FR2476081A1 - 1,2,5-Thiadiazole 1-oxide and 1,1-di:oxide derivs. - useful as anti-ulcer agents - Google Patents

Abstract

1,2,5-thiadiazole 1-oxides and 1,1-dioxides of formula (I) and their salts, hydrates, solvates and N-oxides are new where R1 is OH or NR2R3; R2 and R3 are H, lower alkyl alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, aminoalkyl, mono- or dialkylaminoalkyl, pyrrolidino-, piperidino-, morpholino-, piperazino- or pyridylalkyl, NH2, alkylamino, dialkylamino, CH2CF3, CH2CH2F, OH, alkoxy, 2,3-dihydroxypropyl, CN, cyanoalkyl, amidino, alkylamidino, A(CH2)mZ(CH2)n, or phenyl or phenylalkyl opt. ring-substd. by 1 or 2 gps. , provided that R2 and R3 are not both cycloalkyl, opt. substd. phenyl, NH2, (di)alkylamino, OH, alkoxy, CN, (alkyl) amidino or A(CH2)mZ(CH2)n; or R2+R3 is CH2CH2X(CH2)r, where r is 1-3 and X is CH2, S, O or NR4, provided that X is CH2 when r is 1; R4 is H, alkyl, alkenyl, alkynyl, alkanoyl or benzoyl. Each m is 0-2; each n is 2-4; each Z is S, O, or CH2; each A is a phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl gp. opt. substd. by 1 or 2 substituents, the 1st being selected from alkyl, OH, CF3, halogen, NH2, CH2OH, alkoxy, (CH2)qN:C(NHR4)2 and (CH2)qNR5R6, and the 2nd being selected from alkyl, OH, CF3, halogen, NH2, CH2OH and alkoxy; q is 0-6; each R4 is as defined above or the 2 R4 gps. together form CH2CH2; R5 and R6 are H, alkyl, alkenyl, alkynyl, cycloalkyl or phenyl, but not both cycloalkyl or phenyl, or NR5R6 is pyrrolidino, morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino. p is 1 or 2. (I) are histamine H2 antagonists which inhibit gastric acid secretion and are thus useful as anti-ulcer agents.

Description

1,2,5-thiadiazole-1-oxides and 1,2,5-thiadiazole 1,1-dioxides
3,4 disubstituted, their process of preparation and their
pharmacological application.

 The present invention relates to 1,2,5-thiadiazole 1-3,4-disubstituted oxides and 1,2,5-thiadiazole disubstituted 1,1-dioxides 3,4; it further relates to the pharmacological application of these compounds and more particularly to their application as inhibitors of gastric acid secretion.

Burimamide (IIa), methaamide (IIb) and cimetidine (IIc) are known acid antagonists which can be represented by formula II:

IIa: R2 = H, Z = CH2, X = S burimamide
IIb: R2 = CH3, Z = S, X = S metamide
IIc: R2 = CH3, Z = S, X = NCN cimetidine
Burimamide (IIa) is the first clinically effective acid receptor antagonist. This compound inhibits gastric secretion in animals and humans, but its oral absorption is low.

Météamide (IIb). an antagonist of the acidity later discovered, is more powerful than burimamide and is active when administered orally to man, its clinical use is however limited because of its toxicity (agranulocytosis).

Cimetidine (IIc) is as effective as an acid antagonist as is methacrylate, while not leading to agranulocytosis, and has recently been marketed as an anti-malarial drug. -ulcéreux.

 The period (half-life) of cimetidine is relatively short and its therapeutic dose should therefore be formed into tablets in daily doses of 200-300 mg. In fact, it can be inferred from the foregoing that there is a need for anti-ulcer agents that have a longer duration of action and / or action than cimetidine.

dans laquelle::
p est 1 ou 2;
R1 est un groupe hydroxy ou NR2R3
R2 et R3, indépendamment l'un de l'autre, sont des atomes d'hydrogène,
ou des groupes alkyl(inf), alkényl(inf), alkynyl(inf), cycloalkyl(inf),
cycloalkyl(inf)alkyl)inf), hydroxyalkyl(inf), alkoxy(inf)alkyl(inf),
alkylthio(inf)alkyl(inf), aminoalkyl(inf), alkyl(inf)aminoalkyl(inf),
dîalkyl (inf)aminoalkyl (inf), pyrrolidinoalkyl (inf), pipéridinoalkyl(inf),
morpholinoalkyl(inf), piperazinoalkyl(inf), pyridylalkyl(inf), amino,
alkyl(inf)amino, dialkyl(inf)amino, 2,2,2-trifluoroéthyl, 2-fluoroethyl. The present invention relates to histamine hydrogen antagonists which are effective inhibitors of gastric acid secretion in animals, and in humans, which are useful for the treatment of peptic ulcers and which have the following formula or are N-oxides, solvates, hydrates or non-toxic pharmaceutically acceptable salts of compounds having this formula:

in which::
p is 1 or 2;
R1 is a hydroxy or NR2R3 group
R2 and R3, independently of each other, are hydrogen atoms,
or alkyl (inf), alkenyl (inf), alkynyl (inf), cycloalkyl (inf),
cycloalkyl (inf) alkyl) inf, hydroxyalkyl (inf), alkoxy (inf) alkyl (inf),
alkylthio (inf) alkyl (inf), aminoalkyl (inf), alkyl (inf) aminoalkyl (inf),
alkyl (inf) aminoalkyl (inf), pyrrolidinoalkyl (inf), piperidinoalkyl (inf),
morpholinoalkyl (inf), piperazinoalkyl (inf), pyridylalkyl (inf), amino,
alkyl (inf) amino, dialkyl (inf) amino, 2,2,2-trifluoroethyl, 2-fluoroethyl.

hydroxy, alkoxy (inf), 2,3-dihydroxypropyl, cyano, cyanoalkyl (inf),
amidino, alkyl (inf) amido, A '- (CH 2) n' (CH 2) n ', phenyl, phenyl
alkyl (inf), phenyl substituted or phenylalkyl (inf) substituted in
which phenyl ring may contain one or two substituents
chosen, independently of one another, from the alkyl (inf) groups,
hydroxy, alkoxy (inf) and halogen or a substituent selected from
methylenedioxy, trifluoromethyl and dialkyl (inf) amino;
it being understood that R2 and R3 may not simultaneously be a radiator
cycloalkyl (inf), phenyl, substituted phenyl, amino, alkyl (inf)
amino, dialkyl (inf) amino, hydroxy, alkoxy (inf), cyano, amidino, alkyl
(inf) amidino or A '- (CH2) m, Z' (CH2) n, or that R2 and R3, can
together form a group CH2CH2X (CH2) r-,
r being an integer equal to 1, 2 or 3,
X being a methylene radical, a sulfur or oxygen atom or NR4,
it being understood that when r = 1, X is a methylene radical,
R4 being a hydrogen atom or an alkyl radical (inf),
alkenyl (inf), alkynyl (inf), alkanoyl (inf) or benzoyl, m and m 'independently of one another are equal to 0.1 or 2 n and n' independently of one another are equal at 2.3 or 4
Z and Z 'independently of one another are sulfur or oxygen
or a methylene group,
A and A 'are, independently of one another, a phenyl radical, imidazo
lyle, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,
thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl,
it being understood that A and A 'independently of one another may
have 1 or 2 substituents, the first substituent being chosen
in the group of alkyl (inf), hydroxy, trifluoromethyl, halogen,
amino, hydroxymethyl, alkoxy (inf),

and the second substituent being selected from the group alkyl (inf),
hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, and alkoxy (inf).

q is an integer from 0 to 6, inclusive;
R4 each of the groups, independently of each other, are such
indicated above or both groups R4, form between
they are an ethylene radical, and
R5 and R6 independently of one another are a hydrogen atom
or an alkyl (inf), alkenyl (inf), alkynyl (inf), cyclo group
alkyl (inf) or phenyl
R5 and R6 may not be simultaneously a cyclo group
alkyl (inf) or phenyl or R5 and R6, forming with the atom of a
zote to which they are linked a group that can be pyrroli
dino, morpholino, piperidino, methylpiperidino, N-methylpiperate
razino or homopiperidino.

 The subject of the present invention is also processes for the preparation of the compounds of formula I as well as intermediates for the preparation of this compound of formula I.

 The present invention is intended to cover all tautomeric forms, geometric isomers, optical isomers, and zwitterions of the compounds of formula I as well as their welanges.

In the present description and in the claims to which it leads, the term alkyl (inf) and atkenyl (inf) in their broadest sense is understood to mean linear or branched chains of alkyl, alkenyl, alkynyl, alkoxy and alkylthio groups containing from 1 to 12 carbon atoms. Preferably, these groups contain from 1 to 8 carbon atoms and more particularly they contain from 1 to 6 carbon atoms.

By "pharmaceutically acceptable non-toxic salts" is meant not only the acid addition salts but also the alkali and alkaline earth metal salts. The compounds of formula I lead to metal salts, for example potassium, sodium and calcium salts. It seems that these salts are formed by displacement of a proton of a hydroxy group (when R1 = hydroxy) or of one of the nitrogen atoms adjacent to the thiadiazole nucleus, this however being only theory and not limiting in any way. case the scope of the invention.

 In the compounds of formula I, A and A ', independently of one another, are preferably optionally substituted phenyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl radicals. According to one embodiment of the invention A and A ', independently of each other are phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl radicals, optionally substituted.

A and A 'are more particularly guanidino-substituted thiazolyl groups; dialkyl (inf) aminoalkyl (inf) [and more particularly dimethylaminomethyl-substituted] furyl; alkyl substituted imidazolyl (inf) [and preferably methylel; dialkyl (i.nf) aminoalkyl (inf) [and preferably dimethylaminomethyl] substituted thiazolyl; dialkyl (inf) aminoalkyl (inf) [and preferably dimethylaminomethyl] and dialkyl (inf) aminoalkyl (inf) [and preferably dimethylaminomethyl] substituted phenyl.

It is preferred that m = 0 or I and n = 2 or 3. Preferably X is sulfur, oxygen or methylene (preferably sulfur or oxygen). R1 is preferably NR2R3 in which
R2 and R3 are, independently of each other, preferably selected from the group consisting of hydrogen, alkyl (inf), alkenyl (inf), alkynyl (inf) or
A '- (CH2) m'Z (CH2) n'. In a particular embodiment of the invention
R2 and R3 are both hydrogen atoms or methyl groups.

In a particular embodiment of the invention, R2 is a hydrogen atom and R3 is a hydrogen atom or an alkyl (inf) radical [preferably methyl, ethyl or propyl3, alkenyl (inf) [preferably 2- propenyl], alkynyl (inf) [preferably 2-propynyl or A'-CH 2) m, Z '(CH 2) n, m' being preferably 0 or 1 and n 'preferably 2 or 3 while Z 'is preferably a sulfur or oxygen atom and
A 'is preferably a thiazolyl, phenyl or substituted furyl ring [and preferably a guanidino-substituted thiazolyl; phenyl or furyl substituted dimethylaminomethyl].

dans laquelle
R7 est un bon groupe partant, tel qu'un atome halogène, un groupe
phenoxy, phénoxy substitué, phénylthio, phénylthio substitué,
alkoxy, alkylthio et similaires. Les bons groupes partants sont
bien connus de l'homme de l'art. De préférence R7 est un groupe
alkoxy(inf) (plus précisément méthoxy).The compounds of formula I can be prepared by various methods and preferably from a compound of formula

in which
R7 is a good leaving group, such as a halogen atom, a group
phenoxy, substituted phenoxy, phenylthio, substituted phenylthio,
alkoxy, alkylthio and the like. Good starting groups are
well known to those skilled in the art. Preferably R7 is a group
alkoxy (inf) (more precisely methoxy).

 PREPARATION OF RAW MATERIALS.

The starting materials of formula II wherein p = 2 and each R7 group is chloro, methoxy or ethoxy are well known. Their method of preparation can be found in the article: [J.Org. Chem. 40 2743 (1975)]
The starting materials of formula II or p = 2 can be prepared and each R7 group is a substituted alkoxy, alkylthio, phenoxy, phenylthio, phenoxy or phenylthio group (compounds of formula IV and V) by reaction of the dichloro derivative of formula III with alkanol, alkylthiol, phenol, thiophenol, substituted phenol, thiophenol substituted to obtain the corresponding derivative of formula IV or V wherein R8 is alkyl, phenyl or substituted phenyl according to

The reaction is carried out in an inert organic solvent such as: ether, dimethylformamide or the like. If the R80H or R8SH reagent is liquid, for example, methanol, methanol, ethyl mercaptan or thiophenol, the reaction can be carried out in excess reagent as a solvent. Corresponding raw materials of formula II or p = 1 (compounds of formula VII and
VIII) can be prepared in the same way from a compound of formula II or each R7 is chlorine (compound VI).

Compound VI is a novel compound but it can be obtained from the well-known 3,4-dihydroxy-1,2,5-thiadiazole-1-oxide, itself pre-prepared according to the method described in the article [Org. Prep. Proc., 1, 255 (1969)] by the same method used to obtain the compound of formula III from 3,4-dihydroxy-1,2,5-thiadiazole 1,1-dioxide [cf. org. Chem.

40, 2743 (1975) 1. The starting materials of formulas VII and VIII are novel compounds, the description of which does not appear anywhere in the art.

According to another embodiment, the raw materials of formulas IV and VII can be prepared by reacting a suitably substituted oxyldimidine ester of formula IX with SCl 2 or S 2 Cl 2 in an inert solvent such as dimethylformamide to form 1,2 Corresponding 5-thiadiazole 3,4-disubstituate of formula X, which is then oxidized to the corresponding oxide of formula VII or to 1,1-dioxide of formula IV.

oxaldiimide esters of formula IX, or R8 is a methyl, ethyl, n-propyl, isopropyl, n-butyl and n-pentyl group are known and their preparation appears in the publication [Chem. Ber., 107, 3121 (1974)].

The corresponding derivatives or R8 is a phenyl radical, optionally substituted with an alkyl (inf), an alkoxy (inf), a halogen or a nitro group can be prepared by a similar process. The derivatives of formula X or R8 is a methyl or ethyl group are described in the article [J. Org. Chem., 40, 2749 (1975)].

 The 1,2,5-thiadiazole ring is reported in the literature to be susceptible to oxidation, whereas the oxidation of thiadiazoles by peracids is usually accompanied by core destruction and sulphate ion formation. that attempts to prepare 1,2,5-thiadiazole 1,1-dioxide by means of peracetic oxidation of the nucleus of the same family leads to elimination of the nucleus. It has surprisingly been found that the 1,2,5-thiadiazole 1-3-4-disubstituted oxides of formula VII and the 1,1-dioxides of formula IV can be obtained easily in good yields by oxidation of the 1,2 Corresponding 3,4-disubstituted 5-thiadiazoles of formula X, with a peracid such as m-chloroperbenzoic acid, in an inert solvent such as chloroform.The preparation of 1,2,5-thiadiazole 1-oxide 3, 4-dimethoxy is described in Example 4, step. The corresponding 1,1-dioxide preparation is described below.

TYPE PROCESS NO.

1,2,5-thiadiazole 111-dioxide 3,4-dimethoxy
A solution of 1,2,5-thiadiazole 3,4-dimethoxy (1.48 g 10.1 mmol) prepared according to the method described in J. Org. Chem., 40, 2749 (1975)] in 20 ml of chloroform in 1 minute to a solution of m-chloroperbenzoic acid (4,119, 20.3 mmol, 85% pure) in 60 ml of chloroform with stirring. After stirring for 1 hour at room temperature, the mixture is refluxed for 8 hours, then stirring is continued for 1 hour at room temperature. The reaction mixture is extracted with an aqueous solution of sodium bicarbonate and then with water, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is treated with methanol and filter to obtain 1.03g of product. Recrystallization from methanol gives the title compound: 200-202 ° C), elemental analysis for crude formula
C4H6N204S gives the following results
CHNS
calculated 26.97 3.39 15.72 18.00
found 26.82 3.18 16.09 18.00
A particularly elegant method has been developed whereby a compound of formula VII can be prepared directly by a one-step reaction from a compound of formula IX by reacting the compound with thionyl chloride. .

This reaction is carried out in an inert organic solvent such as methylene chloride, chloroform or the like. Although the reaction can be done without the addition of base as an acid scavenger, it is preferable to add two basic equivalents to eliminate
HCl formed in the reaction.

This gives a higher yield of compound VII. Suitable bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate and organic bases such as triethylamine, pyridine and the like.

 This process not only makes it possible to skip a step, but it is also more economical in that it avoids the use of expensive oxidation agents, such as m-chloroperbenzoic acid. The reaction can be carried out at a temperature of from about -20 to + 250 ° C and preferably from 0 to about 10 ° C.

 The type n 2 process illustrates a specific mode of preparation of the compound of formula VII wherein R 8 is a methyl group.

TYPE N 2 PROCESS.

1, 2,5-thiadiazole 1-oxide 3,4-dimethoxy
A solution of dimethyl oxaldiimidate (4.0 g, 34.5 mmol) and pyridine (5.71 ml, 5.58 g, 70.6 mmol) in 8 ml of CH 2 Cl 2 was added dropwise to a cooled solution of thionyl chloride. (2.61 ml, 4.259, 34.7 mmol) in 18 ml of CH 2 Cl 2, while flushing with nitrogen, at a rate such that the reaction temperature remains between 0 and 150 ° C.

 After stirring for 20 minutes at room temperature, the reaction mixture is washed with two portions of 11 ml of 0.055N aqueous HCl.

The aqueous phase is extracted with 2 portions of 20 ml of CH 2 Cl 2 and the combined organic phases are dried and evaporated to dryness under reduced pressure. The solid residue is recrystallized from isopropyl alcohol to give 3.0 g of the title compound, mp 137 ° -1390 ° C.

The compounds of formula I can be prepared from the compounds of formula II according to other reaction schemes through several families of new intermediates.
REACTION SCHEME 1

 In Reaction Scheme 1, R9 may be -NR2R3 or -NH (CH2) n, Z '(CH2) m, A'.

If A ', Z', m 'and n "are the same as A, Z, m and n, the reaction can of course be carried out in a single step by reacting the compound of formula II with 2 equivalents of A ( CH2) mZ (CH2) nNH2.

The intermediates of formula XI are all new. Intermediates of formula XII are new except for the compound where p = 2, R7 is methoxy and
R9 is morpholino; this compound is described in the article [J. Org. Chem., 40, 2743 (1975)].

The reactions are carried out in an inert organic solvent; methanol has been found to be a readily available suitable solvent. The reaction temperature is not a critical parameter. Most raw materials are very reactive and it is best to perform the reaction at. a temperature below room temperature, for example 0-10 C. With some less reactive compounds, it is necessary to carry out the reaction at room temperature.

 It is sometimes desirable to raise the temperature of the reaction mixture, for example to 50-600C to complete the reaction.

REACTION SCHEME 2

In Reaction Scheme 2, M is a metal cation, preferably
K +, Li + or Na +. The reaction conditions and the solvents are the same as for reaction scheme 1. All the intermediates of formula XI are new compounds.

REACTION SCHEME 3

 In Reaction Scheme 3, RS is -NR 2 R 3 or -NH (CH 2) n -Z '(CH 2) m A', and X is a conventional leaving group. Suitable leaving groups are, for example, fluoro, chloro, bromo, iodo, -03SR "where R'1 is an alkyl (inf) [e.g. methanesulfonate], optionally substituted aryl [e.g. benzenesulfonate, p-bromobenzenesulfonate] or p-toluenesulfonate], 03SF, acetoxy and 2,4-dinitrophenoxy For convenience and for reasons of economy, it is preferable to use a compound where X is chlorine The reaction conditions for the preparation of the compounds of formula XIII, XIV and XV are the same as in Reaction Scheme 1.

The reaction of the compound of formula XV with A (CH 2) m X can be carried out in any inert organic solvent, such as alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone or the like. It is preferable to carry out the reaction in an alkanol such as methanol, ethanol or isopropanol.

The reaction temperature is not critical; the reaction can be carried out at a temperature between 0 C and 200 C approximately. At low temperature, the reaction is slow; while high temperatures normally lead to less pure products due to decomposition and byproduct formation. Normally, it is preferable to carry out the reaction at room temperature. The reaction of the compound of formula
XV with A (CH2) mX to give the compound of formula Ic is preferably conducted in the presence of a base, which facilitates the reaction by acting as an acid acceptor. Suitable bases are, for example, NaOH,
KOH, LiOH, triethylamine, dimethylaniline, sodium ethoxide and the like. If X is a hydroxyl, the reaction can be carried out in a concentrated mineral acid, for example HCl (see Example 25). All the intermediates of formula XIII, XIV and XV are new compounds.

ou
p est 1 ou 2,
R2 et R3 sont indépendamment l'hydrogène, ou un radical alkyl(inf),
alkenyl(inf), alkynyl(inf), cycloalkyl(inf)alkyl(inf), pyridylal
kyl(inf), A'-(CH2)m'Z'(CH2)n'-, phenylalkyl(inf) ou 3,4-méthylène
dioxybenzyle;
étant entendu que R2 et R3 ne sont pas en même temps A'-(CH2)m,Z'(CH2)n, m et m' sont indépendamment égaux à O ou -1; n et n' sont indépendamment 2 ou 3;
Z et Z' sont indépendamment le soufre, l'oxygène ou un groupe
méthylène;
A et A' sont indépendamment un groupe phényle, imidazolyle, thiazolyle,
furyle, thiényle ou pyridyle;;
étant entendu que A et A', indépendamment peuvent comporter un
ou deux substituants, le premier substituant étant choisi parmi
les alkyl(inf)

According to a preferred embodiment of the invention, the compounds of formula I have the structure

or
p is 1 or 2,
R2 and R3 are independently hydrogen, or an alkyl radical (inf),
alkenyl (inf), alkynyl (inf), cycloalkyl (inf) alkyl (inf), pyridylal
kyl (inf), A '- (CH2) n' (CH2) n-, phenylalkyl (inf) or 3,4-methylene
dioxybenzyle;
it being understood that R2 and R3 are not at the same time A '- (CH2) m, Z' (CH2) n, m and m 'are independently equal to O or -1; n and n 'are independently 2 or 3;
Z and Z 'are independently sulfur, oxygen or a group
methylene;
A and A 'are independently phenyl, imidazolyl, thiazolyl,
furyl, thienyl or pyridyl;
it being understood that A and A 'independently may have a
or two substituents, the first substituent being selected from
the alkyl (inf)

and the second substituent being an alkyl (inf),
the R4 groups are independently hydrogen or
alkyl (inf) or both R4 groups form in
seems an ethylene group and;
R5 and R6 are independently hydrogen or alkyl (inf)
or R5 and R6 taken together and with the nitrogen atom to which
they are fixed, can form a pyrrolidino group, morpholino,
piperidino, methylpiperidino, N-methylpiperazino or homopiped
ridino and consist of this compound, or a non-toxic pharmaceutically acceptable salt or hydrate, solvate or N-oxide.

dans laquelle p est 1 ou 2;
Z est le soufre ou un méthylène
R2 et R3 sont indépendamment des hydrogènes ou des alkyl (inf) ou bien
si R2 est l'hydrogène, R3 peut être aussi un alkenyl(inf), alkynyl(inf),
phenylalkyl(inf), cycloalkyl(inf)alkyl(inf), pyridylméthyle ou

According to another preferred embodiment of the invention, the compounds of formula I have the structure

in which p is 1 or 2;
Z is sulfur or methylene
R2 and R3 are independently hydrogen or alkyl (inf) or
if R2 is hydrogen, R3 can also be alkenyl (inf), alkynyl (inf),
phenylalkyl (inf), cycloalkyl (inf) alkyl (inf), pyridylmethyl or

 and R 13 is hydrogen or methyl, and consists of this compound, or a pharmaceutically acceptable non-toxic salt thereof, or a hydrate, solvate or N-oxide.

dans laquelle
p est égal à 1 ou 2;
Z est le soufre ou le méthylène;
chaque groupe R4est indépendamment l'hydrogène ou un méthyle, ou bien
les deux groupes R4 pris ensemble peuvent former un groupe éthylène, et
R2 et R3 sont, indépendamment l'hydrogène ou un alkyl(inf) ou bien si
R2 est l'-hydrogène, R3 peut être aussi un alkenyl(inf), alkynyl(inf)
pyridylmethyle ou un groupement:

et consistent en ce composé, ou un de ses sels non toxique,pharmaceutiquement acceptabl e, ou hydrate, solvate ou N-oxyde. According to another preferred embodiment of the invention the compounds of formula I have the structure

in which
p is 1 or 2;
Z is sulfur or methylene;
each R4 group is independently hydrogen or methyl, or
the two R4 groups taken together can form an ethylene group, and
R2 and R3 are independently hydrogen or an alkyl (inf) or if
R2 is hydrogen, R3 can also be alkenyl (inf), alkynyl (inf)
pyridylmethyl or a group:

and consists of this compound, or a non-toxic, pharmaceutically acceptable, or hydrate, solvate or N-oxide salt thereof.

dans laquelle
p est égal à 1 ou 2;
Z est le soufre ou un méthylène
R2 et R3 sont indépendamment l'hydrogène ou un alkyl(inf), ou bien si
R2 est l'hydrogène, R3 peut être aussi un alkényl(inf), un alkynyl(inf)
ou

According to another preferred embodiment of the invention, the compounds of formula I have the structure

in which
p is 1 or 2;
Z is sulfur or methylene
R2 and R3 are independently hydrogen or an alkyl (inf), or if
R2 is hydrogen, R3 may also be alkenyl (inf), alkynyl (inf)
or

 and R13 is hydrogen or methyl and consists of this compound, or a non-toxic pharmaceutically acceptable salt thereof, or hydrate, solvate or N-oxide.

dans laquelle
p est égal a 1 ou 2;
Z est le soufre ou un méthylène
R2 et R3 sont indépendamment l'hydrogène ou un alky(inf) ou bien, si
R2 est l'hydrogène, R3 peut être aussi un alkenyl(inf), alkynyl(inf)
phénylal kyl (inf), pyridylméthyle, 3,4-méthylénédioxybenzyle ou

According to another preferred embodiment of the invention, the compounds of formula I have the structure

in which
p is 1 or 2;
Z is sulfur or methylene
R2 and R3 are independently hydrogen or an alkyl (inf) or, if
R2 is hydrogen, R3 can also be alkenyl (inf), alkynyl (inf)
phenylal kyl (inf), pyridylmethyl, 3,4-methylenedioxybenzyl or

 and R13 is hydrogen or methyl and consists of this compound, or a non-toxic pharmaceutically acceptable salt thereof, or hydrate, solvate or N-oxide.

dans laquelle
p est égal à 1 ou 2 ; et
R et R sont indépendamment l'hydrogène ou un alkyl(inf) ou bien si
R2 est l'hvdroqène R3 Deut être aussi un alkenyl(inf), alkynyl(inf) ou

et consistent en ce composé, ou un de ses sels non toxique, pharmaceutiquement acceptable, ou hydrate, solvate ou N-oxyde.According to another preferred embodiment of the invention, the compounds of formula I have the structure

in which
p is 1 or 2; and
R and R are independently hydrogen or an alkyl (inf) or if
R2 is the hydrogen R3 D can also be an alkenyl (inf), alkynyl (inf) or

and consists of this compound, or a non-toxic, pharmaceutically acceptable, or hydrate, solvate or N-oxide salt thereof.

dans laquelle
p est égal à 1 ou 2;
Z est le soufre ou un méthylène
R2 et R3 sont indépendamment l'hydrogène ou un alkyl(inf) ou bien si
R2 est l'hydrogène, R3 peut être aussi un alkenyl(inf), alkynyl(inf) ou

According to another preferred embodiment of the invention, the compounds of formula I have the structure -

in which
p is 1 or 2;
Z is sulfur or methylene
R2 and R3 are independently hydrogen or an alkyl (inf) or
R2 is hydrogen, R3 can also be alkenyl (inf), alkynyl (inf) or

 and R5 and R6 are independently hydrogen or an alkyl (inf) and consist of this compound, or a non-toxic, pharmaceutically acceptable salt thereof, or hydrate, solvate or N-oxide.

dans laquelle
p est égal à 1 ou 2
R2 et R3 sont indépendamment l'hydrogène ou un alkyl(inf), ou bien si
R2 est l'hydrogène, R3 peut être aussi un alkényl(inf), alkynyl(inf) ou

According to another preferred embodiment of the invention, the compounds of formula I have the structure

in which
p is 1 or 2
R2 and R3 are independently hydrogen or an alkyl (inf), or if
R2 is hydrogen, R3 may also be alkenyl (inf), alkynyl (inf) or

and R5 and R6 are independently hydrogen or
alkyl (inf) or, if R5 is hydrogen, R6 can
be also an alkenyl (inf) or an alkynyl (inf) or
5 and R6 taken together with the nitrogen atom to which they
are bound can form a pyrrolidino group, morpholino,
piperidino or homopiperidino and consist of this compound, or a non-toxic, pharmaceutically acceptable salt, or hydrate, solvate or N-oxide.

The most particularly preferred compounds according to the present invention are the following: a) 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1-dioxide, b) 3- {2 - [(5-dimethylaminomethyl-2-furyl) -methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1-oxide, c) 3- {2 - [(5-dimethylaminomethyl-2-furyl) -methylthio] ethylamino} -4
ethylamino-1,2,5-thiadiazole 1-1-dioxide, d) 3- {2- (5-dimethylaminomethyl-2-furyl) methylthiolethylamino} -4
(n-propyl) amino-1,2,5-thiadiazole 1,1-dioxide, e) 3-allylanyl-4-yl- (5-diniethylaminomethyl-2-furyl) methylthiol
ethylamino} -1,2,5-thiadiazole 1,1-dioxide; f) 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthiolethylamino} -4
(2-propynyl) amino-1,2,5-thiadiazole 1,1-dioxide, g) 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4
amino-1,2,5-thiadiazole 1,1-dioxide, h) 3- {2- (5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4
amino-1,2,5-thiadiazole 1-oxide, i) 3- {2 - [(5-dimethylaminomethyl) -2-furyl) methylthio] ethylamino} -4
dimethylamino-1,2,5-thiadiazole 1,1-dioxide, j) 3- {4- (5-dimethylamino-2-furyl) butylamino} -4-methylamino-1,2,5
thiadiazole 1,1-dioxide, k) 3,4-bis {2 - [(5-dimethylaminomethyl-2-furyl) methylthiolethylamino}
1,2,5-thiadiazole 1,1-dioxide, 1) 3- {2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -4-methylamino
1,2,5-thiadiazole 1,1-dioxide, m) 3- {2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -4- (2-propynyl)
amino-1,2,5-thiadiazole 1,1-dioxide, n) 3- {2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -4- {2 - [(5
methyl-1H-imidazol-4-yl) methylthio] ethylamino} -1,2,5-thiadiazole
1,1-dioxide, o) 3-f2 - [(2-guanidinothiazol-4-yl) methylthiol-ethylamino} -4-amino-
1,2,5-thiadiazole 1,1-dioxide, p) 3- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1-dioxide, q) 3- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1-dioxide, r) 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4
ethylamino-1,2,5-thiadiazole 1-oxide,
s) 3- {2 - [(5-methylaminomethyl-2-furyl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1 dioxide,
t) 3-amino-4-f2-L (2-guanidinothiazol-4-yl) methylthio] ethylamino
1,2,5-thiadiazole 1-oxide,
u) 3-Benzylamino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio}
ethylamino-1,2,5-thiadiazole 1,1-dioxide,
v) 3- (2 - [(3- (dimethylaminomethylphenylmethylthiolethylamino) -4-
methylamino-1,2,5-thiadiazole 1,1 dioxide,
w) 3-amino-4- {2 - [(3- {dimethylaminomethyl} phenyl) methylthio] ethylamino}
-1,2,5-thiadiazole 1-oxide,
x) 3- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthiolethylamino} -4
methylamino-1,2,5-thiadiazole 1-oxide, y) 3-amino-4- {4- (5-dimethylaminomethyl-2-furyl) -butylamino} 1,2,5
thiadiazole 1,1-dioxide,
z) 3-amino-4- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio} ethyl
amino) -1,2,5-thiadiazole 1,1-dioxide, aa) 3-butylamino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl
amino3-1,2,5-thiadiazole 1,1-dioxide, bb) 3-cyclopropylmethyl-4- {2 - [(5-dimethylaminomethyl-2-furyl) methyl
thio] ethylamino} -1,2,5-thiadiazole 1,1-dioxide, cc) 3- {2- (5-dimethylaminomethyl-2-furyl) methylthio ethylamino-4-
(2-pyridyl) methylamino-1,2,5-thiadiazole 1,1-dioxide, dd) 3-amino-4- {2- [5-dimethylaminomethyl-2-thienyl) -methylthio] ethyl
aminol-1,2,5-thiadiazole 1,1-dioxide, ee) 4-f2-L (5-dimethylaminomethyl-2-thienyl) -methylthiolethylamino} -3-
(1-propylamino) -1,2,5-thiadiazole 1,1-dioxide, ff) 3-f2-E (2-guanidinothiazol-4-yl) methylthiolethylaminol-4-methylamino
1,2,5-thiadiazole 1-oxide, gg) 3-amino-4- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethyl
amino-1,2,5-thiadiazole 1-oxide, hh) 3- [3- (3-dimethylaminomethylphenoxy) propylamino] -4-methylamino
1,2,5-thiadiazole 1,1 dioxide, ii) 3-benzylamino-4- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthiolethyl)
amino} -1,2,5-thiadiazole 1,1-dioxide, (i) 4- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -3
(3-pyridyl) methylamino-1,2,5-thiadiazole 1,1-dioxide,
kk) 3- {2 - [(2- {2,3-dimethylguanidino} thiazol-4-yl} methylthio] ethyl
amine) -4-methylamino-1,2,5-thiadiazole 1,1-dioxide,
II) 3-amino-4- {2 - [(2- {2,3-dimethylguanidino} thiazol-4-yl) methyl
thio] ethylamino} -1,2,5-thiadiazole 1-oxide,
mm) 3-amino-4- [3- (3-dimethylaminomethylphenoxy) propylamino] -1.2.5
thiadiazole 1-oxide,
nn) 3- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthiolethylamino} -4
(2-pyridyl) methylamino 01,2,5-thiadiazole 1,1-dioxide,
oo) 3,4-bis- {2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -1.2.5
thiadiazole 1-oxide,
pp) 3-amino-4- {2 - [(2- (2-methylguanidino} thiazol-4-yl) methylthio] ethylamino) -1,2,5-thiadiazole 1 oxide,
qq) 3-methylamino-4- [3- (3) piperidinomethylphenoxy) -propylamino] 1,2,5
thiadiazole 1,1-dioxide,
rr) 3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5
thiadiazole 1-oxide,
ss) 3- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -4
ethylamino-1,2,5-thiadiazole 1,1-dioxide,
tt) 3-amino-4- [3- (30-piperidinomethylphenoxy) -propylamino] -1,2,5
thiadiazole 1,1-dioxide,
uu) 3-f2 - [(5-diniethylaminomethyl-2-thienyl) methylthio] ethylamino4
[(4-pyridyl) methylaminol-1,2,5-thiadiazole 1,1 dioxide.

dans laquelle
R7 est un groupe partant tel qu'un halogène, alkoxy(inf), alkylthio(inf)
et phénoxy ou phénylthio éventuellement porteurs d'1 ou 2 substituants
choisis parmi les halogènes, les groupes alkyl(inf), alkoxy(inf) et
nitro.The present invention also relates to new raw materials of formula

in which
R7 is a leaving group such as halogen, alkoxy (inf), alkylthio (inf)
and phenoxy or phenylthio optionally carrying 1 or 2 substituents
selected from halogens, alkyl (inf), alkoxy (inf) and
nitro.

According to a preferred embodiment of the compounds of formula IIa,
R7 is alkoxy (inf), phenoxy, substituted phenoxy;
preferably, R7 is a methoxy group.

dans laquelle
p est egal à 1 ou 2;
R7 est un groupe partant tel qu'un halogene, un groupe alkoxy(inf)
alkylthio(inf), phénoxy, phenylthio, phenoxy substitué et phénylthio
substitué dont le noyau phényle peut comporter 1 ou 2 substituants
tels qu'un halogène, alkyl(inf), alkoxy(inf) et nitro; et
R12 est A(CH2)mZ(CH2)nNH-, R2R3N- ou HS(CH2)nNH-;
ou R2 et R3 sont indépendamment l'hydrogène, un groupe alkyl(inf)
alkényl(inf), alkynyl(inf), cycloalkyl(inf), cycloalkyl(inf)alkyl(inf),
hydroxyalkyl(inf), alkoxy(inf)alkyl(inf), alkylthio(inf)alkyl(inf),
aminoalkyl(inf), alkyl(inf)aminoalkyl(inf), dialkyl(inf)aminoalkyl
(inf) , pyrrolidinoalkyl(inf), piperidinoalkyl(inf), morpholinoalkyl
(inf), piperazinoalkyl(inf), pyridylalkyl(inf, amino, alkyl(inf)amino,
dialkyl(inf)amino, 2,2,2-trifluoroéthyl, 2-fluoroethyl, hydroxy,
alkoxy(inf), 2,3-dihydroxypropyl, cyano, cyanoalkyl(inf), amidino,
alkyl(inf)amidino, A'-(CH2)m'Z'(CH2)n'-' phényle, phénylalkyl(inf),
phényle substitue ou phénylalkyl(inf) substitué dont le cycle phényle
peut comporter un ou deux substituants choisis indépendamment parmi
alkyl(inf), hydroxy, alkoxy(inf) et halogène, ou un substituant
choisi parmi méthylénedioxy, trifluorométhyle et dialkyl(inf)amino;
entendu que R2 et R3 ne sont pas en même temps cycloalkyl(inf),
phényle, phényle substitué, amino, alkyl(inf)amino, dialkyl(inf)amino,
hydroxy, alkoxy(inf), cyano, amidino3 alkyl(inf)amidino ou
A'-(CH2)m'Z'(CH2)n'-, ou bien, R2 et R3, forment ensemble
-CH2CH2X(CH2)r- ;
r est un nombre entier égal à 1, 2 ou 3,
X est le méthylène, le soufre , l'oxygène ou N-R4;;
etant entendu que si p=2 et R7 est un méthoxy, R2 et R3 pris ensemble
avec l'atome d'azote auquel ils sont lies ne forment pas un groupe
morpholino, et que si r=1, X est un méthylène;
R4 est l'hydrogène, alkyl(inf), alkenyl(inf), alkynyl(inf)
alkanoyl(inf) ou benzoyle
m et m' sont indépendamment un nombre entier égal à 0,1 ou 2 n et n' sont indépendamment des nombres entiers égaux
à 2, 3 ou 4,
Z et Z' sont indépendamment S, O ou -CH2
A et A' indépendamment, sont des groupes phényle, imida
zolyle, thiazolyle, isothiazolyle, oxazolyle, isoxazolyle,
triazolyle, thiadiazolyle, oxadiazolyle, furyle, thiényle
ou pyridyle et A et A' peuvent comporter indépendamment
un ou deux substituants,
le premier substituant étant un groupe alkyl(inf), hydroxy,
trifluorométhyle, halogene, amino, hydroxyméthyle,
alkoxy(inf)

The present invention also relates to new intermediates of formula

in which
p is 1 or 2;
R7 is a leaving group such as a halogen, an alkoxy (inf) group
alkylthio (inf), phenoxy, phenylthio, substituted phenoxy and phenylthio
substituted whose phenyl ring may contain 1 or 2 substituents
such as halogen, alkyl (inf), alkoxy (inf) and nitro; and
R12 is A (CH2) mZ (CH2) nNH-, R2R3N- or HS (CH2) nNH-;
or R2 and R3 are independently hydrogen, an alkyl group (inf)
alkenyl (inf), alkynyl (inf), cycloalkyl (inf), cycloalkyl (inf) alkyl (inf),
hydroxyalkyl (inf), alkoxy (inf) alkyl (inf), alkylthio (inf) alkyl (inf),
aminoalkyl (inf), alkyl (inf) aminoalkyl (inf), dialkyl (inf) aminoalkyl
(inf), pyrrolidinoalkyl (inf), piperidinoalkyl (inf), morpholinoalkyl
(inf), piperazinoalkyl (inf), pyridylalkyl (inf, amino, alkyl (inf) amino,
dialkyl (inf) amino, 2,2,2-trifluoroethyl, 2-fluoroethyl, hydroxy,
alkoxy (inf), 2,3-dihydroxypropyl, cyano, cyanoalkyl (inf), amidino,
alkyl (inf) amidino, A '- (CH 2) n' (CH 2) n -phenyl, phenylalkyl (inf),
substituted phenyl or substituted phenylalkyl including phenyl ring
may have one or two substituents independently selected from
alkyl (inf), hydroxy, alkoxy (inf) and halogen, or a substituent
selected from methylenedioxy, trifluoromethyl and dialkyl (inf) amino;
understood that R2 and R3 are not at the same time cycloalkyl (inf),
phenyl, substituted phenyl, amino, alkyl (inf) amino, dialkyl (inf) amino,
hydroxy, alkoxy (inf), cyano, amidino3 alkyl (inf) amidino or
A '- (CH2) n' (CH2) n- or R2 and R3 form together
-CH2CH2X (CH2) r-;
r is an integer equal to 1, 2 or 3,
X is methylene, sulfur, oxygen or N-R4;
it being understood that if p = 2 and R7 is methoxy, R2 and R3 taken together
with the nitrogen atom to which they are attached do not form a group
morpholino, and that if r = 1, X is methylene;
R4 is hydrogen, alkyl (inf), alkenyl (inf), alkynyl (inf)
alkanoyl (inf) or benzoyl
m and m 'are independently an integer equal to 0.1 or 2 n and n' are independently of equal integers
at 2, 3 or 4,
Z and Z 'are independently S, O or -CH 2
A and A 'independently are phenyl, imida
zolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl
or pyridyl and A and A 'may independently
one or two substituents,
the first substituent being an alkyl (inf), hydroxy,
trifluoromethyl, halogen, amino, hydroxymethyl,
alkoxy (inf)

and the second substituent being an alkyl group (inf),
hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl
and alkoxy (inf).

q is an integer between 0 and 6 terminals
included
R4 independently are as above or both groups
R4 are interconnected to form an ethylene group;
and
R5 and R6 are independently hydrogen, a radical
alkyl (inf), alkenyl (inf), alkynyl (inf), cycloalkyl (inf),
or phenyl
it being understood that R5 and R6 are not at the same time
cycloalkyl (inf) or phenyl groups, or
R5 and R6 taken together with the azepte atom to which they
are linked, form a pyrrolidino cycle, morpholino,
piperidino, methylpiperidino, N-methylpiperazino or
homopiperidino; and consist of this compound, or a salt thereof, or hydrate, solvate or
N-oxide.

According to a more particularly preferred embodiment of the compounds of formula XVI,
R12 is A (CH3) mZ (CH2) nNH with
A is a phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl group, each of which may have one or two substituents, the first substituent being an alkyl radical (inf)

and the second substituent being an alkyl radical (inf)
Z is sulfur, oxygen or methylene;
m is 0 or 1;
n is 2 or 3;
the groups R4 independently are hydrogen, or alkyl (inf)
or the two R4 groups are linked together to form a
ethylene groups;
R5 and R6 taken independently, are hydrogen or a radical
alkyl (inf) or R5 and R6 taken together with the nitrogen atom
to which they are attached, form a pyrrolidino group, morpholino,
piperidino, methylpiperidino, N-methylpiperazino or homopiperidino; and R7 is an alkoxy (inf)
According to another more particularly preferred embodiment of the compounds of formula XVI
R12 is R2R3Navec
R2 and R3 are independently hydrogen, alkyl (inf), alkenyl (inf),
alkynyl (inf), cycloalkyl (inf) alkyl (inf), pyridylalkyl (inf),
A '- (CH 2) n' (CH 2) n -, phenylalkyl (inf) or 3,4-methylenedioxybenzyl
it being understood that R2 and R3 can not be at the same time
A '- (CH2) n' (CH2) n-;
m 'is equal to O or 1;
n 'is 2 or 3;
Z 'is sulfur, oxygen or methylene; ;
A 'is phenyl, imidazolyl, thiazolyl, furyl, thienyl
or pyridyl, each of these groups may include one or
two substituents
the first substituent being selected from alkyl (inf)

avec
Z est le soufre ou le groupe méthylène et
R18 est l'hydrogène ou le groupe méthyle et R7 est un groupe alkoxy(inf)
Selon un autre mode de réalisation particulièrement préferé des composés de formule XVI

avec
Z est un atome de soufre ou le groupe méthylène
les groupes R4sont indépendamment l'hydrogène ou le méthyle ou bien les
deux groupes R4 pris ensemble, forment un groupe éthylène et R7 est un groupe alkox(inf)
Selon un autre mode de réalisation particulièrement préféré des composés de formule XVI,

avec
R'Best l'hydrogène ou le méthyle;;
Z est le soufre ou un groupe méthylène et R7 est un groupe alkoxy(inf)
Selon un autre mode de réalisation particulierement préféré des composés de formule XVI

avec
R13 est l'hydrogène ou le méthyle
Z est le soufre ou un groupe méthylène et R7 est un groupe alkoxy(inf)
Selon un autre mode de réalisation particulièrement préféré des composés de formule XVI

avec
R5 et R6 sont indépendamment l'hydrogène ou un groupe alkyl(inf)
Z est le soufre ou le groupe méthylène et R7 est un groupe alkoxy(inf)
Selon un autre mode de réalisation particulierement préferé des composés de formule XVI

avec
R5 et R6 sont indépendamment l'hydrogène ou un groupe alkyl(inf) ou si
R5 est l'hydrogene, R6 peut être aussi un groupe alkenyl(inf) ou alky
nyl(inf); ou bien R5 et R6, pris ensemble avec l'atome d'azote auquel
ils sont liés, peuvent former un groupe pyrrolidino, morpholino, pipé
ridino ou homopipéridino et R7 est un groupe alkoxy(inf)
La présente invention a, de plus, pour objet des nouveaux intermédiaires de formule

dans laquelle
p est égal à 1 ou 2
n est un nombre entier compris entre 2 et 4, bornes comprises
R2 et R3 sont indépendamment l'hydrogène, un radical alkyl(inf), alkenyl(inf),
alkynyl(inf), cycloalkyl(inf), cycloalkyl(inf)alkyl(inf), hydroxyalkyl(inf),
alkoxy(inf)alkyl(inf), alkyl(inf)thioalkyl(inf), aminoalkyl(inf),
alkyl(inf)aminoalkyl(inf), dialkyl(inf)aminoalkyl(inf), pyrrolidinoalkyl(inf)
piperidinoalkyl(inf), morpholinoalkyl (inf), piperazinoalkyl (inf) pyri
dylalkyl(inf), amino, alkyl(inf)amino, dialkyl(inf)amino, 2,2,2-trifluo
roéthyle, 2-fluoroethyle, hydroxy, alkoxy(inf), 2,3-dihydroxypropyl,
cyano, cyanoalkyl(inf), amidino, alkyl(inf)amidino, A'-(CH2)m'Z'(CH2)n'-,
phényle, phénylaîkyl (inf), phényle substitué ou phénylalkyl(inf)
substitué dont le cycle phényle peut comporter un ou deux substituants
choisis indépendamment parmi les groupes alkyl(inf), hydroxy, alkoxy(inf)
et les halogènes ou un substituant choisi parmi les groupes méthyléne
dioxy, trifluorométhyle et dialkyl(inf)amino
étant entendu que R2 et R3 ne sont pas en même temps des groupes
cycloalkyl(inf), phényle, phényle substitué, amino, alkyl(inf)amino,
dialkyl(inf)amino, hydroxy, alkoxy(inf), cyano, amidino, alkyl(inf)amidino
ou A'-(CH2)m,Z'(CH2)n,- ou bien R2 et R3 pris ensemble, peuvent former
un groupe -CH2CH2X(CH2) r
r est un nombre entier égal à 1, 2 ou 3
X est un méthylène, le soufre , l'oxygène ou N-R4 étant entendu
que si r=1, X est le méthylène
R4est l'hydrogène, un groupe alkyl(inf), alkényl(inf), alky
nyl(inf), alkanoyl(inf) ou benzoyle m' est un nombre entier égal à 0, 1 ou 2; n' est un nombre entier égal à 2, 3 ou 4;
Z'est lesoufre,l'oxygène ou le groupe méthylène ;
A' est un groupe phényle, imidazoyle, thiazolyle, isothia
zolyle, oxazolyle, isoxazolyle, triazolyle, thiadiazolyle,
oxadiazolyle, furyle, thiényle ou pyridyle
étant entendu que A' peut porter un ou deux substituants
le premier substituant étant un groupe alkyl(inf), hydroxy,
trifluorométhyle, halogène, amino, hydroxyméthyle, alko
xy(inf)

the R4 groups are independently hydrogen or
alkyl groups (inf) or both groups R4 form
together an ethylene group;
R5 and R6 are independently hydrogen or a radical
alkyl (inf) or R5 and R6 together with the atom
of nitrogen to which they are attached form a pyrrolidino group,
morpholino, piperidino, methylpiperidino, N-methylpiperazino,
or homopiperidino and, and R7 is an alkoxy group (inf)
According to another embodiment of the compounds of formula XVI
R12 is HS (CH2) nNH with
n is an integer between 2 and 4 and R7 is an alkoxy group (inf)
According to another particularly preferred mode compounds of formula XVI

with
Z is sulfur or the methylene group and
R18 is hydrogen or methyl and R7 is alkoxy (inf)
According to another particularly preferred embodiment of the compounds of formula XVI

with
Z is a sulfur atom or the methylene group
the R4 groups are independently hydrogen or methyl or the
two R4 groups taken together form an ethylene group and R7 is an alkox (inf) group
According to another particularly preferred embodiment of the compounds of formula XVI,

with
R'B is hydrogen or methyl;
Z is sulfur or a methylene group and R7 is an alkoxy group (inf)
According to another particularly preferred embodiment of the compounds of formula XVI

with
R13 is hydrogen or methyl
Z is sulfur or a methylene group and R7 is an alkoxy group (inf)
According to another particularly preferred embodiment of the compounds of formula XVI

with
R5 and R6 are independently hydrogen or an alkyl group (inf)
Z is sulfur or the methylene group and R7 is an alkoxy group (inf)
According to another particularly preferred embodiment of the compounds of formula XVI

with
R5 and R6 are independently hydrogen or an alkyl group (inf) or
R5 is hydrogen, R6 can also be alkenyl (inf) or alkyyl
nyl (inf); or R5 and R6 taken together with the nitrogen atom to which
they are linked, can form a pyrrolidino group, morpholino, piped
ridino or homopiperidino and R7 is an alkoxy group (inf)
The subject of the present invention is, moreover, novel intermediates of formula

in which
p is 1 or 2
n is an integer between 2 and 4 inclusive
R2 and R3 are independently hydrogen, alkyl (inf), alkenyl (inf),
alkynyl (inf), cycloalkyl (inf), cycloalkyl (inf) alkyl (inf), hydroxyalkyl (inf),
alkoxy (inf) alkyl (inf), alkyl (inf) thioalkyl (inf), aminoalkyl (inf),
alkyl (inf) aminoalkyl (inf), dialkyl (inf) aminoalkyl (inf), pyrrolidinoalkyl (inf)
piperidinoalkyl (inf), morpholinoalkyl (inf), piperazinoalkyl (inf) pyri
dylalkyl (inf), amino, alkyl (inf) amino, dialkyl (inf) amino, 2,2,2-trifluoro
roethyl, 2-fluoroethyl, hydroxy, alkoxy (inf), 2,3-dihydroxypropyl,
cyano, cyanoalkyl (inf), amidino, alkyl (inf) amidino, A '- (CH2) n' (CH2) n-,
phenyl, phenylalkyl (inf), substituted phenyl or phenylalkyl (inf)
substituted whose phenyl ring may contain one or two substituents
independently selected from alkyl (inf), hydroxy, alkoxy (inf)
and halogens or a substituent selected from methylene groups
dioxy, trifluoromethyl and dialkyl (inf) amino
it being understood that R2 and R3 are not at the same time groups
cycloalkyl (inf), phenyl, substituted phenyl, amino, alkyl (inf) amino,
dialkyl (inf) amino, hydroxy, alkoxy (inf), cyano, amidino, alkyl (inf) amidino
or A '- (CH2) m, Z' (CH2) n, - or R2 and R3 taken together, may form
a group -CH2CH2X (CH2) r
r is an integer equal to 1, 2 or 3
X is methylene, sulfur, oxygen or N-R4 being understood
that if r = 1, X is methylene
R4is hydrogen, alkyl (inf), alkenyl (inf), alkyl
nyl (inf), alkanoyl (inf) or benzoyl m 'is an integer of 0, 1 or 2; n 'is an integer equal to 2, 3 or 4;
Z is sulfur, oxygen or the methylene group;
A 'is phenyl, imidazoyl, thiazolyl, isothia
zolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,
oxadiazolyl, furyl, thienyl or pyridyl
it being understood that A 'may carry one or two substituents
the first substituent being an alkyl (inf), hydroxy,
trifluoromethyl, halogen, amino, hydroxymethyl, alko
xy (inf)

and the second substituent is an alkyl (inf), hydroxy,
trifluoromethyl, halogen, amino, hydroxymethyl and alkoxy
xy (inf) ;;
q is an integer between 0 and 6, terminals
included
the groups R4, independently, are as defined
above or both groups R4, taken together,
form a methylene group, and
R5 and R6 are independently hydrogen, a group
alkyl (inf), alkenyl (inf), alkynyl (inf), cycloalkyl (inf)
or phenyl
it being understood that R5 and R6 are not at the same time
cycloalkyl (inf) or phenyl groups or R5 and
R6, taken together with the nitrogen atom to which they
attach, can form a pyrrolidino group,
morpholino, piperidino, methylpiperidino, N-methylpiperate
razino or homopiperidino and consist of this compound, or a salt thereof, or hydrate, solvate or
N-oxide.

According to a preferred embodiment of compounds of formula XVII
R2 and R3 are independently hydrogen, an alkyl group (inf),
alkenyl (inf), alkynyl (inf), cycloalkyl (inf) alkyl (inf), phenylalkyl (inf),
pyridylalkyl (inf), 3-4-methylenedioxybenzyl or A '(CH2) m, Z' (CH2) n, -i being understood that R2 and R are not at the same time A '- (CH2) n' ( CH2) n',
m 'is an integer equal to 0, 1 or 2;
n and n 'are independently an integer of 2, 3 or 4; ;
Z 'is sulfur, oxygen or methylene group
Al is phenyl, imidazolyl, thiazolyl, furyl,
thienyl or pyridyl, each of which may carry one or two
substituents
the first substituent being an alkyl (inf)

and the second substituent being -alkyl (inf) and
R5 and R6 are independently hydrogen or an alkyl group (inf).

avec
Z est le soufre ou le groupe méthylène et
R13 est l'hydrogene ou le groupe méthyle
Dans la présente description, on entend par l'expression "sel non toxique pharmaceutiquement acceptable", un sel de composé de formule I avec un acide organique ou mineral non toxique pharmaceutiquement acceptable.According to another preferred embodiment of the compounds of formula
XVII
n = 2
R2 and R3 are independently hydrogen, alkyl (inf), alkenyl (inf),
alkynyl (inf) and phenylalkyl (inf) or if R2 is hydrogen, R3 can
be

with
Z is sulfur or the methylene group and
R13 is hydrogen or methyl group
As used herein, the term "pharmaceutically acceptable nontoxic salt" means a salt of the compound of formula I with a pharmaceutically acceptable non-toxic organic or mineral acid.

 These acids are well known: they are hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, ethanedisulphonic, benzenesulfonic, acetic, propionic, tartaric, citric, camphosulphonic, and the like. .

 The salts are prepared according to well known methods. It may be noted that some of the compounds of formula I and the intermediates described in this patent can form double or triple salts etc.

It is understood that the salts of the intermediates are not limited to salts with pharmaceutically acceptable non-toxic acids when said intermediates are not used themselves as medicaments.

 It has been found that the number of compounds of formula I of the present invention strongly retain the solvent from which they are recrystallized. In some cases, it appears that the products are true solvates while in other cases the products can retain mainly adventitious solvent or, to form a mixture of solvate with adventitious solvent.

Although it is possible to remove the solvent by drying at elevated temperature, this often has the effect of transforming a well crystallized product into a rubbery solid. Since solvated products generally have sharp melting points, it is common practice to dry the products at room temperature. If retained solvent remains, even after prolonged drying, the solvent content is measured using a suitable method such as NMR. In the examples below, the solvent content (where applicable) is given; the analysis and the melting point correspond to the solvated products, unless otherwise indicated.

 For therapeutic use, the pharmacologically active compound of the invention is normally administered in the form of a pharmaceutical composition containing, as active ingredients, at least one such compound in base form or in the form of a non-toxic acid salt, pharmaceutically acceptable, in combination with a pharmaceutically acceptable carrier.

 The pharmaceutical compositions may be administered orally, parenterally or rectally. A wide range of pharmaceutical forms can be used. Thus, when a solid carrier is used, the preparation may be put in the form of pills, introduced into a hard gelatin capsule in the form of powder or granules or in the form of pellets or tablets. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an aqueous or non-aqueous medium. The pharmaceutical compositions are prepared using standard techniques appropriate to each preparation.

 Preferably, each unit dose contains the active ingredient in an amount of from 0.5 to 150 mg and preferably from 2 mg to about 50 mg.

Preferably, the active ingredient is administered in equal doses two to four times daily. The daily dosage is preferably between 1 and 600 mg and preferably from 4 to 200 mg.

 Histamine H2-receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals and humans according to Brimblecombe et al. fJ. Int. Med. Res., 3, 86 (1975)]. Clinical evaluations of a histamine H2 receptor antagonist, cimetidine, have been shown to be an effective therapeutic agent in the treatment of peptide ulcer disease, according to Gray et al., [Lancet, 1, 8001 (1977)]. One of the standard animal models for determining antisecretory activity on the stomach of histamine H2 antagonists is that of rats with ligated pyres.

In Table I, ED50 gastric antisecretory doses (in pmol / kg), in the rat with ligated pylorus, were recorded for a large number of compounds of the present invention.

DETERMINATION OF THE ACTIVIST GASTRIC ANTISECRIST AT THE RAT HAS SUFFERED
A TWO-HOUR PYLORE LIGATURE (SHAY)
The method of pylorus ligation in rats has been developed by Shay et al., [Gastroenterology, 5, 53 (1945)] to study perforating gastric ulcers; however, as soon as the method was published, it was used as a means of studying gastric secretion in rats [cf.

Shay et al. , Gastroenterology, 26, 906 (1954), Brodie, D., A. Am. J. Dig.

Dis. 11, 231 (1966)]. A variant of this method has been used here to study antisecretory activity on the stomach.

 Male Long Evans rats weighing 280-3009 are used.

The animals are placed in individual cages and fasted for 24 hours by free access to water. Under ether anesthesia, the stomach is accessed by an incision at mid-height and a ligation is carried out with a cotton thread around the pylorus. After closing the wound, the patient is stopped. administration of the ether and administering the test compound or the control vector, either intraperitoneally or subcutaneously, at a rate of 1 ml / kg body weight. All compounds are solubilized with one equivalent of HCl and diluted to the desired volume with water. The animals are returned to their cages, from which the bottles of water are removed and sacrificed two hours later to the ether. The stomach is removed and the gastric secretions of the two hours are collected in a graduated cylinder. to measure their volume.

The titratable acidity is measured by neutralizing a sample of 1 ml at pH7 with a solution of 0.02N NaOH, using an autoburette and an electrometric pH meter (radiometer). The secretion of titratable acids into microequivalents is calculated by multiplying the volume in milliliters by the concentration of acid in milliequivalents per liter. The rate of inhibition of acid secretion is calculated as follows

<tb><SEP> tion <SEP> of acid]. <SEP> [secretion <SEP> of acid
<tb> z <SEP> inhibiton <SEP> of <SEP> L <SEP> (control) <SEP><SEP>]<SEP> (under <SEP> drug)
<tb> secretion <SEP> acid <SEP> (secretion <SEP> acid (control)) <SEP> x100
<Tb>
At least 5 rats are used for each dose and at least three different doses are used to establish a response curve as a function of dosage.

In the beginning, this test was performed using intraperitoneal injections of the test compound or the control vector. However, it was later found that the sensitivity of the test was somewhat better when subcutaneous injections were given, and all subsequent tests were performed using the subcutaneous route. The route of administration of each compound was shown in Table I.

 TABLE 1.

EFFECT OF THE COMPOUNDS OF THE PRESENT INVENTION ON SECRETION
GASTRIC ACID IN THE RAT AFTER 2 HOURS OF LIGATURE OF PYLOR

<tb><SEP> Compound of <SEP> Administration <SEP> SEP Path> ED50 *
<tb> Example <SEP> n <SEP> tration <SEP> Dmoles / kg <SEP>
<tb><SEP> 1 <SEP> ip <SEP> 12.5 <SEP> (4.90-33.0)
<tb><SEP> 2 <SEP> sc <SEP> ~ 10
<tb><SEP> 3 <SEP> ip <SEP> 0.46 <SEP> (0.26-0.74)
<tb><SEP> 7 <SEP> ip <SEP> 31.1 <SEP> (11.1-82.8)
<tb><SEP> 11B <SEP> ip <SEP> 0.69 <SEP> (0.31-1.33)
<tb><SEP> 11C <SEP> sc <SEP> 0.20 <SEP> (0.03-2.9)
<tb><SEP> 12 <SEP> ip <SEP> 0.28 <SEP> (0.11-0.69)
<tb><SEP> 13 <SEP> sc <SEP> 0.46 <SEP> (0.02-3.1)
<tb><SEP> 14 <SEP> sc <SEP> ~ 10
<tb><SEP> 17 <SEP> sc <SEP> 33 <SEP> (8.7-141)
<tb><SEP> 18 <SEP> sc <SEP> 0.38 <SEP> (0.02-5.33)
<tb><SEP> 19 <SEP> sc <SEP> 0.34 <SEP> (0.15-0.81)
<tb><SEP> 20A <SEP> sc <SEP> 1.15 <SEP> (0.32-3.7)
<tb><SEP> 21 <SEP> sc <SEP> 0.30 <SEP> (0.09-1.0)
<tb><SEP> 28 <SEP> sc <SEP> 1.39 <SEP> (0.39-4.91)
<tb><SEP> 31 <SEP> ip <SEP> 0.41 <SEP> (0.19-0.81)
<tb><SEP> 32 <SEP> ip <SEP> 0.08 <SEP> (0.03-0.153 <SEP>
<tb><SEP> 33 <SEP> sc <SEP> 0.57 <SEP> (0.16-1.84)
<tb><SEP> 35 <SEP> sc <SEP> 0.08 <SEP> (0.02-0.22)
<tb><SEP> 36 <SEP> sc <SEP> 1.59 <SEP> (0.48-6.46)
<tb><SEP> 52 <SEP> sc <SEP> ~ 350
<tb><SEP> 65 <SEP> sc <SEP>0; 07 <SEP> (0,02-0,32)
<tb><SEP> 85 <SEP> sc <SEP> 0.14 <SEP> (0.05-0.41) <SEP>
<tb><SEP> 86 <SEP> sc <SEP> 0.04 <SEP> (0.015-0.12)
<tb><SEP> 87 <SEP> sc <SEP> 0.02 <SEP> (0.006-0.04)
<tb><SEP> 88 <SEP> sc <SEP> 0.08 <SEP> (0.04-0.22)
<tb><SEP> 89 <SEP> sc <SEP> 0.25 <SEP> (0.07-0.84)
<tb><SEP> 90 <SEP> sc <SEP> 0.86 <SEP> (0.24-2.69) <SEP>
<tb><SEP> 93 <SEP> sc <SEP> 0.14 <SEP> (0.07-0.32
<tb><SEP> 98 <SEP> sc <SEP> 0.52 <SEP> (0.08-2.33
<tb> 104 <SEP> sc <SEP> 0.61 <SEP> (0.15-1.88
<tb> 105 <SEP> sc <SEP> 1.65 <SEP> (0.45-4.45
<tb> 110 <SEP> sc <SEP> 0.05 <SEP> (0.03-0.14)
<tb> 113 <SEP> sc <SEP> 0.07 <SEP> (0.03-0.14)
<tb> 117 <SEP> sc <SEP> ~ 0.5
<tb> 122 <SEP> sc <SEP> ~ 10.0 <SEP>
<tb> 132 <SEP> sc <SEP> --- 0.04 <SEP>
<tb> 133 <SEP> sc <SEP> ~ 0.04 <SEP>
<Tb>
Figures in parentheses are 95% validity limits
Some of the compounds of the present invention were also tested in the guinea pig isolated right atrium test, in the dog gastric fistula (intravenous) test, and in the Heidenhain (oral) dog test; these tests showed that the compounds showed an activity. The first two tests were carried out according to the protocols described in US Pat. No. 4,112,234. The test on the Heidenhain dog was conducted according to the general method of Grossman and Konturek [Gastroenterology, 66, 517 ( 1974) 1.

Celite is a trade name of the Johns-Manville Company
Products Corporation for a diatomaceous earth.

Skellysolve B is a trade name of Skelly Corporation
Oil Company for a fraction of petroleum ether boiling between 60 and 68 C consisting essentially of n-hexane.

In the expression "flash chromatography" used in certain examples is meant a relatively recent chromatographic technique described by
WCStill et al. in J.Org. Chem., 43, 2923-2925 (1978). It uses a more finely divided chromatographic medium than in conventional techniques and pressures somewhat higher than atmospheric pressure in order to obtain faster chromatographic separations.

 In the following examples, all temperatures are in degrees Celsius.

Other objects and advantages of the present invention will appear on reading the following description and non-limiting examples.
EXAMPLE 1

3- {2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamino} -4- (2-propyl
nyL) amino-1,2,5-thiadiazole 1.1-dioxide
A. 3- (2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamino} -4
methoxy-1,2,5-thiadiazole 1,1-dioxide
To a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dio
xyd (2.09, 11.2 mmol) [prepared according to the described process
in J. Org. Chem., 40, 2743 (1975)] in 200 ml of methanol
at room temperature a solution of 2 - [(5-methyl)
1H-imidazol-4-yl) -methylthiolethylamine (from dichlorhy
drate, 2.739; 11.2 mmol) prepared according to Belgian Patent 779 7751
in 25ml of methanol. After 30 minutes of stirring, we obtain
a methanolic solution of the title compound.

Thin layer chromatography (Silica / CH2Cl2: CH30H (90/10)
give Rf = 0.44
B. 3- {2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamino} -4
(2-propynyl) amino-1,2,5-thiadiazole 1,1-dioxide
To a methanolic solution of the product of step A, one adds
7 ml of 2-propynylamine. After 20 minutes of agitation at the time
ambient temperature, the reaction mixture is evaporated under pressure
reduced, the residual oil is placed on silica gel and chromato
flow through a gradient with a chloride mixture
methylene-methanol. The appropriate fractions are combined to
2.74 g of the title compound as an oil.

Further purification is done by combining the subs
above with that obtained in a second test
identical, the mixture is put on silica gel and chromatography is performed
by an elution gradient using a mixture of methylene chloride
methanol. The right fractions are combined with methanol and
evaporated under reduced pressure to obtain the title compound
(2.93 g) as a friable solid (mp: 82-103 ° C); its spectrum
NMR (100 MHz) in dimethyl sulfoxide d6 indicates the presence
1/3 mole of methanol.

The compound obtained has the empirical formula Cl2H16N602S2, 1/3 CH3OH
and his basic analysis leads to the following results
CHNS
calculated: 42.19 4.97 23.95 18.27
found: 42.05 5.05 24.01 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 suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide
(2.5 g, 14.0 mmol) in 250 ml of well-stirred dry methanol and
cooled to 2 C in a bath of ice water, we add drop by drop
in 25 minutes, a solution of 2 - [(5-methyl-1H-imidazol-4-yl)
methylthiolethyl amine (from the dihydrochloride, 3.42 g, 14.0 mmol)
in 25 ml of methanol. After stirring for 20 minutes at 2 ° C.,
Spoon anhydrous methylamine into the solution for 6 minutes
and continue stirring at room temperature for
30 minutes. The reaction mixture is evaporated under reduced pressure
and the residue is placed on 50 g of silica gel, followed by chromatography with
an elution gradient using a mixture of methylene chloride
methanol. We combine the right fractions to get 3.2 g of the com
posed in section. A complementary purification of the product'par
Column chromatography provides an analytic sample
of the title compound as an amorphous solid (mp: 98
110 C). The NMR spectrum (100 MHz) in dimethyl sulfoxide gives
the following peaks: 6: 7.46 (s, 1H); 3.70 (s, 2H); 2.53 (t, 2H); 2.86 (s,
3H); 2.72 (t, 2H) -; 2.15 (s, 3H).

The compound obtained has the following formula: C10H16N602S2
and his basic analysis leads to the following results
CHNS
calculated: 37.96 5.09 26.56 20.27
Found *: 37.79 5.16 26.52 20.24
*
after correction (1.60% @ water)
EXAMPLE 3

3- {2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -4- {2 - [(5-methyl
1H-imidazol-4-yl) methylthio] ethylamino} -1,2,5-thiadiazole 1,1-dioxide
To a solution of 3- {2 - [(5-methyl-1H-imidazol-4-yl) methylthio} ethyl
lamino) -4-methoxy-1,2,5-thiadiazole 1,1-dioxide [prepared from
2 - {(5-methyl-1H-imidazol-4-yl) methylthio} ethyl dihydrochloride
amine (2.73 g, 11.2 mmol) by the method of step A of the Example
vigorously stirring at -100C, a
solution of 2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamine (obd.
from the dihydrochloride, 3.41 g; 11.2 mmol) [Prepared according to the process
of South African Patent No. 78/2129 1 in 35 ml of methanol. After
30 minutes of agitation at. -10 C, let the solution return to the
ambient temperature. The reaction mixture is evaporated under
reduced and the residue is put on 45 μl of silica gel, then
chromatography with 1 liter of methylene chloride-methanol
(4: 1). The right fractions are combined and evaporated. -It sets the
sidu (5.82 g) over 80 g of aluminum oxide and chromatographed on
using an ethyl acetate-methanol elution gradient. We combine
the right fractions, filter on celite, then evaporate under vacuum
grown to obtain the title compound (2.5 g) as a
amorphous solid containing about 2/3 mole of ethyl acetate,
the NMR spectrum (100 MHz) in dimethyl sulfoxide proves it.

The formula of the compound obtained is: C16H24N10O2S4, 2/3 C4H8O2
and his basic analysis leads to the following results
CHNS
calculated: 38.96 5.14 24.34 22.29
found: 39.08 4.96 24.48 22.26
EXAMPLE 4

3- {2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamino} -4-methylamino
1,2,5-thiadiazole 1-oxide
A. 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide
A solution of 3,4-dimethoxy-1,2,5-thiadiazole (35.2 g;
24.1 mmol) prepared according to the method described in J. Org. Chem.
40, 2749 (1975) 1 in 100 ml of chloroform in 3 minutes at
lution of m-chloroperbenzoic acid (50.7 g, 25.0 miloles, 85% pure)
in 900 ml of chloroform, at 20 ° C., with stirring, using
a cooling bath to prevent the exothermic reaction from exceeding
a temperature of 320C. After stirring for 3 hours at room temperature
room temperature, the excess peracid is reacted with an additional 2.0 g
3,4-dimethoxy-1,2,5-thiadiazole and stirring continued
for 1 hour.

The organic solution is extracted using 300 ml portions
of 1% NaHCO 3 solution, washed with 250 ml of water, dried, and then
pore under reduced pressure to obtain 47.0 g of product. By recris
in isopropyl alcohol the compound is obtained
brick (34.0 g). Additional recrystallization in alcohol
isopropyl provides an analytical sample (mp 135 137 ° C).

The compound obtained has the formula
C4H6N203S
and his basic analysis leads to the following results
CHNS
calculated: 29.63 3.72 17.27 19.77
found: 29.53 3.75 17.26 19.83
B. 3- {2 - [(5-methyl-1H-imidazol-4-yl) methylthiol-ethylamino} -4-methylamino
1,2,5-thiadiazole 1-oxide
A solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide is reacted
obtained in step A above with an equimolar amount of
2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamine, the
3- {2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamino} -4-methoxy
1,2,5-thiadiazole 1-oxide obtained from an excess of methylamine, which
provides the title compound.

EXAMPLE 5

3-hydroxy-4- {2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamino} 1,2,5-thiadiazole 1,1-dioxide
When treating a methanolic solution of 3- {2 - [(5-methyl)
1H-imidazol-4-yl) methylthio] ethylamino} -4-methoxy-1,2,5-thiadiazole
1,1-dioxide [prepared according to the method of Step A of Example 1]
with a solution of sodium hydroxide in methanol by the method
of Example 12, step B, the title compound is obtained.
(MP: 263-2650C with decomposition).

The compound obtained has the formula
C9H13N5S2O3
and his basic analysis leads to the following results
CHNS
calculated: 35.64 4.32 23.09 21.13
found: 35.56 4.38 23.01 21.13
EXAMPLE 6

3- {2 - [(5-diméthylaminothy (2-furyl) -4-methylamino} méthylthioléthylamino
1,2,5-thiadiazole 1,1-dioxide and 3,4-bis- {2 - [(5-dimethylaminomethyl-2)
furyl) methylthio] ethylamino} -1,2,5-thiadiazole 1,1-dioxide
A. 3- {2 - [(5-dimethylaminoethyl-2-furyl) methylthio] ethylamino] -4
methoxy-1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylaminomethyl-2-furyl) -methyl
thio] ethylamine (2.41 g, 11.2 mmol) [prepared according to the method of
Belgian patent 857,3881 in 20 ml of anhydrous methanol, both
to a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide
(2.0 g, 11.2 mmol) in 200 ml of methanol at 80 ° C. with stirring
energetic. After stirring for 15 minutes at 8-100 ° C., a
methanol solution of the title compound.

B. 3- {2 - [(5-dimethylaminoethyl-2-furyl) methylthio] ethylamino} -4-methyl
ylamino-1,2,5-thiadiazole-1,1dioxyde.

Anhydrous methylamine is bubbled into the solution
Thanolic cooled to 1 C of the product of Step A for 6 minutes.

Stirring is continued for 10 minutes and the mixture is evaporated.
under reduced pressure. The residue is put on 45 g of silica gel
is chromatographed using a gradient of elution of chloride of
methylene-nièthanol. The good fractions obtained with the mixture
Methylene chloride-methanol (95: 5) are combined in methanol,
filtered on celite, then concentrated under reduced pressure for donation
the product. Recrystallization in methanol gives the com
in section (1.76 g), (mp: 82-90 ° C). The NMR spectrum (100 MHz)
in dimethyl sulfoxide d6 indicates the presence of 2/3 mole of
methanol.

The compound obtained has the empirical formula C1 3H21N503S2.2 / 3CH3OH
and his basic analysis leads to the following results
CHNS
calculated: 43.10 6.26 18.38 16.83
found *: 43.30 6.12 18.57 16.96
*
after correction (1, @@% @ water)
C. 3,4-bis- {2 - [(5-dimethylaminomethyl-2-furyl) methylthiolethylamino}
1,2,5-thiadiazole 1.1-dioxide
The component eluted the least quickly by the mixture methylene chloride
methanol (9 :: 1) from the chromatography of step B is put on 45 g
of aluminum oxide and chromatography using a gradient of
ethyl acetate-methanol. We evaporate the good fraction and
the residue is triturated in an ether-acetonitrile mixture to obtain
a colorless solid which is collected by filtration to obtain the
cross-titled compound (428 mg) as monohydrate, (mp: 92.5
960C).

The compound obtained has the empirical formula C22H34N6S304, H20
and his elemental analysis leads to the following results:
CHNS
calculated *: 47,12 6,47 14,99 17,15
found **: 47.28 6.48 15.09 17.39
after correction (3.21% water)
after correction (3.32% water)
EXAMPLE 7

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-ethyl
1,1,5-lamino-thiadiazole 1,1-dioxide
A 2 - [(5-dimethylaminomethyl) -2 solution is added at once.
furyl) -methylthiolethylamine (2.41 g, 11.2 mmol) in 20 ml of
dry methanol to a suspension of 3,4-dimethoxy-1,2,5-thiadiazole
1,1-dioxide (2.0 g, 11.2 mmol) in 200 ml of methanol at 1 ° C
with vigorous stirring. After stirring for 15 minutes at 1-50C,
ethylamine (4.0 ml) is added and stirring is continued
for 20 minutes at approximately 50 ° C. The reaction mixture is evaporated
under reduced pressure and the residue is placed on 46 g of silica gel,
then chromatography using a chloride elution gradient
methylene-methanol, combine the correct fractions, evaporate
and triturate the gelatinous residue in the ether and then filter for
obtain the product as a colorless solid (2.81 g).

Two recrystallizations in methanol, and drying on P205
at room temperature for 17 hours give the compound in
heading (PF: 155-1600C with more or less agglomeration a
94-96 C). The NMR spectrum (100 MHz) in dimethyl sulfoxide d6
indicates the presence of about 0.8 moles of methanol.

The compound obtained has the empirical formula C14H23N503S2.4 / 5 CH3OH
and his basic analysis leads to the following results
CHNS
Calculated: 44.54 6.62 17.55 16.07
found: 44.35 6.58 17.44 16.18
EXAMPLE 8

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4- (2-pro
pynyl) amino-1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylaminomethyl) is added dropwise.
2-furyl) -methyl thiolethylamine (2.41 g, 11.2 mmol) in 20 ml of
dry methanol in 25 minutes to a suspension of 3,4-dimethoxy-1,2,5
thiadiazole 1,1-dioxide (2.0 g, 11.2 mmol) in 200 ml of cold CH3OH
at 1 ° C, with stirring. After 15 minutes stirring at 1-20C,
add a solution of 2-propynylamine (4.0 ml)
10 ml of dry methanol and stirring is continued at room temperature
ambient for 1 hour. The reaction mixture is evaporated under
reduced pressure and the residue is placed on 50 g of silica gel, then
chromatography using a chloride elution gradient
Methylene-methanol.We combine the right fractions, evaporate
and recrystallized from methanol to give 4.0 g of product.

Recrystallization in methanol and then in isopropanol
gives the title compound (2.90 g), mp 92-100 C. The spectrum
NMR (100 MHz) in dimethyl sulfoxide d6 indicates that the product
is solvated with 1 mole of methanol.

The compound obtained has the formula
C1 5H2 1N503S2, CH3OH
and his basic analysis leads to the following results
CHNS
Calculated: 46.25 6.06 16.85 15.43
find : . 46.36 6.22 16.95 15.73
EXAMPLE 9

3-methylamino-4- {2 - [(5 - {[N-methyl-N- (2-propynyl) smino} methyl} -2-furyl)
methylthio] ethylamino} -1,2,5-thiadiazole 1,1-dioxide
A. 5 - {[N-methyl-N- (2-propynyl) amino] methyl} -2-furanmethanol
2.49 g of furfuryl alcohol (25.4 mmol) cooled by a bath
water and ice at 5 ° C., 4.0 g of N-me hydrochloride are added.
Thylpropargylamine (37.9mmol) and 3.13ml of 40% formalin
(41.7 mnoles), then shake the mixture while letting it return
at room temperature. After 1 hour of agitation, the solution is
stored at room temperature for 4 1/2 days. The mixture
The reaction mixture is poured into a mixture of water and ice,
strongly basic by adding an aqueous solution of NaOH to
40% and then extracted with 5 portions of chloride
The organic phases are combined and then dried,
filtered and evaporated under reduced pressure; we thus obtain a
oil (quantitative yield). Vacuum distillation leads
to the title compound having a boiling point of 102
106 C (at 0.3 mm Hg).

The compound obtained has the empirical formula: C10H13NO2
and his basic analysis leads to the following results
CHN
Calculated: 67.02 7.31 7.82
found: 66.80 7.44 7.93
B. 2 - [(5 - {[N-methyl-N- (2-propynyl) amino} -methyl} -2-furyl) methylthio]
ethylamine
A solution of 5 - {[N-methyl-N- (2-propynyl) amino] -methyl) -2-
furanmethanol (40.0 g, 223mmol) [as prepared in step
Al in 100 ml ice-cold concentrated HCl is added to a solution
cold stirring (50C) of 27.9 g (24 mmol) of
cysteamine in 125 ml of concentrated hydrochloric acid.
tion is kept at 0 C for 2 1/2 days and then
at room temperature for 7 hours for the reaction to
CHEVE. The reaction mixture is cooled by a water bath and
of ice, then diluted by the addition of 200 ml of water,
alkaline by adding 40% aqueous NaOH solution and then
extracted with 3 portions of methylene chloride. The mixture of
organic phases is dried, filtered and then evaporated under pressure
reduced to yield a thick oil (46.4 g).

Rapid vacuum distillation of the oil leads to the compound
in section (PEb: 136-140 ° C / 0.2 mmHg).

The compound obtained has the empirical formula C12H18N20S
and his basic analysis leads to the following results
CHNS
calculated: 60.47 7.61 11.76 13.46
found: 59.82 7.68 11.61 13.27
C. 3-Methylamino-4- {2 - [(5 - {[N-methyl-N- (2-propynyl) amino] -
methyl-2-furyl) methylthio] ethylamino} -1,2,5-thiadiazole 1,1
dioxide
To a cold stirred suspension (3 ° C) dimethoxy-1,2,5-thiadia-
zole 1,1-dioxide (2.0 g, 11.2 mmol) in 200 ml of dry methanol,
a solution of 2 - [(5 - {[N-methyl-N- (2-propynyl)) is added
aminolmethyl) -2-furyl) methyl thiol-ethylamine (2.68 g, 11.2 mmol)
prepared in step B]. After stirring at 3-7 C for 15 minutes
In the solution, methylamine is bubbled into the solution during
16 minutes. The reaction mixture is evaporated under pressure
reduced and the oily residue formed is placed on 100 g of silica
gel and chromatography using an eluent formed of a mixture
acetonitrile-methanol. Appropriate fractions are combined
and rechromatographed on 100 g of silica gel, the eluent being
formed of a methylene chloride-methanol mixture. Fractions
are dissolved in methylene chloride then
extracted with a 1% aqueous solution of NaOH. The aqueous phase
is brought to pH 9 by addition of a 5% aqueous solution of HCl
and the separated oil is extracted with 3 portions of
methylene. The combined extracts are dried, filtered and evaporated
under reduced pressure; we obtain a mousse.Recrystallization
in isopropyl alcohol leads to the title compound (mp 50
51 C, clear melting 54-560C). The NMR spectrum (100 MHz) in the
dimethyl sulfoxide d6 shows the presence of about 1/4 mole of alcohol
isopropyl.

The compound obtained has the formula
C15H21N5O3S2, 1/4 C3H8O
and his basic analysis leads to the following results:
CHNS
Calculated: 47.47 5.82 17.57 16.09
found: 47.51 6.21 16.40 15.97
EXAMPLE 10

3- {2 - [(5-dimethylaminomethyl-3-methyl-2-furyl) methylthio] ethylamino}
4-methylamino-1,2,5-thiadiazole 1,1-dioxide
A. 5-dimethylaminomethyl-3-methyl-2-furanmethanol
A mixture containing 11.2 g of 3-methyl-2-furfuryl alcohol (0.1
mole) [prepared according to the method described in J. Am. Chem. Soc.,
72, 2195 (1950)], 12.23 g of dimethylamine hydrochloride (0.15
mole) and a 37% aqueous solution of formaldehyde (12 ml, 0.15
mole) is stirred for 150 minutes at approximately 50C and then stored at
room temperature for 15 to 18 hours. The solution is heated
fairy for 10 minutes on a steam bath and then is diluted by
addition of 12 ml of water and made basic by addition of carbonate
The mixture is extracted with ethyl acetate,
then the organic phase is dried, filtered and evaporated under pressure
scaled down; the title compound is obtained, presenting a point
boiling point of the order of 88-96 ° C at a pressure of 0.05-0.08
mm Hg.

B. 2 - [(5-dimethylaminomethyl-3-methyl-2-furyl) methylthiol] ethylamine
To a solution of 2-aminoethanethiol hydrochloride (2.27 g;
20.0 mmol) in 20 ml concentrated HCl, cooled by a water bath
and ice at -10 C, 3.38 g of 5-dimethyla are added dropwise
minomethyl-3-methyl-2-furanmethanol (20.0 mmol) prepared in
step A], and the mixture obtained is stirred for 15 minutes then
canned cold (0 C) for 17 hours. The solution is then rendered
strongly basic by adding an aqueous solution of KOH and then
undergoes 5 successive extractions with the aid of methylene chloride.

The organic phases are combined; the mixture is dried, filtered
and evaporated under reduced pressure. 4.16 g of the compound are obtained.
heading (PEb: 11O-1200C / O, 1 mm Hg.)
C. 3- {2 - [(5-dimethylaminomethyl-3-methyl-2-furyl) methylthio] ethylamine
no} -4-methylamino-1,2,5-thiadiazole 1,1-dioxide
The title compound is prepared from a metha suspension
nol 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide that is made
react with an equimolar proportion of 2 - [(5-dimethylaminomethyl)
3-methyl-2-furyl) -methylthio] ethylamine prepared in the
B1 and 3- {2 - [(5-dimethylaminomethyl-3-methyl-2-furyl) methyl)
thio] -ethylamino} -4-methoxy-1,2,5-thiadiazole 1,1-dioxide resulting
is treated with an excess of methylamine.

EXAMPLE 11

3- {2 - [(5-dimethylaminomethyl-4-methyl-2-furyl) methylthio] -éthylami
4-methylamino-1,2,5-thiadiazole 1,1-dioxide
A. 2-dimethylaminomethyl-3-methylfuran
A stirred solution of 3-methyl-2-furfuryl alcohol (25.2 g;
22.5 mmol) and triethylamine (27.3 g, 27.0 mmol) in 200 ml
of methylene chloride is cooled to -150C by a water bath
and ice then add a solution of thio chloride
nyl (18.0 ml, 24.8 mmol) in 30 ml of methylene chloride,
drip, while maintaining the temperature between -100C
and -15 C. After 15 minutes, the mixture is poured into a bath
of water and ice and the organic layer is collected.
chloromethylamine containing 3-methyl-2-chloromethylfuran
is added to a stirred solution, brought to 0 C, of dimethylamine
(137.0 g, 3.04 moles) in 400 ml absolute ethanol and the solution
The resulting mixture is stirred at ambient temperature for 17 hours. The
The reaction mixture is evaporated under reduced pressure and the residue
is added 400 ml of water and is made strongly basic
by addition of a 40% aqueous solution of NaOH and then undergoes
5 successive extractions with 5 portions of
thylène. The extracts obtained are combined; the mixture is dried,
filter and then evaporated under reduced pressure. 26.0 g of
Title compound (PEb: 64-70 ° C / 20 mm Hg.)
Thin layer chromatography [si] ice / CHCl 3: CH 3 OH (85:15)]
leads to (Rf: 0.50).

B. 2-Chloromethyl-5-dimethylaminomethyl-3-methylfuran
To a solution of 2-dimethylaminomethyl-3-methylfuran (6.5 g, 37.0 g)
moles) [prepared in stage A1 in 250 ml of chloroform,
Paraformaldehyde (1.67 g, 55.7 mmol) and
zinc (312 mg), and then gaseous HCl is slowly bubbled through
the mixture while stirring at room temperature for 15 minutes
Stirring is continued for 2 hours, then bubbled
HCl gas for 15 minutes and stirring of the mixture is continued
for 1 hour. Additional paraformaldehyde is then added
(1.67 g, 55.7 mmol) to the reaction mixture and a
low HCl gas flow in the mixture for 15 minutes.

After stirring for 18 hours at room temperature,
kills the filtration of the reaction mixture on celite and evaporates
the filtrate under reduced pressure, which makes it possible to obtain the compound
in section (4.97 g) which crystallizes when it is abandoned and
uses without further purification in step C.

The NMR spectrum (60 MHz) in CDCl3 gives the peaks of resonances
following
# 6.33 (s, 1H); 4.55 (s, 2H); 4.30 (d, 2H); 2.83 (d, 6H);
2.13 (s, 3H).

C. 2 - [(5-dimethylaminomethyl-4-methyl-2-furyl) methylthio] ethylamine
To a solution of 2-chloromethyl-5-dimethylamino-methyl-3-methyl
furan (773 mg, 3.45 mmol) [prepared in Step B] in 20 ml
concentrated hydrochloric acid and cooled with a bath
of ice water, add 2-aminoethanethiol hydrochloride
(392 mg, 3.45 mmol) and the mixture is stirred for 30 minutes.

The solution is left at 0 ° C. for 3 days, then it is alkalized
strongly using aqueous KOH at 50 C diluted with water, then extracted
with 5 portions of methylene chloride. We dry the ex
combined strokes, filter, and then evaporate under reduced pressure for
obtain the title compound as an oil.

The product is dissolved in absolute ethanol, treated with anhydrous HCl
and finally evaporated under reduced pressure. The residue is dissolved in
hot isopropyl alcohol, treated with charcoal, filter and
concentrated to crystallize the hydrochloride. By recrystallization
in isopropyl alcohol the compound is obtained
in the form of dihydrochloride, (mp: 185-190 ° C. with decomposition).

D. 3- {2 - [(5-Dimethylaminomethyl-4-methyl-2-furyl) methylthio] ethylamino}
4-methylamino-1,2,5-thiadiazole1,1 dioxide
A methanolic suspension of 3,4-dimethoxy-1,2,5 is reacted
thiadiazole 1,1-dioxide with an equimolecular amount of 2 - [(5
dimethylaminomethyl-4-methyl-2-fury) methylthio] ethylamine [prepared
in Step Clon treats 3-I2-C (S-dimethylaminomethyl-4-methyl-2-
furyl) methylthio] -ethylamino} -4-methoxy-1,2,5-thiadiazole 1,1-dioxide
obtained by an excess of methilamine, and thus the compound is obtained
heading.

EXAMPLE 12

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-hydroxy
1,2,5-thiadiazole 1,1-dioxide
A. 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthiolethylamino] -4
methoxy-1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylamines) is added dropwise
nomethyl-2-furyl-methylthio] ethylamine (2.14 g, 10.0 mmol) in
25 ml of dry methanol in 35 minutes to a suspension of 3,4-dim
thoxy-1,2,5-thiadiazole 1,1-dioxide (1.78 g, 10.0 mmol) in
180 ml of well-stirred dry methanol, cooled to 1 ° C by a bath
ice water. After 15 minutes at 0 C, we get a solution
methanol of the title compound. Layer chromatography
Thin [silica CH2Cl2: CH3OH (9: 1)] gives an Rf: 0.48.

A sample of 2.0 ml of solution is acidified with HCl 6, ON
and evaporated under reduced pressure without heating to obtain the
subject compound as hydrochloride. Its NMR spectrum
(100 MHz) in D20 gives the following resonance peaks
d: 6.45 (d, 1H); 6, 19 (d, 1H); 4.14 (s, 2H); 4.0 (s, 3H);
3.64 (s, 2H); 3.37 (t, 2H); 2.65 (s, 6H); 2.61 (t, 2H).

B. 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4
1-hydroxy-12,5-thiadiazole 1.1-dioxide
To a methanol solution of the product of step A cooled to 0 ° C
in an ice-water bath, a solution of hydroxide
sodium pellets (2.10 g, 52.5 mmol) in 25 ml of dry methanol.

After stirring for 2 hours at 0 ° C. and at room temperature for
68 hours the reaction mixture is neutralized by 8.75 ml (52.5
mmol) of aqueous HCl 6, ON and after stirring for 10 minutes,
pore under reduced pressure. The residue is crystallized in EtOH from
95% to obtain the crude product which is dissolved in methanol,
filter to remove NaCl, place on 60 g of silica gel and chroma
graphography using a methylene chloride elution gradient
methanol. The correct fractions are combined and evaporated under
reduced pressure to obtain 3.19 g of product. By recristallisa
in aqueous methanol, the title compound is obtained.
(Mp 109-1220C).

The compound obtained has the empirical formula C12H16N4O4S2
and his basic analysis leads to the following results
CHNS
calculated: 41.61 5.24 16.17 18.51
found: 41.59 5.32 16.33 18.81
EXAMPLE 13

3- {2 - [(5-diméthylaminométhyl020furyl) methylthio] ethylamino} -4-methylamino
1,2,5-thiadiazole 1-oxide
A. 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-methoxy
1,2,5-thiadiazole 1-oxide
A solution of 2 - [(5-dimethylaminomethyl)
2-furyl) -methylthio] ethylamine (3.30 g, 15.4 mmol) in 25 ml of
methanol in 14 minutes to a suspension of 3,4-dimethoxy-1,2,5-
thiadiazole 1-oxide (2.50 g, 15.4 mmol) [prepared according to
method of Example 4, step A] with vigorous stirring,
cooled to 12-15 C in an ice-water bath. The solution is stirred
at room temperature for 1h30 and we get a solution
methanol of the title compound.

B. 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1-oxide
To a methanolic solution of the product of cooled step A
at 5 ° C. with an ice-water bath, anhydrous methylamine is added
for 8 minutes. The reaction mixture is stirred at room temperature
ambient for 17 hours and then evaporated under reduced pressure.

The product is thus obtained in the form of a yellow oil which
place on 55 g of silica gel and chromatography using a gra
methylene chloride-methanol elution. We evaporate the good
fraction, dissolved in methanol and diluted with ether
diethylic acid to give the title compound (2.32 g) as the
form of a solid that is dried in vacuo at room temperature on
P205 for 3 hours (mp 86-920 ° C).

The compound obtained has the formula
C13H21N5O2S2
and his basic analysis leads to the following results
CHNS
calculated: 45.46 6.16 20.39 18.67
found: 45.24 6.24 20.41 18.90
EXAMPLE 14

3-allylamino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino}
1,2,5-thiadiazole 1,1-dioxide
To a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1
dioxide (2.08 g, 11.7 mmol) in 200 ml of methanol, previously
cooled to 0 ° C. in an ice-water bath, it is added dropwise,
in 45 minutes, a solution of 2 - [(5-dimethylaminomethyl-2-furyl) methyl
thylthiolethylamine in 30 ml of methanol. When the addition is
10.5 ml of allylamine are added and the solution is left
stirring at room temperature for 18 hours.On evapore
the reaction mixture under reduced pressure and the residue is placed on
120 g of silica gel, then, chromatography using a gradient
elution methylene chloride-methanol. Fractions are combined
appropriate, evaporate under reduced pressure and recrystallize the
residue in isopropyl alcohol to obtain the compound in ru
brick (mp 83-86 C). NMR spectra (100 MHz) in dimethyl
sulfoxide d6 indicates the presence of about 0.9 mole of isopropyl alcohol.

The compound obtained has the formula
C15H23N5O3S2, 9/10 C3H8O
and his basic analysis leads to the following results
CHNS
calculates: 48; 36 6.92 15.93 14.59
found: 48.46 6.96 16.13 14.58
EXAMPLE 15

3-Methylamino-4- {2 - [(5-methylaminomethyl-2-furyl) methylthio] ethylamino} 1,2,5-thiadiazole 1, Id and 3,4-bis- {2 - [(5-methylaminomethyl)} 2-furyl)
methylthio] ethylamino} -1,2,5-thiadiazole 1,1-dioxide
A. 3-methylamino-4- {2 - [(5-methylaminomethyl-2-furyl) methylthio] ethyl
mino} -1,2,5-thiadiazole 1,1-dioxide
To a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole (1.89 g;
10.4 mmol) in 210 ml of methanol, cooled to 0.degree.
at once, a solution of 2- (5-methylaminomethyl-2-furyl)
methyl thiolethylamine (0.7 g, 3.51 mmol) prepared according to the pro
assigned to the Belgian patent 857,3883 in 21 ml of methanol. We shake
the mixture for 15 minutes and cooled to 10C with a bath
chilled water.Anhydrous methylamine is then bubbled
in the solution for 6 minutes. After 15 minutes of agitation,
the reaction mixture is evaporated under reduced pressure, the
residue on 110 g of silica gel and eluted with an elution gradient
ranging from acetonitrile to acetonitrile-methanol-acid
glacial acetic acid (50: 50: 0.5). Suitable fractions are combined
containing the first eluted compound of Rf: 0.50 [thin layer
silica / CH 3 CN: CH 3 OH: CH 3 COOH (50: 50: 1) 1 and evaporated under pressure
reduced to obtain the title compound as a foam
(Mp: 50-56 ° C).

The NMR spectrum (100 MHz) in dimethyl sulfoxide d6 gives the
following resonance peaks
#: 6.20 (m, 2H); 3.80 (s, 2H); 3.62 (s, 2H); 3.50 (t, 2H);
2.90 (s, 3H); 2.70 (t, 2HY, 2.28 (s, 3H), it also indicates
the presence of about 0.2 moles of methanol.

The compound obtained has the formula
C12H19N503S2, 2 / io CH30H
and his basic analysis leads to the following results
CHNS
calculated: 41.65 5.65 19.96 18.28
Found *: 41.98 5.69 19.54 18.54
* after correction (1.42% 1120)
A. 3,3-bis- {2 - [(5-methylaminomethyl-2-furyl) methylthio] ethylamino}
1,2,5-thiadiazole 1,1-dioxide
Fractions containing the most eluted constituent are combined
slowly during the chromatography of step A, with Rf = 0.07
Thin layer chromatography-silica / CH 3 CN: CH 3 OH: CH 3 COOH (50: 50: 1)],
the mixture is evaporated and the residue is extracted with 2.5N NaOH and ethyl acetate.

The aqueous phase is extracted with several portions of acetate
from then, combine the organic phases, dry, then evaporate
under reduced pressure to obtain the title compound
oil.

The NMR spectrum (100 MHz) in dimethyl sulfoxide d6 gives the peaks
of following resonances:
#: 6.22 (m, 4H); 3.82 (s, 4H); 3.65 (s, 4H @; 3.50 (t, 4H);
2.72 (t, 4H), 2.30 (s, 6H).

EXAMPLE 16

3- {4- (5-dimethylaminomethyl-2-furyl) butylamino} -4-methylamino-1,2,5-thia
1,1-dioxide diazole
A solution of 4- (5-dimethylaminomethyl) is added dropwise.
2-furyl) -butylamine (1.5 g, 7.64 mmol) [prepared according to the process
U.S. Patent 4,128,658] in 40 nil of dry methanol, in
45 minutes, solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide
(1.36 g, 7.64 mmol) in 200 ml of dry methanol, with stirring,
cooled to 3 C in an ice-water bath. After 15 minutes of agitation
at 30 ° C., anhydrous methylamine is bubbled into the solution
cold for 10 minutes.The reaction mixture is evaporated under
reduced pressure and the residue is placed on 60 g of silica gel, then,
chromatography using an acetonitrile-methanol elution gradient
The appropriate fractions are combined to give 2.16 g of product.

Recrystallization from acetonitrile gives the compound
heading $ PF: 152-153 C).

The compound obtained has the formula
C14H23N5O3S
and his elemental analysis leads to the following results:
CHNS
calculated: 49.25 6.79 20.51 9.39
found: 49.41 6.87 20.61 9.28
EXAMPLE 17

3- {2 - [(5-Dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-methylamino 1,2,5-thiadiazole 1,1-dioxide
A. 3-methylamino-4- (2-mercaptoethyl) -1,2,5-thiadiazole 1.1-dioxide
A solution of 2-aminoethanethiol obtained from the
hydrochloride, 91 g; 16.8 moles) in 20 ml. of methanol drop to
drop in 15 minutes, to a suspension of 3,4-dimethoxy-1,2,5-thia
diazole 1,1-dioxide (3.0 g, 16.8 mmol) in 250 ml of methanol,
under vigorous stirring cooled to 1 C by an ice-water bath.

After 10 minutes at 2-4 ° C., methylamine is bubbled
in the cooled solution for 6 minutes and continue
for another 30 minutes at room temperature.

The reaction mixture is evaporated under reduced pressure and
the residue on 45 g of silica gel, then chromatography using
a methylene chloride-methanol elution gradient. We combine
the right fractions, evaporate and recrystallize the product
(2.43 g) in absolute ethanol. By recrystallization in ethanol
absolute, the title compound is obtained (mp 259-260 C with decomposition
position).

The compound obtained has the formula
C5H10N42S2
and his elemental analysis leads to the following results:
CHN
calculated: 27.03 4.54 25.20
found: 27.13 4.55 24.86
B. 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1-dioxide
A mixture of 3-methylamino-4- (2-mercaptoethyl) -1,2,5-thia-
diazole 1,1-dioxide (1.0 g, 4.5 mmol) [prepared in Step A
and 5-dimethylaminomethyl-2-furan-methanol (0.82 g, 4.5 mmol)
[prepared according to the method of J. Chem. Soc., 4728 (1958) 1 in 20 ml
concentrated HCl, in an ice-water bath, for 2 hours,
then allowed to stand for 64 hours at 4 ° C. The reaction mixture is stirred
for 23 hours at room temperature. Evaporate without
heat, under reduced pressure and the residue is taken up in
water and methylene chloride. The aqueous phase is alkalinized
with sodium bicarbonate and extracted with chloride
methylene. The combined organic phases are washed with a
saturated solution of brine, dried and evaporated under high pressure
pick. The residue is placed on 25 g of silica gel and chromatography is carried out.
using a methylene chloride-methanol elution gradient. We
evaporates the good fraction and recrystallizes the product in the
methanol. By recrystallization in methanol, we obtain the com
posed in section (PF: 92-96 C).

EXAMPLE 18

3 - [(5-Di-methylaminomethyl-2-yl) methylthiothetlaminol-4-methyl-amine)
1,2,5-thiadiazole 1-oxide
A. 3-methylamino-4- (2-mercaptoethyl) -1,2,5-thiadiazole 1-oxide
A solution of 2-aminoethanethiol <from
hydrochloride, 2.04 g; 18.0 mmol) in 25 ml of methanol
minutes, to a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1-dioxide
(2.92 g, 18.0 mmol) prepared in Example 4, Step A] in 150 ml
of methanol cooled to 3 ° C. by an ice-water bath, with stirring
After 10 minutes, methylamine is bubbled through
in the solution for 6 minutes and stirring is continued at room temperature.
room temperature for another 20 minutes. We evaporate
the reaction mixture under reduced pressure and put the residue on
45 g of silica gel, then, chromatography using a gradient of
lution of methylene chloride-methanol. We combine the good frac
and evaporated to obtain 2.74 g of product. By recristalli
in methanol and then, in 95% ethanol, the
featured compound (PF: 191-193 C).

B. 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-methyl
1,2,5-lamino-thiadiazole 1-oxide
3-Methylamino-4- (2-mercaptoethyl) -1,2,5-thiadiazole 1 is treated
oxide [prepared in step A] by about one equivalent of 5-dimethyl
Laminomethyl-2-furan-methanol in concentrated HCl according to the method of
Example 25, Step B, the title compound is obtained, identical
to the product of Example 18.

EXAMPLE 19

3- {2 - [(5-dimethylaminomethyl-2-furyl) -4-dimethylamino} méthylthioléthylamino
1,1,5-lamino-thiadiazole 1,1-dioxide
To a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1
dioxide (2.08 g, 11.7 mmol) in 200 ml of methanol cooled to 60C,
a solution of 2 - [(5-dimethyl) is added dropwise in 45 minutes
2-methyl-2-furyl) methylthio] ethylamine (2.5 g, 11.7 mmol) in
50 ml of methanol. When the addition is complete, we make a splash
anhydrous dimethylamine in the solution for 10 minutes while
maintaining the temperature at 60C.After 18 hours of stirring at the
room temperature, the reaction mixture is evaporated under pressure
reduced and the residue is placed on 200 g of silica gel and chromatography
using a methylene chloride-methanol elution gradient. We
combine the right fractions and evaporate them, rechromatography
the residue on 75 g of aluminum oxide using a gradient of eluate
methylene chloride-methanol, the correct fractions are combined
and evaporated under reduced pressure to give the title compound (mp 139-1420C).

The compound obtained has the empirical formula: C19H24N503S2
and his elemental analysis leads to the following results:
CHNS
calculated: 44.90 6.46 18.70 17.12
found: 44.77 6.25 18.89 17.42
after correction (0.512 H20)
EXAMPLE 20

3- {2 - [(2-guanidinothiazol-4-yl) méthylthioléthylamino} -4-methylamino-1,2,5
thiadiazole 1,1-dioxide
A solution of 2 - [(2-guanidinothiazol-4-yl) methylthio] ethyl is added.
lamine (from the dihydrochloride, 4.27 g, 14.0 mmol) in 30 ml
of methanol to a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1
dioxide (2.50 g, 14.0 mmol) in 250 ml of methanol at 10 ° C.
strong agitation. After 15 minutes at 10 ° C., the solution is cooled
at 10C in a cooling bath and the methylamine is bubbled
anhydrous in the solution for 10 minutes.The mixture is evaporated
reaction under reduced pressure and the residue is placed on 60 g of
silica gel, then, chromatography using an elution gradient
methylene chloride-methanol. We place the right fraction
mantle 4.53 g of product on 80 g of aluminum oxide and rechro
with an ethyl acetate-methanol elution gradient. We
combine the right fractions and evaporate to get a foam
which recrystallizes from methanol, 2.38 g of the compound are obtained.
in section (PF: 196-198 C with decomposition).

The compound obtained has the formula
C10H16N8O2S3
and his basic analysis leads to the following results
CHNS
calculated: 31.90 4.28 29.77 25.55
found: 31.85 4.24 29.79 25.45
EXAMPLE 21

3- {2 - [(2-guanidinothiazol-4-yl) methylthiolethylamino) -4- (2-propynyl) amino-1,2,5-t-iadlazole-1-dioxide
A solution of 2 - [(2-guanidinothiazol-4-yl) methylthio] ethyl is added.
lamine (from the dihydrochloride, 3.42 g, 11.2 mmol) in 25 ml
of methanol to a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1
dioxide (2 g, 11.2 mmol) in 200 ml of methanol with stirring
at 8 ° C. After 15 minutes at 8 ° C., the solution is cooled to 10 ° C.
an ice-water bath and add a solution of 6.0 ml of 2-propynyl
laminated in 15 ml of methanol. We remove the ice water bath and we
continue stirring for 15 minutes. The reaction mixture is evaporated
under reduced pressure and the residue is placed on 50 g of silica gel
then chromatography using a chloride chloride elution gradient
thylène-methanol. Two of the fractions give a crystallized product
(1.74 g) from methanol. The product is dissolved in methanol
hot, filter on celite, cool and filter to get the compound
in section (PF: 176-1780C).

The compound obtained has the formula
C12H16N8O2S3
and his elemental analysis leads to the following results:
CHNS
calculated: 35.99 4.03 27.98 24.02
found: 35.82 4.12 28.41 24.28
EXAMPLE 22

3- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1-dioxide
A. N-carbophenoxy-N-methylaminoacetonitrile
To a suspension of diethylaminoacetonitrile hydrochloride (100 g;
0.94 moles) in 1 liter of methylene chloride cooled in a
chilled water bath, triethylamine (260 ml, 1.88 moles) was added
and a solution of chloroformate phenyl (155.0 g, 0.99 mol) in
500 ml of methylene chloride. The reaction mixture is heated to
the reflux temperature for 18 hours and then evaporate under
reduced pressure to obtain a semi-solid that is triturated with 1 liter
of diethyl ether and filter.The filtrate is evaporated under pressure
reduced and distills the residual oil under vacuum; we get the compound
in section (123 g), (PE: 111-113 ° C / 0.25 mm Hg); the NMR spectrum
(60 MHz) in CDCl3 gives the following resonance peaks
6: 7.23 (m, 5H); 4.30 (s, 2H); 3.13 (s, 3H).

B. (N-carbophenoxy-N-methylamino) thioacetamide
A solution of N-carbophenoxy-N-methylaminoacetonitrile is treated
(131.0 g, 0.69 mol) prepared in Step A] and thioacetamide
(57.1 g, 0.71 mol) in 917 ml dry DMF with gaseous HCl until
that an exothermic reaction takes place and then
water bath for 20 minutes. Partially evaporates the mixture
reaction under reduced pressure to remove a part of the soil
Beforehand, the mixture is rendered alkaline with saturated aqueous NaHCO 3 solution.
and put in the presence of water and ether. The aqueous phase is extracted
the ether, the combined phases are combined and washed with water, then
saturated aqueous solution of NaCl, and then dry.
then evaporation of the solvent, an oil is obtained which is triturated with
methylcyclohexane to obtain the product as a solid.

Recrystallization from isopropanol gives the title compound (mp 101-10 ° C).
The compound obtained presents the formula
C10H12N202S
and his elemental analysis leads to the following results:
CHNS
Calculated: 53.55 5.40 12.49 14.30
found: 53.65 5.51 12.69 14.41
C. 4-Chloromethyl-2- (N-carbophenoxy-N-methyl-amino) methylthiazole
To a cooled solution of (N-carbophenoxy-N-methylamino) thioace-
tamide (1.0 g, 4.46 mmol) of dry pyridine (0.36 mL, 4.46 mmol)
in 6 ml of ethanol, a solution of 1,3-dichloropropanone is added
(0.57 g, 4.49 mmol) in 3 ml of absolute ethanol. We heat the
mixture at reflux temperature for 90 minutes, and then
pore under reduced pressure. The oily residue is placed in the presence
of ether and water. The aqueous layer is extracted with ether and the
combination of the ether phases with water, then a solution
Saturated aqueous NaCl and dried. By filtration and evaporation,
1.02 g of the title compound is obtained as a screw oil.
queuse. Thin layer chromatography [silica / CH2Cl2: CH3CN (85:
15)] gives Rf = 0.82. The NMR spectrum (60 MHz) in CDCl 3 gives the
resonance peaks
g: 7.16 (m, 6H); 4.77 (broad s, 2H); 4.60 (s, 2H); 3.07 (wide s,
3H).

D. 2 - {[2- (N-carbophenoxy-N-methylamino) methyl-4-thiazolyl] methylthio}
ethylamine
To a solution of sodium methoxide (26.1 g, 0.48 mol) in 290 ml
of absolute ethanol at 0 ° C. under a nitrogen atmosphere, chlorhy is added
cysteamine drate (27.6 g, 0.24 mole) and 218 ml of absolute ethanol
additional. After stirring for 1 hour at 0 ° C., a solution is added
4-chloromethyl -2- (N-carbophenoxy-N-methylamino) methylthiazole
(72.5 g, 0.24 mol) in 218 ml of absolute ethanol in 15 minutes.
The reaction mixture is stirred at room temperature for 18 hours.
filter, then evaporate under reduced pressure to obtain an oil
that is partitioned between methylene chloride and water.

The aqueous phase is extracted with methylene chloride and
the combined organic phases are washed with water, dried, filtered and
evaporated under reduced pressure to obtain the product (68.5 g)
form of oil which is treated with fumaric acid (23.6 g) in the
n-propanol to obtain the salt (47.0 g). By recrystallization in
absolute ethanol, the title compound is obtained in the form of
fumarate (mp 145-1460 ° C).

The compound obtained has the formula:
C15H19N3O2S2, C4H4O4
and his elemental analysis leads to the following results:
CHNS
calculated: 50.31 5.11 9.27 14.14
found: 50.02 5.16 9.47 14.22
E. 2 - [(2-Dimethylaminomethyl-4-thiazolyl) methyltethionethylamine
To a solution of 2 - {[2- (N-carbophenoxy-N-methylamino) methyl-4-
thiazolyl] methylthio} ethylamine (0.50 g, 1.48 mmol) [prepared in
step D] in 10 ml of dry tetrahydrofuran under a nitrogen atmosphere
lithium aluminum hydride (0.17 g, 4.48 mmol) is added and
the mixture is heated at reflux temperature for 30 minutes.

10 ml of additional tetrahydrofuran are added and
heating for 3 hours. The reaction mixture is treated using
0.17 ml of H2O, 0.17 ml of 15% aqueous NaOH and 0.51 ml of H2O, filter
on celite and dry. The filtrate is filtered and evaporated under reduced pressure.
you; an oil is obtained which is dissolved in absolute methanol, diluted
with diethyl ether and acidified with dry HCl. We collect the
hydroscopic hydrochloride of the title compound and it is
between 2.5N NaOH and methylene chloride. We wash the organic phase
with water, dried and filtered. The filtrate is evaporated under reduced pressure
to obtain the free base of the product under heading in the form of a
oil (0.22 g, 0.95 mmol) which is combined with oxalic acid
anhydrous (0.24 g; i, 90 mmol) in 30 ml of hot acetonitrile. We evaporate
the mixture from absolute ethanol to obtain the bis-oxalate from
topical compound (mp: 169-171 C).

The compound obtained has the empirical formula: C9H17N3O4S2,2C2H2O4
and his elemental analysis leads to the following results:
CHNS
calculated: 37.95 5.15 10.21 15.59
found: 37.95 5.04 9.81 15.27
3- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole 1,1-dioxide
To a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide
(0.74 g, 4.17 mol) in 80 ml of methanol at 6 ° C., dropwise
in 45 minutes, a solution of 2 - [(2-dimethylaminomethyl-4-)
thiazolyl) methyl thio3ethylamine (0.96 g; 4.17 mol) prepared in
step E] to obtain 3- [2- (2-dimethylaminomethyl-4-thiazolyl)]
methylthioethylamino} -4-methoxy-1,2,5-thiadiazole 1,1-dioxide, Rf = 0.64
Esilice / CH2Cl2: CH3OH (9: 1)]. We keep the temperature at 60C
and anhydrous methylamine is bubbled into the solution
for 8 minutes. The reaction mixture is evaporated under pressure
reduced and the residue is placed on 80 g of silica gel, then chroma
tography using a methylene chloride elution gradient
methanol.It combines the right fractions and rechromatography
the residue on 25 g of aluminum oxide using a gradient of elution
methylene chloride methanol to obtain 0.52 g of product.

Recrystallization from an isopropanol-ether mixture
Title compound (mp: 144-1480C) (foam) is obtained.

The compound obtained has the empirical formula:
C12H20N6O2S3
and his basic analysis leads to the following results
CHNS
calculated: 38.28 5.35 22.32 25.55
found: 37.89 5.43 22.19 25.40
EXAMPLE 23

3- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino} -4-methyl
1,2,5-lamino-thiadiazole 1-oxide
A. N-carbethoxy-N-methylaminoacetonitrile
Triethylamine (5.2 ml, 37.6 mmol) is added to a suspension of
methylaminoacetonitrile hydrochloride (2.0 g, 18.8 mmol) in
20 ml of methylene chloride. The suspension obtained is cooled
in an ice-water bath and add a solution of chloroformate
of ethyl (2.14 g, 19.8 mmol) in 10 ml of methylene chloride
in 30 minutes, then, the mixture is heated to the temperature of the re
flow for 18 hours.The reaction mixture is evaporated under
reduced to obtain a semi-solid residue which is triturated
diethyl ether and filtered, the filtrate is evaporated under pressure
reduced to obtain the title compound as a
oil (2.2 g), PE 96-98 ° C / 5.2 mm Hg.

B. (N-carbethoxy-N-methylamino) thioacetamide
A solution of N-carbethoxy-N-methylaminoacetonitrile is treated
(9.8 g, 6.9 mmol) [prepared in Step A], and thioacetamide
(10.35 g, 13.8 mmol) in 175 ml of dry DMF with gaseous HCl;
what happens a vigorous exothermic reaction, it heats
then in a water bath for 15 minutes. We alkalize the mixture
reaction with a saturated solution of NaHCO3, and then ex
ether, wash with water and dry. The ether phase is evaporated
under reduced pressure to obtain a solid residue which is dissolved
in methylene chloride and washes with water.The phase is dried
organic, filter, then evaporated under reduced pressure to ob
hold the product (2.5 g). By recrystallization in a mixture
ethyl acetate-hexane, the title compound is obtained (mp 91
93 C).

The compound obtained has the empirical formula:
C6H12N202S
and his elemental analysis leads to the following results:
CHNS
calculated: 40.89 6.87 15.96 18.92
found: 40.73 6.85 16.13 18.86
C. 2- (N-carbethoxy-N-methylamino) methyl-4-carbethoxythiazole
To a solution of (N-carbethoxy-N-methylamino) -thioacetamide (30.7 g;
0.17 moles) [prepared in step B] in 180 ml of absolute ethanol,
a solution of ethyl bromopyruvate (25.0 ml, 0.20 mol) is added
in 130 ml of absolute ethanol. The reaction mixture is heated to
the reflux temperature for 17 hours, then evaporated under
reduced ratio; the residue is partitioned between ether and water.
the organic phase with water, then a saturated solution of
sodium chloride, dry, filter, evaporate under reduced pressure
to obtain an oil that is placed on silica gel and chromatography
using diethyl ether as eluting solvent. Fractions
Suitable materials give the title compound as an oil. The
thin-layer chromatography Lsilice / CH2Cl2: CH3-CN (85:15) 1 gives
Rf = 0.50. The NMR spectrum (60 MHz) in dimethyl sulfoxide d6
gives the following resonance peaks:
#: 8.49 (s, 1H); 4.79 (s, 2H); 4.23 (m, 4H); 3.00 (s, 3H,;
1.30 (q, 6H).

D. 2-dimethylaminomethyl-4-hydroxymethylthiazole
To a cooled suspension of lithium aluminum hydride (8.4 g;
0.22 moles) in 80 ml of dry tetrahydrofuran, a solution is added
2- (N-carbethoxy-N-methylamino) methyl-4-carbethoxythiazole
(20.0 g, 0.07 mol) [prepared in Step C1 in 160 ml of
dry tetrahydrofuran, in 1 hour. The reaction mixture is heated
at reflux temperature for 8 hours,
it is decomposed with Na2SO4 and 40% aqueous potassium hydroxide.

The mixture is filtered, dried and evaporated under reduced pressure to
4.2 g of the title compound as an oil. The
thin-layer chromatography of aluminum oxide CH3CN gives
Rf = 0.45. The NMR spectrum (60 MHz) in CDCl3 gives the peaks of
following resonances:
6: 7,17 (s, 1H); 4.73 (d, 2H); 3.43 (s, 2H); 3.35 (s, 6H).

E. 2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamine
2-Dimethylaminomethyl-4-hydroxymethylthiazole is reacted
[prepared in Step D] with thionyl chloride and made
react the 2-dimethylaminomethyl-4-chloromethylthiazole obtained with
an equimolar amount of cysteamine hydrochloride and 2 equiva
slow bases according to the general method of Example 33, step D;
thus, the title compound is obtained.

F. 3- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino}
4-methylamino-1,2,5-thiadiazole 1-oxide
A 3,4-dimethoxy-1,2,5-methanolic suspension is reacted.
thiadiazole 1-oxide [prepared in Example 4, Step A] with a
equimolar amount of 2 - [(2-dimethylamino-methyl-4-thiazolyl) methyl)
thiojethylamine [prepared in Example 33, step E] and treated
3- {2- (2-dimethylaminomethyl-4-thiazolyl) méthylthioléthylamino} -4
methoxy-1,2,5-thiadiazole 1-oxide resulting from methylamine,
gets the -compose in heading.

EXAMPLE 24

3-amino-4- {2 - [(2-guanidinothiazol-4-yl) -1,2,5-thia méthylthioléthylamino}
1,1-dioxide diazole
A solution of 2 - [(2-guanidinothiazol-4-yl) is added over 1 hour.
methylthio] ethylamine (2.75 g, 11.9 mmol) [obtained by neutralizing
2 - [(2-guanidinothiazol-4-yl) methylthio] ethyl dihydrochloride
amine (4.0 g, 13.0 mmol) with 2.5N aqueous NaOH followed by an extrac
by ethyl acetate in 30 ml of methanol to a suspension of
3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.12 g, 11.9 mmol)
in 220 ml of methanol cooled at 0 ° C. and with vigorous stirring.

While maintaining the temperature at OOC, ammo is bubbled
anhydrous niac in the solution for 6 minutes and continue
stirring at room temperature for half an hour.

The reaction mixture is evaporated under reduced pressure and the
residue over 120 g of silica gel and chromatographed using a
elution gradient CH 2 Cl 2 -methanol. We bring together the fractions
and evaporate, then rechromatograph the residue on
40 g of silica gel using a CH2Cl2-methanol elution gradient.

Useful fractions are combined, concentrated in vacuo,
filter and dries under high vacuum to obtain the title compound
(Mp 134-149 ° C) (foam); the NMR spectrum (100 MHz) in dimethyl
sulfoxide / D20 / DCl gives the peaks of resonances:
d: 7.16 (s, 1H); 3.84 (s, 2H); 3.52 (t, 2H); 2.75 (t, 2H);
and it indicates the presence of about 1.2 moles of methanol.

The compound obtained has the empirical formula:
C9H14N8O2S3, 6/5 CH3OH
and his elemental analysis leads to the following results:
CHNS
calculated: 30.56 4.72 27.95 23.99
found *: 30,19 4,32 27,91 24,71
after correction (1.31% H20)
EXAMPLE 25

3- {2 - [(2-Oanidinothiazol-4-yl) methylthio] ethylamino} -4- (2-hydroxyethylamino) 1,2,5-thiadiazole 1.1-dioxide
To a suspension of 3,4-dimethoxy-1,2J-5-thiadiazole 1,1-dioxide
(2.05 g, 11.5 moles) in 200 ml of dry methanol at 3 ° C.
energetic treatment, a 30 minute
solution of 2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamine (at
from the dihydrochloride; 3.5 g; 11.5 mmol) in 40 ml of methanol
dry. After 15 minutes at 3 ° C., etha solution is added rapidly.
nolamine (1.03 ml, 17.3 mmol) in 10 ml of methanol, dropwise
drop, and stir for 15 minutes. The reaction mixture is evaporated.
under reduced pressure and the product is obtained under
me of a friable foam that crystallizes in methanol. Two recruits
in methanol give the title compound (PF: re
slow sinification starts at 115 C, decomposition begins at
175 C).

The compound obtained has the empirical formula: C1 1H1 6N803S3
and his elemental analysis leads to the following results:
CHNS
calculated: 32.50 4.46 27.57 23.66
found *: 32.77 4.21 27.90 24.39
after correction (3.85% H20)
EXAMPLE 26

3- {2 - [(5-Dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-hydrazino-1,2,5-thiadiazole @ -dioxide
A solution of 2 - [(5-dimethylaminomethyl) is added dropwise.
2-furyl) -methylthio] ethylamine (2.41 g, 11.2 mmol) in 30 ml of
dry methanol in 45 minutes to a suspension of 3,4-dimethoxy-1,2,5-
Thiadiazole 1,1-dioxide (2.0 g; 11.2 mmol) in 250mide CH3OH, cooled
die in a bath of ice water and energetic agitation. After
Stirring for 15 minutes at 0 ° C., a hydrazine solution is added
anhydrous (1.8 g, 56.13 mmol) in 30 ml dry methanol of a single
and stirring is continued for 30 minutes.The mixture is evaporated
reaction mixture under reduced pressure and the residue is treated
lide with chloroform and then filter to obtain 3.28 g of
poses in rubric (PF: 1700C with decomposition).

EXAMPLE 27

3-methylamino-4- {2 [(2-pyridyl) -1,2,5-thiadiazole méthylthioléthylamino}
1,1-dioxide
A solution of 2 - [(2-pyridyl) methylthio] is added dropwise]
ethylamine (from the dihydrobromide: 3.5 g, 10.6 mmol) [pre
prepared according to the method of the Belgian patent 779,775] in 25 ml of
dry methanol in 30 minutes to a suspension of 3,4-dimethoxy-1,2,5
thiadiazole 1,1-dioxide in 200 ml of dry methanol, with stirring,
cooled to 0-5 C in an ice-water bath. After 15 minutes of
the cold solution is stirred, the methylamine is bubbled
anhydrous in the solution for 15 minutes.The mixture is shaken
reaction at room temperature for 45 minutes, evaporate
under reduced pressure and the residue is recrystallized by means of
methanol. Two recrystallizations in methanol make it possible
hold the title compound (mp: 168-1710C).

The compound obtained has the empirical formula: C1 1H1 5N502S2
and his elemental analysis leads to the following results:
CHNS
calculated: 42.15 4.22 22.35 20.46
found: 42.07 4.75 22.28 20.73
EXAMPLE 28 3- {2 - [(4-methyl-1,2,5-oxadiazol-3-yl) methylthio] ethylamino} -4-methylamino
1,2,5-thiadiazole 1,1-dioxide
A. 3-hydroxymethyl-4-methylfurazan
To a solution of 3-methyl-4-furazancarboxylic acid (27.0 g;
0.21 moles) in 180 ml of tetrahydrofuran (with stirring and re
cold in an ice-cold water bath under a nitrogen atmosphere),
dropwise, a 1.02M solution of borane in tetrahydro
furan (825 ml, 0.84 mole). When the addition is complete,
continue stirring at room temperature for 20 hours
about. Then, 6N HCl is added dropwise until it stops.
hydrogen evolution and the reaction mixture is evaporated under
reduced pressure. The residue is partitioned between methylene chloride
and water is alkalinized with potassium carbonate,
collects the organic phases, dries, then evaporates under pressure
reduced to obtain 21.0 g of product. By vacuum distillation,
the title compound is obtained (PE: 99 C / 1 mmHg).

B. 2- [t4-methyl-1,2,5-oxadiazol-3-yl) methylthio] -ethylamine
A solution of 3-hydroxymethyl is heated under reflux with stirring.
4-methylfurazane (2.49 g, 21.8 moles) [prepared in Step A] and
of 2-amino-ethanethiol hydrochloride (2.48 g, 21.8 mmol) in
60 ml of 48% aqueous hydrobromic acid for 23 hours, then
stirring is continued for 40 hours at room temperature. We
remove excess HBr under reduced pressure and dissolve the residue
oily in isopropanol, filters on celite and recrystallizes the
produced in the filtrate. By recrystallization from isopropanol,
the title compound is obtained in the form of hydrobromide
(Mp 142-143 ° C).

C. 3- {2 - [(4-methyl-1,2,5-oxadiazol-3-yl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1-dioxide
A methanolic suspension of 3,4-dimethoxy-1,2,5-thia is treated.
1,1-dioxide diazole successively by an equimolar amount of
2 - [(4-methyl-1,2,5-oxadiazol-3-yl) methylthio] ethylamine [m.p.
prepared in step B] and an excess of methylamine according to the method
general of Example 2; the title compound is obtained.

EXAMPLE 29

3- {2 - [(5-methyl-1,2,4-oxadiazol-3-yl) methylthio] ethylamino} -4-methylamino 1, 2,5-thladiazole 1,1-dioxide
A. 2 - [(5-methyl-1,2,4-oxadiazol-3-yl) methylthio] ethylamine
Cysteamine hydrochloride (3.03 g, 26.7 mmol) is added
several servings over a 10 minute period to a solution
sodium methoxide (2.89 g, 53.4 mmol) in 50 ml of methanol
at 0 C with stirring. After 70 minutes of agitation at OOC, we add
dropwise a solution of 3-chloromethyl-5-methyl-1,2,4-oxadia-
zole (3.54 g, 26.7 mmol) in 15 ml of methanol in 15 minutes,
and the reaction mixture is allowed to stir at room temperature
room temperature for 16 hours.The mixture is filtered, evaporated and
in isopropanol, then filtered, evaporated under pressure
selected to afford the title compound (5.64 g) as a
yellow oil. The NMR spectrum (60 MHz) in CDCl3 gives the peaks of
following resonances
d: 3.77 (s, 2H); 2.77 (m, 4H); 2.63 (s, 3H).

B. 3- {2 - [(5-methyl-1,2,4-oxadiazol-3-yl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1-dioxide
A methanolic suspension of 3,4-dimethoxy-1,2,5-thiadia is treated
zole 1,1-dioxide successively with 2 - [(5-methyl-1,2,4-oxadiazole)
3-yl) methylthio] ethylamine prepared in step A] and methyl
laminate, according to the general method of Example 2, and the
composed in section.

EXAMPLE 30

3- {2 - [(2-methyl-1,3,4-oxadiazol-5-yl) -4-methylamino} méthylthioléthylamino
1,2,5-thiadiazole 1,1-dioxide
A. 2 - [(2-methyl-1,3,4-oxadiazol-5-yl) methylthio] ethylamine
Cysteamine hydrochloride (1.13 g, 0.01 mol) was added to a
sodium methoxide solution (1.08 g, 0.02 mol) in 20 ml of
methanol at 0 ° C. under an argon atmosphere and with stirring. We shake
the mixture for 1 hour at 0 C then, we add the suspension ob
held, drop by drop, in 25 minutes, with a solution of 2-methyl
5-chloromethyl-1,3,4-oxadiazole (1.32 g, 0.01 mol) [prepared according to
the method described in Hel. Chim. Acta, 55, 1979 (1972) 1 in
15 ml of methanol at 0 C with stirring.
at room temperature for 45 minutes, concentrates almost
dry, then dilute with CH2Cl2, filter, and finally evaporate
under reduced pressure to obtain the title compound (1.92 g)
in the form of a yellow oil. The NMR spectrum (60 MHz) in CDCl3
gives the following resonance peaks:
#: 3.87 (s, 2H); 2.8 (m, 4H); 2.53 (s, 3H).

. 3- {2 - [(2-methyl-1,3,4-oxadiazol-5-yl) methylthio] ethylamino} -4-methyl
1,1,5-lamino-thiadiazole 1,1-dioxide
A suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-diol is treated.
by an equimolar amount of 2 - [(2-methyl-1,3,4-oxadiazole)
5-yl) methylthiolethylamine prepared in step A] and by an excess
methylamine according to the general procedure of Example 2 and
the subject compound.

EXAMPLE 31 3- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -4-methylamino
1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylaminomethyl) is added dropwise.
2-thienyl) -methylthiolethylamine (1.0 g, 4.34 mmol) prepared according to
the method of the Belgian patent 867.105] in 25 ml of dry methanol
in 35 minutes, to a solution of 3,4-dimethoxy-1,2,5-thiadiazole
1,1-dioxide (0.77 g, 4.34 mmol) in 150 ml dry methanol, hand
stirred with 0-3 C in an ice-water bath. When the addi-
tion is complete, methylamine is passed into the solution
for 10 minutes and stirring is continued for 15 minutes.
evaporate the reaction mixture under reduced pressure and place the
residue on 50 g of silica gel then. one chromatographs using a
elution gradient of acetonitrile-methanol. Fractions are brought together
interesting and we get 1.0 g of product. By recrystallation
in methanol, the title compound is obtained (mp 60.5-66 ° C).

EXAMPLE 32 3- {2 - [(5-Dimethylaminomethyl-2-furyl) methylthiolethylamino} -4-ethylamino
1,2,5-thiadiazole 1-oxide
A solution of 2 - [(5-diniethylaminomethyl) is added dropwise.
2-furyl) -methylthio] ethylamine (2.64 g, 12.3 mmol) in 25 ml of
dry methanol in 30 minutes to a solution of 3,4-dimethoxy-1,2,5
thiadiazole 1-oxide (2.0 g, 12.3 mmol) in 75 ml of dry methanol,
cooled to 8 ° C. with an ice-water bath and with stirring ener
cal. After 15 minutes of additional stirring, add
4.0 ml of ethylamine and the mixture is stirred at room temperature
for 1 hour.The reaction mixture is evaporated under pressure
reduced, the residue is placed on 55 g of silica gel, then chroma
tography using a methylene chloride elution gradient
methanol. We gather the interesting fractions, we evaporate under
reduced pressure and the residue is treated with ether and decanted.

The residue is then treated with fresh ether and 1.5 g are obtained.
of the title compound (mp 68-740C).

The compound obtained has the formula:
C14H29N5O2S2
and his elemental analysis leads to the following results:
CHNS
Calculated: 47.04 6.48 19.59 17.94
found: 46.54 6.33 19.37 17.96
after correction (1,242 H20)
EXAMPLE 33

3- {2 - [(5-dimethylaminomethyl-2-furyl) mét
1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylaminomethyl) is added dropwise.
2-furyl) -methylthiolethylamine (2.41 g, 11.2 moles) in 25 ml of
dry methanol in 30 minutes to a suspension of 3,4-dimethoxy-1,2,5-
Thiadiazole 1,1-dioxide (2.0 g, 11.2 mmol) in 200 ml of methanol
dry, cooled to 2 ° C. with an ice-water bath and with stirring ener
cal. After 15 minutes, 4.0 ml of n-propylamine of one
blow and stir the mixture at room temperature for 30 minutes.
utes. The reaction mixture is evaporated under reduced pressure,
the residue is placed on 55 g of silica gel and chromatographed using
reading a methylene chloride-methanol elution gradient. We have
seems the interesting fractions, evaporates under reduced pressure and
crystallize the syrup in ether to obtain 3.7 g of
topical compound (mp: 164-166 C); the NMR spectrum (100 MHz) in
dimethyl sulfoxide d6 indicates the presence of 0.9 moles of methanol
about.

The compound obtained has the empirical formula:
C15H25N5O3S2, 9/10 CH4O
and his elemental analysis leads to the following results:
CHNS
calculated: 45.86 6.92 16.82 15.40
found: 45.60 6.93 17.03 15.47
EXAMPLE 34. 3-Amino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -
1,2,5-thiadiazole 1-oxide
A solution of 2 - [(5-dimethylaminomer) is added dropwise.
thyl-2-furyl) -methylthiolethylamine (3.3 g, 15.4 moles) in 25 ml
methanol in 30 minutes, to a solution of 3,4-dimethoxy-1,2,5-
thiadiazole 1-oxide (2.5 g, 15.4 mmoles) in 75 ml of methanol
with stirring and cooled to 8 ° C. in an ice-water bath.
1 hour 30 minutes of stirring, ammonia is bubbled
anhydrous in the solution for 8 minutes and stirring continued
mixture at room temperature for 30 minutes, evaporate
the reaction mixture under reduced pressure, the residue is placed on
60 g of silica gel and chromatographed using a gradient of e--
methylene chloride-methanol. Fractions are collected
interesting and evaporate, then crystallize the product in the
ketonitrile. By recrystallization from isopropanol, we obtain
2.59 g of the title compound (mp 139-1420C).

The compound obtained has the empirical formula:
C12H19N5O2S2
and his elemental analysis leads to the following results:
CHNS
Calculated: 43.75 5.81 21.26 19.46
found: 43.71 6.05 21.32 19.51
EXAMPLE 35

3-amino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -1,2,5
thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylaminomethyl)
2-furyl) methylthio] ethylamine (2.5 g, 11.7 mmol) in 50 ml of
dry methanol in 45 minutes, to a suspension of 3,4-dimethoxy
thiadiazole 1.1 dioxide (2.08 g, 11.8 mmol)
in 200 ml of dry methanol, cooled to 5 ° C. using a water bath
iced, and with stirring. After 30 minutes, stirring, do
douse anhydrous ammonia in the solution for 10 minutes
and mixing is continued at room temperature
for 8 hours.The reaction mixture is evaporated under pressure
reduced, the residue is placed on 200 g of silica gel and chromatogra
using a methylene chloride-methanol elution gradient.

We collect the interesting fractions and evaporate to obtain
3.6 g of product. By recrystallization from a methanol mixture
ether, the title compound (mp 156-1580 ° C) was obtained.

The compound obtained has the empirical formula:
C12H19N5O3S2
and his basic analysis leads to the following results:
CHNS
Calculated: 41.72 5.54 20.28 18.56
found: 41.50 5.52 20.33 18.74
EXAMPLE 36

3-amino-4- {2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -1,2,5
thiadiazole 1-oxide
A solution of 2 - [(guanidinothiazol-4) is added dropwise
yl) methylthio] ethylamine (from the dihydrochloride, 6.08 g;
20.0 mmol) in 50 ml of methanol, in 45 minutes, to a solution
3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (3.24 g, 20.0 mmol)
in 150 ml of methanol at 5 ° C. with vigorous stirring. After
1 hour stirring at 5-100C, ammonia is bubbled
anhydrous in the solution for 10 minutes and continue
at room temperature for 18 hours. We evaporate the
reaction mixture under reduced pressure, the residue is
65 g of silica gel and chromatographed using a gradient
elution methylene chloride-methanol.The fractions are collected
interesting and then evaporated to obtain 4.16 g of product
from methanol. By recrystallization in methanol, we obtain
appears in section (PF: 167-1700C with decomposition).

The compound obtained has the formula:
C9H14N80S3
and his basic analysis leads to the following results:
CHNS
Calculates: 31.20 4.07 31.35 27.76
found: 30.39 3.97 32.25 27.91
*
after correction (0.48% H20)
By recrystallization of the crude product in 95% ethanol,
the title compound is obtained as monohydrate
(Mp 136-1380C with decomposition).

The compound obtained has the empirical formula:
C9H14N8OS3, H2O
and his elemental analysis leads to the following results:
CHNS
Calculates: 29.66 4.42 30.75 26.39
found: 29.92 4.42 30.84 26.58
A sample of the product is suspended in the form of
free base in 95% ethanol, treated with an equivalent of
Aqueous HCl 6, ON and filtered to obtain the hydrochloride (mp 200
201 C with decomposition).

The compound obtained has the empirical formula:
C9H15ClN8OS3
and his basic analysis leads to the following results:
CHNS
Calculated: 28.23 3.95 29.26 9.26
found *: 28.26 3.83 29.41 9.53
* after correction (1.02SH20)
EXAMPLE 37

3-Benzylamino-4- {2 - [(5-dimethylaminomethyl-2-furyl) -methylthio] ethylamino} 1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylaminomethyl) -2-
furyl) methylthiolethylamine (2.4 g, 11.2 mmol) in 30 ml of
dry methanol in 35 minutes to a solution of 3,4-dimethoxy-1,2,5-
thiadiazole 1,1-dioxide (2.0 g, 11.2 mmol) in 200 ml of methanol
dry cooled to 1-3 C in an ice-water bath, with stirring. After
Stirring for 15 minutes at 1-30C, benzylamine (1.8 g,
1.83 ml; 16.8 mmol) and the solution is stirred for 1 hour at room temperature
room. The reaction mixture is evaporated under reduced pressure
and the residue is placed on 50 g of silica gel and then chromatographed
using a methylene chloride-methanol elution gradient.

We collect the interesting fractions and we obtain 4.1 g of pro
Duit. Recrystallization from aqueous methanol and then
thanol, the title compound is obtained (mp 152 C with decomposition
tion); the NMR spectrum (100 MHz) in dimethyl sulfoxide d6 in
indicates the presence of about 1.0 mole of methanol.

The compound obtained has the empirical formula: C19H25N503S2, CH40
and his elemental analysis leads to the following results:
CHN
Calculates: 51.37 6.25 14.98
found: 51.51 6.05 14.78
EXAMPLE 38

3- {2 - [(3- {dimethylaminomethyl} phenyl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(3- {dimethylaminomer
thyl) phenyl) methylthio} ethylamine (2.51 g, 11.2 mmol) prepared
according to the method of Belgian Patent 867,106] in 25 ml of
dry methanol in 30 minutes to a suspension of 3,4-dimethoxy-1,2,
5-thiadiazole 1,1-dioxide (2.0 g, 11.2 mmol) in 200 ml of metha
dry mass with stirring cooled to 20C in an ice-water bath.

After stirring for 15 minutes at 2-5 ° C., methyl is bubbled
anhydrous lamination in the solution for 10 minutes and shake the
solution at room temperature for 30 minutes. We evaporate
then the reaction mixture under reduced pressure and place
the residue on 60 g of silica gel and chromatographed using a
elution gradient CH2Cl2-niethanol. We bring together the fractions
and 2.96 g of product are obtained. By recrystallization
in acetonitrile and then in methanol, the compound is obtained
in section (PF: 152-158 C); the NMR spectrum (100 mHz) in the dimé
thyl sulfoxide d6 indicates the presence of 0.6 mole of methanol in
viron.

The compound obtained has the empirical formula:
C15H23N5O2S2, 3/5 CH4O
and his elemental analysis leads to the following results:
CHNS
calculated: 48.20 6.59 18.02 16.49
found: 47.99 6.78 17.81 16.09
EXAMPLE 39

3-amino-4 {2 - [(3- {dimethylaminomethyl] phenyl} methylthio] ethylamino} -1,2,5
thiadiazole 1-oxide
A solution of 2 - [(3-dimethylaminomethyl) is added dropwise.
phenyl) -methylthio] ethylamine (2.77 g, 12.3 mmol) in 25 ml of
dry methanol in 45 minutes to a solution of 3,4-dimethoxy-1,2,5
thiadiazole 1-oxide (2.0 g, 12.3 mmol) in 100 ml of methanol
dry, cooled to 50C in an ice-water bath and under stirring
vigorous.When the addition is complete, stirring continues
of the solution at room temperature for 1 hour 30, and then
it is cooled to 50 ° C. and anhydrous ammonia is bubbled through
the solution during 8 r, linutes. After 16 hours of agitation at the
at room temperature, the mixture is evaporated under reduced pressure,
the residue is put on 55 g of silica gel and
using a CH2Cl2-methanol elution gradient. We bring together
interesting fractions and we obtain 3.0 g of product by crystal
in acetonitrile. By recrystallization from acetone,
the title compound is obtained (mp 122-1250 ° C).

The compound obtained has the empirical formula:
C14H21N50S2
and his elemental analysis leads to the following results:
CHNS
Calculated: 49.53 6.23 20.63 18.89
found: 49.18 6.08 20.93 19.25
EXAMPLE 40

3- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] - @
mino-1,2,5-thiadiazole 1-oxide
A solution of 2 - [(5-dimethylaminomethyl) is added dropwise.
2-thienyl) methylthio] ethylamine (1.5 g, 6.5 mmol) in 25 ml of
dry methanol in 45 minutes to a solution of 3,4-dimethoxy-1,2,5-
thiadiazole 1-oxide (1.06 g, 6.5 mmol) in 150 ml of dry methanol,
cooled to 3 C in an ice-water bath, with stirring. After
15 minutes at 30 ° C., anhydrous methylamine is bubbled through
the solution for 5 minutes and continue the agitation of the so
lution for 15 minutes.After 16 hours resting at the temperature
ambient, the reaction mixture is evaporated under reduced pressure
and the residue is put on 75 g of silica gel and then chromatography
using an elution gradient of acetonitrile e-methanol. We gather
fractions of interest to obtain a crystallized product
by recrystallization from acetonitrile. A recrystallization
in acetonitrile gives the title compound
(Mp 98.6-102 ° C).

The compound obtained has the empirical formula:
C13H21N50S3
and his elemental analysis leads to the following results:
CHNS
calculated: 43.42 5.89 19.48 26.76
found: 43.70 5.58 19.71 26.79
EXAMPLE 41

3-amino-4- {4- (5-dimethylaminomethyl-2-furyl) butylamino}
zole 1,1-dioxide
A solution of 4- (5-dimethylaminomethyl) is added dropwise.
2-furyl) -butylamine (1.61 g, 8.2 mmol) in 25 ml of dry methanol,
in 35 minutes to a suspension of 3,4-dimethoxy-1,2,5-thiadiazole
1,1-dioxide (1.46 g, 8.2 mmol) in 150 ml of dry methanol, cooled
die at 0-3 C by an ice-water bath and stirring. After 15
minutes of stirring, anhydrous ammonia is bubbled through
the solution for 5 minutes and the solution is stirred for 30 minutes.
minutes. The reaction mixture is evaporated under reduced pressure,
and the residue is placed on 60 g of silica gel and chromatography is carried out
using an acetonitrile-methanol elution gradient. We gather
ble the interesting fractions and evaporate to obtain 1.68 g
by recrystallization in acetonitrile, we obtain
the above issues (PF: 154-156 C).

The compound obtained has the empirical formula: C1 3H2 1N503S
and his elemental analysis leads to the following results:
CHNS
Calculated: 47.69 6.47 21.39 9.80
found: 47.73 6.28 21.43 9.84
EXAMPLE 42 3-amino-4- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino} -
1,2,5-thiadiazole 1,1-dioxide
A solution of 2- (2-dimethylaminolethyl)
4-thiazolyl) methylthioethylamine (0.9 g, 3.89 mmol) in 20 ml
of dry methanol in 40 minutes to a suspension of 3,4-dimethoxy
1,2,5-thiadiazole 1,1-dioxide (0.69 g, 3.89 mmol) in 70 ml of
methanol, with stirring, at 80C. Ammonia is bubbled
anhydrous in the solution for 8 minutes then, leave the solution
stirring at room temperature for 18 hours.

The reaction mixture is evaporated under reduced pressure and
put the residue on 150 g of silica gel and chromatography
using an elution gradient of acetonitrile-methanol. We
combines the good and interesting fractions and evaporates for
obtain 0.66 g of product. The foam is dissolved in 2-propanol
and evaporated to dryness to obtain the title product (PF: 60
650C); the NMR spectrum (100 MHz) in dimethyl sulfoxide d6
indicates the presence of about 0.15 moles of 2-propanol.

The compound obtained has the empirical formula:
C11H18N6S3O2, 3/20 C3H8O
and his elemental analysis leads to the following results:
CHNS
calculated: 37.02 5.21 22.62 25.89
Found *: 36.75 5.13 21.75 25.03
*
after correction (2.79% H2O)
EXAMPLE 43

3- {2 - [(2-guanidinothiazol-5-yl) -4-methylamino} méthylthioléthylamino
1,2,5-thiadiazole 1,1-dioxide
A. Methyl 2-guanidino-5-thiazolecarboxylate hydrochloride
A solution of amidinothiourea (117 g, 099 mmol) is stirred.
and ethyl chloro-α-formylacetate so g; 1.0 mole) in 3.5
liters of absolute ethanol at room temperature for 18
hours, then heated at reflux temperature for 1 hour.

Ethyl chloro-α-formylacetate (20.09, 0.13) is then added
mole) and 1 hour later another 20.0 g of chloro-a were added.
ethyl formylacetate. After 2 hours of additional heating
at reflux temperature, the reaction mixture is evaporated under
reduced pressure and the residue is triturated with 1.5 liters of acetone,
in the filter and gets 103 g of product. By recrystallization
in 2-propanol gives the title compound (mp 204-206 ° C).

The compound obtained has the empirical formula: C7H11ClN402S
and its elemental analysis leads to the following results:
CHN Cl S
Calculated: 33.53 4.43 22.35 14.14 12.79
found: 33.38 4.40 22.54 13.97 12.92
B. 2-guanidino-5-hydroxymethylthiazole
2-Guanidino-5-thiazolecarboxylate hydrochloride is added
of ethyl (1.0 g, 3.99 mmol) [prepared in Step A] at a
suspension of lithium aluminum hydride (0.46 g; 12-1 mmol)
in suspension in 25 ml of tetrahydrofuran, cooled in
a bath of ice water.The mixture is then heated to the temperature
reflux for 2 hours, cooled, decomposed by 0.46 ml
of water, 0.46 ml of 15% NaOH and 1.38 ml of H 2 O, and filtered. Dry
the filtrate and evaporated under reduced pressure to obtain
0.61 g of product. By recrystallization from acetonitrile,
the title compound is obtained (mp: 168-1700C).

The compound obtained has the empirical formula:
C5H8N40S
and his elemental analysis leads to the following results:
CHNS
calculated: 34.87 4.68 32.54 18.62
found: 34.55 4.52 32.63 18.54
C. 2 - [(2-Guanidinothiazol-5-yl) methylthio] ethylamine
The cysteamine hydrochloride (10.6 g, 9.3 mmol) was dissolved and
2-guanidino-5-hydroxymethylthiazole (16.0 g, 9.3 mmol) [pre
prepared in step B] in 80 ml of concentrated HCl and the mixture is stirred
solution at room temperature for 1 hour, then warm
at reflux temperature for 3 hours. We cool the
the reaction mixture, the alkalinity (pH 11) with 40% aqueous NaOH and the
filter to obtain 15 g of product. By recrystallization in
acetonitrile, the title compound (mp 150-15 ° C) was obtained.

The compound obtained has the empirical formula: C7H1 3N5S2
and his elemental analysis leads to the following results:
CHNS
calculated: 36.34 5.66 30.27 27.72
found: 36.29 5.70 30.40 27.64
D. 3- {2 - [(2-Guanidinothiazol-5-yl) methylthio] ethylamino} -4-methyl
1,1,5-lamino-thiadiazole 1,1-dioxide
A 2 - ((2-guanidinothiazol-5) solution is added dropwise.
yl) -methylthio] ethylamine (2.0 g, 8.64 mmol) [prepared in
step C] in 60 ml of methanol in 40 minutes, to a suspension of
3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.54 g, 8.64 mmol)
in 160 ml of methanol, with vigorous stirring, cooled
at 8 C in a bath of ice water. While maintaining the tempe
at 8 ° C., anhydrous methylamine is bubbled into the
the solution for 8 minutes. After 18 hours of agitation at the
room temperature, the reaction mixture is evaporated under reduced pressure.
reduced and the residue is placed on 175 g of silica gel, then
chromatography by an elution gradient of acetonitrile-methyl-
ethanol. We bring together the good and interesting fractions and we get
1.3 g of product. By recrystallization in methanol
contains the title compound (mp: 225-2260C with decomposition).

The compound obtained has the empirical formula: C10H16N802S3
and his elemental analysis leads to the following results:
CHNS
calculated: 31.90 4.28 29.76 25.55
found: 32.07 4.14 29.91 25.60
EXAMPLE 44

3-amino-4- {2 - [(2-guanidinothiazol-5-yl) methylthio] ethylamino} -1,2,5
thiadiazole 1-oxide
A solution of 2 - [(2-guanidionthiazol) is added dropwise
5-yl) methylthio] ethylamine (3.0 g, 1-3.0 mmol) [prepared in
Example 43, step C] in 70 ml of methanol in 40 minutes at
a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.1 g;
13.0 mmol) in 200 ml of methanol, cooled to 8 ° C. under
vigorous stirring, then anhydrous ammonia is bubbled
in the solution for 8 minutes. After 18 hours of agitation
at room temperature the reaction mixture is evaporated under
reduced pressure, then the residue is placed on 225 g of silica gel
and chromatographed with an acetonitrile-me-
ethanol. The interesting fractions are combined and 3.6 g are obtained.
of the title compound (mp 85-132 ° C); the NMR spectrum (100 MHz)
in dimethyl sulfoxide d6 indicates the presence of 0.3 mol
about acetonitrile,
The compound obtained has the empirical formula:
C9H14N8OS3, 3/10 C2H3N
and his elemental analysis leads to the following results:
CHNS
calculated: 32.24 4.22 32.41 26.71
found: 32.63 4.33 32.55 26.62
after correction (1.84X H20)
EXAMPLE 45

3-cyclopropylamino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio]
ethylamino} -1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method Example 8 except that we reme
place 2-propynylamine by an equimolar amount of cyclo
propylamine, and the product is recrystallized from methanol.

Recrystallization from isopropanol gives 3.5 g of
in issue (PF: 194-1950C with decomposition). The spec
NMR (100 MHz) in dimethyl sulfoxide d6 indicates the meadow
about 1.0 mole of isopropanol.

The compound obtained has the empirical formula: ClsH23NsO3S2sC3H80
and his elemental analysis leads to the following results:
CHN
Calculated: 48.52 7.01 15.72
found: 48.36 6.95 14.87
EXAMPLE 46 3-cyclopropylmethylamino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio]
ethylamino} -1,2,5-thiadiazole 1,1-dioxide
The general procedure of Example 8 is repeated except that the
2-propynylamine by an equimolar amount of cyclopropylmethyl
amine, and crystallize the product from methanol. By
recrystallization from methanol gives 1.6 g of the compound
in section (PF: 86-89 C with decomposition); the NMR spectrum
(100 MHz) in dimethyl sulfoxide d6 indicates the presence of
1.25 moles of methanol.

The compound obtained has the formula:
C16H25N5O3S2, 5/4 CH4O
and his basic analysis leads to the following results:
CHN
Calculated: 47.13 6.88 15.93
found: 47.40 6.49 15.77
after correction (0.68% H20)
EXAMPLE 47

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-morpho
lino-1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 19 except that
replaces dimethylamine with an equimolar amount of
pholine. After column chromatography, crystallize
the product from isopropanol. The mixture is diluted with
skellysolve B and filtered to give the title compound (mp: 122-1270C).

The compound obtained has the empirical formula:
C16H25N504S2
and his elemental analysis leads to the following results:
CHN
Calculated: 46.24 6.06 16.86
found: 45.82 6.06 16.62 *
after correction (0.61% H20)
EXAMPLE 48

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4- (2-metho
xyethylamino) -1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 8 except that
place 2-propynylamine by an equinolar amount of 2-metho
xyéthylamine. After performing column chromatography,
the residue is treated with isopropanol, evaporated almost to dryness
and cooled, 3.79 g of product are obtained. Recrystallization
in isopropanol provides the title compound (mp: 56
580C); the NMR spectrum (100 MHz) in dimethyl sulfoxide d6 in
indicate the presence of 0.6 mole of isopro-panol.

The compound obtained has the empirical formula:
C15H25N504S2, 2/5 C3H80
and his elemental analysis leads to the following results:
CHN
calculated: 45.90 6.83 15.93
found: 45.50 6.72 15.63
*
after correction (0.74% H2O)
EXAMPLE 49

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino] -4
pyrrolidino-1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 19 except that
replaces dimethylamine with an equimolar amount of pyr
rolidine. The reaction mixture is evaporated under reduced pressure.
pickled, treated with isopropanol and filtrate, to obtain 3.9 g of
featured in section (PF: 151-1520C).

The compound obtained has the empirical formula:
C16H25N503S2
and his elemental analysis leads to the following results:
CHN
calculated: 48.09 6.31 17.53
found: 48.00 6.10 17.71
EXAMPLE 50

3- {2 - [(5-dimethylaminomethyl-2-furyl) -4-méthylthioléthylamino} Piperi
dino-1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 19 except that
replaces dimethylamine with an equimolar amount of pipé
ridine. Chromatography makes it possible to obtain 3.8 g of product.

Recrystallization from hot aqueous ethanol yields
the title compound (mp 106-1080C).

The compound obtained has the empirical formula: C 18 H 27 N 5 O 3 S 2
and his elemental analysis leads to the following results:
CHN
Calculated: 49.37 6.58 16.94
found *: 49,17 6,52 17,14
after correction (0.2% H 2 O) EXAMPLE 51. 3-Butylamino-4- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylate
mino} -1,2,5-thiadiazole 1,1-dioxide
The procedure is as in the general method of Example 8 except that
place 2-propynylamine by an equimolar amount of butyla
mine. The crude product is chromatographed 3 times and
hot dry under high vacuum for 3 hours 30 minutes for
obtain 1.81 g of the title compound as a foam
more or less rubbery.

The compound obtained has the empirical formula:
C16H27N503S2
and his elemental analysis leads to the following results:
CH
Calculated: 47.86 6.78 17.44
found: 47.60 6.81 17.81
*
after correction t1,34% H2O)
EXAMPLE 52

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4 - [(2-py
ridyl) methylamino} -1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 8 except that
replaces 2-propynylamine with an equimolar amount of
2-aminomethylpyridine. We gather the interesting fractions
Column chromatography and we get 3.9 g of-pro
Duit. By 2 recrystallizations in isopropanol, we obtain
in the section (PF: 43-450C). We are recrystallizing an exchange
in absolute ethanol and the solid is heated under vacuum
at 60 C for 6 hours to obtain a fade. Dissolve hot
this melted in isopropanol, isolated by filtration at temperature
room temperature and dried under high vacuum to obtain the compound
heading (PF: 45-470C); the NMR spectrum (100 MHz) in dimethyl
sulfoxide d6 indicates the presence of 1.25 moles of isopropanol
about.

The compound obtained has the empirical formula:
C18H24N60352, 5/4 C3HsO
and his elemental analysis leads to the following results:
CHN
Calculated: 51.05 6.70 16.42
Found *: 51.08 6.32 16.03
* after correction (0.58% H2O)
EXAMPLE 53

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio} ethylamino] -4-hydro
xylamino-1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 8 except that
replaces 2-propynylamine with an equimolar amount of hydroxy
the mine. The crude reaction mixture, which
allowed to deposit the product in the form of an oil until
that all the product crystallizes, then filtered and dried;
2.59 g of the title compound are obtained (mp 203-2050 ° C).

The compound obtained has the empirical formula: C12H19N504S2
and his elemental analysis leads to the following results:
CHNS
calculated: 39.87 5.30 19.38 17.74
found: 39.53 5.04 19.61 17.62
* after correction (1.18% H2O)
EXAMPLE 54

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-dodecyl
1,1,5-lamino-thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylamino) is added dropwise
methyl-2-furyl) -methylthio] ethylamine (2.41 g, 11.2 mmol) in
25 ml of methanol to a cold suspension of 3,4-dimethoxy-1,2,5
thiadiazole 1,1-dioxide (2.0 g, 11.2 mmol) in 200 ml of
thanol with energetic agitation. After 15 minutes of agitation a
2-5 C., a solution of dodecylamine is added in one go
(4.15 g, 22.4 mmol) in 25 ml of methanol and continue to
at room temperature for 18 hours. We filter the
reaction mixture and evaporated under reduced pressure,
the residue on 60 g of silica gel and chromatographed with a
eluting methylene chloride-methanol.
good fractions, evaporate and rechromatograph the residue on
60 g of silica gel using an acetonitrile elution gradient
methanol. We combine the interesting fractions of the second
chromatography, concentrated under reduced pressure and isolated
the product crystallized by filtration, dried and obtained 2.13 g
of the title compound (mp: 136-139 C).

The compound obtained has the empirical formula:
C24H45N5O3S2
and his elemental analysis leads to the following results:
CHNS
Calculated: 55.89 8.79 13.58 12.43
found: 56.16 8.57 13.38 12.61
EXAMPLE 55

3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4-metho
xyamino-1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 8 except that
replaces 2-propynylamine with an equimolar amount of
thoxyamine. The reaction mixture is stirred at room temperature
ambient during 16 hours, during this time a
crystallized precipitate. The solution is cooled and filtered,
The product thus isolated is dried and 3.8 g of the compound are obtained.
heading (PF: 224-226C with decomposition).

The compound obtained has the empirical formula:
C13H21N504S2
and his elemental analysis leads to the following results:
CHNS
Calculated: 41.59 5.64 18.65 17.08
found: 41.25 5.54 18.50 17.16
*
after correction (0.79% H2O)
EXAMPLE 56 3- {2 - [(5-Dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -4-pro-
pylamino-1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 31 except that
replaces methylamine with an equimolar amount of propyla
mine. Chromatography gives 3.5 g of crystallized product.

Recrystallization from acetonitrile gives the compound
in section (PF: 194-1960C with decomposition).

The compound obtained has the empirical formula:
C15H25N5O2S3
and its basic analysis leads to the following results:
CHNS
Calculated: 44.64 6.24 17.35 23.84
found: 44.66 6.02 17.88 23.87
EXAMPLE 57

3-amino-4- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamino}
1,2,5-thiadiazole 1-oxide
A solution of 2 - [(5-dimethylaminomer) is added dropwise.
2-thienyl) methylthio] ethylamine (2.84 g, 12.3 mmol) in
25 ml of methanol in 35 minutes, with a solution of 3,4-dimethoxy
1,2,5-thiadiazole 1-oxide (2.0 g, 12.3 mmol) in 200 ml of
methanol with stirring, cooled to 3 C with an ice-water bath.

After stirring for 15 minutes, ammonia is bubbled
anhydrous for 5 minutes in the solution. We evaporate the mixture
reaction under reduced pressure, the residue is placed on 60 g of
silica gel and chromatographed using an elution gradient
methylene chloride-methanol. We collect the fractions of interest
and 1.73 g of product are obtained. By recrystallization in
acetonitrile, the title compound is obtained (mp 149-1520 ° C).
with decomposition).

EXAMPLE 58 3- (2 - [(5-Dimethylaminomethyl-2-thienyl) methylthi
ridyl) methylamino] -1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 31 except that
replaces methylamine with an equimolar amount of 3-amino
methylpyridine. Interesting fractions of chromatography
on column give 3.10 g of the title compound as
of an oil. The product is dissolved in an excess of 5% HCl,
evaporate and triturated in isopropanol to obtain a product
solid. Recrystallization from 95% aqueous ethanol
obtain the title compound as the dihydrochloride
(Mp 143-146 ° C).

The compound obtained has the empirical formula:
C18H26Cl2N6O2S3
and his elemental analysis leads to the following results:
CHNS
calculates: 41.13 4.99 15.99 18.30
found *: 41.25 4.90 16.18 18.52
*
after correction (@@@@% H2O)
EXAMPLE 59. 3-amino-4- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -
1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(5-dimethylamino) is added dropwise.
2-thienyl) -methylthiolethylamine (2.0 g, 8.68 mmol) in
25 ml of methanol in 35 minutes, to a solution of 3,4-dimethoxy-
1,2,5-thiadiazole 1,1-dioxide (1.55 g, 8.68 mmol) in 200 ml
of methanol, cooled to 3 C by an ice-water bath, under
tation.After 15 minutes of stirring, it is bubbled
anhydrous monia in the solution for 10 minutes. We evaporate
the reaction mixture under reduced pressure and 3.3 g are obtained
of the title compound.

The NMR spectrum (100 MHz) in dimethyl sulfoxide d6 gives the
resonance peaks:
#: 6.88 (d, 1H); 6.78 (d, 1H); 4.03 (s, 2H); 3.61 (s, 2H);
3.54 (t, 2H); 2.74 (t, 2H); 2.22 (s, 6H);
it also indicates the presence of 2/3 mole of methanol approximately.

EXAMPLE 60

3-benzylamino-4- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethyl
lamino] -1,2,5-thiadiazole 1,1-dioxide
The procedure is as in the general procedure of Example 31 except that
place the methylamine by an equimolar amount of benzylamine.

The reaction mixture is evaporated under reduced pressure to give
hold the product. By recrystallization from methanol with a
treatment with charcoal, 2.63 g of the title compound are obtained
(Mp 203-205.5 ° C with decomposition).

The compound obtained has the formula:
C19H25N502S3
and his elemental analysis leads to the following results:
CHNS
Calculated: 50.53 5.58 15.51 21.30
found: 50.79 5.34 15.78 20.94
EXAMPLE 61

3- [3- (3-diméthylaminométhylphénoxy) propylamino] -4-methylamino
1,2,5-thiadiazole 1,1-dioxide
A solution of 3- [3- (dimethylamino)
methyl) phenoxy] -propylamine (2.73 g, 14.0 mmol) [prepared
according to the process of Belgian Patent 867,106] in 50 ml of
methanol in 60 minutes to a suspension of 3,4-dimethoxy-1,2,5-
thiadiazole 1,1-dioxide (2.5 g, 14.0 mmol) in 250 ml of
methanol cooled to 4 ° C., by an ice-water bath, with stirring
After stirring for 20 minutes, methylamine is bubbled through.
anhydrous in the solution for 10 minutes.They are evaporated
the reaction mixture under reduced pressure and the residue is
75 g of silica gel and chromatographed using a gradient
Elution methylene chloride-methanol. We gather the frac
Interestingly, they are evaporated and then dissolved in the
n-propanol and treated with one equivalent of HCl to obtain
the product in the form of hydrochloride. By recrystallization
in aqueous ethanol, the title compound under
the hydrochloride form (mp 140-1450 ° C).

The compound obtained has the empirical formula: C15H24ClN4O3S
and his elemental analysis leads to the following results:
CHNS C1
calculated: 46.20 6.20 17.96 8.22 9.09
found *: 46,21 6,06 18,24 8,38 9,05
after correction (3.79S H20)
EXAMPLE 62

3- {2 - [(2-diméthylaminométhylthiazol-5-yl) methylthio] ethylamino] -4
methylamino-1,2,5-thiadiazole 1,1-dioxide
A. 5-carbethoxy-2- (N-carbophenoxy-N-methylamino) methylthiazole
(N-Carbophenoxy-N-methylamino) thioacetamide (46.7 g;
0.21 moles) with ethyl α-formylchloroacetate (30.0 g, 0.20).
moles) in 270 ml of 1,2-dichloroethane and heated to reflux
during 2 hours. A supplement of å-formylchloroacetate is added
of ethyl (3.0 g, 0.02 moles) and heating is continued for
1.5 hours. The reaction mixture is extracted using 2
300 ml portions of cold aqueous solution of
5% sodium, then washed with 2 portions of 300 ml of water, then
it is dried over Na2SO4 by evaporation, the product is obtained
in the form of an oil that crystallizes slowly.By recreating
2-propanol, 26 g of the compound are obtained.
heading (PF: 81-83 C)
The compound obtained has the empirical formula: C15H16N2O4S
and his elemental analysis leads to the following results:
CHNS
Calculates: 56.24 5.03 8.74 10.01
found: 56.48 4.97 8.54 10.17
B. 2-hydroxymethyl-5-dimethylaminomethylthiazole
5-Carbethoxy-2- (N-carbophenoxy-N-methylamino) is added
methylthiazole (19.8 g, 0.62 moles) prepared in step AJ
to a suspension of lithium aluminum hydride (6.12 g;
0.16 moles) in 544 ml of dry tetrahydrofuran, cooled
at 5 ° C. with stirring. The reaction mixture is then carried.
reflux for 30 minutes and cool to room temperature.
ambient temperature, then decomposes, filter on celite and
evaporated under reduced pressure. The residue is dissolved in 80 ml
3N HCl and extracted with ether. The pH of the phase is adjusted
aqueous H8 and extracted with methylene chloride. We dry
the organic phase, filtered and then evaporated under vacuum to obtain
6.0 g of the title compound as an oil. The NMR spectrum
(60 MHz) in CDCl3 gives the following resonance peaks:
#: 7.50 (s, 1H); 4.85 (s, 2H); 4.15 (s, 1H); 3.75 (s, 2H);
2.35 (s, 6H).

C. 2-Chloromethyl-5-dimethylaminomethylthiazole hydrochloride
Thionyl chloride (27.4 g;
0.16 moles) to a solution of 5-hydroxymethyl-2-dimethylamino
methylthiazole (8.9 g, 52.0 mmol) [prepared in Step B]
in 300 ml of methylene chloride cooled in a bath
ice water. The reaction mixture is then heated to
flow for 2 hours, cooled and evaporated under pressure
pick to obtain 12.3 g of product. By recrystallization in
acetonitrile, the title compound (mp 143-1440 ° C) was obtained.

The compound obtained has the empirical formula: C7H12Cl 2N2S
and his basic analysis leads to the following results:
CHN Cl
calculated: 37.01 5.32 12.33 31.63
Found *: 36.88 5.11 12.14 31.65
after correction (0.91% H2O)
D. 2 - [(2-dimethylaminomethylthiazol-5-yl) methylethio] ethylamine
Cysteamine hydrochloride (0.2 g, 1.76 mmol) was dissolved
and 5-chloromethyl-2-dimethylaminomethyl hydrochloride
thiazole (0.4 g, 1.76 mmol) prepared in step C] in
2.5 ml of concentrated HCl and the solution is heated to 100 ° C.
in the oil bath. After 2 hours, the mixture is evaporated under
reduced pressure and the residue is made alkaline with a
aqueous solution of 40% NaOH. The aqueous phase is extracted
with methyl acetate and then the organic phase is dried,
filter, evaporated to obtain 0.3 g of the title compound under
the shape of an oil. The NMR spectrum (60 MHz) in COCl3 gives
the following resonance peaks:
d: 7.50 (s, 1H); 3.95 (s, 2H); 3.76 (s, 2H); 2.85 (m, 4H);
2.40 (s, 6H); 1.85 (s, 2H).

3- {2 - [(2-Dimethylaminomethylthiazol-5-yl) methylthio] ethylamino}
4-methylamino-1,2,5-thiadiazole 1,1-dioxide
A solution of 2-L (2-dimethylamino) is added dropwise
methylthiazol-5-yl) methylthio] ethylamine (1.55 g, 6.7 mmol)
[prepared in step D] in 60 ml of methanol in 40 minutes,
to a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole
1,1-dioxide (1.19 g, 6.7 mmol) in 130 ml of methanol
cold at 8 C. When the addition is complete, it is bubbled
anhydrous methylamine delta in the solution for 8 minutes,
then stirred at room temperature for 16 hours in
viron. The reaction mixture is evaporated under reduced pressure
then, the residue is chromatographed on 150 g of silica gel
using an elution gradient acetonitrile e-methanol. We have
seems interesting fractions to get 1.05 g of pro
Duit. Recrystallization from 2-propanol gives the
by title compound (MP: 170-172 C).

The compound obtained has the empirical formula: C12H20N602S3
and his elemental analysis leads to the following results:
CHNS
calculated: 38.28 5.36 22.33 25.56
found: 38.31 5.32 22.13 25.96
EXAMPLE 63

3- {2 - [(2-Guanidinothiazol-4-yl) methylthiolethylamino] -4-methylamino1,2,5-thiadiazole 1-oxide
We operate according to the general method of Example 20 except that
replaces 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with
an equimolar amount of corresponding 1-oxide. We gather
Column chromatography fractions of interest
and 4.5 g of product is obtained. By recrystallization in
the absolute ethanol gives 3.05 g of the title compound.
(Mp 175-177 ° C).

The compound obtained has the empirical formula:
C10H16N8OS3
and his elemental analysis leads to the following results:
CHNS
Calculated: 33.32 4.47 31.09 26.68
found: 33.10 4.42 31.00 26.51
EXAMPLE 64

3- {2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -4-hydroxy
thiadiazole 1-oxide
A solution of 2 - [(2-guanidinothiazol) is added dropwise
4-yl) methylthio] ethylamine (4.15 g, 17.9 moles) in 50 ml
methanol in 30 minutes to a solution of 3,4-dimethoxy-1,2,5-
thiadiazole 1-oxide (2.91 g, 17.9 moles) in 350 ml of
thanol, cooled in an ice-water bath. We treat the melan
reaction with a solution of NaOH (pellets) (3.58 g;
89.5 mmol) in methanol. After about 16 hours of
at room temperature, the mixture is neutralized by
14.9 ml (89.5 mmol) of 6% aqueous HCl, and after 10 minutes,
evaporated under reduced pressure. Triturate the solid residue
during hours with 70 ml of water, at room temperature. We filter and
recubi-llele product. By recrystallization in water, we obtain
the subject compound (mp: 148-1510C).

The compound obtained has the formula:
C9H13N7O2S3
and his elemental analysis leads to the following results:
CHNS
Calculated: 31.11 3.77 28.22 27.69
found *: 30.95 3.76 28.27 28.11,
after correction (5.52% H2O)
EXAMPLE 65

3-amino-4- {2 - [(2-methylguanidino} thiazol-4-yl) methylthio] -éthylami
1,2,5-thiadiazole 1-oxide
A. 2 - {[2- (2-methylguanidino) thiazol-4-yl] methylthio] ethylamine
Cysteamine hydrochloride (1.89 g, 16.6 moles) is mixed
and 2- (2-methylguanidino) -4-chloromethyl hydrochloride
thiazole (4.0 g, 16.6 mmol) prepared from (N-methyl)
midino) thiourea and 1,3-dichloro-2-propanone] in 20 ml
concentrated HCl and the solution is heated in an oil bath at
10u C. After 2 hours of heating, the mixture is evaporated
under reduced pressure and the residue is basified by means of a
aqueous solution of 40% NaOH. The aqueous phase is extracted
repeatedly with methyl acetate and dried
organic phase, filtered and evaporated to obtain 3.35 g of
The NMR spectrum (60 MHz) in D20 gives
the following resonant carasteristic peaks
# 6.52 (s, 1H); 3.60 (s, 2H); 2.70 (m, 7H).

B. 3-amino-4- {2 - [(2- (2-methylquanidino} thiazol-4-yl) methylthio]
ethylamino} -1,2,5-thiadiazole 1-oxide
A solution of 2 - {[2- (2-methylguanidino) is added dropwise
thiaszol-4-yl] -methylthio} ethylamine (2.1 g, 8.56 mmol) [prepa-
re in step A] in 50 ml of methanol in 30 minutes,
a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.39 g;
8.56 moles) in 170 ml of methanol, cooled to 70 ° C. We do
bubble anhydrous ammonia into the solution for 7 minutes
and then stirred at room temperature for about 16 hours.

The reaction mixture is evaporated under reduced pressure and
chromatography the residue on 100 g of silica gel (230-400 mesh)
by "flash chromatography", using an elution gradient
acetonitrile-methanol. We combine the interesting fractions,
evaporate and chromatography the residue on an "HPLC" system
preparative HPLC on silica gel v-porasil. Fractions are brought together
interesting, concentrated to a small volume and filtered for
obtain the title compound (mp: 86-910C); the NMR spectrum
(100 MHz) in dimethyl sulfoxide d6 indicates the presence
about 0.8 moles of ethanol.

The compound obtained has the empirical formula:
C10H16N80S3, 8/10 C2H60
and his elemental analysis leads to the following results:
CHNS
Calculates: 35.06 5.28 28.20 24.21
found: 35.66 5, U5 28.33 23.96
after correction (1.64% H2O)
EXAMPLE 66

3-amino-4- [3- (30diméthylaminométhylphénoxy) propylamino] -1,2,5-thiadia
zole 1-oxide
A solution of 3- [3- (dimethylamino)
methyl) phenoxypropylamine (2.5 g, 12.9 mmol) in 35 ml of
methanol in 30 minutes to a solution of 3,4-dimethoxy-, 2,5-
thiadiazole l-oxide dnas 200 ml of methanol cooled to 2 ° C
in a bath of ice water, with stirring. After 15 minutes
agitation, anhydrous ammonia is bubbled through the
solution for 5 minutes. The reaction mixture is then evaporated
under reduced pressure to obtain a crystal product
Lisa. By 2 recrystallizations in methanol, we obtain the
title compound (MP: 165.5-166.5 C with decomposition).

The compound obtained has the empirical formula: C, 4H21N502S
and his elemental analysis leads to the following results:
CHNS
Calculated: 51.99 6.55 21.66 9.92
found: 51.58 6.49 22.03 10.19
EXAMPLE 67

3-amino-4- {2 - [(2-méthylaminothiazol-4-yl) methylthio] ethylamino}
1,2,5-thiadiazole 1-oxide
A. 2 - [(2-methylaminothiazol-4-yl) methylthio] ethylamine
Chlorhydratedecysteamine (2.8 g, 24.6 mmol) was dissolved
and 2-methylamino-4-chloromethylthiazole (4.0 g, 24.6 mmol)
prepared from N-methylthiourea and 1,3-dichloro-2
propane] in 20 ml of concentrated HCl and the solution is warmed
in an oil bath at a temperature of 1000C. After 30 hours
heating, the reaction mixture is evaporated under pressure
reduced and the residue is basified with a solution
aqueous 40% NaOH. The aqueous phase is extracted using a
methylated, dried, filtered and evaporated to obtain 1.75 g
of the title compound as an oil which is used
in step B without further purification.

B. 3-amino-4- {2 - [(2-methylaminothiazol-4-yl) methylthio] ethylamino} -
1,2,5-thiadiazole l-oxide
The product of step A, above, is reacted successively.
with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide and then ammonia
anhydrous according to the general method of Example 65, step B and
it is chromatographed as usual. Fractions are brought together
of "flash chromatography" and are evaporated
to obtain 0.5 g of product in the form of foam. By recris
in acetone, the title compound is obtained
(Mp 180-1830C with decomposition).

The compound obtained has the empirical formula:
C9H14N60S3
and his elemental analysis leads to the following results:
CHNS
Calculated: 33.94 4.43 26.39 30.21
found: 33.96 4.11 26.27 30.44
after correction (1.41X H20)
EXAMPLE 68

3-amino-4- {2 - [(2- {2,3-dimethylguanidino} thiazol-4-yl) methylthio] ethyl
lamino} -1,2,5-thiadiazole 1-oxide
A. 2 - [(2- {2,3-dimethylguanidino} thiazol-4-yl) dihydrochloride
méthylthioléthylamine
Cysteamine hydrochloride (2.25 g, 19.6 mmol) was dissolved
and 4-chloromethyl-2- (2,3-dimethylguanidino) thiazole (5 g;
19.6 mmol) prepared from 1,3-dichloro-2-propanone and
(N, N'-dimethylamidino) thiourea, itself prepared from
of dimethyl cyanodithioiminocarbonate and methylamine]
in 17.5 ml concentrated HCl and heated in an oil bath
a temperature of 100 C. After 24 hours of heating, one evaluates
pore the reaction mixture under reduced pressure and recryst
tallise the residue in absolute ethanol to obtain the composition
is in heading (PF: 243-245 C).

B. 3-amino-4- {2 - [(2- (2,3-dimethylguanidino} thiazol-4-yl) methylthio] ethylamino} -1,2,5-thiadiazole oxide
The product of step A above is successively reacted
with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide and ammonia
anhydrous according to the general method of Example 65, Step B. On
evaporates the crude reaction mixture under reduced pressure and
recrystallizes the residue in methanol to obtain the compound
in section (PF: 201-2030C with decomposition).

The compound obtained has the empirical formula:
C11H18N8OS3
and his basic analysis leads to the following results:
CHNS
Calculated: 35.28 4.84 29.92 25.69
found: 34.93 4.56 30.27 25.92
* after correction (0.88% H20)
EXAMPLE 69

3,4-bis- {2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -1,2,5
thiadiazole 1-oxide
To a solution of sodium methoxide (2.16 g, 40 mmol)
in 100 ml of CH3OH cooled to 0 ° C. in an ice-water bath,
2 - [(2-guanidinothiazol-4-yl)) dihydrochloride is added
thylthiolethylamine (6.09 g, 20.0 mmol) and after 20 minutes
stirring, the solution is treated with 3,4-dimethoxy-1,2,5
thiadiazole 1-oxide (1.62 g, 10 moles). Stir the mixture
65 hours at room temperature and evaporated
under reduced pressure.The residue is chromatographed on 100 g
of silica gel (230-400 mesh) by "flash chromatography" in
using an acetonitrile-methanol elution gradient. We gather
interesting fractions, evaporates and the chromatography is
residue on a preparative HPLC system using silica gel
u-porasil. We combine the interesting fractions and evaporate
under reduced pressure to obtain the title compound under
the shape of an amorphous sokide. The NMR spectrum (100 MHz) in
dimethyl sulfoxide d6 indicates the presence of about 0.11 mole
ethanol.

The compound obtained has the empirical formula: ClgH2 4N120Ss, Ifi oo C2H60
and his elemental analysis leads to the following results:
CHNS
calculated: 34.42 4.39 29.71 28.33
found: 34.95 4.41 29.04 27.71
after correction (1.86% H2O)
EXAMPLE 70

3- {2 - [(2-aminothiazol-4-yl) methylthio] ethylamino} -4-methylamino-1,2,5
thiadiazole 1,1-dioxide
A. 2 - [(2-Aminothiazol-4-yl) methylthio] ethylamine dichlorydrate
Cysteamine hydrochloride (5.65 g, 50.0 mmol) was dissolved
and 2-amino-4-chloromethylthiazole hydrochloride (9.25 g;
mmol) in 70 ml of concentrated HCl and then heated to 105 ° C.
oil bath. After 64 hours of heating, we evaporate melan
under reduced pressure and the residue is triturated in acetone.

The product is redissolved in ethanol, filtered and dried
to obtain the title compound (mp 170-2000C).

The compound obtained has the formula:
C6H1 3C1 2N3S2
and his elemental analysis leads to the following results:
CHNS Cl
calculated: 27.48 4.90 16.02 24.46 27.04
found: 27.29 5.07 15.91 24.15 27.24
B. 3- {2 - [(2-Aminothiazol-4-yl) methylthio] ethylamino} -4-methyl
1,1,5-lamino-thiadiazole 1,1-dioxide
A solution of 2-L (2-aminothiazol-4-) is added dropwise.
yl) methylthiol-ethylamine (from the dihydrochloride 3.0 g;
11.4 mmol) [prepared in step A] in 25 ml of methanol
in 1 hour 30 minutes to a partial suspension at 5 C, under
agitation, 3,4-dimethoxy-1,2,5-thiadiazole 1 * 1-dioxide
(2.03 g, 11.4 mmol) in 55 ml of methanol. After 90 minutes
stirring, anhydrous methylamine is bubbled into the
the solution for 30 minutes and stirred at 50C for 19 minutes.
hours. The reaction mixture is evaporated under reduced pressure
and the residue is mixed with 400 g of silica gel and chromatography is carried out
using acetone methylene chloride (7: 3). We
brings together the interesting fractions and evaporates to get
the product. By recrystallization in 95% ethanol,
obtain the title compound (mp 200-201 C).

The compound obtained has the empirical formula:
C9H14N602S3
and his elemental analysis leads to the following results:
CHNS
calculated: 32.32 4.32 25.13 28.76
found: 32.25 4.20 25.06 29.14
EXAMPLE 71

3-amino-4- {2 - [(2-diméthylaminomèthylthiazol-5-yl) methylthio] ethylamino}
1,2,5-thiadiazole 1-oxide
A solution of 2 - [(2-dimethylamino) is added dropwise
ethylthiazol-5-yl) methylthio] ethylamine (2.05 g, 8.86 mmol)
[Prepared in Example 62, step D1 in 70 ml of methanol
a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.44 g;
8.88 mmol) in 170 ml of methanol cooled to 8 ° C. under stirring
tion. Anhydrous ammonia is bubbled into the solution
for 8 minutes then stir at room temperature
for half an hour. The reaction mixture is evaporated under
reduced pressure and the residue is triturated with acetonitrile
to obtain 1.76 g of product. The product is purified by "chro
flash matography "on 100 g of silica gel (230-400 mesh) using
a mixture of acetonitrile-methanol. Fractions are brought together
interesting, evaporate and recrystallize the residue in
acetone, the title compound is obtained (mp 131-1330 ° C).

The compound obtained has the empirical formula:
C11H17N6OS3
and his elemental analysis leads to the following results:
CHNS
calculated: 38.13 5.24 24.26 27.76
Found *: 37.86 5.06 24.34 27.68
*
after correction (0.49% H20)
EXAMPLE 72

3-amino-4- {2 - [(2-aminothiazol-4-yl) methylthio] ethylamino} -1,2,5-thia
diazole 1-oxide
A solution of 2 - [(2-aminothiazol) is added dropwise
4-yl) methylthiol-ethylamine (from the dihydrochloride, 2.62 g;
10.0 mmol) [prepared in Example 70, Step A] in 20 ml
of methanol in 30 minutes to a solution of 3,4-dimethoxy
1,2,5-thiadiazole 1-oxide (1.62 g, 10.0 moles) in 50 ml
of methanol cooled to 5 ° C., with stirring. After 1 hour and
half of stirring, anhydrous ammonia is bubbled through
the solution for 30 minutes and keep the solution at
50C for 17 hours. The reaction mixture is then evaporated.
under reduced pressure and the residue is chromatogra
on a preparative HPLC system, using silica gel
-porasil. We combine the interesting fractions and evaporate
under reduced pressure to obtain the title compound under
the shape of an amorphous solid. The NMR spectrum (100 MHz) in the
dimethyl sulfoxide d6 indicates the presence of 0.4 moles of etha
about nol.

The compound obtained has the empirical formula:
C8H12N6OS3, 2/5 C2H6O
and his elemental analysis leads to the following results:
CHNS
Calculated: 32.74 4.50 26.03 29.80
found: 32.39 4.28 28.39 30.02
after correction (1.39% H2O)
EXAMPLE 73

3-methylamino-4- [2 - [(2- (2,3-diméthylguanidio] thiazol-4-yl) -méthylthiol
ethylamino] -1,2,5j-triadiazole 1,1-dioxide
A solution of 2 - [(2-f2,3-dimethyl) is added dropwise.
guanidino] thiazol-4-yl) methylthio] ethylamine (2.5 g, 9.64 mmol)
[Prepared in Example 68, step A1 in methanol in 40 ml.
with a suspension of 3,4-dimethoxy-1,2,5-thiadiazole
dioxide (1.72 g, 9.64 mmol) in 270 ml of cooled methanol
at 8 C with stirring. Anhydrous methylamine is bubbled
in the solution for 7 minutes and then evaporate the solution
under reduced pressure. The residue is subjected to chromatography
on 100 g of silica gel (230-400 mesh) by flash chromatography "
and we bring together the interesting fractions evaporates them and gets
2.5 g of product in the form of a foam By recristallisa
in aqueous ethanol, the title compound is obtained.
(Mp 132-1370 ° C).

The compound obtained has the empirical formula:
C12H20N802S3
and his elemental analysis leads to the following results:
CHNS
calculated: 35.63 4.98 27.70 23.78
Found *: 35.74 5.04 27.87 23.56
*
after correction (4.7% H2O)
EXAMPLE 74 3- [2- [2-dimethylaminothiazol-4-yl) methylthio] ethylamino] -4-amino-1,2,5-diol
thiadiazole 1-oxide
A. 2 - [(2-dimethylaminothiazol-4-yl) methylthio] ethylamine
Cysteamine hydrochloride (5.24 g, 45.9 mmol) was dissolved
and 2-dimethylamino-4-chloromethylthiazole hydrochloride
(9.8 g, 45.9 mmol) [prepared from N, N-dimethylthiourea
and 1,3-dichloro-2-propanone] in 45 ml concentrated HCl
and heated in an oil bath at 1000C for 96 hours.
pore the mixture under reduced pressure and alkalize the
sidu with 40% aqueous NaOH solution. We extract
the aqueous phase with methyl acetate, then dry
pore to obtain the title compound as a
oil used in step B without further purification.

The NMR spectrum (60 MHz) in D20 gives the resonance peaks
following:
#: 6.97 (s, 1H); 3.94 (s, 2H); 3.67 (s, 3H); 3.15 (s, 3H);
3.05 (m, 4H).

B. 3- {2 - [(2-dimethylaminothiazol-4-yl) methylthio] ethylamino} -4-amino-1,2,5-thiadiazole oxide
A solution of 2-1 (2-dimethylaminothiazole) is added dropwise.
zol-4-yl) -methylthio] ethylamine (3.5 g, 16.1 mmol) [prepared
in step A] in 70 ml of methanol in 30 minutes at a
3,4-Dimethoxy-1,2,5-thiadiazole 1-oxide (2.61 g;
mmol) in 200 ml of methanol at 7 ° C., with stirring. We do
bubble anhydrous ammonia into the solution for 8 minutes
and after 30 minutes of stirring, evaporated under reduced pressure.

The residue is triturated in isopropanol and then dissolved in
methanol, filter and evaporate to obtain the product. We could
product by flash chromatography on 100 g of silica
gel (230-400 mesh), using a mixture of methylene chloride
methanol. We combine the interesting fractions and we re-chro
matography on HPLC, on column -porasil of silica gel. We
collect the interesting fractions and evaporate under pressure
reduced to give the title compound (mp 116-1220C); the
NMR spectrum (100 MHz) in dimethyl sulfoxide d6 indicates the
presence of Y3 mole of ethanol approximately.

The compound obtained has the empirical formula:
C10H15N2O @ 3, 1/3 C2H6O
and his elemental analysis leads to the following results:
CHN
calculated: 36.83 5.22 24.16
Found *: 36.61 4.06 24.22
after correction (i1.92 H20)
EXAMPLE 75

3- {2 - [(2-diméthylaminothiazol-4-yl) -4-methylamino} méthylthioléthylamino
1,2,5-thiadiazole 1,1-dioxide
A 2 - [(2-dimethylamino) solution is added dropwise.
thiazol-4-yl) methylthiolethylamine (2.5 g, 11.5 mmol)
d in Example 74, step A] in 30 minutes to a suspension
3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.05 g; 11.5
moles) in 200 ml of methanol at 7 ° C., with stirring. We do
douse anhydrous methylamine in the solution during
7 minutes and after stirring for 30 minutes, the mixture is evaporated
lange under reduced pressure. The residue is recrystallized
methanol to obtain 1.6 g of product. By two recristal
in 2-methoxyethanol, the compound in
heading (PF: 227-229 C).

EXAMPLE 76

3- {2 - [(2- {2-imidazolidinyl} iminothiazol-4-yl) methylthio] ethylamino} -4
methylamino-1,2,5-thiadiazole 1,1-dioxide
A. 2 - [(2- (2-Imidazolidinyl) iminothiazol-4-yl) methylthio] ethylamine
Cysteamine hydrochloride (2.22 g, 19.5 mmol) was dissolved and
2 - [(2-imidazolidinyl) imino] -4-chloromethyl hydrochloride
thiazole (4.94 g, 19.51 mmol) [prepared from 1,3-dichloro
2-propanone and N- (2-imidazolidin-2-yl) thiourea which is it
even prepared from 2- (cyanimino) imidazolidinel in 20 ml
concentrated HCl and the mixture is heated to 100 ° C. in an oil bath.
for five and a half hours. The reaction mixture is evaporated under
reduced pressure and the residue is basified with NaOH
40%. The aqueous phase is extracted with methyl acetate,
dry, then evaporate to obtain 2.02 g of the title compound
used in the next step without further purification.

B. 3- {2 - [(2- (2-Imidazolidinyl) iminothiazol-4-yl) methylthiolethyla
mino} -4-methylamino-1,2,5-thiadiazole 1,1-dioxide
A solution of 2 - [(2- {2-imidazolidinyl} is added dropwise
iminothiazol-4-yl) methylthio] ethylamine (2.02 g, 7.85 mmol)
prepared in step A] in 85 ml of methanol in 40 minutes at
a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide
(1.4 g, 7.85 mmol) in 190 ml of methanol at 8 ° C. with stirring.

Anhydrous methylamine is bubbled into the solution
for 7 minutes, and after 30 minutes stirring at room temperature
room temperature, the mixture is evaporated under reduced pressure to obtain
3.5 g of product. The product is subjected to chromatography
on a preparative HPLC system using silica gel p-pora
sil. We collect the interesting fractions, we evaporate them and
the residue is recrystallized from methanol to obtain the
in the section (PF: 229-2310C). By recrystallization in
aqueous ethanol, the title compound is obtained (mp: 136
140 C) which resolidifies and resumes at PF: 219-2240C.

The compound obtained has the empirical formula: C12H18N2O2S3
and his elemental analysis leads to the following results:
CHNS
calculated: 35.81 4.51 27.84 23.90
found *: 35.51 4.43 27.98 23.56
*
after correction (4.59% H2O)
EXAMPLE 77 3- {2 - [(5-Dimethylaminomethyl-2-thienyl) methylthiolethylamino} -4 - [(2-pyridyl)
methylamino] -1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 31 except that
replaces methylamine with an equimolar amount of 2-amino
methylpyridine. By column chromatography of the crude solid,
3.08 g of product is obtained. Recrystallization in isopro
panol gives the title compound (mp 162-164 C with decompo
sition).

The compound obtained has the empirical formula: C1 8H24N60253
and his elemental analysis leads to the following results:
CHN
Calculated: 47.76 5.34 18.57
found: 47.80 5.32 18.75
EXAMPLE 78 3- {2 - [(5-Dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -4 - [(4-
pyridyl) methylamino] -1,2,5-thiadiazole 1,1-dioxide
We operate according to the general method of Example 31 except that
replaces methylamine with an equimolar amount of 4-amino
methylpyridine. After chromatography, the product is dissolved
in hot isopranol, decants insoluble materials and treats
the solution with anhydrous HCl to obtain the title compound
in the form of hydrochloride.The salt is dissolved in water and
it is made alkaline with a saturated aqueous solution of CO3HNa to
obtain, after filtration, the title compound in the form of
free base (mp 88-90 ° C).

The compound obtained has the crude formula;
C1 8H24N602S3
and his elemental analysis leads to the following results:
CHN
Calculated: 47.76 5.34 18.57
found *: 47.54 5.32 19.09
after correction (3.73% H20)
EXAMPLE 79

3- {2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -4-ethylamino = 1,2,5-thiadiazole 1,1-dioxide
One operates according to the general method of Example 31 except that
place the methylamine by an equimolar amount of ethylamine. We
dissolves the appropriate fractions of the chromatography on
column in hot isopranol and saturated with anhydrous HCl. We re
picks up the solid crystallized by filtration, washed with acetone
and dried to obtain 2.9 g of the title compound as
hydrochloride (mp: 246-247 C with decomposition).

The compound obtained has the empirical formula:
C14H24ClN5O2S3
and its elementary analysis leads to the following results:
CHN Cl
Calculated: 39.47 5.68 16.44 8.32
found: 39.81 5.74 16.62 8.2D
EXAMPLE 80

3-methylamino-4- {3- (3-piperidinomethylphenoxy) propylamino} -1,2,5-thiadiazole 1,1-dioxide
A solution of 3- (3-piperidinomethyl) is added dropwise.
phenoxy) propylamine (2.35 g, 9.45 mmol) [prepared according to the
assigned to United Kingdom Patent Application 2,023,133] in
30 ml of methanol in 40 minutes, to a partial suspension of
3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (9.68 g, 9.45 nimol-es)
cooled to 10C in an ice-water bath with stirring After
15 minutes, anhydrous methylamine is bubbled through the
solution for 5 minutes and the solution is stirred at room temperature
room temperature for 30 minutes.The reaction mixture is evaporated
under reduced pressure and the residue is chromatographed by "chroma
flashgraphy "on 100 g of silica gel (230-400 mesh) using
a methanol-acetonitrile mixture. Fractions are collected
interesting and evaporated to obtain 2.2 g of product. By
recrystallization in acetonitrile with charcoal treatment,
the title compound (mp 182-184 ° C) is obtained.

The compound obtained has the empirical formula:
C18H27N503S
and his elemental analysis leads to the following results:
CHNS
calculated: 54.94 6.92 17.80 8.15
found: 54.90 7.07 18.14 8.29
EXAMPLE 81

3-amino-4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole 1-oxide
A solution of 3- (3-piperidinomethyl) is added dropwise
phenoxy) propylamine (from the dihydrochloride, 4.0 g; 12.4
nimoles) in 40 ml of methanol in 50 minutes, to a solution
3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.01 g, 12.4 mmol)
in 200 ml of methanol cooled to 0 ° C. in an ice-water bath,
and with stirring. After 15 minutes, ammo is bubbled
anhydrous niac in the solution for 5 minutes and shaken into
the solution is then left at room temperature for 17 hours.
evaporates the reaction mixture under reduced pressure and
matography the residue by "flash chromatography" on 100 g of
silica gel (230-400 mesh) using a methanol-acetone mixture
nitrile. Interesting fractions are combined and evaporated for
obtain 4.18 g of product. By recrystallization in methanol
aqueous 95S, the title compound is obtained (mp: 155-1570C).
with decomposition).

The compound obtained has the empirical formula:
C17H25N502S
and his elemental analysis leads to the following results:
CHNS
calculated: 56.17 6.93 19.27 8.82
found: 55.97 7.04 19.57 8.63
EXAMPLE 82

3-amino-4- [3- (3-pipéridinométhylphenoxy) propylamino] -1,2,5-thiadiazole
1,1-dioxide
A solution of 3- (3-piperidinyl) is added dropwise
thylphenoxy) -propylamine (from dihydrochloride, 4.0 g;
12.4 mmol) in 35 ml of methanol in 65 minutes, at a pressure of
partial pension of 3,4-dimethoxy 1,2,5-thiadiazole 1-oxide
(2.22 g, 12.4 mmol) in 200 ml of methanol, cooled to 2 ° C.
in a bath of ice water and stirring. After 15 minutes
anhydrous ammonia is bubbled into the solution during
5 minutes and the solution is stirred at room temperature
for 30 minutes.The reaction mixture is evaporated under
reduced and the residue is placed on 100 g of silica gel (23U
400 mesh) and chromatography by "flash chromatography" to
using a methanol-acetonitrile mixture. We bring together
interesting fractions and evaporated to obtain 3.2 g of
product. The NMR spectrum (100 MHz) in dimethyl sulfoxide
d6 presents the following resonance peaks:
6: 7.2 (m, 1H); 6.9 (m, 3H); 4.1 (t, 2H); 3.5 (t, 2H);
3.4 (s, 2H); 2.3 (m, 4H); 2.0 (m, 2H0; 1.4 (broad s, 6H).

EXAMPLE 83 3- {2 - [(5-Dimethylaminomethyl-2-thienyl) methylthio] ethylamino} -4- (3,4-methyl)
1,2,4-thiadiazole 1,1-dixoyde lenedioxybenzylamino)
A solution of 2 - [(5-dimethylaminomer) is added dropwise.
2-thienyl) -methylthiolethylamine (2.02 g, 8.8 mmol) in
30 ml of methanol in 40 minutes to a solution of 3,4-dimethoxy
1,2,5-thiadiazole 1,1-dioxide (1.56 g, 8.8 mmol) in 200 ml
of methanol cooled to 0 ° C. in an ice-water bath and under
agitation. After 20 minutes, piperonylamine (1.46 g;
9.6 mmol) and mixing is continued at room temperature
ambient for 3 hours. Then evaporate almost dry,
added ethyl ether and filtered to obtain 3.47 g of
product. Recrystallization from methanol gives the
under cover (PF: 180-182 C).

The compound obtained has the empirical formula:
C20H25N5O4S3
and his elemental analysis leads to the following results:
CHN
calculated: 48.46 5.08 14.13
found: 48.92 4.88 14.52
after correction (0.38% H20)
EXAMPLE 84

3-Amino-4- {2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino} 1,2-thiadiazole 1-oxy ~
A. 6- (N, N-dimethylcarbamyl) -2-carbomethoxypyridine
A solution of 6-carbomethoxy-2-picolinic acid is heated
(22.8 g, 0.13 mol) in 80 ml of thionyl chloride in bath
of oil at a temperature of 100 C for 3 hours. We evaporate
the solution under reduced pressure and the residue is dissolved in
200 ml of dioxane and this solution is added dropwise to
a solution of dimethylamine (70 g) in dioxane. We shake
the reaction mixture for 2 hours and let stand at
4 C for about 16 hours, filtered and evaporated under pressure
The residue is dissolved in toluene, diluted
methylcyclohexane and filtered to obtain 20.7 g of
compound in heading (PF: 90-92 C).

The compound obtained has the formula:
C10H12N29
and his elemental analysis leads to the following results:
CHN
calculated: 57.68 5.81 13.46
found: 57.64 5.85 13.77
B. 6-dimethylaminomethyl-2-hydroxymethylpyridine
A solution of 6- (N, N-dimethylcarbamyl-2-carbomethoxy) -
pyridine (20.3 g, 97.5 mmol) prepared in Step Ai in
200 ml of tetrahydrofuran to a suspension of the hydride of
thium aluminum (9.6 g, 0.25 moles) in 500 ml of tetrahydrofuran
ranne. The mixture is heated to the temperature of reflux under at
nitrogen for 3 hours, then leave at room temperature
ambient for 16 hours. The mixture is broken down using
a saturated aqueous solution of Na 2 SO 4, filter, then dry
evaporated under reduced pressure. The residue is put on 275 g of oxide
of aluminum and eluted with methylene chloride. We are gathering
the interesting fractions and evaporated to obtain 5.2 g
of the title compound.

The NMR spectrum (60 MHz) in CDCl3 shows the resonance peaks
following:
6: 7.38 (m, 3H); 4.75 (s, 2H); 3.58 (s, 2H); 2.27 (s, 6H).

C. Z - [(6-dimethylamindomethyl-2-pyridyl) methylthio] ethylamine
Cysteamine hydrochloride (3.58 g, 31.5 mmol) was dissolved
and 6-dimethylaminomethyl-2-hydroxymethylayridine (5.0 g;
30.1 mmol) [prepared in step B] in 50 ml of 48% HBr
and the solution is heated to reflux temperature during
12 hours and let stand 8 hours at room temperature
ature. The reaction mixture is evaporated under reduced pressure
up to half of its solid flight, it is alkalinized with aqueous NaOH
at 40% and extracted with several portions of chloride
methylene. The organic phases are combined, washed with the help of
a small amount of water and a brine solution then,
it is dried and evaporated under reduced pressure to obtain 3.14 g
of the title compound.

The NMR spectrum (60 MHz) in CDCl3 shows the resonance peaks
following:
6: 7.5 (m, 3H); 3.83 (s, 2H); 3.56 (s, 2H); 2.7 (m, 4H);
2.28 (s, 6H).

D. 3-amino-4- {2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethyl
Lamino) -112,5-thiadiazole 1-oxide
A methanolic solution of 3,4-dimethyl is successively treated
thoxy-1,2,5-thiadiazole 1-oxide by an equimolar amount of
2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamine [pre
trimmed in step C] and an excess of ammonia. We get the com
posed in section.

 Of course, the present invention is not limited to the examples and embodiments mentioned above; it is capable of numerous variants accessible to those skilled in the art, depending on the applications envisaged and without departing from the spirit of the invention.

Claims (31)

 1. As new industrial products, the compounds having the following formula, as well as the pharmaceutically acceptable n-oxides, solvates, hydrates and non-toxic salts of said compounds having the following formula:

 in which:  p is 1 or 2;  R1 is a hydroxy or NR2R3 group  R2 and R3, independently of each other, are hydrogen atoms,  or alkyl (inf), alkenyl (inf), alkynyl (inf), cycloalkyl (inf) groups  cycloalkyl (inf) alkyl (inf), hydroxyalkyl (inf), alkoxy (inf) alkyl (inf),  alkylthio (inf) alkyl (inf), aminoalkyl (inf), alkyl (inf) aminoalkyl (inf),  dialkyl (inf) aminoalkyl (inf), pyrrolidinoalkyl (inf), piperidinolakyl (inf)  morpholinoalkyl (inf), piperazinoalkyl (inf), pyridylalkyl (inf), amino,  alkyl (inf) amino, dialkyl (inf) aniino, 2,2,2-trifluoroethyl, 2-fluoroethy  hydroxy, alkoxy (inf), 2,3-dihydroxypropyl, cyano, cyanoalkyl (inf),  amidino, alkyl (inf) amidino, A '- (CH 2) n') CH 2) n ', phenyl, phenyl  alkyl (inf), substituted phenyl or phenylalkyl (inf) substituted in  which phenyl ring may contain one or two substituents  chosen, independently of one another, from the alkyl (inf) groups,  hydroxy, alkoxy (inf) and halogen or a substituent selected from  methylenedioxy, trifluoromethyl and dialkyl (inf) amino group ::  it being understood that R2 and R3 may not simultaneously be a radiator  cycloalkyl (inr), phenyl, substituted phenyl, amino, alkyl (inf)  amino, dialkyl (inf) amino, hydroxy, alkoxy (inf), cyano, amidino, alkyl  (inf) aniidino or A '- (CH2) 0.7' (CH2) n 'or that R2 and R3 may  together form a group CH2CH2K (CH2) r-,  r being an integer equal to 1, 2 or 3,  X being a methylene radical, a sulfur or oxygen atom or NR @,  it being understood that when r = 1, X is a methylene radical,  R4 being a hydrogen atom or an alkyl radical (inf),  alkenyl (inf), alkynyl (inf), alkanoyl (inf) or benzoyl, m and m 'independently of each other are equal to 0.1 or 2 n and n' independently of each other are equal to 2.3 or 4 Z and Z 'independently of one another are a sulfur or oxygen atom  or a methylene group, A and A 'are, independently of one another, a phenyl radical, imidazo  lyle, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,  thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl,  it being understood that A and A 'independently of one another may  have 1 or 2 substituents, the first substituent being chosen  in the group of alkyl (inf), hydroxy, trifluoromethyl, halogen,  amino, hydroxymethyl, alkoxy (inf),

 alkoxy (inf).  hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, and  and the second substituent being selected from the group alkyl (inf),  razino or homopiperidino.  dino, morpholino, piperidino, methylpiperidino, N-methylpiperidine  zote to which they are linked a group that can be pyrroli  alkyl (inf) or phenyl or R5 and R6, forming with the atom of a  R5 and R6 may not be simultaneously a cyclo group  alkyl (inf) or phenyl  or an alkyl (inf), alkenyl (inf), alkynyl (inf), cyclo group  R5 and R6 independently of one another are a hydrogen atom  they are an ethylene radical, and  indicated above or both groups R4, form between  R4 each of the groups independently of one another are such  q is an integer from 0 to 6, inclusive;  A being able to consist of a hydrogen atom when Z = S and m = O  2.- Compounds according to claim 1, characterized in that in formula I, R1 is NR2R3.  3. Compounds according to claim 1 or 2, characterized in that in formula I  p is equal to 1 or 2,  R1 is NR2R3,  R2 and R3, independently of one another, are the hydrogen atom,  an alkyl radical (inf), alkenyl (inf), alkynyl (inf), cycloalkyl (inf) al  kyl (inf), pyridylalkyl (inf), A '- (CH2) n' (CH2) n-, phenylalkyl (inf),  or 3,4-methylenedioxybenzyl; with the understanding that R2 and R3 are not  at the same time a radical A '- (CH2) n' (CH2) n-;  m and m 'are independently 0 or 1;  n and n 'are independently 2 or 3;  Z and Z 'are independently sulfur, oxygen or a methyl group;  A and A 'are independently phenyl, imidazolyl, thiazolyl,  furyl, thienyl or pyridyl;  it being understood that A and A 'independently may have a  or two substituents, the first substituent being selected from  the alkyl (inf)

 ridino and consist of this compound, or a non-toxic pharmaceutically acceptable salt or hydrate, solvate or N-oxide.  piperidino, methylpiperidino, N-methylpiperazino or homopiped  they are fixed, can form a pyrrolidino group, morpholino,  or R5 and R6 taken together and with the nitrogen atom to which  R5 and R8 are independently hydrogen or alkyl (inf)  seems an ethylene group and;  alkyl (inf) or both R4 groups form in  the R4 groups are independently hydrogen or  and the second substituent being an alkyl (inf),  4. - Compounds according to any one of claims 1 to 3, characterized in that they correspond to the formula:

  wherein: p is 1 or 2; Z is sulfur or methylene R2 and R3 are independently hydrogen or alkyl (inf) or  if R2 is hydrogen, R3 can also be alkenyl (inf), alkynyl (inf),  phenylalkyl (inf), cycloalkyl (inf) alkyl (inf), pyridylmethyl or

 and R13 is hydrogen or methyl, and consists of this compound, or a non-toxic, pharmaceutically acceptable salt thereof, or hydrate, solvate or N-oxide.  5. Compounds according to any one of claims 1 to 3, characterized in that they correspond to the formula

 in which  p is 1 or 2;  Z is sulfur or methylene;  each R "group is independently hydrogen or methyl, or  the two R4 groups taken together can form an ethylene group, and  R2 and R3 are independently hydrogen or an alkyl (inf) or if  R2 is hydrogen, R3 can also be alkenyl (inf), alkynyl (inf)  pyridylmethyl or a group:

 and consists of this compound, or a non-toxic, pharmaceutically acceptable, or hydrate, solvate or N-oxide salt thereof.  6. Compounds according to any one of claims 1 to 3, characterized in that they correspond to the formula:

 in which  p is 1 or 2;  Z is sulfur or methylene  R2 and R3 are independently hydrogen or an alkyl (inf), or if  R2 is hydrogen, R3 may also be alkenyl (inf), alkynyl (inf)  or

 and R13 is hydrogen or methyl and consists of this compound, or a non-toxic pharmaceutically acceptable salt thereof, or hydrate, solvate or N-oxide.  7. Compounds according to any one of claims 1 to 3, characterized in that they correspond to the formula:

 in which  p is 1 or 2;  Z is sulfur or methylene  R2 and R3 are independently hydrogen or an alkyl (inf) or, if  R2 is hydrogen, R3 can also be alkenyl (inf), alkynyl (inf)  phenylalkyl (inf), pyridylmethyl, 3,4-methylenedioxybenzyl or

 and R13 is hydrogen or methyl and consists of this compound, or a non-toxic pharmaceutically acceptable salt thereof, or hydrate, solvate or N-oxide.  and consists of this compound, or a non-toxic, pharmaceutically acceptable, or hydrate, solvate or N-oxide salt thereof.

 R is hydrogen, R may also be alkenyl (inf), alkynyl (inf) or  R and R are independently hydrogen or an alkyl (inf) or if  p is 1 or 2; and  in which

 8- Compounds according to any one of claims 1 to 3, characterized in that they correspond to the formula:  9.- compounds according to any one of claims 1 to 3, characterized in that they meet the formula:

 in which  p is 1 or 2;  Z is sulfur or methylene  R2 and R3 are independently hydrogen or an alkyl (inf) or if R2 is hydrogen, R3 can also be alkenyl (inf), alkynyl (inf) or

 and R5 and R6 are independently hydrogen or an alkyl (inf) and consist of this compound, or a non-toxic, pharmaceutically acceptable salt thereof, or hydrate, solvate or N-oxide.  10.- compounds according to any one of claims 1 to 3, caract en enris en enes that'il meet the formula:

 in which  p is 1 or 2  R2 and R3 are independently hydrogen or an alkyl (inf), or if  R2 is hydrogen, R3 may also be alkenyl (inf), alkynyl (inf) or

 piperidino or homopiperidino and consist of this compound, or a non-toxic, pharmaceutically acceptable salt, or hydrate, solvate or N-oxide.  are bound can form a pyrrolidino group, morpholino,  5 and R6 taken together with the nitrogen atom to which they  be also an alkenyl (inf) or an alkynyl (inf) or  alkyl (inf) or, if R5 is hydrogen, R6 can  and R5 and R6 are independently hydrogen or  11. A compound according to claim 1 consisting of 3- [2- [(5-dimethylamino-methyl-2-furyl) -methylthio] ethylamino} -4- (n-propyl) amino-1,2,5-thiadiazole 1, 1-dioxide.  12. A compound according to claim 1 consisting of 3- [2- [(5-diniethylamino-methyl-2-furyl) -methylthio] ethylamino} -4-amino-1,2,5-thiadiazole 1,1-dioxide.  13. A compound according to claim 1 consisting of 3-f2 - [(2-guanidinothiazol-4-yl) methylthiolethylamino} -4-amino-1,2,5-thiadiazole 1,1-dioxide.  14. A compound according to claim 1 consisting of 3- {20 [(5-dimethylaminomethyl-2-thienyl) methylthiolethylamino} -4-methylamino-1,2,5-thiadiazole 1,1-dioxide.  A compound according to claim 1 consisting of 3-amino-4- [2 - [(2-guanidino-4-thiazol-4-yl) -methylthio] ethylamino} -1,2,5-thiadiazole-1-oxide.  16. A compound according to claim 1 consisting of 3-amino-4- {2 - [(2-guanidino thiazol-4-yl) -methylthiolethylamino} -1,2,5-thiadiazole 1-oxide monohydrate.  17. Compound according to claim 1 consisting of 3-amino4- {2 - [(2-guanidinothiazol-4-yl) -methylthio] ethylamino} -1,2,5-thiadiazole 1-oxide hydrochloride.  18. A compound according to claim 1 consisting of 3-amino-4- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino} -1,2,5-thiadiazole 1,1-dioxide.  19. Compound according to claim 1 consisting of 3-amino-4- [3- (3-dimethylaminomethylphenoxy) -propylamine} -1,2,5-thiadiazole 1-oxide.  20. A compound according to claim 1 consisting of 3-methylamino-4- [3- (3-pi-peridinomethylphenoxy) -propylamino] -1,2,5-thiadiazole 1,1-dioxide.  21. A compound according to claim 1 consisting of 3-amino-4- [3- (3-piperidino methylphenoxy) -propylamino] -1,2,5-thiadiazole 1-oxide.  22.- As new industrial products, the compounds of formula

  in which  p is 1 or 2  n is an integer between 2 and 4 inclusive  R and R3 are independently hydrogen, alkyl (inf), alkenyl (inf),  alkynyl (inf), cycloalkyl (inf), cycloalkyl (inf) alkyl (inf), hydroxyalkyl (inf),  alkoxy (inf) alkyl (inf), alkyl (inf) thioalkyl (inf), aminoalkyl (inf),  alkyl (inf) aminoalkyl (inf), dialkyl (inf) aminoalkyl (inf), pyrrolidinoalkyl (inf)  piperidinoalkyl (inf), morpholinoalkyl (inf), piperazinoalkyl (inf) pyri  dylalkyl (inf), amino, alkyl (inf) amino, dialkyl (inf) amino, 2,2,2-trifluoro  roethyl, 2-fluoroethyl, hydroxy, alkoxy (inf), 2,3-dihydroxypropyl,  cyano, cyanoalkyl (inf), amidino, alkyl (inf) amidino, A '- (CH2) n' (CH2) n-,  phenyl, phenylalkyl (inf), substituted phenyl or phenylalkyl (inf)  substitutes whose phenyl ring may have one or two substituents  independently selected from alkyl (inf), hydroxy, alkoxy (inf)  and halogens or a substituent selected from methyleneal groups  dioxy, trifluoromethyl and dialkyl (inf) amino  it being understood that R2 and R3 are not at the same time groups  cycloalkyl (inf), phenyl, substituted phenyl, amino, alkyl (inf) amino,  dialkyl (inf) amino, ydrxy, alkoxy (inf), cyano, amidino, alkyl (inf) amidino  or A '- (CH2) n' (CH2) n- or R2 and R3 taken together can form  a group -CH2CH2X (CH2) r-i  r is an integer equal to 1, 2 or 3  X is a methylene, sulfur, oxygen or N-R4 being heard  that if r = 1, X is methylene  R "is hydrogen, an alkyl (inf), alkenyl (inf), alkyl group  nyl (inf), alkanoyl (inf) or benzoyl  m 'is an integer equal to 0, 1 or 2;  n 'is an integer equal to 2, 3 or 4;  Z is sulfur, oxygen or the methylene group;  A 'is phenyl, imidazoyl, thiazolyl, isothia  zolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,  oxadiazolyl, furyl, thienyl or pyridyl  it being understood that A 'may carry one or two substituents  the first substituent being an alkyl (inf), hydroxy,  trifluoromethyl, halogen, amino, hydroxymethyl, alko  xy (inf)

N-oxide.  razino or homopiperidino and consist of this compound, or a salt thereof, or hydrate, solvate or  morpholino, piperidino, nièthylpiperidino, N-methylpiped  attach, can form a pyrrolidino group,  R6, taken together with the nitrogen atom to which they  cycloalkyl (inf) or phenyl groups or R5 and  it being understood that R5 and R6 are not at the same time  or phenyl  alkyl (inf), alkenyl (inf), alkynyl (inf), cycloalkyl (inf)  R5 and R6 are independently hydrogen, a group  form an ethylene group, and  above or both groups R4, taken together,  the groups R4, independently, are as defined  included  q is an integer between 0 and 6, terminals  xy (inf) ;;  trifluoromethyl, halogen, amino, hydroxymethyl and alkoxy  and the second substituent is an alkyl (inf), hydroxy,  23. As a new drug, any composition containing as active principle a compound according to any one of claims 1 to 21, in basic form or in the form of a non-toxic acid addition salt, pharmaceutically acceptable, in association with a suitable carrier, vehicle or excipient.  24. The composition as claimed in claim 23, characterized in that the active principle consists of 3-amino-4-2 - [(2-guanidinothiazol-4-yl) -methylthio] ethylamino-1> 2,5-thiadiazole. 1-oxide monohydrate  Composition according to Claim 23, characterized in that the active principle is 3-amino-4- {2 - [(2-guanidinothiazol-4-yl) -methylthio] ethylamino} -1,2 hydrochloride, 5-thiadiazole 1-oxide.  As a novel medicament, any composition containing as an active ingredient an amount effective to inhibit the gastric secretion in animals and man of any of the compounds of claims 23 to 25.  27. As a novel medicament for inhibiting gastric secretion in animals and in humans, and in particular for the treatment of peptic ulcers, any composition containing, in combination optionally with a carrier, vehicle or excipient, one or more compounds having the following formula, or the pharmaceutically acceptable N-oxides, solvates, hydrates or non-toxic salts of compounds having the formula:

 in which::  p is 1 or 2;  R1 is a hydroxy or NR2R3 group  R2 and R3, independently of each other, are hydrogen atoms,  or alkyl (inf), alkenyl (inf), alkynyl (inf), cycloalkyl (inf) groups  cycloalkyl (inf) alkyl (inf), hydroxyalkyl (inf), alkoxy (inf) alkyl (inf),  alkylthio (inf) alkyl (inf), aminoalkyl (inf), alkyl (inf) aminoalkyl (inf),  dialkyl (inf) aminoalkyl (inf), pyrrolidinoalkyl (inf), piperidinoalkyl (inf)  morpholinoalkyl (inf), piperazinoalkyl (inf), pyridylalkyl (inf), amino,  alkyl (inf) amino, dialkyl (inf) amino, 2,2,2-trifluoroethyl, 2-fluoroethy  hydroxy, alkoxy (inf), 2,3-dihydroxypropyl, cyano, cyanoalkyl (inf),  amidino, alkyl (inf) amido, A '- (CH 2) n' (CH 2) n ', phenyl, phenyl  alkyl (inf), substituted phenyl or phenylalkyl (inf) substituted in  which phenyl ring may contain one or two substituents  chosen, independently of one another, by the alkyl groups (inf),  hydroxy, alkoxy (inf) and halogen or a substituent selected from  methylenedioxy, trifluoroinethyl and dialkyl (inf) amino;  it being understood that R2 and R3 may not simultaneously be a radiator  cycloalkyl (inf), phenyl, substituted phenyl, amino, alkyl (inf)  amino, dialkyl (inf) amino, hydroxy, alkoxy (inf), cyano, amidino, alkyl  (inf) amidino or A '- (CH 2) n' (CH 2) n 'or that R 2 and R 3 may  together form a group CH2CH2X (CH2) r-,  r being an integer equal to 1, 2 or 3,  X being a methylene radical, a sulfur or oxygen atom NR4,  it being understood that when r = 1, X is a methylene radical,  R4 being a hydrogen atom or an alkyl radical (inf),  alkenyl (inf), alkynyl (inf), alkanoyl (inf) or benzoyl, m and m 'independently of one another are equal to 0.1 or 2 n and n' independently of each other are equal to 2.3 or 4 Z and Z 'independently of one another are a sulfur or oxygen atom  or a methylene group, A and A 'are, independently of one another, a phenyl radical, imidazo  lyle, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,  thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl,  it being understood that A and A 'independently of one another may  have 1 or 2 substituents, the first substituent being chosen  in the group of alkyl (inf), hydroxy, trifluoromethyl, halogen,  amino, hydroxymethyl, alkoxy (inf),

 hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, and alkoxy (inf).  and the second substituent being selected from the group alkyl (inf),  razino or homopiperidino.  dino, morpholino, piperidino, methylpiperidino, N-methylpiperate  zote to which they are linked a group that can be pyrroli  alkyl (inf) or phenyl or R5 and R6, forming with the atom a'a  R5 and R6 may not be simultaneously a cyclo group  alkyl (inf) or phenyl  or an alkyl (inf), alkenyl (inf), alkynyl (inf), cyclo group  R5 and R6 independently of one another are hydrogen  they an ethylene radical, and  indicated above or both groups R4, form between  R4 each of the groups independently of one another are such  q is an integer from 0 to 6, inclusive;  wherein R9 is -NR2R3, or in an inert organic solvent and, if appropriate, converting the resulting product to a pharmaceutically acceptable, hydrate, solvate or N-oxide non-toxic salt by a method known per se.  halogens, the alkyl (inf), alkoxy (inf) and nitro groups, with a compound of formula A (CH 2) m Z (CH 2) n NH 2, then with a compound of formula R 9 H,  phenylthio may contain 1 or 2 substituents chosen from  R7 is halogen, -alkoxy (inf), alkylthio (inf), phenoxy or  p is 1 or 2;   in which:

 28 - Process for the preparation of the compounds according to any one of Claims 1 to 21, in which R1 is NR2R3, characterized in that a compound of formula:  29. The process as claimed in claim 28, wherein R9H is the group A (CH2) mZ (CH2) nNH2, characterized in that the reaction is carried out in a single step with two equivalents of A (CH2) mZ (CH2) nNH2.  among the halogen atoms, the alkyl (inf), alkoxy (inf) and nitro groups, first with one equivalent of a compound of the formula A (CH 2) m Z (CH 2) n -NH 2 in an organic solvent and are treated the product obtained with potassium hydroxide, lithium hydroxide or sodium hydroxide and, where appropriate, converting the resulting product according to a process known per se, into a non-toxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide.  phenoxy or phenylthio, which may have 1 or 2 substituents chosen  R7 are both halogen, alkoxy (inf), alkylthio (inf),  p is 1 or 2;  in which:

R 1 is OH, characterized in that a compound of formula:  30 .- A process for the preparation of a compound according to claim 1, wherein  solvate or N-oxide.  in one of its pharmaceutically acceptable non-toxic salts, hydrates,  in the presence of a base; - and if necessary, transform the resulting product, according to a process with  a group 03SF, acetoxy or 2,4-dinitrophenoxy,  methyl or bromine,  R1l is an alkyl (inf), phenyl or phenyl radical substituted by a group  which X is fluorine, chlorine, bromine, iodine, a group -O3SR'1, where  in an inert organic solvent; ; the resulting product is treated with a compound of formula A (CH 2) n X in the  R10 is the group -NR2R3,  HS (CH2) nNH2 and R10H wherein n = 2 or 3  halogen, alkyl (inf), alkoxy (inf) and nitro, - successively, in any order, with compounds of formula  phenylthio may contain 1 or 2 substituents chosen from  R7 is a halogen, an alkoxy (inf), alkylthio (inf), phenoxy or  p is 1 or 2;  in which:

 31. - Process for the preparation of a compound according to any one of claims 1 to 21, in which RI is -NR2R3, characterized in that a compound of formula: