (3.58 g; 31.5 mmoles) and 6-dimethylaminomethyl-2-hydroxymethylpyridine (5~0 g; 30.1 mmole~ tprepared in Step B] were dissolved in 50 ml of 48%
hydrobromic acid and the solution heated at reflux temper-atu.re for 12 hours and then allowed to stand at ambient temperatu~e for 8 hours. The reaction mixture was evapora-ted under reduced pressure to h~l~ volume, made basic with 40% aqueous NaOH and extracted with se~eral portio~s of methylene chloride. The combined organic phase was washed with a small amount of water and sa~urated brine solution then dried and eYaporated under reduced pressure to yield 3.14 g of the title compound.

The NMR spectrum (60 ~Hz) in CDC13 gave the following resonances ~: 7.5 ~m, 3H); 3.83 (s, 2H); 3.56 (s, 2~);
.7 (m, 4H); 2.28 ~s, 6H).

D. 3-Amino-4-{2-~(6-dimethylaminomethyl-2-pyridyl?-methyl~hiolethylamino}-1,2~5-~hiadiazole l-oxide When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole l-oxide is successively treated with an equimolar ~ 09.~9 amount of 2- t(6~dime~hylaminomethyl-2-pyridyl)methylthio]-ethylamine [prepared in Step Cl and excess ammonia, the title compound i~ thereby produced.

Example 137 _ ____ ethylamino}-1,2,5-thiadiazole 1,l-dioxide When a methanolic solution of 3,4-dimethoxy-1,2,5- -thiadiazole l,l-dioxide is successively treated with an equimolar amount of 2-t(6-dimethylam$nomethyl-2-pyridyl)-me~hylthio~ethylamine ~p~epaxed in Exam~le 136, Step Cl and excess ammonia, the title compound is thereby produced.
.

Example 138 3-{2-~S-Guanidino-1,2,4-thiadlazol-3-yl)me.thylthio]-e~hylamino}-4-methylamino-1,2,5-~hiadiazole_l,1-dioxide When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide is su~cessively treated with an equimolar amount of 2-~5-guanidino-1,2,4-thiadiazol-3-yl)-methyl~hio~ethyl~mine ~prepared accordLng to ~he procedure described in published European Patent Application 6679 and excess methylamine, the tltle compound is thereby produced.

Example 139 3-~mino-4-~2-~(5 uanidino-1,2,4-thiadiazol-3~Yl)methYlthio3-ethylamino~-1,2,5-thiadiazole l,l-dioxide -- When a methanolic solution of 3, 4-dimethoxy-1, 2, 5-~ 9~9 thiadia~ole l,l-dioxide is successively treated with an equimolar amount of 2-~5-guanidino-1,2,4-thiadiazol-3-yl)-methylthiojethylamine and excess ammonia, the title compound is thereby produced.

Example 140 3-Amino-4-{2-t(S- uanidino-l 2 4-~hiadiazol-3- l)meth lthio]-!l ~ . . Y~ _ Y _ I
eth~lamino} 1,2,5-thiadiazole l-oxide When a methanolic solution of 3,4-dime~hoxy-1,2,5-thiadiazole l-oxide is successively treated with an e~ui molar amount of 2-t~5-guanidino-lt2~4-thiadiazol-3-yl)-methylthio]ethylamLne and excess ammonia, the title compound is there~y producede .
ExamDle 141 3-~2-t(S-~uanidino-1,2,4-oxadiazol-3-yl)meth~lthiol-et~ylamino}-4-methylamino-1,2,5-thiadiazole 1,1 dioxide ~ en a methanolic solution of 3,4-dimethoxy-1,2,5-~hiadiazole 1,l-dioxide is successively tseated with an equimolar amount of 2-[~5-guanidino 1,2,4-oxadiazol-3-yl)-methylthio~ethylamLne [prepared according to the procedure described in published European ~atent Application 6286 and excess methylamine, the title compound i5 thereby produced.

Example 142 3-~mino- t2-~tS-guanidino-1,2,4-oxad azol~yl)met ethvlamino}-1,2,5-thiadiazole l,l-dioxide 12~9~

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide is successively treated with an equimolar amount of 2-t(s-guanidino-l~2~4-oxadiazolo3~yl)-methylthio3ethylamine and excess ammonia, the title compound is thereby produced.

Example 143 3-Amino-4 {2-1(5-guanidino-1,2,4-oxadiazol 3-yl ? methylthio~_ ethylamino}-1,2,5-thiadiazole l-oxide When a me~hanolic solution of 3,4-dimethoxy-1,2,5-~hiadiazole l-oxide is successively treated with an equimolar amount of 2-~tS-guanidino-1,2,4-oxadiazol-3-yl)methylthio]-ethylamine and excess ammonia, the title compou~d is thexeby produced.

Example 144 The general procedur~ of Example 132 is repeated, except ~hat the 3-~3-piperidinomethylphenoxy)propylamine utilized therein is replaced by an equimolar amount of a) 3-(3-pyrrolidinomethylphenoxy)propylamine, b) 3-f3-(4-methylpiperidinolmethylphenoxy]propylamine, c) 3-t3-homopiperidinomethylphenoxy)propylamine, d) 3-(3-morpholinomethylphenoxy)propylaminel and 2 e) 3-~3-tN-methylpiperazino)methylphenoxylpropylamine , respect-ively, and there i5 there~y produced a) 3-Methylamino-4-~3-(3-pyrrolidinomethylphenoxy~propylamino]-1,2,5-thiadiazole l,l-~ioxide, mp 156-157C, b) 3-Methylamino-4-{3-13-(4-methylpiperidino)methylphenoxy3-propylamino~ ,S-~hiadiazole l,l-dioxide, mp 186-189C, , . .

209~9 c) 3-Methyl~mino-4-t3-(3-homopiperidinomethylphenoxy)-propylaminol-1,2,5-thiadiazole l,l-dioxide, mp 1?4-176C as the hydrochloride~
d) 3-~1ethylamino-4^t3-(3-morpholinomethylphenoxy)propylamino]-1,2,5~thiadiazole l,l-dioxide, mp 162-163C, and e) 3-Methylamino-4-~3-t3-~N-methylpiperaZino)methylphenoXy~-propylamino}-1,2,5-thiadiazole l,l-dioxide, respectively.

The above starting materials ~1~ and (2~ are prepared by hydrogenation o~ a mixture of N-t3-(3-formylphenoxy)-propyl]phthalimide and the correspon~ing morpholine orN-methylpiperazine over 10% palladium/carbon catalyst and then removal of the phthalimido protecting group with hydrazine. The other starting materials are prepared according to the procedures described in published U.X.
Patent Application 2,023,133.

Example 145 The gener~l procedure of Example 133 is repeated, except that the 3-(3-piperidinomethylphenoxy)propylamine utilized therein is replaced by an equimolar amount of a) 3-(3-pyrxolidinomethylphenoxy)propylamine~
b) 3-t3-~4-methylpiperidino)methylphenoxy]propylamine~
c) 3-(3-homopiperidinomethylphenoxy)propylamlne, d) 3-~3-~heptame~hyleneiminomethyl)phenoxy3propylamine, e) 3-~3-morpholino~ethylphenoxy)propylamine and f) 3-~3-(N-methylpiperazino)mekhylphenoxy~propylamine, respecti~ely, and thera is thereby produced at 3~Amino-4-t3-(3Opyrrolidinomethylphenoxy3propylamino]-~,2,5-thiadiazole l-oxide~ mp 168-170C ~dec.) b) 3-Amino-4-{3-t3-(4-methylpiperidino)methylphenoxy~-- propylamino~-1,2,5-thiadiazole l-oxide, ~p 157-159C, Q9!~9 c) 3-Amino-4-~3-(3-homopiperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole l-oxide, mp 167-169C, d) 3-A~ino-4-{3-[3-(heptamethyleneiminomethyl)phenoxy~-propylamino}-1,2,5-thiadiazole l-oxide, mp 154-157~C, e) 3-Amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole l-oxide and f) 3-~mino-4-{3-~3-~N-methylpiperazino)methylphenoxy~-propylamino}-1,2,5-thiadiazole l-oxide, respectively.

Example 146 The general procedure of Example 134 is repeated, except that the 3-(3-piperidinomethylphenoxy)propylamine utilized therein is replaced by an equimolar amount of a) 3-(3 pyrrolidinomethylphenoxy~propylamine, bj 3-~3-(4-me~hylpiperidino)me~hylphenoxy]propylamine, c) 3-(3-homopiperidinomethylphenoxy)propylamine, d) 3-~3-morpholinomethylphenoxy)propylamine and e) 3-13-(N-methylpiperazino)methylp~enoxy~propylamine, respectively, and there is the_eby produced a) 3-Amino~4-[3-(3-pyrrolidinomethylphenoxy)propylamino~-1,2,5-~hiadiazole l,l-dioxide, mp 160-163C (dec.) b) 3-Amino-4-{3-~3-~4-methylpiperidino)methylphenoxy3propylamino}-1,2,5-thiadiazole l,l-dioxide, c) 3-Amino-4-[3-~3-homopiperidinomet~ylphenoxy)prapylamino~-1,2,5-thiadiazole l,l-dioxide, d) 3-Amino-4-t3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole l,l-dioxide, mp 172-174~C ~dec.), and e) 3-Amino-4-~3-[3-tN-methylpiperazino)methylphenoxy]-propylamino}-1,2,5-thiadiazole l,l-dioxide, respectively.

- Example 147 The general procedure of Example 132 is repeated, except that the methylamine utilized therein is replaced by an equimolar amount of ethyl amine, 209!9~.9 propylamine, n-butylamine, allylamine, 2-propynylamine, cyclopropylamine, aminome~hylcyclopropane, ethanolamine, 2-methoxyethylamine, 2,2,2-~rifluoroethyl~mine, 2-fluoroethyla~ine, hydroxyamine, 3-aminopropionitrile benzy~amine, 3-methoxybenzylamine, 4-methoxybenzylamine~
3,4-dimethoxybenzylamine, piperonylamine,.
4-chlorobenzylamine, 2~aminomethylpyridine, 3-aminomethylpyridin and 4-aminometh~lpyridine, respectively, and there is thereby produced 3-E~hylamino-4-t3-(3-piperidinomethylphenoxy)propylaminol-1,2,5-~hiadiazol~ l,l-dioxide, 3-Propyla~ino-4-t3-(3-piperidinomethylphenoxy)propylamino~-1,2,5-thiadiazol~ dioxide, 3-Bu~ylamino-4-t3-~3-piperidinomethylphenoxy)propylamino]-1,2,5-~hi~diazole ~ dioxide, 3-Allylamino-4-[3-(3-piperidinomeShylphenoxy)~ropylamino]-1,2,5-thiadiazole l,l-dioxide, 3-(2-Propynyl)amlno-4-[3-(3-piperidinomethylphenoxy)-propylamino~-1,2,5-thiadiazole 1,l-dioxide, 3-(Cyclopropylamino~-4-~3-~3-piperidinomethylphenoxy)-propylamino]-1,2,5-thiadiazole 1,1-dioxide, ~ 9~19 3-t(Cyclopropyl)me~hylamino3-4-t3- (3-piperidinomethylphenoxy) -propylamino]-1,2,5-thiadiazole 1,1-diox~de, 3-(2-~ydroxyethylamino)-4-t3-(3-piperidinomethylphenoxy)-propylaminol-1,2,5-thiadia~ole l,l-dioxide, 3-(2-Methoxyethylamino)-4-t3-~3-piperidinomethylphenoxy)-propylamino~-1,2,5-thiadiazole 1,l-dioxide, 3-S2,2,2-trifluoroethyl~mino)-4-[3-(3-piperidinomethylphenoxy)-propyt.amino]-1,2,5-thiadiazole l,l-dioxide, 3-(2-Fluoroethylamino3-4-~3-(3-piperidinomethylphensxy)-propylaminoJ-1,2,5-thiadiazole 1,l-dioxide, 3-Hydroxyamino-4-[3-(3-piperidLnomethylphenoxy~propylamino3-1,2,5-thiadiazole l,l-dioxide, 3-(3-Cyanopropylamino9-4-[3-~3-piperidinomethylphenoxy)-propylamino3 1,2,5-thiadiazole l,1-dioxide, 3-Benzylamino-4~[3-(3-piperidinomethylphenoxy~propylæmino3-1,2,5-thiadiazole l,1-dioxide, 3-(3-Methoxybenzylamino)-4-~3-(3-piperidinomethylphenoxy)-propylaminol-1,2,5-~hladiazole ~,l-dioxide, 3-t4-~ethoxybenzylamino)-4-~3-~3-piperidinomethylphenoxy)-propylamino]-1,2,5-thiadiazole l,l-dioxide, 3-(3,4-Dimethoxybenzylamino)-4-~3-(3-piperidinomethylphenoxy)-propylamino]-1,2,5-thiadiazole 1,l-dioxide, 3 (3,4-Methylenedioxybenzylamino)-4-~3-t3-piperidinomethyl-phenoxy)propylaminol-1,2,5-thi~diazole l,~-dioxide, 3~~4-Chlorobenæylamino)-4-t3-(3-piperidinomethylphenoxy)-propylamino]-1,2,5-thiadiazole l,l-dioxide, 3-[(2-Pyridyl)methylamino3-4-~3-(3-pipexidinomethylphenoxy)-propylamino3 1,2,5-thiadiazole l,l-dioxide, 3-~(3-Pyridyl)methylami~ol-4-~3-(3-piperidinom~thylphenoxy)-propylamino]-1,2,5-thiadiazole l,l-dioxide, and 3-~(4 Pyridyl)methylamino3-4-t3-(3-piperidinomethylphenoxy)-propylaminol-1,2,5-thiadiazole 1,l-dioxide, respectively.

~0~ 9 Example 148 The general procedures of Example 147 are rPpeated except that the 3,4-dimethoxy-1,2,5-thiadiazole l,l-dioxide utilized therein is replaced ~y an equimolar amount of 3,4-d~methoxy-l t 2,5-thiadiazole l-oxide, and there are thereby pro~uced 3-E~hylamino-4-t3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole l-oxide, 3-Propylamino-4~t3-t3-piperidinomethylphenoxy~propylamino]-1,2,5-thiadlazole l-oxide, 3-Butylamino-4-13-(3-piperidinomethylphenn~y)propyla~ino~
1,2,5-th~adiazole 1 oxide, 3-Allylamino-4-E3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole l-oxide, ~-(2-Propynyl)amino-4-13-~3-piperidinomethylphenoxy)-propylamino~-1,2,5-thiadiazole 1 oxide, 3-~Cyclopropylamino)-4-[3-~3-piperidinomethylphenoxy)-propylamino3 -1, 2,5-thiadiazole l-oxide, 3-~(Cyclopropyl)methylamino~-4- [3- ~3-piperidinomethylphenoxy) -propylamino]-1,2,5-thiadiazole l-oxide, 3-(2-Hy~roxyethyl~mino)-4-t3-(3-piperidinomethylphenoxy)-propylamino~-1,2,5-thiadiazole l-oxide, 3-(2-Methoxyethylamino)-4-~3- (3-piperidinomethylphenoxy) -propylamino~-1,2,5-thiadiazole l-oxide, 3-~2,2,2-Trifluoroethylamino)-4-[3-(3-piperidinomethylphe~oxy)-propylamino3-1,2,$-thiadiazole l-oxide, 3- ~-Fluoroethylamino) -4- 13-(3-piperidinomethylphenoxy)-propylamino] 1, 2, 5-thiadiazole l-oxide, ~Hydroxyamino-4- E 3- (3-piperidinomethylphenoxy ~ propylamino 1 ~
1,2,5-thiadiazole l-oxide, 3-~3-Cyanopropylamino~-4-13-(3-~iperidinomethylphe.~oxy)-propylamino]-1,2,5-thiadiazole l-oxide, 3-3enzylamino-4- [3- ~3-piperidinomethylphenoxy)propylaminol-~ g~

1,2,5-~hiadiazole l-oxide, 3-(3-Me~hoxybenzylamino)-4-13-t3-piperidinomethylphenoxy)-propylamino]-l r 2,5-thiadiazole l-oxide, 3-(4-Methoxybenzylamino~-4-[3-(3-piperidinomethylphenoxy~-propylamino]-1,2,5-thiadiazole l-oxide, 3-~3,4-Dimethoxybenzy~amino)-4-t3 t3-piperidinomethylphenoxy)-propylamino~-1,2,5-thiadiazole l-oxide, 3-(3,4-Methylenedioxybenzylamino)-4-[3-(3-piperidinomethyl phenoxy)propyl~mino~-l,2,5-~hiadiazole l-oxide, 3 (4-Chlorobenzylamino)-4-~3-(3-piperid~nomethylphenoxy)-propylamino]-1,2,5-thiadiazole l-oxide, 3-t(2-Pyridyl)methylamino~-4-~3-(3-piperidinomethylphenoxy)-propylamino3-1,2,5-~hiadia~ole l-oxide 3- E (3-Pyridyl)methylamino]-4-[3-(3-piperidino~ethylphenoxy)-propylaminol-1,2,5~thiadiazole l-oxide, mp 139.5-143C, and 3-~(4-Pyridyl)methylamino~-4-[3-(3-piper~dinomethylphenoxy3-propylamino~-1,2,5-thiadiazole l-oxide~ respectively.

Example 149 3-t(3 ~ ri~ thYlaminol-4-[3-t3-piperidinomethylph~ y ~roDylamino~-1,2 ~

A solution of 3-(3-piperidînomethylphenoxy~propylamine (from the dihydrochloride, 3.21 ~; 10.~ mmoles) in 30 ml of methanol was added dropwise over a period of 60 ~inutes to a partial solution of 3,4~dimethoxy~1,2,5-thiadia~ole l-oxide (1.62 g; 10.0 mmoles~ ~hat had been cooled ~o 5-7 in an ice-water bath. After 3 hours at ambient temperature, a so~ution of 3-~minomethylpyridine (1.14 g; 10.5 mmoles) in

10 ml of methanol wa~ added and the s~lution was then stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue chromatographed by flash ,: .

~ 0~ 9 chromatography on 100 g of silica gel (230-400 mesh) usins methylene chloride-methanol-ammonia. The appropriate fractions were combined, evapora.ed and triturated with aoetonitrile to give 4.05 g of product. Recrystallization from isopropyl alcohol yielded the title compound, mp 139.5-Anal- Calc'd- fo~ C23H30t~6O2S: C, 60.77, H, 6.65; N, 18~49;
S, 7~04 Found: Cr 60 . 66; H~ 6 . 64; ~ 18 . 22;
5, 7.~2.

Example 150 3-Amino-4-[3-(3-guanidinophenoxy)pro~ylamino3-1,2,5-thiadiazole l-oxide A. N-13-(3-litrophenoxY~Propyl~Phthali de I

A partial suspension of m-nitrophenol ~6.0 g; 43.0 mmoles), N-(3-~romopropyl)phthalimide ~10.0 g; 37.0 mmoles~
and potass~um carbonate t8.0 g; 58.0 mmoles) in 50 ml of ~ was stirred at ambient temperature for 70 hours. The reaction mixture was diluted with 80 ml of water and filtered to gi~e product. Recrystallization from 2-methoxyethanol yielded 9.15 g of the title compound, mp 149-152.
Anal. Calc'd. for C~7H14N205 C, 62.57; H, 4.32; M, 8.59.
Found: C, 62.49; ~, 4.30; N, 8.71.

B. N-[3-(3-Am_nophenoxy~ro~yl~hthalimide .

A suspension cf ~-[3-(3-nitrophenoxy)propyl]phthalimide ~1.0 g; 3.1 mmoles) [prepared in Step A] and 10% palladium on carbon ~0.2 g) in 100 m~ or 2-methoxyethanol was hydrogenated in a Parr ~pparatus at ambient t2mper~ture for 45 minutesO ~he reaction mixture was filtered and the filtrate was e~aporated to dryness to give 0.91 g of crude produ~t.

2C~9~9 ~ n analytical sample was pr~pared by flash chroma-tography on silica gel using methylene chloride-methanol and re rystallization from absolute ethanol yielded the ~itle compound, mp 157-162~
Anal~ Calc'd- for C17H16~23 Found- C, 69.00; H, 5.54; N, 9.52.

C. N- [3- ~3-Guanidinopnenoxv) propYl]phthalimide A mixture of crude ~.~ t3-(3-aminsphenoxy)propyl3-pht~alimide (13 . 27 g; 45. 0 ~:~moles) [prepared in Step B], 50%
aqueous cyanamide t7.9 ml) and 121t hydrochloric acid (3.78 ml;
45.0 mmoles~ in 3g.4 ml of absolute ethanol was heated at reflux for 2-1/4 hours. An additional 7.9 ml of 50~ aqueous cyanamide was added and heating was continued for 15 hours.
The reaction mixture was evaporated under reduced pressure and ~he residue chromatographed by flash chromatogra~hy on 120 g of silica gel ~230-400 mesh) using methylene chloride-methanol. The appropriate fractions were combined, evapora~ed and triturated with cold acetonitrile ~o give 5.B5 g of product. Recrystallization from absolute ethanol yielded the title compound as a hydrochloride salt, mp 185-187.
Anal. Calc'd. for C18H18N403-RCl: C, 57~68; H, 5.11; ~J. 14~95;
Cl, ~.46.
Found: C, 57.65; H, 5.55; ~1, 15.08;
C~, 9.16.

D. 3-(3-GuanidinophenoxY)~roDylamine To a partial suspension of N- E3- ~3-guanidinophenoxy) -propyl]phth~limide hydrochloride (1.0 g; 2.g5 m~oles) in 10 ml of 95% aqueous ethanol was added 0~27 ml of hydrazine hydrate.
The mixture was stirred at ambient temperature ~or 17 hours and evaporated under reduced pressure to giva the title compound. The product was used without further purification in Step E.

r~ ~ ~Z09~9 E. 3-Amino-4-~3-(3-quanidino~henoxY)p~pylamino]-1,2,5-thiadiazole l-oxide To a solu~ion of crude 3-(3-guanidinophenoxy)propylamine ~prepared in Step D~ in 10 ml of methanol was added 3-amino-4-methoxy-1,2,5-thiadiazole l-oxide ~0.59 g; 4.0 mmoles) and ~he mixture was stirred a~ ambient temperature for 17 hours and then heated at 50 for 7 .5 hours. The reaction mixture was filtered, evaporated under reduced pressure and the residue was chromatographed by flash chro~atography on 75 g of silica gel ~230-400 mesh) using methanol-methylene chloride.
The appropriate fractions were combined and evaporated under redu~ed pressure to yield 0.25 g of the title compound as an oil; TLC ~silica gel/CII2C12:CH3O~ (4:})~ ga~e R'=0.21~

The NMR spectrum (60 ~z) in d6 dimethyl sulfoxide gave the following resonances ~: 9.33 (s, lH); 8.43 ts, 2~);
7.52 ~m, 4~); 7.43 (m, lH); 6.83 (m, 3H); 4.13 tbroad t, 2H);
3.51 (broad t, 2H); 2.10 ~broad t, 2H).

ExamPle 151 3-Amino-4-{2-.t(5-p~peridlnomethyl-2-furyl?methylthio]-eth lamino~-1,2,5-thiadia2O1e l-oxida Y _ _ ~ _ _ A. 3-A~ino-4-methoxY-1,2,5 thiadiazole l-oxide A 2.75 l~ solution of ammonia (56.0 ml; 0.154 m~ole) in methanol was added dropwise over 1 hour to a well-stirred solution of 3,4-dimethoxy-1,2,5-thiadiaæole l-oxide (24.3 g;
0.15 mole) in 725 ml of methanol at 20. The resultant solution was stirred at ambient temperature for 3 hours and then was concentrated to about 125 ml at reduced pressure.
After 16 hours at 0, the mixture was filtered and dried to give 19.9 g of product.

An analytical sample was prepared by recrys~allization ~rom methanol ~o yield the title compound, mp 182-184 (dec.) ~'~0~3~
-16~
Anal. Calc'd. for C3HSN302S: C, 24.49; H, 3.43; N, 28.56;
S, 21.79.
Found: C, 24.22; H, 3.63; N, 23.60;
S, 21.g2.

B. 3-Amino-4-{2-~(5-piperidinomethyl 2-furyl)-methvlthio]ethvlamlno}~l,2,5-thiadiazole ~-oxide A solution of 2-~S-piperidinomethyl-2-furyl)methyl~hio]-ethylamine t4.0 g: 15.7 ~moles) [prepared according to the procedure described in Belgian Patent 857,388 ~U.S, Patent 4,128,658)~ in 25 ml of methanol was added all at once to a stirred suspension of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.31 g; 15.7 mmoles) tprepared in Step AJ in 25 ml of methanol at ambient te~perature. Af~er stirring for 16 hours, the solution was evaporated under reduced pressure and the residue chromatograp~ed by flash chromatog~aphy on 100 g of silica gel ~230-400 mesh) using methanol-acetcnitrile. The appropriate fractions were combined and evaporated to give 3.71 g of product. Recrystallization from 95% aqueous ethanol with charcoal treatment yielded the title compound, mp 161-163.
Anal. Calc'd. for C15H23N502S2: C, 48.76; H, 6.27; N, 18.96;
S, 17.36.
Found: C, 48.86; H, 6.16; 1~, 19.66;
S, 17.63.

Claims (19)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition useful in the treatment of peptic ulcers, in unit dosage form, which comprises a peptic activity-inhibiting amount of pepstatin and an effective anti-ulcerogenic amount of a compound of the formula wherein p is 1 or 2;
R1 is hydroxy or NR2R3;
R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower) alkyl, (lower)alkoxy(lower)alkyl, (lower)-alkylthio(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R2 is hydrogen, R3 may also be cyclo(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)-alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino(lower) alkyl, pyridyl(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)-alkoxy, 2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, A'-(CH2)mZ'(CH2)n,-, phenyl, phenyl(lower)alkyl, substituted phenyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy,(lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; or R2 and R3, taken together, may be -CH2CH2X(CH2)r-;
r is an integer of from 1 to 3, inclusive;
X is methylene, sulfur, oxygen or N-R4, provided that, when r is 1, X is methylene;
R4 is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)-alkynyl, (lower)alkanoyl or benzoyl;
m and m' each are independently an integer of from zero to 2, inclusive;
n and n' each are independently an integer of from 2 to 4, inclusive;
Z and Z' each are independently sulfur, oxygen or methylene;
A and A' each are independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, and -(CH2)qNR5R6, and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower) alkoxy;
q is an integer of from 0 to 6, inclusive; R14 and R15 independently are hydrogen or (lower)alkyl, or, if R14 is hydrogen, R15 also may be (lower)alkanoyl or benzoyl, or R14 and R15, taken together, may be ethylene; and R5 and R6 each are independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl, phenyl or phenyl(lower)alkyl, provided that R5 and R6 may not both be cyclo(lower)alkyl or phenyl; or R5 and R6, taken together with the nitrogen atom to which they are attached may be pyrrolidino, methylpyrrolidino, dimethyl-pyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, homopiperidino, heptamethyleneimino or octamethyleneimino, or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

2. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2;

R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, (lower)-alkylthio(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R2 is hydrogen, R3 may also be cyclo(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)-alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino(lower)-alkyl, pyridyl(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selectad from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)-alkoxy, 2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, A'-(CH2)m,Z'(CH2)n,-, pheny1, phenyl(lower)alkyl, substituted phenyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; or R2 and R3, taken together, may be -CH2CH2X (CH2)r-;
r is an integer of from 1 to 3, inclusive;

X is methylene, sulfur, oxygen or N-R4, provided that, when r is 1, X is methylene;
R4 is hydrogen, (lower)alkyl, (lower)alkenyl (lower)-alkynyl, (lower) alkanoyl or benzoyl;
m and m' each are independently an integer of from zero to 2 . inclusive;
n and n ' each are independently an integer of from 2 to 4, inclusive;
Z and Z ' each are independently sulfur, oxygen or methylene;
A and A' each are independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl, provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, and -(CH2)qNR5R6, and thesecond substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy;
q is an integer of from 0 to 6, inclusive; R14 and R15 independently are hydrogen or (lower)alkyl, or, if R14 is hydrogen,R15 also may be (lower)alkanoyl or benzoyl, or R14 and R15, taken together, may be ethylene; and R5 and R6 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl, phenyl or phenyl(lower)alkyl, provided that R5 and R6 may not both be cyclo(lower)alkyl or phenyl; or R5 and R6, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethyl-pyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, homopiperidino, heptamethyleneimino or octamethyleneimino, or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

3. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2;
R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl,(lower)alkynyl, cyclo(lower)alkyl (lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, 2-fluoroethyl or 2,2,2-trifluoroethyl, or, when R2 is hydrogen, R3 also may be pyrrolidino (lower) alkyl, piperidino(lower)alkyl, morpholino-(lower)alkyl, piperazino(lower)alkyl, pyridyl(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)-alkoxy, hydroxy, amino and halogen, hydroxy, A'-(CH2)m,Z 'CH2)n,-, phenyl(lower)alkyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino;
m and m' each are independently an integer of from zero to 2, inclusive;
n and n ' each are independently an integer of from 2 to 4, inclusive;
Z and Z' each are independently sulfur, oxygen or methylene;
A and A' each are independently phenyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, and -CH2) qNR5R6, and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy;
q is an integer of from 0 to 6, inclusive; R14 and R15 independently are hydrogen or (lower)alkyl, or R14 and R15, taken together may be ethylene; and R5 and R6 each are independently hydrogen, (lower)alkyl, (lower)alkenyl or (lower)alkynyl; or R5 and R6, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, homopiperidino, heptamethyleneimino or octamethyleneimino, or a nontoxic pharma-ceutically acceptable salt, hydrate or solvate thereof .

4. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2;
R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl or cyclo ( lower ) alkyl (lower) alkyl, or, when R2 is hydrogen, R3 also may be pyriodyl(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, A'-(CH2)m,Z' (CH2)n!-, phenyl(lower) alkyl or 3, 4-methylenedioxybenzyl;
m and m' each are independently zero or 1;
n and n' each are independently 2 or 3;

Z and Z' each are independently sulfur, oxygen or methylene;
A and A' each are independently phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, and -CH2NR5R6, and the second substituent being selected from (lower)alkyl;
R14 and R15 independently are hydrogen or (lower)alkyl, or R14 and R15, taken together, may be ethylene; and R5 and R6 each are independently hydrogen or (lower)-alkyl; or R5 and R6, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, homopipexidino, heptamethyleneimino or octamethyleneimino, or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

5. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2; Z is sulfur or methylene; R2 and R3 each are independently hydrogen or (lower)alkyl, or, when R2 is hydrogen, R3 also may be (lower)alkenyl, (lower)alkynyl, phenyl(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, pyridylmethyl or R16 is methyl and R13 is hydrogen or methyl, or R16 and R13, taken together with the nitrogen atom to which they are attached, may be piperidino; or nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

6. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2; Z is sulfur or methylene; R14 and R15 independently are hydrogen or methyl, or, R14 and R15, taken together, may be ethylene; and R2 and R3 each are independently hydrogen or (lower)alkyl, or, when R2 is hydrogen, R3 also may be (lower)alkenyl, (lower)alkynyl, pyridylmethyl, or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

7. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2; Z is sulfur or methylene; R2 and R3 each are independently hydrogen or (lower)alkyl, or when R2 is hydrogen, R3 also may be (lower)alkenyl, (lower)alkynyl or and R13 is hydrogen or methyl; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

8. - A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2;. Z is sulfur or methylene; R2 and R3 each are independently hydrogen or (lower)alkyl, l, or, when R2 is hydrogen, R3 also may be (lower)alkenyl, (lower)alkynyl, phenyl(lower)alkyl, pyridylmethyl, 3,4-methylenedioxybenzyl or ;

and R13 is hydrogen or methyl; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

9. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2; and R2 and R3 each are independently hydrogen or (lower)alkyl, or, when R2 is hydrogen, R3 also may be (lower) alkenyl, (lower)alkynyl or or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

10. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2; Z is sulfur or methylene; R2 and R3 each are independently hydrogen or (lower)alkyl, or, when R2 is hydrogen, R3 also may be (lower)alkenyl, (lower)alkynyl or and R5 and R6 each are independently hydrogen or (lower)alkyl, or, R5 and R6, taken together with the nitrogen atom to which they are attached, may be piperidino; or a nontoxic, pharma-ceutica11y acceptable salt, hydrate or solvate thereof.

11. A composition of Claim 1 wherein the compound of Formula I has the structure wherein p is 1 or 2; Z is oxygen or sulfur; R2 and R3 each are independently hydrogen or (lower)alkyl, or, when R2 is hydrogen, R3 also may be (lower)alkenyl, (lower)alkynyl, pyridylmethyl or and R5 and R6 each are independently hydrogen or (lower)alkyl, or, when R5 is hydrogen, R6 also may be (lower)alkenyl or (lower)alkynyl; or R5 and R6, taken together with the nitrogen to whioh they are attached, may be pyrrolidino, methylpyrxolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, homopiperidino or heptamethyleneimino;
or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.

12. A composition of any one of Claim 1 - 3 wherein the dosage of pepstatin is from about 100 to about 175 mg and the dosage of the compound of Formula I is from about 2 to about 100 mg.

13. A composition of any one of Claims 1-3 wherein the dosage of pepstatin is from about 100 to about 175 mg and the dosage of the compound of Formula I is from about 4 to about 50 mg.

14. A composition of any one of Claims 1-3 wherein the dosage of pepstatin is from about 100 to about 175 mg and the dosage of the compound of Formula I is from about 2 to about 100 mg, and wherein the pepstatin is in the form of pepstatin floating minicapsules.

15. A composition of any one of Claims 1-3 wherein the dosage of pepstatin is from about 100 to about 175 mg and the dosage of the compound of Formula I is from about 4 to about 50 mg, and wherein the pepstatin is in the form of pepstain floating minicapcules.

16. A pharmaceutical composition useful in the treatment of peptic ulcers, in unit dosage form, which comprises from about 100 to about 175 mg of pepstatin and from about 2 to about 15 mg of 3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]-ethylamino}-1,2,5-thiadiazole l-oxide or a nontoxic pharmaceutically acceptable acid addition salt, hydrate or solvate thereof.

17. A pharmaceutical composition useful in the treatment of peptic ulcers, in unit dosage form, which comprises from about 100 to about 175 mg of pepstatin and from about 2 to about 15 mg of 3-amino-4-(2-[(2-guanidinothiazo1-4-yl)methylthio}}ethylamino}-1,2,5-thiadiazole l-oxide or a nontoxic pharmaceutically accept-able acid addition salt, hydrate or solvate thereof.

18. The composition of Claim 16 wherein the pepstatin is in the form of pepstatin floating minicapsules.

19. The composition of Claim 17 wherein the pepstatin is in the form of pepstatin floating minicapsules.