LU84484A1 - 1-OXIDES AND 1,1-DIOXIDES OF 1,2,5-THIADIAZOLES 3,4-DISUBSTITUDES - Google Patents

Description

DESCRIPTIVE MEMORY

FILED IN SUPPORT OF AN APPLICATION

OF

DEVELOPMENT PATENT TO

i PATENT OF INVENTION

|

FORMED BY

i BRISTOL-MYERS COMPANY

l - - I - - | i for j 1-Oxides and 1,1-dioxides of 1,2,5-thiadiazoles 3,4-disubstituted.

Burimamide (Ha) was the first Eg receptor antagonist to be clinically effective.

It inhibits gastric secretion in humans and animals, but its absorption after administration by i

oral is poor- P

/ *

K I II

he. JL; ® ^ CHgZCHgCHgBH-C-BHGHs lia; E ^ H, Z = CHp, X = S burimamide • r ^

He b; 3 ^ = CH ^, Z = S, X = S metiamide Ile; K ^ = CH ^, Z = S, X = NCN cimetidine

Methiamide (Ilb), which is a Hg receptor antagonist evaluated later, is more potent than burima-mide and is active when administered orally in humans. However, its clinical interest is limited due to its toxicity (agranulocytosis). Cimetidine (Ile) is an Hg receptor antagonist as effective as metiamide but does not cause agranulocytosis and has recently been released as an ulcer drug. The half-life of cimetidine is relatively short, so that this compound should be administered several times a day in doses of 200-390 mg presented in tablet form. It would therefore be interesting to have drugs against ulcers which have a more lasting activity and / or which are more powerful than cimetidine.

The present invention relates to histamine Hg receptor antagonists which are effective inhibitors of acidic gastric secretion in humans and animals, which are useful for the treatment of "peptic ulcer and which have the formula: <«P

U k

X, 1 where p represents 1 or 2; - 2 - i / K1 represents a hydroxyl radical or NE2! ^; B2 and E ^ each independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower), cycloalkyl (lower), alkyl (lower), hydroxyalkyl ( lower), alkoxy (lower) alkyl (lower), alkylthio (lower) -alkyl (lower), aminoalkyl (lower), alkyl (lower) -aminoalkyl (lower), dialkyl (lower) aminoalkyl (lower), pyrrolidinoalkyle (lower), piperidinoalkyle (lower), mo ^ pholinoalkyle (lower) pipérazinoalkyle, (lower), pyridylalkyle (lower), amino, alkyl (lower) amino, dialkyl (lower) amino, 2,2,2-trifluoroethyl , 2-fluoro-ethyl, hydroxyl, alkoxy (lower), 2,3-dihydroxypropyl, cyano, cyanoalkyl (lower), amidino, alkyl (lower) -amidino, A'-ÎCHg) »Z'ÎCÏÏg) phenyl, phenylalkyl ( lower), substituted phenyl or substituted (lower) phenylalkyl, the phenyl ring of which can carry one or two selected substituents. independently from the alkyl (lower), hydroxyl, alkoxy (lower) and halogen atoms radicals or a substituent chosen from the methylenedioxy, trifluoromethyl and dialkyl (lower) amino radicals, with the restriction that E2 and E ^ cannot all represent two 'of the cycloalkyl (lower), phenyl, substituted phenyl, amino, alkyl (lower) amino, dialkyl (lower) -amino, hydroxyl, alkoxy (lower), cyano, amidino, 2 alkyl (lower) amidino or A' radicals -ÎCHg) ^ »Z '(CB ^) ^ - *; or E - and E ^ can together represent a radical -Ci ^ CEgXtCHg) ^ -; ! r represents 1, 2 or 3; - »X represents a methylene radical, a sulfur or oxygen atom or an E-E ^ radical with the restriction that when r represents 1, X represents a methylene radical; E1 * - represents a hydrogen atom or an alkyl - 3 - (lower), alkenyl (lower), alkynyl (lower), alkanoyl (lower) or benzoyl radical; m and m 'each independently represent O, 2 or 2; "n and n 'each independently represent 2, 3 or 1 *; Z and Z * each independently represent a sulfur or oxygen atom or a methylene radical; A and A' each independently represent a phenyl, imidazolyl, thiazolyl radical, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, uryl, thienyl or pyridyl, it being understood that A and A 'may independently comprise one or two substituents, the first substituent being chosen from halogen atoms and alkyl radicals (lower) , hydroxy-le, trifluoromethyl, amino, hydroxymethyl, alkoxy (lower), I EHE **> - (Cïï2) ü = cy et - (CH2) qIÏK5B6, and the second substituent being chosen from halogen atoms and alkyl radicals (lower), hydroxyl, trifluoromethyl, amino, hydroxymethyl and alkoxy (lower); k

q represents O, 1, 2, 3, 5 or 6, each radical B

. being independently as defined above or else the k two radicals B together forming an ethylene radical, and 5 6 B 'and E independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl ( lower), cycloalkyl (lower) or phenyl, 5 6 with the restriction that B ^ and E cannot both represent “cycloalkyl (lower) or phenyl radicals; 5 6 or else B and E taken together with the nitrogen atom to which * they are united may represent a pyrrolidino, morpholino, pipêridino, methylpiperidino, N-methylpiperazino or homopiperidino radical; as well as a non-toxic pharmaceutically acceptable salt, hydrate, eolvate or K-oxide of such a compound.

The present invention also relates to processes for preparing the compounds of formula I and intermediates for the preparation of the compounds of formula I.

the present invention relates to all tautomeric forms, geometric isomers, optical isomers and possible zwitterionic forms of the compounds of formula I, in addition to their mixtures. For the purposes of the invention, by "alkyl (lower), alkenyl (lower), alkynyl (lower), alkoxy (lower) and alkylthio (lower) radicals" is generally meant alkyl, alkenyl, straight or branched chain alkynyl, alkoxy and alkylthio of 1 to 12 carbon atoms. Preferably, these radicals have 1 to 8 carbon atoms and more preferably 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 have been found to form metal salts such as potassium, sodium and calcium salts.

It is to be envisaged that these salts are formed by displacement of a proton of the hydroxyl radical (when H * "represents a hydroxyl radical) or of one of the adjacent nitrogen atoms of the thiadiazole ring, but this hypothesis j n ' is in no way limiting for the invention.

In the compounds of formula I, A and A 'preferably independently represent phenyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxa- * diazolyl, furyl, thienyl or pyridyl radicals. With special preference, A and A 'independently represent phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl radicals which may be substituted. Particularly preferred radicals A and A 'are guanidino-substituted thiazolyl, furyl dialkyl (lower) aminoalkyl (lower) - substituted (and especially dimethylaminomethyl e-substituted), imidazolyl al% le (lower) -substituted (and especially methyl-substituted), thiazolyl dialkyl (lower) -aminoalkyl (lower) -substituted (and especially dimethyl-aminomethyl-substituted), phenyl dialkyl (lower) amino-alkyl (lower) -substituted (and especially dimethylamino-substituted) ) and dialkyl (lower) amino-alkyl (lower) -substituted (and especially dimethylamino-methyl-substituted) thienyl.

It is preferable that m represents zero or 1 and that n represents 2 or 3. Preferably, Σ represents a sulfur or oxygen atom or a methylene radical (and most advantageously a sulfur or oxygen atom). preferably represents a radical DE2! * 3 where E2 and E3 preferably each independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower) or A '- (CH2) m, Z radical '(CHg) ^, -. In particularly preferred embodiments, E2 and E3 both represent hydrogen atoms or methyl radicals. In other particularly preferred embodiments, E2 represents a hydrogen atom and E? represents a hydrogen atom or an alkyl radical (lower) (especially methyl, ethyl or propyl),, alkenyl (lower) (especially 2-propenyl), alkynyl (lower) (especially 2-propynyl) or A '- (CH2 ) m, Z '(CHg) ^, ”* where m' preferably represents zero or 1 and n 'preferably represents 2 or 3, Z' preferably represents an oxygen or sulfur atom and A 'preferably represents a thiazolyl, phenyl or substituted furyl radical (and especially a guanidino-substituted thiazolyl or phenyl or dimethylaminomethyl-substituted furyl thiazolyl radical).

The compounds of formula I can be prepared according to different methods, preferably from a compound of formula: * <s%

lï E

M

B? V

η where R 'represents an easily eliminated radical, such as a halogen atom or a phenoxy, substituted phenoxy, phenylthio, ph.enylth.io substituted radical, alkoxy, alkylthio etc.

Suitable eliminable radicals are known to the specialist. Preferably, R represents an (lower) alkoxy radical (especially methoxy).

Preparation of starting compounds

The starting compounds of formula II where p represents 2 and each R represents a chlorine atom or a methoxy or ethoxy radical are known and their preparation is described in J. Qrg. Chem. 40, 2743 (1975) - The starting n compounds of formula II where p represents 2 and each E represents an alkoxy, alkylthio, phenoxy, phenyl- | thio, substituted phenoxy or substituted phenylthio (compounds of formulas IV and V) can be prepared by reaction of the dichloro compound of formula III with alkanol, alkyl thiol, phenol, thiophenol, substituted phenol or substituted thiophenol * leading to the compound corresponding

O

of formula IV or V where R represents an alkyl, phenyl or substituted phenyl radical, as illustrated below: - 7 - 02 / s \

B B

U

02 E60 OR8

/ \ 'IV

E R

M

"" <! » III ^ S s \

xxx B R

8 E ° S SR °

V

This reaction is carried out in an inert organic solvent such as ether, dimethylformamide etc. when the reagent R ° OH or R ° SH is liquid, like methanol, ethanol, ethyl mercaptan or thiophenol, the reaction can be carried out in an excess of this reagent serving as solvent, the compounds corresponding starting points

of formula II where p represents 1 (compounds of formulas VII

and VIII) can be obtained in the same way from n of a compound of formula II where each E represents a chlorine atom (compound of formula VI).

0

S

/ NOT.

B B

0 8 / - \ 8

s E 0 OR

i / \ 1.11

M

Cl Cl a / E \

VI B B

\ _ÿ e8s se8

VIII

- 8 -

Compound VI is new, but can be prepared from the 3-^-dihydroxy-1,2,5-thiadiazole 1-oxide which is a known compound [itself obtained as described in Org. Prep. Proced., 1_, 255 (1969)] by the same method as that applied for the preparation of the compound of formula III starting from 1,1-dioxide of 3, V-dihydroxy-l, 2,5-tMadiasole [J. Org. Chem.,] +0, 27 ^ 3 (1975)] · The starting compounds of formulas VII and VIII are new and have not yet been described in the literature ”

Alternatively, the starting compounds of formulas IV and VII can be prepared by reacting a suitably substituted oxal-diimidate which is an ester of formula ΙΣ with SClg or SgClg in 1111 inert solvent such as dimethylformamide for the formation of 1,2,5 “tbiadiazole 3” V-disubstituted corresponding to formula Σ, which is in turn oxidized to the corresponding 1-oxide of formula VII or to the corresponding 1,1-dioxide of formula IV.

E80 OE8 E80v OE8 Compound

• W YX VII

// \\ ouS ^ ClT ζ '- EN EH *' * V / S 2 [0] X Compound

IV

O

The oxaldiimidates of formula IX where B represents a methyl, ethyl, n-propyl, i-propyl, n-butyl or n-pen-tyle radical are known and their preparation is described in Chem.

** Ber ", 107, 3121 (197½) · The corresponding compounds in

O

the formula of which B represents a phenyl radical optionally bearing one or more alkyl (lower), alkoxy (lower), nitro or halogen atoms can be prepared in an analogous manner, the compounds of formula X where B8 represents a radical methyl or ethyl are described _ 9 _ | in J. Org. Chem., 4θ, 27k9 (X975).

The literature specifies that the 1,2,5-thiadiazole nucleus is sensitive to oxidation, that the oxidation of thiadiazoles by peracids is usually accompanied by the destruction of the cycle and the formation of the sulfate ion and that tests for the preparation of 1,2,5-1,2,5-thiadiazole dioxide from the cyclic compound by oxidation using peracetic acid lead to the breaking of the cycle. The Applicant has discovered with surprise that the 1-oxides of 1,2,5-thiadiazoles 3Λ ~ disubstituted of formula VII and "1,1-dioxides of 1,2,5-thiadiazoles Si ^ -disubstituted of formula IV can be prepared easily and with a good yield by oxidation of the 1,2,5-thiadiazole 3,1 * -disubstituted corresponding to formula Σ by means of a peracid such as m-chloroperbenzoic acid in an inert solvent such as chloroform. preparation of the 3-^-dimethoxy-1,2,5-thiadiazole 1-oxide is illustrated in Example 1 *, stage A and the preparation of the corresponding 1,1-dioxide is illustrated below.

Illustrative process n ° 1 1.1— 3-dimethoxy dioxide — 1,2,5-thiadiazole

A solution of 3, ^ - dimé-thoxy-1,2,5-thiadiazole (1Λ8 g, 10.1 millimoles) [prepared as described in J. Org. Chem., 27 ^ -9 (1975) 3 to a stirred solution of m-chlorqperbenzoic acid (**, 11 g, 20.3 millimoles, titer 85%) in 60 ml of chloroform. After 1 hour of stirring at room temperature, the mixture is heated to reflux for 8 hours, then stirred at room temperature for a further 1 hour. The reaction mixture is extracted with aqueous sodium bicarbonate and water, then the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure.

- 10 -

Methanol is added to the residue and the whole isolex 1.03 g of the product is filtered. Pax xecxistallisation in methanol, one obtains the xechexché compound melting at 200-202 °. Lice analysis C ^ H ^ NgO ^ S

calculated C, 26.97; ff; 3.39; N, 15.72; S, 18, OC # * found C, 26.82; H, 3.18; K, 16.09; S, 18.00% la Demandexesse has now discovered a particularly elegant process according to which a compound of formula VII can be prepared in one stage directly from a compound of formula ΙΣ by reaction of the latter with thionyl chloride .

E80 DE8 E80. .OR8

Vc 'SOOlg ^ V-jT

'NnH ^ H H

\ g /

ΙΣ S

O

VII

This reaction is carried out in an inert organic solvent such as methylene chloride, chloroform, etc. Although the reaction can be carried out without the addition of a base as an acid acceptor, it is preferable to add approximately two equivalents of a base for eliminating the hydrogen chloride released by the reaction, the yield of compound of formula VII increases under these conditions, the suitable bases are in particular inorganic bases, such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, in addition to organic bases such as triethylamine, pyridine * etc. This process not only eliminates a stage, but also I is more economical because it avoids the use of expensive oxidants such as m-chloroperben-zoic acid. the reaction can be carried out at a temperature of from about -20 to + 25 ° and preferably from about 0 to 10 °. Illustrative process No. 2 describes the preparation of the coe-

Q

posed of formula VII where represents a methyl radical according to this procedure.

Illustrative process n ° 2 »1-Oxide of λΛ-dimethoxv-l.2.5-thiadiazole

A solution of dimethyl oxal-diimidate (V, 0 g, 3 ^, 5 millimoles) in pyridine (5.71 ml, 5.58 g, 70.6 millimoles) is added dropwise to 8 ml of methylene chloride to a cold solution of thionyl chloride (2.61 ml, 25 g, 3H-> 7 millimoles) in 18 ml of methylene chloride under a stream of nitrogen at a dehit such that the reaction temperature is maintained between 0 and 15 °. After stirring for 20 minutes at room temperature, the reaction mixture is washed with two 11 ml volumes of 0.055 B aqueous hydrogen chloride. The aqueous phase is extracted with two 20 ml volumes of methylene chloride, then combine the organic phases and dry them before evaporating to dryness under reduced pressure. The solid residue is recrystallized from isopropanol to obtain 3.0 g of the desired compound, melting at 137-139 °.

the compounds of formula I can be prepared from a compound of formula II according to other reaction schemes by passing through various new intermediate compounds.

j Reaction diagram 1! '(0) p

Compound A (CH2) niZ (CH2) iiKB2 IÏ N

"- A (CH2) mZ (CH2) nMH r _ 1? _ X xi k9h b9h

Ψ V

* i ° k X "\ H - ** M9 7 V" "îV ^ œ bv ni la 9

In reaction scheme 1, B can represent a radical -NE2!? 3 or -ÏÏH (C ^) .Z’CCBg), A ’. when A ’, Z ', m' and n 'are the same as A, Z, m and n, the reaction can obviously be executed in one stage per reaction! of the compound of formula II with two equivalents of the compound of formula the intermediate compounds of formula 21 are all new, the intermediate compounds of formula 2ZI are new with the exception of that 7 in the formula of which p represents 2, E 'represents a g methoxy radical and E represents a morpholino radical, which has been described in J. Org. Chem., 1 + 0.27 * + 3 (1975). the reactions are carried out in an inert organic solvent; methanol is a suitable and readily available solvent, the reaction temperature is not critical, most starting materials are highly reactive and it is best to run the reaction below! room temperature, for example from 0 to 10 °. With some less reactive compounds, it is favorable to run the reaction at room temperature. It is sometimes desirable to then raise the temperature of the reaction mixture (for example to a value of 50 to 60 °) to complete the reaction.

Reaction diagram 2, (t !?

Compound A (CH2) mZ (CH2) nRH2 If JS

- ^ Ώ

A (CH2)] IZ (0H2) nm ^ V

. (B0) P

M

ΑζΟΗ ^ ΖζΟΗ ^ ΙΕΤ OH

Ib

In reaction scheme 2, M represents a metal cation, which is preferably a K +, li + or Ha + cation. the reaction conditions and solvents are as described in connection with reaction scheme 1. All the intermediate compounds of formula XI are new.

Reaction scheme 3

Compound

II

° H \ ^ HS (CH2) nMH2 1 (0) (0) p

n π H N

yj \ j, M, 0,, / Λ 7 E 'IT HS (CH-) HH B'

ΠΗ XIV

- 14 -

XIII XIV

\ ^ (CH2) nKH2 j

(0) P

/ S \ N Ίί H,. ·

PS (CH2) nKH VU

'A (CH2) ffiZ

(B0) P ✓ \

2î S

ACCH ^ SCaLjyffl B10

Ic. In the reaction scheme 3 "B * -® represents a radical -OT ^ E3 or -KH (CE2) n, -Z '(0¾ ^, A' and X is a conventional eliminative radical. Suitable eliminable radicals are, for example: example, fluorine, chlorine, bromine and iodine atoms and radicals -O ^ SB11 where E11 represents an alkyl (lower) radical (for example methanesulfonate), aryl or substituted aryl (for example benzenesulfonate, p-bromobenzenesulfonate or p-toluenesulfonate), O ^ SF, acetoxy and 2, V-dinitrophenoxy For reasons of convenience and economy, the Applicant prefers to use a compound in the formula of which X represents chlorine, the reaction conditions for the preparation of compounds of formulas XIII, XIV and XV are as described in connection with reaction scheme 1, The reaction of the compound of formula XV with the compound of formula A (C ^) Z can be carried out in an inert organic solvent, such as an alkanol, acetonitrile, dimethylformamide, dimethyl tallow oxide, acetone etc. Request it esse prefers to carry out the reaction in an alkanol such as methanol, ethanol or isopxopanol. The reaction temperature is not critical and the reaction can be carried out at a temperature of about 0 to 200 °. The reaction is slow at high temperature, but the high temperatures lead to less pure products by decomposition and formation of by-products. We normally prefer to carry out the reaction at room temperature. The reaction of the compound of formula XV with the compound of formula A (CH2) mZ leading to the compound of formula le is preferably carried out in the presence of a base which facilitates the progress of the reaction by acting as an acid acceptor. Suitable hashes are, for example, sodium, potassium or lithium hydroxide, triethylamine, dimethylaniline, sodium ethylate etc. When Z represents a hydroxyl radical, the reaction can be carried out in a concentrated mineral acid, for example hydrochloric acid (see example 25). All the intermediate compounds of formulas XXII, XXV and XV are new.

According to a preferred embodiment, the invention relates to the compounds of formula I- above: K K - 16 - where p represents 1 or 2; K2 and independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower) alkyl (lower), pyridylalkyl (lower), A '- (ÖHg ^ .Z '(CHg) ^ .-, phenylalky-le (lower) or 3,1 * -methylenedioxÿbenzyle, with the restriction that K2 and cannot both represent radicals. A' - (CH2), Z '(CH2) n, -; m and m 'each independently represent 0 or 1; n and n ·' each independently represent 2 or 3; Z and Z 'each independently represent an oxygen or sulfur atom or a methylene radical; A and A' represent each independently a phenyl, imidazolyl, thiazolyl, furyl, thienyl or! pyridyl radical, it being understood that A and A 'can independently comprise one or two substituents, the first substituent being chosen from (lower) alkyl radicals, __ .BHB1 * · c, -n = c ΖΓ h. And -cHpirara, and the second substituent being chosen from alkyl radicals (lower); each represented independently a hydrogen atom or an alkyl radical (lower) or both B * 1- together represent an ethylene radical, E ^ and E ^ each independently represent a 5 “hydrogen atom or an alkyl radical (lower ) or else E and j taken together with the nitrogen atom to which they are united can represent a pyrrolidino, morpholino, piperidôno, methylpxpérridino, N-methylpiperazino or homopiperidino radical; as well as a non-toxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide of such a compound.

m

According to another preferred embodiment, the invention relates to the compounds of formula I below: the "Ie

# 3 W

nch2_ß y — ch2zch2ch2mh. κκ2 »3

cb3 ^ O

where p represents 1 or 2, Z represents a sulfur atom or a methylene radical, B2 and each independently represent a hydrogen atom or an (lower) alkyl radical or else when E2 represents a hydrogen atom, can also represent a alkenyl (lower), alkynyl (lower), phenylalkyl (lower), cycloalkyl (lower) alkyl (lower), pyridylmethyl or -ch2ch2zch2 - ^^ - ch2h ^ radical represents a hydrogen atom or a methyl radical, as well as 'a non-toxic pharmaceutically acceptable salt, hydrate, solvate or'. E-oxide of such a compound.

According to another preferred embodiment, the invention relates to the compounds of formula I below: j H (0) „a-" Xi M "· Ξ CH2ZCH2CH2HH 1ΠΓΕ3 If where p represents 1 or 2, Z represents a sulfur atom or a methylene radical, each B ** independently represents a hydrogen atom * or methyl radical or "well the two B1 * taken together may represent an ethylene radical, E2 and each independently represent an atom of hydrogen or an (lower) alkyl radical or else when E2 represents a hydrogen atom, can also represent an alkenyl (lower), alkynyl (lower), pyridylmethyl,

H

• s /%

V-H = c 3_I

A_l Nudes. or - 0¾ ^ Btag1 -CHjCS ^ OHg -K 2 as well as a non-toxic pharmaceutically acceptable salt, hydrate, solvate or E-oxide of such a compound.

According to another preferred embodiment, the invention relates to the compounds of formula X below: E1 ^ s (°) p

X \\ V / EK

ch3 ^ \ CH2ZCH2CE2EH 'EE2! ^ where p represents 1 or 2; Z represents a sulfur atom or a methylene radical, E2 and E ^ each independently represent a hydrogen atom or an (lower) alkyl radical or else when E2 represents a hydrogen atom, E * can also represent a radieειΐ alkenyl (lower), alkynyl (lower) or rCHgCHgSCHg * · * F * ·· 3 represents a hydrogen atom or a methyl radical, as well as a non-toxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide d 'such a compound.

According to another preferred embodiment, the invention relates to the compounds of formula I below: w <°> p N J? y — C ^ ib 1CH2 -C ^ Λ- CHgZCHgCHgKH '^ ^ lîITB3 ch3 ^ 5 where p represents 1 or 2, Z represents a sulfur atom or a methylene radical, E2 and E ^ each independently represent a hydrogen atom or an alkyl radical (lower) or when E2 represents a hydrogen atom, can also represent an alkenyl (lower), alkynyl (lower), phenyl-alkyl (lower), pyridylmethyl, 3, V-methylenedioxyben-zyle radical or - ch2 ™ 2ëc% ^ ~ 3 ^ 0n £ K \ ra 5 S 3 represents a hydrogen atom or a methyl radical as well as a non-toxic pharmaceutically acceptable salt, hydrate, solvate or E-oxide of such a compound.

: According to another preferred embodiment, the subject of the invention is the compounds of formula I below: w "ä" ï w ^ CH ^ CH ^ Hgïïir HB2 ^ - 20 - where p represents 1 or 2, B2 and B ^ each independently represent a hydrogen atom or an (lower) alkyl radical or else when E2 represents a hydrogen atom, E? can also represent an alkenyl (lower), alkynyl (lower) radical or

H

"RQ.

-CH2CH2SCH2 ^ as well as a non-toxic pharmaceutically acceptable salt, hydrate, solvate or li-oxide of such a compound.

According to another preferred embodiment, the invention has for ob ^ and the compounds of formula I below: <°> p

/ ¾. 's'S''s U

<JL

BCH2- ^ x ^ —CH2ZCH2CH2MH - ^ ^ ïïb ^ b3 e6 / where p represents 1 or 2; Z represents a sulfur atom or a methylene radical, K2 and each independently represents a hydrogen atom or an alkyl radical (lower) or else when B2 represents a hydrogen atom, B ^ can also represent an alkenyl radical (lower) , alkynyl (lower) or

! " AT

! -ch2ch2zch2ch2n ^ ^ B ^ and B ^ each independently represent a hydrogen atom or an alkyl radical (lower), as well as a non-toxic pharmaceutically acceptable salt, hydrate, solvate or H-oxide of such a compound.

- 21 -

According to another preferred embodiment, the subject of the invention is the compounds of formula I below: (s0) pr fi I \ v _ // X NCH2 — OGHgOHgCHgBH ^ NI ^ E3 y where p represents 1 or 2, K2 and B ^ each independently represent a hydrogen atom or an alkyl radical (lower) or else when B2 represents a hydrogen atom, B ^ can also represent an alkenyl (lower), alkynyl (lower) or -ch2ch2ch20-V radical ^ L ch2ïï ^ 5 6 K and B each independently represent an atom of hy- 5

drogen or an (lower) alkyl radical, or else when S

represents a hydrogen atom, B ^ can also represent an alkenyl (lower) or alkynyl (lower) radical, or 6 also B and B, taken together with the nitrogen atom to which they are united, can represent a pyrrolidino radical , morpholino, piperidino or homopiperidino, as well as a non-toxic pharmaceutically acceptable salt, hydrate, solvate or H-oxide of such a compound.

the particularly preferred compounds forming the subject of the invention are: a) 1,1-dioxide of 3 ~ [2 - [(Ç-dimethylaminomethyl-B-furyl ^ ethylthioJethylaminoJ'-if-methylamino-1jB ^ -thiadiazole, b) 3 “1-oxide {2- [(5-dimethylaminomethyl-2- f uryl) methylthio] ethylaminoj -V-methyl amino-1,2,5-thiadiazole, c) 3,1-dioxide - {2- [(5-dimethylaminomethyl- 2-furyl) methyl thi o] ethyl amino] -V-ethyl amino-1,2,5-thi adi az ol e, d) 3 “1,1-dioxide [2- [(5 “dimethylaminomethyl-2 ~ i ury 1) m ethyl thi o] and t hyl amino] -lt- (n-pxopyl) amino-1,2,5-thi a-diazole, e) le 1 , 3-allylamino-1-dioxide-VJ ^ 2- [[(5-di-methyl aminom ethyl-2-f uxyl) methylthi o] ethyl aminoj -1,2,5-thi a-diazole, i) 1, 3 “1-dioxide {_ 2- [(5-dimethylaminomethyl-2-fuxyl) m ethyl thi o] ethyl amino] -lf- (2-pxopynyl) amino-1,2,5-thiadiazole, g) on 1, 3 ~ 1-dioxide {2 - [(5-dimethylaminomethyl-2-fuxyl) methylthioJ ethyl amino] -1 * -amino-1,2,5-thiadiazole, h) 1-oxide of 3- {2- (5-dimethylaminomethyl-2-iuxyl ) methyl thi o] ethyl amino] -if-amino-1,2,5-thiadiazole, i) 1,1-3- {2- [(5-dimethylaminomethyl-2-fuxyl) m ethyl thi o] dioxide ethylamino] -1 * -dim ethyl amino-1,2,5-thiadiazole, 5) 3- ^ if- (5-dimethylamino-2-iu-xyl) butylaminoj - ^ - methylamino-1,1-dioxide , 2,5-thiadiazole, k) 3, V-his-1,1-dioxide {2- [(5-dimethylami-name ethyl-2- £ uxyl) m ethyl thi o] ethylamino] -1,2 , 5-thiadiazole, l) 1,1-dioxide 3 ~ {2 - [(2-guanidinothiazol-lf-yl) methylthio] ethylamino] -Vm ethyl amino-1,2,5-thiadiazole, m) 1 , 3- {2- dioxide ([(2-guanidinothiazol-l * -yl) methylthlo] ethylamino] -k- (2-pxopynyl) amino-1,2,5-thiadiazole, "n) le 1,1 -3 ”dioxide [2- [(2-guanidinothiazol- 1f-yl) methylthio] ethylamino] [2- [(5-methyl-1H-imidazol-lf- yl) methylthio] ethylamino] -1,2,5- thiadiazole, o) 3- [2- [1,2-dioxide ((2-guanidinothiazol-lf-yl) methylthio] ethylamino] -V-amino-1,2,5-thiadiazole, p) 1,1- 3 ~ dioxide (2- [(2-dimethylaminomethyl- - 23 - ^ -thiazolyl) methylthio] ethylamin oj -V-methylamino-1,2,5-thiadiazole, q) 3- {2 - dioxide ({(5-dimethylaminomé-thyl-2-thi enyl) m ethylthi o] ethyl aminoj -V- methyl amino-1, 2,5-thiadiazole, t) 3- (2- [(5-dimethylaminomethyl-2-iuxyl) methyl thio] 1-oxide) ethylaminoj-lf-ethylamino-1,2,5-thiadiazole, s) 3- {2- [(5-methylaminomethyl-2-i nryl) m ethyl1Μ o J ethylaminoj -1 * —methylamino-1, 2,5-thiadiazole, 1,1-dioxide (t) 1- 3-amiüo-1i— (2- [(2-guanidinothiazol- ^ yl) methylthio] ethylaminoj -1,2,5-thiadiazole oxide, u) 3-benzylamino-V- 1,1-dioxide [(5-dimé-thylamïnométhyl-2-; fuxyl) methylthio] ethyl aminoj-1,2,5-thia-diazole, v) 3- (2- [(3- (dimethylaminomé-thylj) 1,1-dioxide phenyl) methylthio] ethylanri noj -V-methylamino-1,2,5-thiadiazole, w) 3-E-1-oxide Eunino-V- (2- [(3- {dimethylamino-methylphenyl) methylthi o ] ethylaminoj -1,2,5-thiadiazole, x) 3 ~ 1-oxide {{2- [(5-dimethyl ami-nom ethyl-2- thi enyl) m thylthi o] ethyl aminoj -Vm é thyl amino- 1,2,5-thi adi az oie, y) le 1 , 3-amlno-V-1-dioxide ([(5-dimethylamino-methyl-2-fuxyl) hutyl aminoj -1,2,5-thiadiazole, z) 3-amino-lf- 1,1-dioxide ( 2- [(2-dimethylami-nomethyl-V-thi az olyl) methylthio] ethylaminoj -1,2,5-thiadiazole, aa) 3 * 1,1-dioxide * hutylamino-lf- [2 - [(5 -dimé-thylaminométhyl-2- £ uxyl) methylthio] ethylaminoj -1,2,5-thi adia-zole, hb) 3-1,1-dioxide ~ cyclopxopylmethyl-1i— £ 2- [(5-dimethylaminomethyl-2 -fuxyl) methylthio] ethylaminoj-1,2,5-thiadiazole, cc) 3- (2- [(5-dimethylaminomethyl- - 24-2-fuxyl) methylthio] ethylaminoJ-1f- [( 2-pyxidyl) methylacino] - 1.2.5- thiadiazole, dd) 3-amino-1,1-dioxide! - {2 - [(5-dimethyl-aminomethyl-2-thienyl) methylthio] ethylamino} -l , 2,5-thia-diazole, ee) 1,1-dioxide of! F- [2- [(5-dimethylaminomé-thy 1-2-thi eny 1) m ethylthi o] ethylamino] -3- (1 -pxopylamino) - 1.2.5- thi adi az ole, ff) 3-1-oxide {2- [(2-guanidinothiazol-lf-yl) m é thy 1t h ± o] ethyl aminoj-lf-m ethyl amino-1,2,5-thiadiazole, gg) 3-friend 1-oxide no-if- £ 2- [(5-dimethylamino-methyl-2-thienyl) methylthio] ethylaminoj -1,2,5-thiadiazole, hh) 1,1-dioxide 3 ~ [3-G-dimethylaminomethyl-phenoxy ^ xopylaminoj-V-methylamino-l, 2,5-thiadiazole, ii) 3-henzylamino-1f-1,1-dioxide {{[(5-di-methylaminomethyl-2-thienyl) methylthio) ethylaminoJ-l , 2,5-thiadiazole, 33) If- {2- [(5-dimethylaminomethyl-2-thi enyl) mé thyl thi o] é thyl amino J ~ 3 - (3 -pyiidyl) methyl amino-1,2,5-thiadiazole, tk) 3-1,1-dioxide [2 - [(2- £ 2,3-dimethylguani-dino J thi az ol-h-yl) methylthi o] é t hyl amin oJ -lf-m ethyl amino-1,2,5-thiadiazole, 11) 3-1-oxide-amino-lf- ^ 2- [(2- ^ 2,3-dimethyl-guanidinoj thi az ol- lf-yl) methyltM o] ethyl amino J -1,2,5-thi a-diazole, mm) 3-amino-if-1-oxide [3- (3-dimethylamino-methylphenoxy) pxopyl amino] -1 , 2,5-thi adiaz ol e, nn) 3 “1,1-dioxide {2 - [(5-dimethylaminomé-thyl-2-thi enyl) methyl thi o] ethyl aminoj -lf- [(2- pyxidyl) m ethylamino] -! , 2,5-thiadiazole, 00) the 1-oxide of 3, ^ - ΐ> ϊε- {2- [(2-guanidinothiazol- - 25 - ^ -yl) methylthio] ethylaminoJ-1,2,5-thiadiazole, pp) 3-amino-V-1-oxide [2- [(2- ^ 2-methylguani-dinoj thi az ol-lf-yl) m ethylthi o] ethyl aminoj -1,2,5-thiadi az ol e, qq) 3_methylamino-V-1,1-dioxide- [3- (3-pi ~ · p éxidinomé thy lphén oxy) pxopy1 àmin o] -1,2,5-thiadiazole, Ψ xx) 1-oxide of 3 ~ amiQO "'1 +“ [3- (3 “Piperidium-thylphenoxy) pxopylamino] -l, 2,5-thiadiazole, ss) 1,1-dioxide 3 ~ [2 - [(5-dimethylamino- m ethyl-2 - thi eny 1) m ethyl thi o] ethylaminoj -lj — ethylamino-1,2,5-thiadiazole, tt) 3-amino-1-1,1-dioxide * - [3 "(3 ~ Pipexidino-methylphenoxy) pxopyl amino] -1,2,5-thiadiazole, uu) 3 ~ {2- [(5-dimethylaminomé-thyl-2-thienyl) methylthio] ethylaminoj -V- [( 4-pyxidyl) methyl-amino] -1,2,5-thi adi az ol e ·

According to another aspect, the invention has for object the new compounds of depoxt of foxmule: 0

H N

\ J na η where each E 'xepxpose an eliminating xadical chosen from halogen atoms and xadicals alkoxy (lower) and alkylthio (lower) and xadical phenoxy and phenylthio which possibly pox 1 or 2 substituents chosen paxmi halogen atoms and xadicals alkyl (inflexible), alkoxy (inflexible) and nitxo.

According to a pxéféxée embodiment, in 7 the compounds of formula lia, each radical B 'is an xadical alkoxy (lower), phenoxy or phenoxy substituted 7 and most advantageously each xadical B is a xadical methoxy.

j · i i - 26 -

According to another aspect, the invention relates to the new intermediates of formula:

<g> P

NN .. xv2 E12 E7 where p represents 1 or 2, n Ή 'represents an eliminable radical chosen from halogen atoms and alkoxy (lower), alkyl-thio (lower), phenoxy, phenylthio, substituted phenoxy and phenylthio radicals substituted which 'the phenyl ring can carry 1 or 2 substituents chosen from halogen atoms and alkyl (lower), alkoxy (lower) and nitro radicals, E ^ 2 represents a radical B2 ^!? - or HStCH ^ KH- where B2 and E · ^ each independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower), cycloalkyl (lower) to alkyl (lower), hydroxyalkyl (lower) radical. ), alkoxy (lower) alkyl (lower), alkylthio (lower) -alkyl (lower), aminoalkyl (lower), alkyl (lower) -aminoalkyl (lower), dialkyl (lower) aminoalkyl (lower), pyrrolidinoalkyl (lower), piperidinoalkyle (lower), morpholinoalkyle (lower), pipérazinoalkyle (lower), pyridylalkyle (lower) ), amino, lower alkyl amino, dialkyl lower amino 2,2,2-trifluoroethyl, 2-fluoroethyl, hydroxyl, alkoxy (lower), 2,3-dihydro-xypropyl, cyano, cyanoalkyl (lower) , amidino, alkyl- (lower) amidino, Α'-ίΟΗ ^^, Ζ '(0Η2) η "-, phenyl, phenyl-alkyl (lower), substituted phenyl or substituted phenylalkyl (the phenyl ring of which may bear a or two substituents chosen independently from the radicals "alkyl (lower), hydroxyl, alkoxy (lower) and halogen atoms or a substituent chosen from the radicals methylenedioxy, trifluoromethyl and dialkyl (lower) amino, with the restriction that B ^ and B ^ cannot both represent cycloalkyl (lower), phenyl, substituted phenyl, amino, alkyl (lower) amino, dialkyl (lower) amino, hydroxyl, alkoxy (lower), cyano, amidino, lower alkyl amidino or A'-ÇCHg ^, Z '(CH ^) ^ "-; or else and B ^ taken together can represent a radical -C ^ CHgXiCHg) ^ -; r represents 1, 2 or 3, X represents a methylene radical, a sulfur atom 2.

or oxygen or a NB radical, 7 with the restriction that when p represents 2 and B represents a methoxy radical, E ^ and E ^ taken together with the nitrogen atom to which they are united cannot represent a morpholino radical and that when r represents 1, X represents a methylene radical; E ^ represents a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), alkanoyl (lower) or benzoyl radical; m and m 'each independently represent O, 1 or 2; n and n 'each independently represent 2, 3 or b-, Z and Z' each independently represent a sulfur or oxygen atom or a methylene radical; A and A 'each independently represent a phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, "furyl, thienyl or pyridyl radical, it being understood that A and A' can independently comprise one or two substituents, the first substituent being chosen from halogen atoms and alkyl (lower), hydroxyl, trifluoromethyl, amino, hydroxymethyl, alkoxy (lower) and EHE radicals ** - (CH2) gH = C ^ and - (CH2 ) gNE5E6 and the second substituent being chosen from halogen atoms and alkyl radicals (lower), hydroxyl, trifluoromethyl, amino, hydroxymethyl and alkoxy (lower); q represents O, 1, 2, 3, 5 or 6; h.

each B independently is as defined above or else the two B * 1 "together represent an ethylene radical, and 5 6 B and E each independently represent your hydrogen atom or an alkyl (lower), alkenyl radical (lower -rior), alkynyl (lower), cycloalkyl (lower) or phenyl, with the restriction that B ^ and B6 cannot both represent cycloalkyl (lower) or C g phenyl or E? and B ° taken together with 1 the nitrogen atom to which they are linked can represent a pyrridino, morpholino, piperidino, methylpiperidino, H-methyl-piperazino or homoperidino radical, as well as a salt, hydrate, solvate or H-oxide of such a compound .

According to a more preferred embodiment, in the compounds of formula XVI, IP "2 represents a radical A (CH2) mZ (CH2) nBH-where A represents a phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl radical, each of which may carry one or two substituents, the first substituent being chosen from the alkyl radicals (lower) and HHE1 * -N = C ^ and -CH2NB? B6 ^ HHE1 * - 29 - and the second substituent being chosen from the alkyl radicals (lower) ); Z represents a sulfur or oxygen atom or a "methylene radical; m represents 0 or 1; n represents 2 or 3; each B ** - independently represents a hydrogen atom or an (lower) alkyl radical or else the two E ** taken together can represent an ethylene radical; and each independently represent a hydrogen atom or an alkyl radical (lower) or else B ^ and E ^ taken together with the nitrogen atom to which they are united can represent a radical pyrrolidino, morpholino, pipéridino, methylpiperidino, K- methylpiperazino or homo-piperidino; Π E 'represents an (lower) alkoxy radical.

According to another preferred embodiment, in the compounds of formula ZVI, E12 represents a radical E2E3E-, B2 and E ^ each independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower) radical. alkynyl (lower), cycloalkyl (lower) alkyl (lower), pyridylalkyl (lower), A '- (CH2) m, Z' (CH2) n, -, phenylalkyl- (lower), or 3, ^ - methylenedioxybenzyle , with the restriction that E2 and cannot represent 'both radicals A' - (CH2) m, Z '(CH2) ii, -; "M 'represents 0 or 1; n 'represents 2 or 3; - Z 'represents a sulfur or oxygen atom or a methylene radical; AT.' represents a phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl radical, each of which may carry one or -30 - two substituents, the first substituent being chosen from the alkyl radicals (lower) and NHE1 * -K = C ^ and -CHDHE ^ E6 ·. 2 L.

each B independently represents a hydrogen atom or an alkyl radical (lower) or else the two E ^ taken together can represent an ethylene radical; E ^ and B ^ each independently represent a hydrogen atom 5 6 or an (lower) alkyl radical or else E and E taken together with the nitrogen atom to which they are united may represent a pyrrolidino, morpholino, piperidino radical, methylpiperidino, K-methylpiperazino or homo-piperidino; n represents an (lower) alkoxy radical.

According to another more preferred embodiment, in the compounds of formula XVI, B * "2 represents a radical n represents 2, 3 or ** and * 7 B 'represents an alkoxy radical (lower).

According to a particularly preferred embodiment, in the compounds of formula XVI, B * "2 represents ^ HCB2 - CÏÏ2ZCH2CH2EH-" ^ where Z represents a sulfur atom or a methylene radical; represents a hydrogen atom or a methyl radical; B ^ represents an (lower) alkoxy radical.

According to another particularly preferred embodiment, in the compounds of formula XVI, - 31 -

E12 Jepresente ifH

ETN c

\ S

C = N — S0 * \ *** Λ iï H N - '\' CHgZOHgCHgMH- Z represents a sulfur atom or a methylene radical; each B ^ independently represents a hydrogen atom k or a methyl radical or the two E taken together may represent an ethylene radical; n E 'represents an alkoxy radical (lower).

According to another particularly preferred embodiment, in the compounds of formula 271, E12 represents ^ 3 p H3 ° \ -3 | ch2zch2ch2hh- & represents a hydrogen atom or a methyl radical; Z represents a sulfur atom or a methylene radical; B ^ represents an (lower) alkoxy radical.

According to another particularly preferred embodiment, in the compounds of formula 271, E12 represents

^ J

KCH2 - <^ —çh2zch2ch2m-

JLf's

& represents a hydrogen atom or a methyl radical; Z represents a sulfur atom or a methylene radical; "É! Represents an (lower) alkoxy radical.

According to “ru”, another particularly preferred embodiment in the compounds of formula 271, E12 represents - 32 - ^ nch2 <^ J.ch2 ZCH2CE2im- and E ^ each independently represent a hydrogen atom or an (lower) alkyl radical; Z represents a sulfur atom or a methylene radical; B'7 represents an (lower) alkoxy radical.

According to another particularly preferred embodiment, in the compounds of formula XVI, B12 represents n 6 ^ πσΗ24 ^^ οσΗ2θΗ20Η2ΕΗ- B ^ and each independently represent a hydrogen atom or an (lower) alkyl radical or else when E ^ represents a hydrogen atom, B ^ can also represent an alkenyl (lower) or alkynyl (lower) radical or also and B ^ taken together with the nitrogen atom to which they are united s can represent a pyrrolidino, morpholino radical, piperidino or homopiperidino; 7 E 'represents an (lower) alkoxy radical.

According to another aspect, the invention relates to the new intermediaries of formula: "" *

3Ï N

\\ ^ XVII

HS (CE2) nHH '^ ÏÏB2! ^ Where p represents 1 or 2; n represents 2, 3 or 1j; E2 and E ^ each independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower), cycloalkyl (lower), alkyl (lower), hydroxyalkyl ( lower), - 33 - alkoxy (lower) alkyl (lower), alkylthio (lower) al-kyle (lower), aminoalkyl (lower), alkyl (lower) ami-noalkyl (lower), dialkyl (lower) aminoalkyl (lower Erieur), pyrrolidinoalkyle (lower), piperidinoalkyle (lower), moipholinoalkyle (lower), pipéxazinoalkyle (inferior), * pyridyl alkyl (inferior), 'amino, alkyl (inferior) amino, dialkyl (lower) amino, 2,2, 2-trifluoroethyl, 2-fluoroethyl, hydroxyl, alkoxy (inflexible), 2,3-dihydroxypropyl, cyano, cyanoalkyl (lower), amidino, alkyl (lower) ami-dino, A '- (CH2) m, Z' (CH2) n, -, phenyl, phenyüalkyl (lower), substituted pienyl or phenylalkyl (lower), the phenyl ring of which can carry one or two substituents chosen independently from halogen atoms and alkyl radicals (lower), hydroxyl and alkoxy (lower) or a substituent chosen from methylenedioxy, tri-fluorine radicals adorned thyle and dialkyl (inflexible) amino, with the restriction that and cannot both represent cycloalkyl (lower), phenyl, substituted phenyl, amino, alkyl (lower) amino, di alkyl (thin) amino, hydroxyl, alkoxy (lower), cyano, amidino, lower (alkyl) amidino or A'-ÎCB ^^ radicals .Z '(CHg) ^ -, or else and E? taken together may represent a radical -CH2CH2Z (CH2) I-; r represents 1, 2 or 3, Σ represents a methylene radical, a sulfur atom of li or oxygen or an N-B radical, with the restriction that when r represents 1, Σ represents a methylene radical; 'B1 * represents a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), alkanoyl (lower) or benzoyl radical; m 'represents O, 1 or 2; n 'represents 2, 3 or 1 *, Z' represents a sulfur or oxygen atom or a methylene radical; A 'represents a phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadia-zolyl, oxadiazolyl, fuxyl, thienyl or pyridyl radical, being as extended as A' can comprise * one or two substituents, the first substituent being chosen from halogen atoms and alkyl (lower), hydroxyl, trifluoromethyl, amino, hydroxymethyl, alkoxy (lower), HHE1 * · - (0¾) Ν = (Τ and - (0¾) ÏÏB ^ E6 , c * ^ vk ^ y.

^ HHE * and that the second constituent is chosen from halogen atoms and alkyl radicals (lower), hydroxyl, trifluoromethyl, amino, hydroxymethyl and alkoxy (lower); q represents O, 1, 2, 3, J or 6; each il * independently is as defined above or the two E * 1- taken together may represent an ethylene radical; K 6 B and E each independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower) or 5 6 phenyl radical, with the restriction that and E cannot all represent two of the cycloalkyl (lower) or 5 6 phenyl radicals, or else E and E taken together with the nitrogen atom to which they ring united may represent a pyrrolidino, morpholino, piperidino, methylpiperidino, E-methylpiperazino radical or homopiperidino, „as well as a hydrated, solvated or H-oxide salt of such a compound ·

According to a preferred embodiment, in the compounds of formula XVIX, B2 and K3 each independently represent a hydrogen atom or an (lower), alkenyl (lower) alkyl radical.

laughing), alkynyl (lower), cycloalkyl (lower) alkyl (lower), phenylalkyl (lower), pyridylalkyl (lower), at *. 3 Λ-methylenedioxybenzyle or A '(CHg ^ tZ' (CHg) ^, -; with the restriction that E2 and B ^ 'cannot both represent radicals A' - ^ CHg ^ .Z '(CH2) n, - ; m 'represents O, 1 or 2; n and n' each independently represent 2, 3 or V; Z 'represents a sulfur or oxygen atom or a methylene radical; A' represents a phenyl, imidazolyl, thiazolyl radical, furyl, thienyl or pyridyl, each of which may carry one or two substituents, the first substituent being chosen from the alkyl radicals (lower), m2 -N = CT and -CH ~ lfB5B6 and the second substituent being chosen from the alkyl radicals (lower) ; ç 6

By and B each independently represent a hydrogen atom or an (lower) alkyl radical.

According to another more preferred embodiment, in the compounds of formula XVII, n represents 2; E2 and B ^ each independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower) radical; alkynyl (lower or phenylalkyl (lower) or when B2 represents a hydrogen atom, E ^ can represent ^ 36 - / - ^ B13 -CELCELZCHjj VgE9N ^ 2 2 2 B / 1¾

- S \ -N = C

-tCH2CH2SOH2 </ e \ ^^ nn.

Λ- /. 0¾ -CHgCHgSCHg / -v -QH2CH2SCH2— ^ J ^ -CHgN ^ NCH3 ^ -H or -CH2Cn2SCE2 ^ Π> ° -CTgGHgZG ^ -Js ^^ - CSH ^^; f Z represents a sulfur atom or a methylene radical, represents a hydrogen atom or a methyl radical. . For the purposes of the invention, by "pharmaceutically acceptable non-toxic salt" is meant the salt of a compound of formula I formed with a pharmaceutically acceptable non-toxic organic or inorganic acid. Such acids are conventional and are in particular hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, malic acid, fumaric acid, acid suc-; kinic, oxalic acid, benzoic acid, methanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, tartaric acid, citric acid, l camphosulfonic acid etc. The salts are obtained according to known methods. It is obvious to the specialist that some of the compounds of formula I and some of the intermediates described form disels, trisels etc. It should also be noted that the salts of these intermediate compounds are not limited to the salts formed with non-toxic pharmaceutically acceptable acids when these intermediate compounds are not themselves used as medicaments.

The Applicant has discovered that many of the compounds of formula I prepared according to the invention vigorously fix the solvents in which they have been crystallized. Sometimes it appears that the products are true solvates ^ but in other cases the products may simply contain parasitic solvent or may consist of a mixture of solvate with a little parasitic solvent. Although the solvent can be removed by drying at elevated temperature, this I 4 · * operation often changes a well crystallized product to a gummy solid. Since solvates usually have well-defined melting points, common practice is to dry the products at room temperature. When solvent remains even after long drying, the amount remaining is determined, for example. by nuclear magnetic resonance troscopy. The examples below indicate the quantity of solvent (as the case may be) 4 and the analyzes and iusion points are the analyzes and melting points of the solvated products, unless otherwise indicated.

b For therapeutic purposes, the pharmacologically active compounds of the invention are normally administered in the form of a pharmaceutical composition comprising as main active ingredient or as one of the main active ingredients at least one such compound in the form of the state of a pharmaceutically acceptable non-toxic acid addition salt, in association with a pharmaceutically acceptable excipient.

The pharmaceutical compositions can be administered orally, parenterally or rectally as a suppository. Many pharmaceutical forms are suitable. When using a solid excipient, the composition may be presented in the form of tablets, be introduced into a hard gelatin capsule in the form of powder or granules, or be presented in the form of lozenges to be sucked or of tablets. When using a liquid excipient, the composition can be presented in the form of syrup, emulsion, soft gelatin capsule, sterile solution to be infected or aqueous or non-aqueous liquid suspension. The pharmaceutical compositions are prepared according to the usual methods suitable for the purposes envisaged.

Preferably, each unit dose contains about 0.5 to 150 mg and more preferably about 2 to 50 mg of active ingredient. The active ingredient is preferably administered in equal doses two to four times a day. The total daily dose is preferably about 1 to 600 mg and more preferably about 1 to 200 mg.

histamine receptor antagonists - have been shown to be effective inhibitors of gastric secretion in humans and animals, see Brimblecom.be 4 et al., J. Int. Med. Kes., 86 (1975). clinical evaluation of cimetidine, which is a 1¾ histamine receptor antagonist, has revealed that this compound is an effective therapeutic agent for the treatment of peptic ulcer, voices Gray et al., Lancet, _1 8001 ( 1977). one of the standardized animal models for determining the capacity of a histamine receptor antagonist to inhibit gastric secretion is that carried out on the rat after ligation of the pylorus, Table I below indicates the activity of inhibition of the gastric secretion DEijq (in micromoles / kg) in the rat after ligation of the pylorus for many compounds of the invention.

Determination of the activity of inhibition of gastric secretion after 2 hours in the rat after ligation of the pylorus according to Shay The test with ligation of the pylorus in the rat was developed by Shay et al., Gastroenterology, 5., 53 (19 ^ 5) for the study of perforating gastric ulcers, * but after its publication this process was also applied as a means of studying gastric secretion in rats, see Shay et al-, Gastroenterology-26, 906 (19¾), Brodie, DA Am. J. Dig. Dis., 11, 231 (1966). A variant of this procedure is applied for the evaluation of the capacity of the compounds of the invention to inhibit gastric secretion.

Male rats of the Long Evans strain - 40 - weighing from 260 to 300 g are chosen. The animals are placed in individual cans and allowed to soak for 2½ hours, but with unlimited water. Under ether anesthesia, the stomach is released by a midline incision * and a cotton thread is tied around the pylorus!> After closure of the wound, the administration of the ether is stopped and the test compound or the control excipient is administered intraperitoneally or subcutaneously in a volume of 1 ml / kg. All the compounds are solubilized with 1 equivalent of hydrochloric acid and brought to the appropriate volume with water.

The animals are then returned to their cage from which the bottles containing water have been removed and the animals are sacrificed 2 hours later by administration of ether.

The stomach is removed and the accumulated gastric secretion collected for 2 hours in a graduated test tube to assess the volume. The titratable acidity is measured by titrating a 1 ml sample to pH 7.0 with 0.02 N sodium hydroxide, using an automatic burette and an electrometric pH meter (from the Badio-meter brand). The production of titratable acid in microequivalents is calculated by measuring the volume in milliliters by the concentration of P acad in milliequivalents per liter.

Or calculate the inhibition of acid production as a percentage using the following formula of acid, acid (control) (drug), x 100 ii Production of acid acid acid (control) j

Gn uses at least five rats for each dose and at least three doses are chosen to determine a response curve depending on the dose. Initially, the test is carried out by intraperitoneal injection of the compound to be examined or of the control excipient. However, experience has shown that the test is somewhat more sensitive when the ad-; administration is carried out by subcutaneous injection, all the following tests are performed by subcutaneous injection. The mode of administration of each compound is specified in Table I.

TABLE I

Effect of the compounds of the invention on the production of gastric acid in 2 hours in rats after ligation of the pyloie

Composed of Mode d * administra- DE ^ -, * .umoles / kg example n ° tion - 1 iP * 12.5 (if, 90-33.0) 2 sc * <v 10 3 iP- 0Λ6 (0 , 26-0.71 *)! 7 i-P ”31.1 (11.1-82.8) 11 B i-p. 0.69 (0.31-1.33) 11 C S.c. 0.20 (0.03-2.9) 12 i-p. 0.28 (0.11-0.69) 13 sc 0.1 * 6 (0.02-3.1) 11 * sc ~ 10 -17 sc 33 (8.7-lifl) 18 sc 0.38 ( 0.02-5.33) 19 sc 0.31 * (0.15-0.81) 20 A sc 1.15 (0.32-3.7) 21 sc 0.30 (0.09-1, 0) 28 · sc 1.39 (0.39-lf, 9l) 31 iP- 0.1 * 1 (0.19-0.81) 32 iP- 0.08 (0.03-0.15). 33 sc 0.57 (0.16-1.81 *) 24 sc 0.08 (0.02-0.22) 25 sc 1.59 (0.1 * 8-6.1 * 6) - OJ _ TABLE I (contd.) 'Composed of Admin Mode- DEcq * .umoies / kg example n ° tion · 52 sc ** 350 65 sc 0.07 (0.02-0.32) 85 sc 0.1½ (0.05-0, m) 86 sc 0.0½ (0.015-0.12) 87 sc 0.02 (0.006-0.0½) 88 sc 0.08 (0.01 + -0.22) 89 sc 0.25 (0.07-0.8½) 90 sc 0.86 (0.2 ^ 2.69) 93 sc 0.1½ (0.07-0.32) 9B sc 0.52 (0.08- 2.33) 10½ sc 0.61 (0.15-1.88) io5 sc 1.65 (0.1 + 5 - ^ -, ½¾ 110 SC 0.05 (0.03-0.1½) 113 sc 0.07 (0.03-0.1½) 117 sc ^ 0.5 122 sc λ, 10.0 132 sc ~ 0.0½ 133 s * c · v O * 05 * - · * I, es values in parentheses are 95% reliability limits.

Some of the compounds of the invention have also revealed to experience activity during the test on the right atrium isolated from guinea pigs, during the test of gastric fistula in dogs (intravenous route) and during test following Heidenhain in dogs (oral). The first two tests are performed as described in U.S. Patent No. ^ 112.23½.

The test following Heidenhain in dogs is carried out in the general manner described by Grossman and Konturek, i Gastroenterologe, 66, 517 (197½) ·

The product sold under the name of Celite by Johns-îianville Products Corporation is a diatomaceous earth. The product sold under the name Skellysolve E by the Skelly Oil Company is a fraction of petroleum ether boiling at 60-68 ° and consisting essentially of n-hexane.

By "flash chromatography", which is discussed in some examples, is meant a relatively new chromatography technique described by V. C. Still et al. in J. Org. Chem., 2923-2925 (1978).

More finely divided chromatographic media under somewhat superatmospheric pressure are used to provide faster chromatographic separation.

In the examples, all the temperatures are given in degrees centigrade.

EXAMPLE 1 - 1,1-1) 1 oxide of 3- [2 - [(5-methyl-15-imidazolyl-V-yl) methyl-thiolethylamino) -h- (2 - propynyl) amino-1,2,, 5-thiadiazole A. ll-3-f dioxide 2-Γ f 5-TOethyI - 1H-iIΓίidazol-½-yl) methvlthio ^ -ethyla ^ Eino '^ -lt-methoxv-1,2,5-thiadiazole

Add a solution of 2 ~ [(5-methyl-1H-III-lida-z ol - ^ - yl) methylthio] ethylamine (obtained from the dihydrochloride, 2.73 and U "2 millimoles) [prepared con-" according to Belgian patent no. 779.775] in 25 ml of methanol to a well-stirred suspension of 3, ½-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g, 11.2 millimoles ) [prepared according to the method described in J. Org. Chem., 27½3 (1975)] - After 3 ° stirring, a methanolic solution of the desired compound is obtained. Thin layer chromatography [EiOg / CHgClgsCH ^ OH (90:10)] indicates an ET of 0.1 * 1 *.

; B. 3-ί2-Γ-1,1-dioxide (5-methyl-1H-imidazol- ^ l * -yl) methylthio] ethylamino) -1 * - (2-propynyl) amino-1,2,5- thiadiazole

7 ml of 2-propynylamine are added to the methanolic solution of the product obtained in stage A. After 20 minutes of stirring at room temperature, the reaction mixture is evaporated under reduced pressure and the oily residue is deposited on silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Combine suitable fractions to obtain 2.71 * g of the desired compound which is an oil.

An additional purification is carried out by combining the above product with that obtained during a second analogous experiment, then the mixture is deposited on silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Qn combines the appropriate fractions with methanol and evaporates under reduced pressure to obtain the desired compound (2.93 g) which is a friable solid having a melting point of 82-103 °. The nuclear magnetic resonance spectrum (100 MHz) in dimethyl-; f hexadeuterated sulfoxide reveals the presence of 1/3 mole of methanol.

Analysis for C-j ^ H ^ N ^ OgSg.l / S CH ^ GH

calculated C, 1 * 2.19; H, 1 *, 97; H, 23.95; S, 18.27% r found C, 1 * 2.05; H, 5.05; H, 2l *, 01-, S, 18.1 * 5% EXAMPLE 2 - 1.1-3-Î2-T dioxide f5-methvl-1H-ïTn-tdazol-l * -yl) -methylthi ο 1 ethvl amino) -l * -methvlamino-l. 2,5-thi adi az goose

A solution of 2- [(5-methyl-1H-imidazol-V-yl) methylthio] ethylamine (obtained from the dihydrochloride, 3, V2 g, 1V, 0 millimoles) is added dropwise over 25 minutes. 25 ml of methanol to a well-stirred suspension of 3,1 * -dioxide * -di.methoxy-1,2,5-thiadiazole (2.5 g, * H *, 0 millimoles) in 250-ml of dry methanol which was cooled to 2® in an ice and water bath. After stirring for 20 minutes at 2 °, anhydrous methylamine is bubbled through the solution for 6 minutes and stirring is continued at room temperature for 30 minutes.

The reaction mixture is evaporated under reduced pressure and the residue is deposited on 50 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Combine suitable fractions to obtain 3.2 g of the desired compound. By further purification of this product on a chromatographic column, an analytical sample of the desired compound is obtained, which is an amorphous solid having. a melting point of 98-110 °. the nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethyl sulfoxide comprises the following resonances è>: 7, h6 (s, 1H); 3.70 (s, 2H); 2.53 (t, 2H); 2.86 (s, 3H); 2.72 (t, 2H); 2.15 (s, 3H).

Analysis for calculated C, 37.96; H, 5.09; N, 26.56; S, 20.27% found C, 37.79; H, 5.16; N, 26.52; S, 20.2 * $ (correction for 1.60% H ^ O) EXAMPLE 3 - 1,1-Dioxide of 3 ~ {2 - [(2-guanidinothiazol-1t-yl) methylthio] - ethylamino? -Tt- ^ 2 - / (l> -meth: yl-1H-imidazol-1 <~ yl) methylthio7-. ethylaminof-1. 2.5-thiadiazole.

A solution of 2 - [(2-guaninothinothiazol - ^ - yl) methylthio) ethylamine (obtained from the dichloxhydrate, 3Λ1 B »H» 2 millimoles) [prepared * according to the process of the South patent African n ° 78/2129) in? 35 ml of methanol to a well-stirred solution at -10 ° of * 1,1-di-oxide of 3 _ £ 2- [(5-m ethyl-1H-imi daz ol - ^ - yl) m ethylthi o] - »Ethylamino} methoxy-1,2,5-thiadiazole [prepared from 2- £ dihydrochloride (5_methy 1 -lH-imidaz ol -1! —Y 1) methyl-thiojethylamine (2.73 E» H »2 millimoles ) according to the process of stage A of example 1]. After 30 minutes of stirring at -10 °, the solution is allowed to warm up to room temperature. Or the reaction mixture is evaporated under reduced pressure and the residue is deposited on g of silica gel which is chromatographed with 1 liter of a mixture Of: l) methylene chloride and methanol- The appropriate fractions and the evaporated, then the residue (5.82 g) is deposited on 80 g of aluminum oxide which is chromatographed with gradient elution using ethyl acetate and methanol. The appropriate fractions are combined. , they are filtered on Celite and they are evaporated under high vacuum to obtain the desired compound (2.5 g) which is an amorphous solid containing about 2/3 moles of ethyl acetate as indicated by spectroscopy of nuclear magnetic resonance (100 MHz) in hexadeuterated dimethylsulfoxide.

Analysis for ^ 6 ^ 2 ^ - ^ 10¾¾ * calculated c, 38.96; H, 5, IV; M, 2 ^, 3 ^; S, 22.29% found C, 39.08; H, 1 *, 96; lî, 2lf, if8; S, 22.26% EXAMPLE h - ~ 1-Oxide of 3 * ~ f2- [(5-methyl-1H-imidazol - ^ - yl) methylthio] - ethvlamino} - ^ - methyl amino-1, 2,5-thiadiazole A- 1 — Oxide of 3, if-dimethoxy-1 - 2,5-thi adiazole A solution of 3 »^ ~ dimé - 47 - tboxy-1,2,5- is added over 3 minutes thiadiazole (35.2 g, 2 ^, 1 millimoles) [prepared as described in J. Org. Chem., ^ 0, 2749 (1975)] in 100 ml - of chloroform to a stirred solution of m-chloroper- benzoic acid (50.7 g, 25.0 millimoles, 85% titer) in * 900 ml of chloroform at 20 ° using a cooling bath to prevent the exothermic reaction from exceeding 32 °. After 3 hours of stirring at room temperature, the excess peracid is reacted with an additional 2.0 g of 3 Λ-dimethoxy-1,2,5-thiadiazole and the mixture is stirred for a further 1 hour.

The organic solution is extracted twice with 300 ml of a 1% solution of sodium bicarbonate, washed with 250 ml of water, dried and evaporated under reduced pressure to obtain k-7.0 g of the product.

By recrystallization from isopropanol, the desired compound is obtained (3 * f, 0 g). By additional recrystallization from isopropanol, an analytical sample is obtained having a melting point of 135-137 ° - Analysis for C ^ H ^ NgO ^ S: calculated c, 29.63-, H, 3.72; N, 17.27; S, 19.77% • found C, 29.53; h, 3.75; N, 17.26; S, 19.83% B. 1-Qxvde de λ- (2- [f 5-Tnéthv1-lïï-imidszol - ^ - vl Ί-méthvlthio 1 éthvlamino] - ^ - methylaroino-1 T2t 5-thiadiazole

A 3.1-dimethoxy-1,2,5-thiadiazole 1-oxide solution obtained in stage A is reacted with an equimolar amount of 2- [(5-methyl-1H-imidazol-1 * -yl) methyl, thylthio] ethylami ne, then reacting the 3 “1-oxide {2- [(5-methyl-1H-imidazol-1i — yl) methylthio] ethylamino] -V- - 1,2-methoxy, 5-thiadiazole resulting with an excess of methyl amine to thereby obtain the desired compound.

EXAMPLE 5 - 1,1-Dioxide of 3 ~ hydroxy-V-f 2 ~ r (5-meth: yl-1B-imidazol- * f-: 7l) - methylthiolethylamino) -! , 2i5-thiadiazole

Or reacts a methanolic solution of 1,1-; 3- [2 - [(5-methyl-1H-imidazol-1 * -yl) methylthio] ethyl-r aminoJ - ^ - methoxy-1,2,5-thiadiazole dioxide [prepared by the process * of stage A of example] with a solution of sodium hydroxide in methanol according to the general method of Example 12 (stage B) to obtain the desired compound having a melting point of 263-265 ° (decomposition).

Analysis for calculated C, 35.61 *; H, · 1 *, 32; H, 23.09; S, 21.13% found C, 35.56; H, 1 *, 38; N, 23.01; S, 21.13% • RTEMPEE 6 - I, 1-Dioxide of 3 ~ f 2— [(5-dimethylaminomethyl-2-furyl) methyl-thi ο 1 ethyl 1 amino] -hm ethyl amino-1,2,5 ~ thi adi az ol e and 1,1- 3,1 * dioxide -bis-f2 - [(5-dimethylaminomethyl-2-furyl) mé-thylthio] éthylamino} -1,2,5-thiadiazole A. 1, 1-Di oxide of 3 ~ f 2-Γ (5-dimethylaminomethyl · - 2-f uryl) methylthio] ethylamino} -lf-methoxy-1,2,5-thiadiazole A solution of 2 - [( 5-di-methylaminomethyl-2-furyl) -methylthio] ethylamine (2.1 * 1 g, II, 2 millimoles) [prepared according to the method of Belgian patent n ° 857-388] in 20 ml of dry methanol in a suspension well stirred, cooled to 8 ° 3, ¼-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g, 11.2 millimoles) in 200 ml of methanol. After 15 minutes of stirring at 8-10 °, a methanolic solution of the desired compound is obtained - • B. 1,1-Di oxide of 3-f 2-Γ (5-dimethvlaTnTTiométhvI-2-f uxyl) methylthi ο 1 ethylamino] -l * -m ethyl amino-1,2,5-thiadia- 1 zole

Anhydrous methylamine is bubbled for 6 minutes into the methanolic solution cooled to 1 ° of the product from stage A. Stirring is continued for 10 minutes, then the mixture is evaporated under reduced pressure.

The residue is deposited on 1 + 5 g of silica gel which is chromated ogxapjiie with gradient elution using methylene chloride and methanol. Combine suitable fractions collected with methylene chloride and methanol (95: 5) in methanol, filter through Celite, then concentrate under reduced pressure to obtain the desired compound. By recrystallization from methanol, the desired compound is obtained (1.76 g) having a melting point of 82-90 ° and whose nuclear magnetic resonance spectrum · (100 MHz) in hexadeuterated dimethyl sulfoxide reveals the presence of 2/3 mole of methanol.

Analysis for .2 / 3 CH ^ OH

calculated C, 1 + 3.10; H, 6.26; N, 18.38; S, 16.83% found C, 1 + 3.30; H, 6.12; N, 18.57; S, 16.96% (correction for 1.72% HgO) C. ll-Dioxide of 3 A-bis-f2- | ~ (5-dimethylamino-methyl-2-f urypmethylthiol ethylamino} -1,2,5- thiadiazole The component eluted most slowly using methylene chloride and methanol (9: 1) is deposited on 1 + 5 g of aluminum oxide during chromatography at stage B, then chromatography is carried out with elution at gradient using ethyl acetate and methanol.

The suitable fractions are evaporated and the residue is triturated in ether and acetonitrile to obtain a colorless solid which is collected by filtration to obtain the desired compound (1 + 28 mg) in the form of the monohydrate having a point of 92.5-96 ° fusion.

Analysis for C22H3i + N6S3 ° ij- * H2 ° calculated C, 1 + 7.12; H, 6.1 + 7; N, ll +, 99; S, 17.15% found C, 1 + 7.28; H, 6.1 + 8; N, 15.09; S, 17.39% - 50 - calculated lice HgO = 3 "21% txouved lice HgO = 3" 32% EXAMPLE 7 -% I. 1-Dioxide of ^ -f 2-Γ ^ -dimethylaminomethyl-P-fury ^ methyl -thiolethylamino} -V-ethylamino-1.2.5-thiadiazole "

Or add at once a solution of 2 - [(5-di-methylaminomy thy 1 -2 -fury 1) m é t hy 1 tiiio] é thy 1amine (2, ¼ g »II, 2 millimoles) in 20 ml of dry methanol to a well-stirred suspension and cooled to 1 ° 3-1-dioxide-1 * -dimethoxy-1,2,5-thiadiazole (2.0 g, 11.2 millimoles) in 200 ml of methanol. After 15 minutes of stirring at 1-5 ° "(1 ml of thyamine Of, 0 ml) is added and stirring is continued at approximately 5 ° for 20 minutes. The reaction mixture is evaporated under reduced pressure and the residue sux ** 6 g of silica gel is deposited which is chromatographed with gradient elution ion using methylene chloride and methanol. The appropriate fractions are combined, evaporated and the gelatinous residue is triturated in ether, then collected by filtration to obtain the desired product which is a colorless solid (2.81 g). By two recrystallizations from methanol with drying over phosphorus pentoxide at room temperature for 17 hours, the desired compound is obtained having a melting point of 155-160 ° after variable sintering at 9k - 96 ° and whose spectrum of Nuclear key resonance (100 MHz) in dimethyl tallow hexadeuterated oxide reveals the presence of approximately 0.8 mole of methanol.

Analysis for CH ^ OH

calculated C, H, 6.62; N, 17.55; fi, 16.07% found C, 11.55; H, 6.58; H, 17, Mt; S, 16.18% EXAMPLE 8 - 1.1-PioYvda of ^ -f2-Γ (5-dimethvlaminomethvl-2-furvl) methvl- thio1ethvlaninol-V- (2 — Dro-Dvnxl) amino-1.2.5-thiadiazole Add drop drop in 25 minutes a solution of 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] -ethylamine (2, ML g, 11.2 millimoles) in 20 ml of dry metha-nol to a well-stirred and cooled suspension at 1 ° I, 1, 3, ^ “dimethoxy-1,2,5-thiadiazole dioxide (2.0 g, II, 2 millimoles) in 200 ml of methanol. After 15 minutes of stirring at 1-2 °, a solution of 2-propynylamine 0 + (0 ml) in 10 ml of dry methanol is added all at once and stirring is continued at room temperature for 1 hour. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 50 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. The appropriate fractions are combined, evaporated and the residue is crystallized from methanol to give 0.1 g of the desired product. By recrystallization from methanol, then from isopropanol, the desired compound is obtained (2.90 g) having a melting point of 92-100 ° and whose nuclear magnetic resonance spectrum (100 MHz) in dimethyl sulfoxide hexadeuterated reveals that it is solvated with 1 mole of methanol.

Analysis for ^ 0 ^ S2 * CH3 ^ calculated C, ^ -6.25; H, 6.06; N, 16.85; S, ΐ5Λ3% found C, Mi, 36; H, 6.22; N, 16.95; S, 15.73% TXRIjEIÆ 9 - - 1T1-Di oxide dp. ^ -methvlamino- ^ f- (2-Γ (5-t rN-methvl-K- (2-pro- • pTOvl) aminolmethvl} -2-f uryl) methvlthio ~ l ethvlamin o3 -1 T2T 5-thiadiazole A. 5- f Γ N-metfryl-N- (2-nr onvnvl amino] m éthvl} -2-fnyanrieTn ethanol

N-methylpropargyl hydrochloride Ot, 0 g, 37 g (9 mmol) and aqueous formaldehyde (3.13 ml "* + 1" 7 mmol) are added to furfuryl alcohol ( 2.1 * 9 g, 25, k millimoles) which has been cooled to 5 ° in an ice and water bath and the mixture is stirred while being allowed to warm up to room temperature. After 1 hour of stirring, the solution is left to stand at room temperature for 1 * 1/2 days. Qu pour the reaction mixture into ice water and strongly alkalinize with aqueous sodium hydroxide to then extract it five times with methylene chloride. The mixture of organic phases is dried, filtered and evaporated under reduced pressure to obtain the product which is an oil (quantitative yield). By vacuum distillation, the desired compound is obtained boiling at 102-106 ° / 0.3 mm Hg.

Analysis for ^ 0 ^ 13 ^ (½: calculated C, 67.02; H, 7.31; N, 7.82% found C, 66.80; H, 7, * A-; K, 7.93% B. 2-Γ (5-fΓN-methvl-N- (2-pr onvnvl) amino1-methvlf-2-f uryDmethvlthiol ethvlamine

A solution of 5 ~ [[N-methyl-lf- (2-pro-pynyl) aminojmethyl} -2-furanemethanol (1 * 0.0 g, 223 millimoles) [prepared in stage A] in 100 ml of is added. concentrated hydrochloric acid frozen in a stirred solution and cooled to 5 ° of eysteamine hydrochloride (27.9 g, 21 *, 6 millimoles) in 125 ml of concentrated hydrochloric acid. The solution is left to stand at 0 ° for 2 1/2 days, then at room temperature for 7 hours to allow the - reaction to complete. The reaction mixture is cooled in an ice-water bath, diluted with 200 ml of water, it is strongly alkalinized with 1% aqueous sodium hydroxide and then extracted three times with methylene chloride. The mixture of organic phases is dried, filtered and evaporated under reduced pressure to obtain the product which is a thick oil (^ -6, ½ g) · By rapidly distilling the oil in vacuo, obtains the desired compound boiling at 136-1 ^ -0 ° / 0.2 mm Hg.

Analysis for C12H1BN20S

calculated C, 60.1 * 7; H, 7.61; N, 11.76; S, 13.1 * 6% found C, 59.82; H, 7.68; N, 11.61; S, 13.27% C. ll-3-methvlamino-V-Î2 — Γ dioxide (5- (ΓΝ-methvl-N- (2-propynyl) aminolmethvl-2-f urvll methvlthiol ethvl-amino} -! „ 2.5 ~ thiadiazole

Add a solution of 2- [(5 - {[lî-methyl-Iï- (2-pr opynyl) amino] methyl} -2-f uryl) methylthio] ethylami ne (2.68 g, 11.2 millimoles) [prepared in stage B] to a stirred suspension and cooled to 3 ° of 1,1-dioxide of 3, ^ - dimethoxy-1,2,5-thiadiazole (2.0 g, 11.2 millimoles) in 200 ml of dry methanol. After 15 minutes of stirring at 3-7 °, methylamine is bubbled through the solution for 16 minutes. The reaction mixture is evaporated under reduced pressure, then the oily residue is deposited on 100 g of silica gel which is chromatographed while maintaining a gradient using acetonitrile and methanol.

The appropriate fractions are combined and chromatographed again on 100 g of silica gel, maintaining a gradient using methylene chloride and methanol. The appropriate fractions are dissolved in methylene chloride and the solution is extracted with 1% aqueous sodium hydroxide. The aqueous phase is brought to pH 9 with 5% aqueous hydrochloric acid, then the separated oil is extracted three times with methylene chloride. The mixture of extracts is dried, filtered and evaporated under reduced pressure to obtain a foam. By xecxistallisation in isopxopanol, the desired compound is obtained having a melting point of ~ 50-51e and a clear melting point of 5k ~ 56e and whose nucleaix magnetic xesonance spectrum (100 MHz) in hexadeuterated dimethylsuifoxide xevele la about ipol of isopxopanol.

Lice analysis C ^ Hg ^ N ^ O ^ E ^ .lA · C ^ HgO: calculated C, 1 * 7Λ7; H, 5.82; ' N, 17.57; S, 16.09% t found X, 1 * 7.51; H, 6.21; N, 16.1 * 0; S, 15.97% EXAMPLE 10 - 1,1-Dioxide of 3 ~ [2 ~ Γ (5-dimethvlaminomethyl-3-methyl-2-furyl) m ethy1thi ο 1 ethyl amino} —V-methylamino-1. 2.5-thiadiazole A. 5-Dim ethyl aminomé thyl -3 -m ethyl -2-f ur arm em ethanol The mixture is stirred for 2 hours and 3 ° minutes at about 5 ° ^ then at room temperature overnight a mixture containing 3 ~ methyl-2-fuxfuxyl alcohol (11.2 g, 0.1 mole) [pxaxed according to the pxocédé decxit in J. Am. Chem. Soc., 72, 2195 (1950)], dimetbylamine hydrochloride (12.23 g, 0.15 mole) and 37% aqueous foxmaldehyde (12 ml, 0.15 mole ') - The solution is heated for 10 minutes in a steam bath, diluted with 12 ml of water and made alkaline with sodium carbonate.

The mixture is extracted with ethyl acetate, then dried, the organic phase is filtered and evaporated under reduced pressure to obtain the desired compound boiling at 88-96 ° / 0.05-0, 08 mm Hg.

- B. 2-T (5-dimethylaminomethyl-3-methyl-2-furyl) - m éthvlthi ο1éthylamine

5-dimethylaminomé-thyl-3 ~ methyl-2-furannemethanol (3.38 B "20.0 millimoles) [prepared in Stage A] is added dropwise to a solution of 2-aminoethanethiol hydrochloride (2.27 g , 20.0 millimoles) in 20 ml

CC

of concentrated hydrochloric acid which was cooled to -10 ° in an ice-salt bath and the mixture was stirred for 15 minutes and allowed to cool in xeposex at 0 ° overnight. After 17 hours, the cold solution is strongly alkalized with an aqueous solution of potassium hydroxide, then it is extracted five times with methylene chloride. The mixture of organic extracts is dried, filtered and evaporated under reduced pressure to obtain the desired compound g) boiling at 110-120 ° / 0.1 mm Hg.

C. l.l-3-f2-rC5-dimethvlaminométhvl-3-méthvl-2-f uryPméthylthioléthylaminoÎ-V-methylaniino-1,2,5-thiadiazole

Reaction of a methanolic suspension of 1.1, 3, ^ - dimethoxy-1,2,5-thiadiazOle dioxide with an equimolar amount of 2- [(5-dimethylaminomethyl-3-methyl-2-furyl) methylthioJ ethylamine (prepared in stage B), then the reaction of 3 “1,1-dioxide {2- [(5-dimethylaminomethyl- 3-methyl-2-u uryl) methylthi o] ethylamino} -4 ~ methoxy-1,2, 5-thiadiazole resulting with an excess of methylamine give the desired compound.

EXAMPLE 11 1.1 - Lioxide of 3-Î2-T (5-dimethylaminomethyl-1 <—methyl-2-furyl) methylthio 1 ethylamino) - ^ - methyl amino-1.2.5-thia-diazole A. 2-Mmethylaminomethyl-3 -métbv'l fnrannp * A stirred solution of 3-methyl-2-furfuryl alcohol (25.2 g, 22.5 mmol) and triethylamine (15.2 g, 22.5 mmol) is cooled to -15 ° in an ice and salt bath. 27.3 g, 27.0 millimoles) in 200 ml of methylene chloride and a solution of thionyl chloride (18.0 ml, 2 ^, 8 millimoles) in 3 ° ml of chloride is added dropwise to it - 56 - methylene keeping the temperature between -10 and -15 ° · After 15 minutes, the mixture is poured into water and - ice and the organic layer is separated. The phase in methylene chloride, which contains 3 * "methyl-2-chloromethylfuran, is added 1 to a stirred solution at 0 ° of dimethylamine (137.0 g, 3 * 01 * moles) in ^ 00 ml of absolute ethanol. , then the resulting solution is stirred for 17 hours at room temperature, the reaction mixture is evaporated under reduced pressure and the residue is mixed with ** 00 ml of water, then it is strongly alkalized with hydroxide. boiling aqueous sodium and extracted five times with methylene chloride The mixture of extracts is dried, filtered and evaporated under reduced pressure to obtain 26.0 g of the desired compound boiling at 6: 70 am ° / 20 mm Hg. Thin layer chromatography [silica / CHCl ^ rCH ^ GH (85:15)] indicates an Rf of 0.50.

Bm 2-Chloron; éthvl-5-dimethvlaEinométhvl - ^ - méthvlfuranne

Paraformaldehyde (1.67 g, 55.7 mmol) and zinc chloride (312 mg) are added to a solution of 2-dimethylaminomethyl-3-methylfuran (6.5 g, 37.0 mmol) [prepared in the stage A] in 25Ö ml of chloroform and a slow stream of gaseous hydrogen chloride is bubbled through the mixture which is stirred at room temperature for 15 minutes. Stirring is continued for 2 hours, then bubbled hydrogen chloride gas for 15 minutes, after which the mixture is stirred for another 1 hour. At this time, additional paraformaldehyde (1.67 g, 55.7 millimoles) was added to the reaction mixture and a slow stream of hydrogen chloride gas was passed through for 15 minutes. After 18 hours of stirring at room temperature, the reaction mixture is filtered on Celite and the filtrate is evaporated under reduced pressure to obtain the desired compound (4.97 g)? which crystallizes at rest and which is used without further purification at stage C.

- The nuclear magnetic resonance spectrum ~ (60 MHz) in deuterated chloroform comprises the following resonances b: 6.33 (s, 1H), 4.55 (s, 2H); 4.3 ° (d, 2H); 2.83 (d, 6H); 2.13 (s, 3H).

C. 2-Γ (5-Pimethylaminomethyl-4-methvl-2 - furTl ') - methvlthiol ethvlamine

Qn adds 2-aminoethanethiol hydrochloride (392 mg, 3.45 millimoles) to a solution of 2-chloromethyl-5-dimethylaminomethyl-3-methylfuran (773 mg, 3.45 millimoles) (prepared in stage B) in 20 ml concentrated hydrochloric acid which was cooled in an ice and water bath, then the mixture was stirred for 30 minutes. Or let the solution stand at 0 ° for 3 days, then strongly alkalinize with 50% aqueous potassium hydroxide, dilute with water and extract it five times with methylene chloride. Qn. the mixture of extracts is dried, filtered and evaporated under reduced pressure to obtain the desired compound which is an oil.

This product is dissolved in absolute ethanol and anhydrous hydrogen chloride is added to the solution which is then evaporated under reduced pressure. Qn dissolve the residue in hot isopropanol, add charcoal, filter everything and concentrate the filtrate to crystallize the hydrochloride. By recrystallization from * isopropanol, the desired compound is obtained in the form of its dihydrochloride having a melting point of 185-190 ° '(with decomposition).

P. l.l-3-Î2-r dioxide (5-diméthvlaminométhy1 -4-- 58 - néthvl-2-fur.vl) methylthio1éthylamino} ^ - méthvlamino-1.2. 5-thiadiazole? By reaction of a methanolic suspension of * 1,1-di-oxide of 3} V-dimethoxy-1,2,5-thiadiazole with an equimolar amount of 2- [^ -dimethylaminomethyl - ^ - niétliyl-2-fUTyl) methylthj ojéthyl ami rie (prepared in stage C), then by reaction of the 1,1-dioxide of 3 - (. 2- [(5-dimethylamino-met3iyl-1f-methyl-2-furyl) methylthio] étliylamino} -1t-méthoxy - 1,2,5-thiadiazole with an excess of methylamine, the desired compound is obtained.

EXAMPLE 12 - 1.1 - Dioxide of ^ .- ^ 2-Γ (5-dimethviaminométhvl-2-furvl) méthvl-thi oléthvlamino) -U — hvdroxv-1.2.5-thiadiazole A. 1.1-Dioxide of 3-Î2-T ( 5-dimethvlaminomethl-2-furvl) m ethvlthio 1 ethylamino} —V — methoxy — 1,2,5-thiadiazole A solution of 2- [(5-dimethylaminomethyl-2-fury0methylthiojethylamine) is added dropwise over 35 minutes 2.1¼ g, 10.0 millimoles) in 25 ml of dry methanol to a well-stirred suspension of 1,1-di-oxide of 3, ^ - dimetho-xy-1,2,5-thiadiazole (1.78 g, 10.0 millimoles) in 180 ml of dry methanol which is cooled to 1 ° in a water and ice bath. After 15 minutes at 0 °, a methanolic solution of the desired compound is obtained. [silica / CHgClgtCH ^ CH (9: 1)] indicates a Bf of 0.1 * 8.

Acidify a 2.0 ml aliquot of the solution with hydrochloric acid 6, ON and evaporate under reduced pressure without heating to obtain the desired compound in the form of its hydrochloride. The nuclear magnetic resonance spectrum (100 MHz) in U ^ O includes the following S resonances: 6.1 * 5 (d, 1H); 6.19 (d, 1H); 1 *, 11 * (s, 2H); 1 *, 0 (s, 3H); 3.6¼ (s, 2H); - 59 - 3.37 (t, 2H); 2.65 (s, 6H); 2.61 (t, 2H).

B. 1TI-Dioxide of 3-? 2-Γ (5-dimethylaminométfrvl- * 2, -furyl Wthvl thj oléthvlamino} -l * -: hvdroxT-l .2.5-thj adi erol e * Add a solution of pellets of sodium hydroxide (2.10 g, 52.5 millimoles) in 25 ml of dry methanol with methanolic solution of the product from stage A cooled to 0 ° in an ice and water bath After stirring at 0 ° for 2 hours and at room temperature for 68 hours, the reaction mixture is neutralized with 8.75 ml (52.5 millimoles) of aqueous hydrochloric acid 6, ON and after 10 minutes of stirring ^ the mixture is evaporated under reduced pressure Gn crystallizes the residue in 95% ethanol to obtain the crude product which is dissolved in methanol ^ after which the solution is filtered to separate the sodium chloride and the solution is deposited on 60 g of gel. silica which is chromatographed with gradient elution using methylene chloride and methanol.

Combine suitable fractions and evaporate under reduced pressure to obtain 3.19 g of product.

By recrystallization from aqueous methanol, the desired compound is obtained having a melting point of 109-122 °. Analysis for: cq2Hl8¾¾¾ calculated C, 1 * 1.61; H, 5.21 *; H, 16.17; S, 18.51% found C, 1 * 1.59; H, 5.32; N, 16.33; S, 18.81% (correction for 1.1¾¾ H ^ O) EZEMPIÆ 13 - 1-Qxvde de 3-ί2-Γ (5-dimethvlaminomethyl-2-furvl) methvl-thiol ethylamino) -1 * -methyl amino-1 , 2,5-thiadiazol e A. 1-Oxide of 3-Î2-r (5-dimethvlaminométhvl-2-f uryl) méthvlthio1 éthylamino) -! * - méthoxy-l, 2.5-thiadiazole

A solution of 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl- - 60 - amine (3 "30 E" 15 "1 * millimoles) in 25 ml of methanol is added dropwise over 11 minutes. a well-stirred suspension of 3-^-dimethoxy-1,2,5-thiadiazole 1-oxide (2.50 g, 15.1+ millimoles) [prepared * according to the method of example k, stage A] qu 'was cooled to 12-15 ° in a water bath and. of ice. The solution is stirred at room temperature for 90 minutes to obtain a methanolic solution of the desired compound.

B. 1-3-f2-ff5-dimethvlaminomethyl-2-furyl oxide ~) methylthio1ethylamino) -V-methylamino-l .2.5-thiadiazole

Qn adds for 8 minutes anhydrous methylamine to the methanolic solution of the product of stage A cooled to 5 °. The reaction mixture is stirred for 17 hours at room temperature, then it is evaporated under reduced pressure to obtain the product which is a yellow oil which is deposited on 55 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Qn evaporate the appropriate fractions, the residue is dissolved in methanol and the solution is diluted with diethyl ether to obtain the desired compound (2.32 g) which is a solid which is dried under vacuum at room temperature in the presence of phosphorus pentoxide for 3 hours and which then melts at 86-92 °.

Analysis for ci3H21N5 ° 2S2 calculated C, 1 + 5Λ6; H, 6.16; K, 20.39; -S, 18.67% found C, 1 * 5.21 +; E, 6.2l +; N, 20.1 + 1; S, 18.90% EXEKPIiE 11+ - 1.1-Dioxide of ^ -allvlamino-l + -f 2-Γ (^ -dimethylaminomethyl-2-furvl) methvlthi oléthvlamino} -1.2.5-thiadiazole t Add dropwise to 1 +5 minutes a solution of 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] -ethylamine in 30 ml of methanol to a partial suspension of 1,1-dioxide of 3, l + -dimethoxy-1,2,5 -thiadiazole (2.08 g, 11.7 millimoles) in 200 ml of methanol which is cooled to 0 ° in an "ice and water bath. At the end of the addition, 10 , 5 ml of allylamine and the solution * is stirred at room temperature for 18 hours. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 120 g of silica gel which is chromatographed with gradient elution with methylene chloride and methanol. Combine suitable fractions, evaporate under reduced pressure and crystallize the residue in isqpropanol to obtain the desired compound having a melting point of 83 ^ 86 ° and whose spectrum nuclear magnetic resonance (100 MHz) in hexadeuterated dimethyl sulfoxide indicates the presence of about 0.9 moles of isopropanol.

Analysis for C ^ c ^^^ O ^ Sg. 0.90 ^ 00 calculated C, 1 * 8.36; H, 6.92; N, 15.93; S, 11 *, 59% found C, 1 + 8.1 * 6; H, 6.96; H, 16.13; S, ll +, 58% ΕΣΕΜΡΙΕ 15 - ll-hioxvde de 3-méthvl Ητη · ϊ · ηο-1 * -ί2- [f 5-Tnéthyl aTnnoTnéthyl-2-furvl ^ éthvlthioléthylamlnoÎ-1.2.5-thiadiazole and 1.1-dioxide de 3.1 * -bis-f2 ~ rf5-methvlaminométhTl-2-furvl) méthvlthio1 -éthvl aminci-1.2.5-thiadiazole A. ll-hioxvde de 3-méthv] amino-l * -f 2-f (5-ffiéthTl-aminométhyl -2-f uryl) methvlthio1 ethylamino] -! 2,5-thiadiazole Qu adds in one go a solution of 2 - [(5-me-thylaminomethyl-2-fuTyl) methylthio] ethylamine (0.7 g, 3.5l millimoles) [prepared according to the method of Belgian patent n ° 857 * 388] in 21 ml of methanol in a partial suspension of 3, l * -dimethoxy-1,2,5-thiadiazole (1.89 g, 10.5 millimoles ) in 210 ml of methanol which has been cooled to 8 °. The mixture is stirred for 15 minutes and cooled to 1 ° in an ice and water bath, then anhydrous methylanine is bubbled through the solution for 6 minutes.

After 15 minutes of stirring, the reaction mixture is evaporated under reduced pressure and the residue is deposited on 110 g of silica gel which is eluted with an ace-tonitrile gradient to acetonitrile-methanol-glacial acetic acid ( 50: 50: 0.5). Combine suitable fractions containing the first eluted constituent whose Ef is 0.50 [silica / CH ^ CE thin layer chromatography: CK ^ OH: CH ^ COOH (50: 50: 1)] and evaporated under pressure reduced to obtain the desired compound which is a foam having a melting point of 5 ° -56 °.

The nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethyl sulfoxide comprises the following resonances 6: 6.20 (m, 2H); 3.80 (s, 2H); 3.62 (s, 2H); 3.50 (t, 2H); 2.90 (s, 3H); 2.70 (t, 2H); 2.28 (s, 3H) and further reveals the presence of about 0.2 mole of methanol.

Analysis for £ ΐ2Ηΐ9 ^ 5 ^ 3δ2 * ® ’^ CH ^ OH

calculated C, 1 * 1.65; H, 5.65; 2f, 19.96; S, 18.28% found C, 1 * 1.98; H, 5.69; N, 19.5 ^ ·; S, 18.1% (correction for 1.5% HgO) B. 1,1-Dioxide of 3 A-bis- [2-r (5-methvlaininomé-thyl-2-furyl) methylthio1éthylamino3-l, 2,5 -thiadiazole

The fractions containing the component eluted most slowly from the chromatography carried out in stage A and having a Bf of 0.07 are combined [silica / CB ^ thin layer chromatography CN: CH ^ OH: CH ^ COOH (50: 50: 1 )], the mixture is evaporated and the residue is partitioned between 2.5n sodium hydroxide and ethyl acetate. The aqueous phase is extracted several times with ethyl acetate, then the organic extracts are mixed, dried and evaporated under reduced pressure to obtain the desired compound which is an oil.

The nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethyl sulfide comprises the following resonances 6: 6.22 (m, VH); 3.82 (s, VH); 3.65 (s, VH); 3.50 (t, VH); 2.72 (t, VH); 2.30 (s, 6H).

^ EXAMPLE 16 - 1.1- Dloxvdfi of 3-fV- (5-dimethvlamin0Eethvl-2-XurvL) butyl-amino] -V-methvlamino-1,2,5-thiadiazole

A solution of V- (5-dimethylaminomethyl-2-furyl) butylamine (1.5 g, 7.6 V millimoles) is added dropwise over V5 minutes [prepared according to the method of United States patent no. V.128.658] in VO ml of dry methanol to a stirred solution of 1,1-dioxide of 3, V-dimethoxy-1,2,5-thiadiazole (1.36 g, 7.6V millimoles) in 200 ml of methanol dry which has been cooled to 3 ° in a water and ice bath. After 15 minutes at 3 °, anhydrous methylamine is bubbled for 10 minutes into the cooled solution. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 60 g of silica gel which is chromatographed with gradient elution using acetonitrile and methanol. Combine suitable fractions to obtain 2.16 g of the desired compound. By recrystallization from acetonitrile, the desired compound is obtained having a melting point of 152-153 ° *

Analysis for ^ 1 ^ 23 ^ 5 ^ 3 ^ calculated C, V9.25; H, 6.79; E, 20.51; S, 9.39% found C, V9, V1; H, 6.87; E, 20.61 '; S, 9.28% - EXAMPLE 17 - '1.1 - Pi oxide of (5-fl-methyl-ami-nomp-trhyl-P-fnryT Ίτηρ ·) · ^ · ^ thio1éthvlamiho3-V-méthvlamino-l.2.5-thiadiazole A J-.l-Dioxide of 3-methvl amino-V-f2-mercaTvhn · - - 64 - ethvl) -1. 2.5-thiadiazole

A solution of 2-aminoethanethiol (obtained from the hydrochloride hydrate, 1.9 g, 16.8 millimoles) in 20 ml of methanol is added dropwise over 15 minutes to a well-stirred suspension of 1, 1, 3-U-dioxide-dimethoxy-1,2,5-thiadiazole (3.0 E 16.8 millimoles) in 250 ml of methanol which was cooled to 1 ° in a water bath After 10 minutes at 2 ° C., methylamine is bubbled through the cooled solution for 6 minutes and the stirring is continued for a further 30 minutes at room temperature. The reaction mixture is evaporated under reduced pressure. and deposit the residue on k5 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Gn combines the appropriate fractions, they are evaporated and the product is crystallized (2, ** 3 g) in absolute ethanol By recrystallization from absolute ethanol, the desired compound is obtained having a melting point of 259-260 ° (with decomposition).

Analysis for c5hioki1.02 ^ 2 'calculated C, 27.03; H, 1 *, 5V; N, 25.20% found C, 27.13; H, 1f, 55; K, 21 *, 86% B. l-3-Î2-T-Dioxide (5-dimethvlaminométhvl-2-furyDméthvlthiol éthvlamino] - ** - mettrylamino-l, 2.5-thiadiazole

AT

Stirred in a water and ice bath for 2 hours, then allowed to stand at 0 ° for 6¼ hours, a mixture containing 3-methylamino-l-1,1-dioxide * - (2-mercapto ~ éthyL) - 1,2,5-thiadiazole (1.0 g, **, 5 millimoles) [prepared - in stage A] and 5-dimethylaminomethyl-2-furanemethanol (0.82 g, 1.5 *, 5 millimoles) [prepared according to the method described in J. Chem. Soc., 728 (1958)] in 20 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 23 hours at room temperature, evaporated without heating under reduced pressure and the residue is subjected to partition between water and methylene chloride.

The aqueous phase is made alkaline with sodium hicarhonate and extracted with methylene chloride. The organic extracts are mixed and washed with saturated brine, then dried and evaporated under reduced pressure. Qn deposit the residue on 2? g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Qn evaporates the suitable fraction and the product is crystallized from methanol. By recrystallization from methanol, the desired compound is obtained having a melting point of 92-96 °.

EZEKPIÆ 18 - 1-Qyvde of λ- [2-Γ (5-diEethylaminométhvl-2-furvl) methylthio1-ethylann nol - ^ - méthvlamino-1.2 «5-thiadiazole A. 1-Qyvde de H-roéthvlainino-lfr- (2 -merea'Dtoétfrvl ') - 1.2.5- thiadiazole

A solution of 2-aminoethanethiol (obtained from the hydrochloride, 2.04 g, 18.0 millimoles) in 25 ml of methanol is added dropwise over 30 minutes to a well-stirred suspension of 3-dioxide 3 , Η — dimethoxy- 1.2.5- thiadiazole (2.92 g, 18.0 millimoles) [prepared in example k, stage A] in 150 ml of methanol which was cooled to 3 ° in a water bath and ice. After 10 minutes, anhydrous methylamine is bubbled through the solution for 6 minutes and stirring is continued at room temperature for another 20 minutes. The reaction mixture is evaporated under reduced pressure and the residue is deposited on k5 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Combine suitable fractions and evaporate to obtain 2.7k g of the product. By recrystallization from inethanol and then from 95% ethanol, the desired compound is obtained having a melting point of 191-193 °.

B. l-0> rvde de 3-Î2- [f S-aiméthylaminométhvl ^ -fu-rvl ^ éthvlthioléthylaminol-U-mfethvlamino-l .2.5-thiadiazole

By reaction of 3-methylamino-4— (2-mercaptoethyl) -1,2-thiadiazole 1-oxide [prepared in stage A] with approximately 1 equivalent of 5-dimethylaminomethyl-2-furan-methanol in concentrated hydrochloric acid, according to the procedure of Example 2 ?, stage B, the desired compound is obtained identical to the product of Example 18.

E3ŒKPIÆ 19 - 1.1-Dioxide of 3-Î2-f (5-cHméthVI amiuométhyl-2-furvDméthvlthiol éthvlaminoî -V-diméthyl ami no-1,2,5-thi adi a-zole

A solution of 2- [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamine (2.5 g, 11.7 millimoles) in 50 ml of methanol is added dropwise over k-5 minutes to a partial suspension of 1 , 3, V-dimethoxy-1,2,5-thiadiazole 1-dioxide (2.08 g, 11.7 millimoles) in 200 ml of methanol which was cooled to 6 °. At the end of the addition, anhydrous dimethylamine is bubbled through the solution for 10 minutes while the temperature is maintained at 6 °. After 18 hours of stirring at room temperature, the reaction mixture is evaporated under reduced pressure and the residue is deposited on 200 g of silica, which is chromographed with gradient elution using methylene chloride and methanol. . Combine the appropriate fractions and evaporate them, then chromatograph the residue again on 75 g of alumina with gradient elution using methylene chloride and methanol. The suitable fractions are combined and evaporated under reduced pressure to obtain the desired compound having a melting point of 139-1½0.

Analysis for * calculated C, ¥ t, 90; H, 6.1 * 6; N, 18.70; S, 17.12% found C, ¥ *, 77; H, 6.25; N, 18.89; S, 17, ½% (correction for 0.5l% H2O) EZEMPEE 20 - 1,1-Dioxide of 3-Γ2-Γ (2-guanidinotfaiazol - i + -vl ') methylthio'l-ethylaminol-h — methvlamino- 1.2.5-thiadiazole

A solution of 2 - [(2-guanidinothiazol-1 * -yl) methylthio] ethylamine (obtained from dichlorohydrate, 1 *, 27 g, 1 ^, 0 millimoles) in 30 ml of methanol is added. a well-stirred suspension of 1,1-dioxide of 3, ^ "dimetho-xy-1,2,5-thiadiazole (2.50 g, ll *, 0 millimoles) in 250 ml of methanol at 10 °. After 15 minutes at 10 °, the solution is cooled to 1 ° by means of a cooling bath and bubbled anhydrous methylamine in the solution for 10 minutes. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 60 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. The appropriate fraction containing 1.53 g of product is deposited on 80 g of alumina and it is again chromatographed with gradient elution using ethyl acetate and methanol. The combined fractions are combined and evaporated to obtain a foam which is crystallized from methanol to collect the desired compound (2.38 g) having a melting point of 196-198 ° (with decomposition).

Analysis for ^ 0 ^ 16¾¾¾ calculated C, 31.90; H, 1 *, 28; N, 29.77; S, 25.5 ^ - 68 - found C, 31.85; H, N, 29.79; S, 25, ^ 5¾ EXAMPLE 21 - * 1.1-1-Γ2-Γ dioxide (2-ruanidinothiazol-V-vl) methylthio] - 9 ethylamino) -V- (2 - pronynyl) amino-1,2,5-thiadiazole * Add a solution of 2- [(2-guanidinothiazol-

VS

lf-yl) methylthio] ethylamine (obtained from the dichlorohydrate, 3, ½ g 11.2 millimoles) in 25 ml of metbanol to a well stirred suspension and cooled to 8 ° of 1,1-di-oxide of 3 ^ “dimethoxy-1,2,5-thiadiazole (2.0 g, 11.2 millimoles) in 200 ml of methanol. After 15 minutes at 8-10 °, the solution is cooled to 1 ° using an ice bath and a solution of 6.0 ml of 2-propynylamine in 15 ml of methanol is added thereto. The ice bath is removed and stirring is continued for 15 minutes. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 50 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Among the fractions, two give the crystalline product (1.7½ g) after crystallization from methanol. The product is dissolved in hot methanol, the solution is filtered through Celite, cooled and filtered again to obtain the desired compound having a melting point of 176-178 °.

Analysis for cp2Hl6l802S3 calculated C, 35.99; H, 1 *, C3; K, 27.98; S, 2 ^ 02 # found C, 35.82; H, ^ 12; II, 28, S, 2 ^ 28% EXAMPLE 22 - 1,1-Dioxide of λ-12-Γ (2-dimethylaminomethyl-V-thiazolyl) - * methylthiol ethylamino} -V-methylamino-1.2.5-thiadiazole A. N-Carbonhenoxy-N-methylaminoacetonitrile Qn adds triethylamine (260 ml, 1.88 mole) and a solution of phenyl chloroformate (155.0 g, 0.99 mole) in 500 ml of methylene chloride to a suspension of methylaminoacetonitrile hydrochloride (100 g, »0.9½ mole) in 1 liter of methylene chloride (cooled in water and ice bath). The reaction mixture is heated at reflux for 18 hours, then evaporated under reduced pressure to obtain a semi-solid which is triturated with 1 liter of diethyl ether and filtered. The filtrate is evaporated under reduced pressure and the residual oil is distilled to obtain the desired compound (123 g) boiling hot at 111-113 ° / 0.25 Eg and whose nuclear magnetic resonance spectrum (60 MHz) - in deuterochloroform includes the following resonances S: 7.23 (m, 5H); 4.3 ° (s, 2H); 3.13 (s, 3H).

B. (N-Carbophenoxy-Nm ethylamino) thi oac etamide Hydrogen chloride gas is added to a solution of B-carbophenoxy-1-methylaminoacetonitrile (131.0 g, 0.69 mole) [prepared in stage A] and of thioacetamide (57.1 g, 0.71 mole) in 917 ml of dry dimethylformamide until an exothermic reaction takes place, then the mixture is heated in a steam bath for 20 minutes. The reaction mixture is partially evaporated under reduced pressure to remove part of the solvent, then it is made alkaline with a saturated aqueous solution of sodium bicarbonate and partitioned between ether and water. Qu extract the aqueous phase with ether and then mix the ethereal extracts and wash with water and a saturated aqueous solution of sodium chloride, after which they are dried. By filtration and - evaporation of the solvent, an oil is obtained which is triturated in methylcyclohexane to obtain the product in the form of a solid. By recrystallization from isqprqpa-nol, the desired compound is obtained having a melting point of 101-103 °.

Lice analysis C ^^ H ^ gN ^ OgB

calculated C, 53.55; H, 5ΛO; If, 12.1 * 9; S, 11+, 30 ^ found C, 53.65; H, 5.5l; N, 12.69; S, 11 +, 1 + 1% * C. ^ -Chlorométhvl - 2 - ('Iv-carbo, pherox'v ‘~ E ~ gi éthvl-

VS

amino'imethvlthiazole

A solution of 1,3_dichloropropanone (0.57 g, h, k9 millimoles) in 3 ml of absolute ethanol is added to a xefxoid solution of (N-carbophenoxy-N-methylamino) thioaeetamide (1.0 g, 1+, 1 + 6 millimoles) and dry pyxidine (0.36 ml, 4.46 millimoles) in 6 ml of absolute ethanol. The mixture is heated at reflux for 90 minutes, then evaporated under reduced pressure and the oily residue is subjected to partition between ether and water. The aqueous layer is extracted with 1 ether, then the ethereal extracts are combined and washed with water and with a saturated aqueous solution of sodium chloride, after which they are dried. By filtration and evaporation, 1.02 g of the desired compound is obtained, which is a viscous oil - thin layer chromatography [silica / CHgClg: CH- ^ CII (85:15)] gives an Ef of 0.82. the nuclear magnetic resonance spectrum (60 MHz) in deuterochloroform includes the following resonances: 7.16 (m, 6h); 4.77 (br s, 2H); 4.60 (s, 2H); 3.07 (br s, 3H).

D. 2- {Γ 2 - Çlf-C arb onh en oxy-If-m é thy 1 amin o ~) m éthvl - 4-thi az ol vl Iméthvl thi ο 1 éthvl amine

Cysteamine hydrochloride (27.6 g, 0.2½ mole) and a further 218 ml of absolute ethanol * are added to a solution of sodium methylate (26.1 g, 0.1 + 8 mole) in 290 ml of absolute ethanol at 0 ° in a nitrogen atmosphere. After 1 hour of stirring at 0 °, a solution of 1 + -ehloromethyl-2- (Ii-carbophenoxy-If-inethyl-amino) methylthiazole (72.5 g, 0.2V drown) in 218 ml is added over 15 minutes. absolute ethanol. The reaction mixture is stirred at room temperature for 18 hours, filtered and evaporated under reduced pressure to give an oil which is partitioned between methylene chloride and water . Qn extract the aqueous phase with methylene chloride, then combine the organic extracts and wash with water, dry them, filter them and evaporate under reduced pressure to obtain 68.5 g of the product which is an oil which is reacted with fumaric acid (23.6 g) in n-propanol to obtain the salt (V7.0 g). By recrystallization from absolute ethanol, the desired compound is obtained in the form of its fu-marate having a melting point of 1V5-1V60.

Analysis for calculated C, 50.31; H, 5.11; N, 9.27; S, 1V, 1V # found C, 50.02; H, 5.16; K, 9, V7; S, IV, 22% E- 2-Γ (r2-Dimethylaminomethyl-V-thiazolvl) methvl-thiol ethylamine

Qn added in a nitrogen atmosphere lithium aluminum hydride (0.17 g, V, V8 millimoles) to a solution of 2- 2- (N-carbophenoxy-N-methylamino) methyl-V-thiazolyl] methylthio | ethylamine (0.50 g, 1, V8 millimole) [prepared in stage D] in 10 ml of dry tetrahydrofuran and the mixture is heated at reflux for 30 minutes. An additional 10 ml of tetrahydrofuran is added and heating is continued for 3 hours. 0.17 ml of water, 0.17 ml of 15? Aqueous sodium hydroxide and 0.5l ml of water are added to the reaction mixture which is filtered through Celite and then dried . The filter is filtered and evaporated under reduced pressure to obtain an oil which is dissolved in absolute ethanol, after which the solution is diluted with diethyl ether and acidified with chloride. dry hydrogen. The hygroscopic hydrochloride was collected from the desired compound and partitioned between 2.5N sodium hydroxide and methylene chloride. The organic phase is washed with water, dried and filtered. The filtrate is evaporated under reduced pressure to obtain the free base of the desired compound which is an oil (0.22 g, 0.95 millimole ) which is mixed with anhydrous oxalic acid (0.21+ g, 1.90 millimole) in 30 ml of hot acetonitrile. The mixture is evaporated with hot absolute ethanol to obtain the desired compound under form of its bis-oxalate having a melting point of 168-171 °.

Analysis for C7¾ · 202¾ 0 ^ calculated C, 37.95; H, 5.15; E, 10.21; S, 15.59% found C, 37.95; H, 5.0+; K, 9.81; S, 15.27% P. l.l.-3-Γ2-Γ dioxide (2-dimethylaminomethyl-h-tbi agolvllméthvlthiol éthvlaminol -1 + -méthy] ami no-1.2.5-thiadiazole

Qn is added dropwise in 1 + 5 minutes a solution of 2- [(2-dimethylaminomethyl-1 + -thiazolyl) methyl-thio] ethylamine (0.96 g, 1 +, 17 millimoles) [prepared in stage E] to a suspension cooled to 6 ° 1,1-dioxide 3j ^ -dimethoxy-1,2,5-thiadiazole. (0.71+ g, 1+, 17 milliv. ...

moles) in 80 ml of methanol to obtain the 1,1-dioxide of 3-12- [(2-dimethylamâ nomethyl-i + -thiazolyl) methylthio] -ethylaminoJ-l + -methoxy-1,2,5-thiadiazole including Ef is 0.6 · + [silica / CHgClgîCH ^ QH (9: 1)]. Qn maintains the temperature at 6 ° and bubbled anhydrous methylamine for 8 minutes in the solution. The reaction mixture is evaporated off under reduced pressure and the residue is deposited on 80 g of silica gel which is chromatographed - 73 - with gradient elution using methylene chloride and methanol. The appropriate fractions are combined and the residue is chromatographed again on 25 g of alumina with gradient elution using methylene chloride and methanol to give 0.5 "of the product. By recrystallization from a mixture of isopropanol and ether, the desired compound is obtained having a melting point of 1 ^ -1 ^ 8 ° (foaming).

Analysis for ci2H20N6 ° 2S3

calculated C, 38.28; H, 5.35; N, 22.32; S, 25.55¾ found C, 37.89; H, 5Λ3; N, 22.19; S, 25, W

EXAMPLE 23 1-Cbrvde de 2-Γ (, 2-dimethvlaminométhvl-V-thiazolvl ') methyl-thiol étfrylamino} -h-méthvlamino-l, 2.5-thiadiazole A. N-Carbethoxv-N-methvlaminoacetonitrile

Qn is added triethylamine (5.2 ml, 37.6 mmol) to a suspension of methylaminoacetonitrile hydrochloride (2.0 g, 18.8 mmol) in 20 ml of methylene chloride. The resulting suspension is cooled to ice bath and a solution of ethyl chloroformate (2.1½ g, 19.8 millimoles) in 10 ml of methylene chloride is added over 30 minutes, then the mixture is heated to reflux for 18 hours. The reaction mixture is evaporated under reduced pressure to obtain a semi-solid residue which is triturated in diethyl ether and filtered, after which the filtrate is evaporated under reduced pressure to obtain the desired compound which is an oil ( 2.2 g) coal at 96-98 ° / 5.2 mm Hg.

B. fN-Carhethoxv-K-methvlamino) thioac etamide Qn adds hydrogen chloride gas to a solution of W-carbethoxy-N-methylaminoacetonitrile (9.8 g, 6.9 millimoles) [prepared in Stage A] and thioacetamide (10.3? g, 13, ß millimoles) in 17? ml dry dimethylformamide until a vigorous exothermic reaction takes place, after which the mixture is heated in a steam bath for 15 minutes. Qu alkalinize the reaction mixture with saturated sodium bicarbonate solution, then extract with ether, wash with water and dry. Evaporate the ethereal phase under reduced pressure to obtain a solid residue which is dissolved in methylene chloride, after which the solution is washed with water. The organic phase is dried, filtered and evaporated under reduced pressure to obtain the product (2.5 g). By recrystallization from a mixture of ethyl acetate and hexane, the desired compound is obtained having a melting point of • 91-93 °.

Analysis for calculated C, 1 + 0.89; H, 6.87; N, 15.96; S, 18.92% found c, 1 + 0.73; H, 6.85; N, 16.13; S, 18.86% C. 2- (N-C arbé th oxy-N-m ththl amino) m éthvl-lf-c a rb é-thoxythiaz oie

A solution of ethyl bromopyruvate (25.0 ml, 0.20 mole) in 130 ml of absolute ethanol is added to a solution of (Nc arbethoxy-III-m ethyl amino) thi o ac et amide ( 30.7 g, 0.17 mol) (prepared in stage B) in 180 ml of absolute ethanol. The reaction mixture is heated at reflux for 17 hours, then evaporated under reduced pressure and the residue is partitioned between ether and water. The organic extract is washed with water and with a saturated sodium chloride solution, dried, filtered and evaporated under reduced pressure to obtain an oil which is deposited on silica which is chromatographed by elution with diethyl ether. suitable fractions give the desired compound _ 7 ^ _ which is an oil whose thin layer chromatography [silica / CHgClgîCH ^ CN (85:15)] indicates an Rf of 0.50.

The nuclear magnetic resonance spectrum (60 MHz) in hexadeuterated dimethylsuifoxide comprises the following cS resonances: 8.1 * 9 (s, 1H); l *, 79 (s, 2H); **, 23 (m, i * H); 3.00 (s, 3H); 1.30 (q, 6H).

D. 2-Dlm éth vl amin om éthvl -l * -hvdr oxvm é t hvl thi az ol e

A solution of 2- (I-carbethoxy-1-methyl amino) m ethyl 1-1 * -c arbethoxy thi az ol e (20.0 g, 0.07 mole) [prepared in stage Cj is added in 160 ml of dry tetrahydrofuran in 1 hour to a cooled suspension of hydride of 1 i thi ητη-al wrn τνί um (8.1 * g, 0.22 mole) in 80 ml of dry tetrahydrofuran. The reaction mixture was heated to reflux for 8 hours, then cooled and decomposed using sodium sulfate and 1% C aqueous potassium hydroxide. The mixture is filtered, dried and evaporated under reduced pressure to obtain 1.2 g of the desired compound, which is an oil, where thin layer chromatography (alumina / CH ^ CN) indicates a Bf of 0.1. * 5- The nuclear magnetic resonance spectrum (60 MHz) in deuterochloroform includes the following on resonances: 7.17 (s, 1H); l *, 73 (d, 2H); 3, ½ (s, 2H) d 3.35 (s, 6h).

E- 2-Γ (2-him ethvl aminométhvl-l * -thi az ol ~ vl ~) méthvl-thiol éthvlamine

By reaction of 2-dimethylaminomethyl-i * -hydroxy-methylthiazole [prepared in stage D] with thionyl chloride, then by reaction of 2-dimethylaminomethyl-l * -, resulting chloromethylthiazole with 1 molar equivalent of cysteamine hydrochloride and 2 - basic equivalents, according to the general procedure of Example 33, step! D, the desired compound is obtained.

_ 76 - F. l-Oxvde de 3-12-Γfê-diméthylaminométhvl-1 * -thiazolvl) m éth vl t hi ο Ί éthv I aminol -tfr-méthvlamino-1 .2,5-thiadiazole

By reaction of a methanolic suspension of 3,1 * -dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in the example stage A] with- 1 equimolar amount of 2- [(2-dimethylaminomethyl- l + -thi az olyl) m ethyl thi o] ethyl amine [prepared in Example 33 »stage EJ, then by reaction of 1-oxide of 3- [2- [((2-dimethylaminomethyl-V * thiazolyl) mé-thylthio ] ethylamino} -V-methoxy-1,2,5-thiadiazole resulting with methylamine, the desired compound is obtained. EXAMPLE 2k - I, 1-Dioxide of 3-amino-it-f2- [(2-puanidinothiazol-lf-vl Methyl thi ol éth vl amirio ^ —1.2.5-thiadiazole ..

A solution of 2 - [(2-gua-nidino thi az ol-U - y 1) methyl thi o J ethyl amine (2.7 5 g, 11.9 millimoles) is added over 1 hour [obtaining by neutralization of 2- [(2-guanidinothiazol-1f-yl) methylthio] ethyl amine dihydrochloride (b, O g, 13.0 millimoles) with 2.5 H aqueous sodium hydroxide and by extraction with ethyl acetate] in 30 ml of methanol to a well stirred suspension and cooled to 0 ° of 3, h-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.12 g, II, 9 millimoles) in 220 ml of methanol. Maintaining the temperature at 0 °, anhydrous ammonia is bubbled for 6 minutes into the solution and stirring is continued for 30 minutes at room temperature. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 120 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. The appropriate fractions are combined and evaporated, then the residue is chromatographed again on ** - 0 g of silica gel with elution with grease using methylene chloride and methanol.

Qa combines the appropriate fractions, they are concentrated under vacuum, they are filtered and they are dried under high vacuum to obtain the desired compound having an melting point of 13 ^ - 1 ^ 9 ° (foaming) whose "spectrum of nuclear magnetic resonance (100 MHz) "in the system (CD ^ SO / DgO / DCl includes the following resonances £: 7, 16 (s, 1H); 3" ® * (s, 2H); 3> 52 (t , 2H); 2.75 (t, 2H) and reveals the presence of about 1.2 moles of methanol.

Analysis for C ^ H-j ^^^ S ^ -l, 2011 ^ OH

calculated C, 30.56; H, 1.72,; K, 27.95; S, 23.99% found C, 30.19; H, '1 *, 32; N, 27.91; S, 21 *, 71% (correction for 1.31% HgO) EXAMPLE 25 - 1,1-Dioxide of 3 ~ (2 ~ Γ (2-p; uanidinothiazol-l * -? L) méthvlthio1r · éthvlamino | -l * - (2-hvdroxvéthvlamino) -l, 2, 5-tMadiazole.

A solution of 2- [(2-guanidinothiazol-1 * -yl) methylthio] ethylamine (obtained from the dihydrochloride; 3.5 g, 11.5 millimoles) is added dropwise over 30 minutes. ml dry methanol to a well stirred suspension of 1,1-dioxide 3, l * -dimethoxy-1,2,5-thiadiazole (2.05 g, 11.5 millimoles) in 200 ml dry methanol at 3 ° . After 15 minutes at 3 °, a solution of ethanolamine (1.03 ml, 17.3 millimoles) in 10 ml of methanol is rapidly added dropwise and stirring is continued for 15 minutes. Qn the reaction mixture is evaporated under reduced pressure to obtain the product in the form of a friable foam which is crystallized from methanol.

-By two recrystallizations from methanol, the desired compound is obtained which is slowly resinified from 115 ° and whose melting decomposition begins at 175 °.

Analysis for calculated C, 32.50; H, 1 * Λ6; N, 27.57; S, 23.66ce, found c, 32.77; H, l *, 21d N, 27.90; S, 21 +, 39% (correction for 3 »85% HgO) EXAMPLE 26 - 1.1- Dioxide of 3- (2-Γ (5-dimethylaminomethyl-2-fuxvl ^ neth.yl-thlol ethhl amino} -V-hvdràzino -1.2.5-thiadiazole

Qu add dropwise in b5 minutes a solution of 2- [^ “dimethylaminomethyl ^ -furyl ^ ethylthioj-ethylamine (2.1 + 1 g, 11.2 millimoles) in 30 ml of dry methanol to a well stirred suspension of 1 , 3.1 * 1-dioxide-dimethoxy-1,2,5 “thiadiazole (2.0 g, 11.2 millimoles) in 250 ml of methanol which was cooled in an ice and water bath. After 15 minutes of stirring at 0 °, a solution of anhydrous hydrazine (1.8 g, 56.13 millimoles) in 30 ml of dry methanol is added all at once and stirring is continued for 30 minutes. We. the reaction mixture is evaporated under reduced pressure and chloroform is added to the solid residue, then the whole is filtered to obtain 3.28 g of the desired compound having a melting point of 170 ° (with deconposition).

E7ETÜPIE 27 - 1.1— 3 ~ dioxide methylamino-1 + - [2-Γ (2-pyridyl) methylthiol - ethylamino} -1,2,5-thiadiazole

A solution of 2 - [(2-pyridyl) methylthio] ethylamine (obtained from the dihydrobromide, 3.5 g, 10.6 millimoles) is added dropwise over 3 ° minutes [prepared according to the process of the Belgian patent # 779.775] in 25 ml of dry methanol to a well-stirred suspension of 3, ^ - dimethoxy-1,2,5-thiadiazole 1,1-dioxide in 200 ml of dry methanol which was cooled to 0-5 ° in an ice and water bath. After 15 minutes of stirring the cold solution, anhydrous methylamine is bubbled for 15 minutes in the solution. The reaction mixture is stirred at room temperature for 5 minutes, evaporated under reduced pressure and the residue is crystallized from methanol. Pax two xecxistallisations in methanol, one obtains the compound xechexché having a melting point of 168-171 °.

Lice analysis cn% 5K5 ° 2S2 calculated c, 1 + 2.15; h, 82; N, 22.35; S, 20.1 * 6 # found C, ** 2.07; H, V, 75; N, 22.28; S, 20.73% EXAMPLE 28 - 1,1-Dioxide of 3 ~ {2-f (^ - methvl-1,2,5-oxadiazol-3-vl ~) méthvl-fh-i olefhvl aminol-h- methvlamino-1 -2.5-thiadiazole A. 3-Hvdxoxvmethvl-V-methvlfurazane

A 1.02K solution of boxane in tetrahydrofuran (825 ml, 0.81 * mole) is added dropwise to a stirred solution of 3-methyl-1 * -fuTazanecarboxylic acid (27.0 g, 0.21 mole ) in 180 ml of tetrahydrofuran which has been cooled in an ice and water bath. At the end of the addition, the mixture is stirred overnight at room temperature. After 20 hours, 6U hydrochloric acid is added dropwise until the evolution of hydrogen is completed, after which the reaction mixture is evaporated under reduced pxession. When the residue is partitioned between methylene chloride and water, the system is made alkaline with potassium carbonate and the extracts in methylene chloride are combined, then dried and evaporated under reduced pressure to obtain 21.0 g of the product. Pax vacuum distillation, the desired compound is obtained boiling at 99 ° / l mm Hg.

B. 2-Γ0 * · -Methvl-1,2,5-oxadiazol ~ 3-yl) methylthioΙέ thvl amine

Qn stirred and heated at reflux for 23 hours, then stirred at room temperature for VO hours a solution of S-bydroxymethyl - ^ - methylfurazane (2.1 * 9 g, 21.8 millimoles) [prepared in stage A] and 2-aminoethanethiol hydrochloride (2.4 g, 21.8 millimoles) in 60 ml "of aqueous hydrobromic acid" The excess hydrobromic acid is removed under reduced pressure and the oily residue in isopropanol, the solution is filtered on Celite and the product of the filtrate is crystallized. By recrystallization from isopropanol, the desired compound is obtained in the form of its bromhy-drate having a melting point of 1 ^ 2-1½0.

C. l.l-Dioxide of 3-t2-f Ofr-methyl-1,2,5-oxadia-zol-Vvl) méth ~ ylthio1 éthvlamino} - ** - methylamino-l. 2.5-thiadia - zole

By reacting your methanolic suspension of 1,1-dioxide of 3, V-dimethoxy-1,2,5 “thiadiazole successively with 1 equimolar amount of 2- [0 * -methyl-1,2,5-oxadiaz0I-3- yl) methylthio] ethylamine [prepared in stage B] and an excess of methyl amine according to the general procedure of Example 2, the desired compound is obtained. EXEKPIîE 29 - l.I-Dioxide of 3 ~ [2 - [(5 ~ methyl-1,2,1 * -oxadiazol-3-yl) methyl-thiol ethyl] aminol -if — methvlamino-1. 2. 5-tM adi a zol e A. 2 — Γ (5-Methyl-1, oxadiazol-3-yl) methyl-thi 01 ethyl amine "Cün is gradually adding cysteamine hydrochloride (3.03 g, 26.7 millimoles) in 10 minutes to a stirred solution of sodium methylate (2.89 g, 53, ** millimoles) in 50 ml of methanol at O0. After 70 minutes of stirring at 0 °, a solution of 3 ~ chloromethyl-5-methyl-l, 2, lf-oxadiazole (3, ¾ g, 26.7 millimoles) in 15 ml is added dropwise over 15 minutes. of methanol and the reaction mixture is stirred for 16 hours at room temperature.

The mixture is filtered, evaporated and the residue 3 is redissolved in isopropanol, then the solution is filtered and the filtrate is evaporated under reduced pressure to obtain the desired compound (5.6½ g) which is an oil yellow. The nuclear magnetic resonance spectrum (60 MHz) in deuterochloroform includes the following B resonances: 3.77 (s, 2H); 2.77 (m, 1 * H); 2.63 (s, 3H).

B. 1,1-Dioxide of 3- (2-Γ (5-methvl-l, 2A-oxadiazol- 3-vl) methylthio1 ethylamino} -V-methylamino-1, 2 „5-thiadiazole By reacting a methanolic suspension of 3, ^ -dimethoxy-1,2,5-thiadiazole 1,1-dioxide successively with 2 - [(5-methyl-1,2,1i-oxadiazol-3-yl) -methylthio] ethylamlne [ prepared in Stage A] and methylamine, according to the general procedure of Example 2, the desired compound is obtained-ΕΣΕΜΡΙΕ 30 - 1.1-Pioxide of 3- [2-r (2-methyl-1,3) , 1i - oxadiazol-5-vl) methyl-thi o1éth ~ ylamino) -U — méthvlaTnÎTio-1.2. 5-thiadiazole A. 2-Γ (2-Methyl-1,3 A-oxadiazol-5-vl) methyl-thi ο 1 ethyl amine

Cysteamine hydrochloride (1.13 S> 0.01 mole) is added to a stirred solution of sodium methylate (1.08 g, 0.02 mole) in 20 ml of methanol at 0 ° in an argon atmosphere. The mixture is stirred for 1 hour at 0 ° and the resulting suspension is added dropwise over 25 minutes to a stirred solution of 2-methyl-5-chloromethyl-1,3-1-th -oxadiazole (1.32 g , 0.01 mole) [prepared by the method described in Hel. Chim. Acta, 55, 1979 (1972)] in 15 ml of methanol at 0 °. The reaction mixture is stirred for 5 minutes at room temperature, concentrated almost to dryness, then diluted with chloride. _ Methylene, filtered and the filtrate is evaporated under reduced pressure to obtain the desired compound (1.92 g) which is a yellow oil. The nuclear magnetic resonance spectrum (60 MHz) in deuterochloroform includes the following on resonances: 3.87 (ε, 2H); 2.8 (m, 1 <-H); 2.53 (s, 3H).

B. 1,1-Dioxide of 3 ~ [2 - [(2-methyl-1,3, V-oxadiazol-5-vl) methvl thi ο1éthyiamino] -V-methylamino-1.2 "5-thi adi az ole

By reacting a suspension of 1, 3-dimethoxy-1,2,5-thi adi azie goose with an equi molar amount of 2 - [(2-methyl-1,3,1 + -oxadiazol-5yl) methylth.io] -ethylamine [prepared in stage A] and an excess of methylamine according to the general procedure of Example 2, the desired compound is obtained.

EXAMPLE 31 - 1,1-Dioxide of 3 ~ (2 - [(5-dimethylaminomethyl-2-thienyI) -methvlthiolethylaminol-V-methylami-no-l .2.5-thiadiazole

Qn is added dropwise in 35 minutes a solution of 2 - [(5_dimethylaminomethyl-2-thényl) methylthio] -ethylamine (.1.0 g, millimoles) [prepared according to the process of Belgian patent n ° 867.105] in 25 ml of dry methanol to a stirred solution of 3,1 * -dimethoxy-1,2,5-thiadiazole 1,1-dioxide (0.77 g, 31 * millimoles) in 150 ml of dry methanol which was cooled to 0-3 ° in a water and ice bath. At the end of the addition, anhydrous methylamine is bubbled through the solution for 10 minutes and stirring is continued for 15 minutes. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 50 g of silica gel which is chromatographed with gradient elution using acetonitrile and methanol. Qn combines the appropriate fractions to obtain 1.0 g of product. By recrystallization from methanol, the desired compound is obtained having a melting point of 60.5-66 °.

* EXAMPLE 32 - 1-3-Î2-T (5-dimethylamlnomethyl-2-furvl) methyl- ’thio1ethylamino} -l * -ethvlaminovl .2.5-thiadiazole oxide

A solution of 2 - [(5-dimethylaminomethyl-2-furyl) -methylthio] -ethylamine (2.61 * g, 12.3 millimoles) in 25 ml of dry methanol is added dropwise over 30 minutes to a good solution. stirred with 3-l-dimethoxy-1,2,5-thiadiazole 1-oxide (2.0 g, 12.3 millimoles) in 75 ml of dry methanol which was cooled to 8 ° in a water bath and ice. After 15 minutes, 1 * 0 ml of ethylamine is added and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 55 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. The appropriate fractions are combined, they are evaporated under reduced pressure ”, the residue is taken up in ether and the whole is decanted. The residue is taken up in fresh ether to obtain 1.5 g of the desired compound having a melting point of 68-7½ ° ·

Analysis for 5¾¾ calculated C, 1 * 7.0 *; H, 6.1 * 8; K, 19.59; S, 17.91 *% found C, 1 * 6.51 *; H, 6.33; H, 19.37; S, 17.96% (correction for l.2l *% I ^ O) EXAMPLE 33 - 1.1-Dioxide of λ-ί2- [f5-dimethy: i amtnométhvl-2-fmryl) méthvl-thioléthvlamino) -V-nronylamino- l, 2.5-thiadiazole

A solution of 2- [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl-amine (2.1 * 1 g, 11.2 millimoles) in 25 ml of dry methanol is added dropwise over 3 ° minutes. é a well stirred suspension of 1,1-dioxide of 3, i »-dimethoxy- 1,2,5-thiadiazole (2.0 g, 11.2 millimoles) in 200 ml of dry methanol which was cooled to 2 ° in a water and ice bath. After 15 minutes, 0.1 ml of n-propylamine is added all at once and the mixture is stirred at room temperature for 3 ° timed. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 55 g of silica gel as chromatography with gradient elution using methylene chloride and methanol.

Combine the appropriate fractions, evaporate under reduced pressure and crystallize the syrup in ether to obtain 3 * 7 S of the desired compound having a melting point of 161 + -166® and whose magnetic resonance spectrum nuclear (100 MHz) in hexaeuterated dimethylsulfoxide reveals the presence of about 0.9 mole of methanol.

Analysis for 5 ^ 3 ^ 2 - 0.9 CH ^ O

calculated C, if5.86; H, 6.92; K, 16.82; S, found C, if5 "60; H, 6.93; N, 17.03; S, 15, W ΈΣΕΜΡΙΕ 3b -Part I

1-Oxide of 3-aii! Ino-it — r2- [fl? -Dimeth7Taminor! Ethyl-2-furvlV methylthiolethvl aminoj-1,2,5-thi acliazol p

A solution of 2 - [(5-dimethylaminomethyl-2-fuxyl) methylthio] ethyl-arrnne (3.3 g, 15, if millimoles) in 25 ml of methanol is added dropwise over 30 minutes. well stirred solution of 1-oxide of 3, 1-dimethoxy-1, 2,5-thiadiazole (2.5 g, 15, if millimoles) in 75 ml of methanol which was cooled to 8 ° in a water bath and of ice. After 90 minutes, anhydrous ammonia is bubbled through the solution for 8 minutes, then the mixture is stirred at room temperature for 30 minutes. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 60 g of silica Rel which is chromatographed with gradient elution using methylene chloride 4 and methanol. The appropriate fractions are combined and evaporated, then the product is crystallized from acetonitrile. By recrystallization from isopropanol, 2.59 g of the desired compound is obtained having a melting point of 139-1½0.

Analysis for C12E19K5 ° 2S2 calculated C, 1 * 3.75; H, 5.81; K, 21.26; S, 19, "* 6% found C, 1 * 3.71; H, 6, θ5; K, 21.32; S, 19.5l%

Part II

3-Amino-4- {2- [2- ((5-dimethylaminotnethyl-2-furyl) methyl-thio] ethylamino3-1,2,5-thiadiazole dioxide

Qn stirred at room temperature for 16 hours a mixture of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (17.16 g, 0.117 mole) and 2 - [(5-dimethylaminomethyl- 2-furyl) methylthio] ethylamine (25.0 g, 0.117 mole) in 250 ml of methanol, cooled to 0 ° and the precipitate is collected by filtration. The solid is recrystallized from 50% aqueous methanol to obtain the desired compound in the form of a colorless crystalline powder, mp 153-154 ° (decomposition) which is identical to the compound prepared in Example 34.

Analysis for ci2Hi9N5 ° 2S2: calculated C, 43.75; H, 5.81; N, 21.26; S, 19.47% found C, 43.36; H, 5.54; N, 20.91; S, 19.88% (corrected for 0.3% H ^ O) JEXEKPI · *: 35 - ll-Moxvde de 3-πττηηο-1 + -Γ2-Γ (5-dimethvlaTOinoinéttnrl-2-furvDméthvltMol ethyl aminol-1 T 2.5-thiadiazole

A solution of 2- [(5-d.im ethy 1 aminomethy 1 -2-f ury1) m ethylthi o] -ethylamine (2.5 g, 11.7 millimoles) in 50 ml is added dropwise in b5 minutes. of dry methanol to a well stirred suspension of 3-V-di-methoxy-1,2,5-thiadiazole 1,1-dioxide (2.08 g, 11.8 millimoles) in. 200 μl of dry methanol which has been cooled to 5 ° in a water - and ice bath. After 30 minutes, am- is bubbled. anhydrous moniac in the solution for 10 minutes, then the mixture is stirred at ambient temperature for 8 hours. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 200 g of silica gel which is chromatographed with elution at gradient using methylene chloride and methanol. Combine suitable fractions and evaporate to obtain 3.6 B of product. By recrystallization from a mixture of methanol and ether, the desired compound is obtained having a melting point of 156-558 °.

Analysis for C12H19K5 ° 3S2 calculated C, 1 * 1.72; H, 5.5V; K, 20.28; S, 18.56%

found C, VI, 50; H, 5.52; 2J, 20.33; S, 18.7V% EXAMPLE 36 -Part I

Ü-'Orvrie de 3-aroino-V-f2-Γ (2-euanidinothiazol-V-vl ') Eethvl-thi ο 1 ethvl amino] -1,2.5-thiadiazole.

A solution of 2- [(guanidinothiazol-V'-yl) methylthio] ethylamine (obtained from the dihydrochloride, 6.08 g, 20.0 millimoles) in 50 ml of methanol is added dropwise over 5 minutes. a well-stirred solution of 3-V-dimethoxy-1,2,5-thiadiazole 1-oxide (3.2 V g, 20.0 millimoles) in 150 ml of methanol which was cooled to 5 ° * After 90 minutes of stirring at 5-10 °, anhydrous ammonia is bubbled through the solution for 10 minutes and stirring is continued for 18 hours at room temperature. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 65 g of silica gel as chromatography with gradient elution using methylene chloride and methanol. Combine the appropriate fractions in methanol and evaporate to obtain ^ -, 16 g of product. By recrystallization from methanol, the desired compound is obtained having a melting point of 167-170 ° (with decomposition).

Analysis for C ^ H ^ NgOS ^ calculated C, 31.20; H, V, 07; M, 32.35; S, 27.76% found C, 30.39; H, 3.97; N, 32.25; S, 27.91% (corrected for 0.28% EgO)

By recrystallization of the crude product from 95% ethanol, the desired compound is obtained in the form of its monohydrate having a melting point of 136-138 ° (with decomposition).

Analysis for CgH ^ IigOS ^ .E20 calculated 0.29.66; H, 1 *, 1 * 2; K, 30.75; S, 26.39% found C, 29.92; Η,> Λ2; N, 30, © f; S, 26.58%

A sample of the product is suspended in the form of the free base in 95% ethanol and 1 equivalent of 6.01 aqueous hydrochloric acid is added thereto, then the whole is filtered to obtain the hydrochloride having a point of melting of 200-201 ° (with decomposition) -Analysis for C ^ H ^^ ClKgOS ^.

calculated C, 28.23; E, 3.95; N, 29.26; Cl, 9.26% s found C, 28.26; E, 3.83; N, 29, ** 1; Cl, 9.53% (correction for 1.02% H ^ O)

Part II

1-3-Amino-4- {{2- [(2-guanidinothiazol-4-yl) methylthio] -ethylamino} -1,2,5-thiadiazole A-1-3-amino-4-methaxy- oxide l, 2,5-thiadiazole

A solution 2.75 N of ammonia (56.0 ml, 0.154 millimole) in methanol is added dropwise over 1 hour to a well-stirred solution of 3,4-dimethoxy-1,2-oxide. , 5-thiadiazole (24.3 g, 0.15 mole) in 725 ml of methanol at 20th C. The resulting solution is stirred at room temperature for 3 hours, then concentrated to about 125 ml under reduced pressure. -After 16 hours at OeC, the mixture is filtered and dried to obtain 19.9 g of product.

An analytical sample is prepared by recrystallization from methanol to obtain the desired compound, m.p. 182-184 ° (decomposition).

Analysis for C ^ H ^ N ^ O ^ S: calculated, 24.49; H, 3.43; N, 28.56; S, 21.79% found C, 24.22; H, 3.63; N, 28.60; S, 21.92% B. 1-3-Amino-4- {2 [(2-guanidinothiazol-4-yl) methylthio] -ethylamino} -1,2,5-thiadiazole oxide

1 oxide of 3-amino-4-methoxy-1,2,5-thiadiazole (519.4 g, 3.53 moles), [prepared in Stage A], is added, followed by 115.8 ml of water to a solution of 2 - [(guanidinothiazol-4-yl) methylthio] -ethylamine (816.5 g, 3.53 moles) in 7790 ml of methanol. The reaction mixture is stirred at 24 ° for 5 hours, then an additional 1012 ml of water is added and stirring is continued for 17 hours. The resulting precipitate is collected by filtration, which is washed with cold methanol and dried in air. By recrystallization of the crude product, in two batches, in a 2-methoxyethanol-water mixture, a yield of 80 is obtained. % the desired compound in the form of a light yellow powder containing 1 mole of water, mp 144.5-146 ° (decomposition).

*

This product is identical to the compound prepared in Example 36. Analysis for CgH- ^ NgOS ^ .fl ^ O: calculated C, 29.66; H, 4.42; N, 30.74; S, 26.39; H2O 4.93% found C, 29.47; H, 4.35; N, 30.86; S, 26.47; H00 5.17% ΈΣΕΗΡΕΕ 37 - 1 Ι-.l-Benzylamino-V- dioxide (2-f (^ -dimethylaminomethyl-2-f urvl ^ τηéthvlthiο 1 ethyl amino} -1,2.5-thiadiazole

A solution of 2 -. [(5-dimethylaminomethyl-2-fuxyl) inethyltliio] ethylamine (2.1f g, 11.2 millimoles) in 30 ml of dry methanol is added dropwise over 35 minutes to a stirred solution. 3,4-dimethoxy-1,2,5-thiadiazole 1,1-oxide (2.0 g, 11.2 millimoles) in 200 ml of dry methanol which was cooled to 1-3® in a water bath water and ice.

After 15 minutes at 1-3, benzylamine (1.8 g, 1.83 ml, 16.8 millimoles) is added and the solution is stirred for 1 hour at room temperature. The reaction mixture is evaporated under reduced pressure and the residue is deposited on silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Combine suitable fractions to obtain 4.1 g of the product. By recrystallization from aqueous methanol, then from methanol, the desired compound is obtained having a melting point of 152 ° (with decomposition) and whose nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethyl sulfoxide reveals the presence of about 1.0 mole of methanol.

Analysis for C ^ Hg ^ N ^ O ^ Sg-CH ^ O

calculated C, 51.37; H, 6.25; N, 14.98? £ found C, 5l, 5l; H, 6.05; M, 14.78? " EXAMPLE 38 - 1,1-1) 1 oxide of 3-Î2-T (3-j> diméthy.laminométhvl ^ xiényl) methyl-thioléthvlamino} -4-méthvlamino-1,2,5-thiadiazole

A solution of 2 - [(3- ^ dimethylaminomethyl | phenyl) methylthio] -, ethylamine (2.5l g, 11.2 millimoles) is added dropwise over 30 minutes [prepared according to the method of Belgian patent n ° 867.106] in 25 ml of dry methanol to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2,0 g, 11,2 millimoles) in 200 ml of dry methanol than cooled to 2 ° in an ice and water bath. After 15 minutes at 2-5®, anhydrous methylamine is bubbled through the solution for 10 minutes, then the solution is stirred at room temperature for 30 minutes. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 60 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Combine suitable fractions to obtain 2.96 g of product. By recrystallization from acetonitrile, then from methanol, the desired compound is obtained having a melting point of 152-558 ° and whose nuclear magnetic resonance spectrum (100 MHz) in hexa-deuterated dimethylsulfoxide reveals the presence of about 0.6 mole of methanol.

Analysis for ci5 ^ 23 ^ 5¾¾ calculated C, * 1-8.20; H, 6.59; N, 18.02; S, 16.1 * 9 # found C, * f7.99; H, 6.78; B, 17.81; S, 16.09 # EXAMPLE 39 - 1 — Cbrvde de λ-ami no-h-Î2-r n-fdiméthvlaminQméthy33phénvl) m-th-rl thiο 1 ethylaminol —1.2. 5-thiadiazole

A solution of 2- [(3- £ dimethylaminomethyl2phenyl) methylthio] ethyl-amine (2.77 g, 12.3 millimoles) in 25 ml of dry methanol is added dropwise in * 1-5 minutes to 25 ml of dry methanol. 3-* -f-dimethoxy-1,2,5-thiadiazole 1-oxide (2.0 g, 12.3 millimoles) in 100 ml of dry methanol which was cooled to 5 ° in a water bath and of ice. At the end of the addition, the solution is stirred at room temperature for 90 minutes, then cooled to 5 ° and bubbled there for 8 minutes with "anhydrous ammonia. After 16 hours of stirring at tem at room temperature, the reaction mixture is evaporated under reduced pressure and the residue is deposited on 55 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol, which combines the appropriate fractions in 1 acetonitrile to obtain 3.0 g of product By recrystallization from acetone, the desired compound is obtained having an melting point of 122-125 °.

Analysis for ^ 1 ^ 21 ^ 50¾ calculated C, 1 + 9.53; Hy 6.23; N, 20.63; S, 18.89% found C, 1 + 9.18; H, 6.08; N, 20.93; S, 19.25% EXAMPLE 1 + 0 - 1-3-12-Γ -Qioxide (5-dimeth ~ ylaminometh: 7l-2-thien: yl) methyl-thiol ethvlaminol-lf-methvlamino-1.2.5-thiadiazole

A solution of 2 - [(5-dimethylaminomethyl-2-thienyl) methyl-thio] ethylamine (1.5 g, 6.5 millimoles) in 25 ml of dry methanol is added dropwise over 1 + 5 minutes to a solution. stirred with 3, ½-dimethoxy-1,2,5-thiadiazole 1-oxide (1.06 g, 6.5 millimoles) in 150 ml of dry methanol which was cooled to 3 ° in a water bath and of ice. After 15 minutes at 3 °, OO bubbled anhydrous methylamine into the solution for 5 minutes, then the solution was stirred for 15 minutes. After standing overnight at room temperature, the reaction mixture is evaporated under reduced pressure and the residue is deposited on 75 g of silica gel which is chromatographed with gradient elution using acetonitrile and methanol. The appropriate fractions are combined to obtain the crystalline product from its solution without the ace-tonitrile. By recrystallization from 1 'acetonitrile, the desired compound is obtained having a melting point of 98.5-102 °.

Analysis for ^ 3 ^ 21 ^ 50¾ calculated C, 1 + 3 ^ 2; H, 5.89; K, 19.1 + 8; S, 26.76% found C, 1 + 3.70; H, 5.5S; ”, 19.71; S, 26.79% BOEMIE 1 + 1 - l.l-hioxvde de 3-amino-l + -fi + - (5-dimethvlaminomethyl-2-furvl) - _ 0? - butvlaminol -1.2.5-thiadiazole

Qn added drop by drop in 3? minutes a solution of i * - (5-dimethylaminomethyl-2-furyl) butyl amine (1.61 g, 8.2 millimoles) in 25 ml of dry methanol in a "well-stirred suspension of 1,1-dioxide 3", l * -dimetho-xy-l, 2,5-thiadiazole (1.4-6 g, 8.2 millimoles) in 150 ml of dry methanol which was cooled to 0-3 ° in a water and After 15 minutes, anhydrous ammonia is bubbled through the solution for 5 minutes, after which the solution is stirred for 30 minutes, then evaporates the reaction mixture under reduced pressure and the residue is deposited on 60 g of gel. of silica which is chromatographed with gradient elution using acetonitrile and methanol, the appropriate fractions are combined and evaporated to give 1.68 g of product. By crystallization from acetonitrile, the desired compound is obtained having a melting point of 154-156 (with decomposition) Analysis for C-, calculated C, 1 * 7.69; H, 6.1, * -7; N, 21.39; S, 9.80% found C , 1 * 7.73; H, 6.28; H, 21.43; S, 9.8 "*% EXAMPLE 1 * 2 - 1,1-hio 3-amino-4-f2-r xyde (g-dïméthvlRminométhvl-4-tblazo1-vl) méthvlthio1étTrv1 amino '} -1.2.5-thiadiazole

A solution of 2- [(2-dimethylaminomethyl-1 * -thiazolyl) roethylthio] - "ethylamine (0.9 g, 3.89 millimoles) in 20 ml of dry methanol is added dropwise over 1 * 0 minutes. well stirred suspension of 1,1-di oxide of 3> 4 “dimethoxy-1,2,5-thiadiazole (0.69 g, 3.89 millimoles) in 70 ml of methanol which was cooled to 8 °, then Anhydrous ammonia is bubbled through the solution for 8 minutes, after which the solution is stirred at room temperature for 18 hours, the reaction mixture is evaporated under reduced pressure and the residue is deposited. on 150 g of silica gel which is chromatographed with gradient elution using acetonitrile and methanol, which combines the appropriate fractions and is evaporated to obtain 0.66 g of product. The resulting foam is dissolved in 2-propanol and the solution is evaporated to dryness to obtain the desired compound having a melting point of 60-6 ° and whose nuclear magnetic resonance spectrum (100 MHz) is hexadeuterated methyl sulfoxide reveals the presence of about 0.15 mole of 2-propanol.

Analysis for 02.0.15 C ^ HgO

calculated C, 37.02; H, 5.21; W, 22.62; S, 25.8995 found C, 36.75; H, 5.13; N, 21.75; S, 25.0395 (correction for 2.79% HgO) TTKMPTiR 1 + 3 - 1.1-3-f2 dioxide - [(2-guaTn‘dinothiazol-5-vl) methvlthio1r etbvlaminol -h-mefhyl amino-l. 2.5-thiadiazole (A) CM orhvidate 2-guanidinQ-5-thiazolecarbo-yvlate

Stirred at room temperature for 18 hours, then heated at reflux for 1 hour a solution of amidinothiourea (117 g, 0.99 mole) and chloro-a-formyl ethyl acetate (150 g, 1, 0 mole) in 3500 ml of absolute ethanol. Then, a supplement of ethyl chloro-a-for-mylacetate (20.0 g, 0.13 mol) is added and 1 hour later a new supplement of ethyl chloro-a-formylacetate (20, 0 g). After a further 2 hours of heating at reflux, the reaction mixture is evaporated under reduced pressure and the residue is triturated in 1500 ml of acetone, after which the whole is filtered to obtain 1Q3 g of product. By recrystallization from 2-propanol, the desired compound is obtained having a melting point of 20 ^ -206 °.

CM

Lice analysis C ^ H ^ CIK ^ O ^ S

calculated C ,. 33.53; H, V, V3; LT, 22.35; Cl, 1V, 1V; S, 12.7¾¾ found C, 33.38; H, V, VO; N, 22.5V; Cl, 13.97; E, 12.92% (B) 2-ftUHntdino-5-h ~ vdroxvméthvlthiazole * Ethyl 2-guanidino-5-thia-zolecarboxylate hydrochloride (1.0 g, 3.99 millimoles) is added stage A] to a suspension of lithium aluminum hydride (0.1 + 6 g, 12.1 millimoles) in 25 ml of tetrahydrofuran which was cooled in an ice and water bath. The reaction mixture is then heated at reflux for 2 hours *, then cooled and decomposed by the addition of 0.1 + 6 ml of water, 0.1 + 6 ml of 15% sodium hydroxide and 1.38 ml of water, after which it is filtered. The filtrate is dried and evaporated under reduced pressure to obtain 0.61 g of product. By recrystallization from aetoni-trile, the desired compound is obtained having a melting point of 168-170 °.

Analysis for C ^ HgN ^ OS

calculated C, 3V, 87; H, l +, 68; K, 32.5V; S, 18.62% found C, 3V, 55; H, V, 52; 1.32.63; S, 18.5V # (C) 2-Γ f2-Guanidinothia? Ol-5-vl) meth ^ lth-î oleth-vl- amine

Cysteamine hydrochloride (10.6 g, 9.3 millimoles) and 2-guanidino-5-hydxoxymethylthiazole (16.0 g, 9.3 millimoles) [prepared in Stage B] are dissolved in 80 ml of hydrochloric acid concentrated and the solution is stirred for 1 hour at room temperature, after which it is heated to reflux: for 3 hours. The reaction mixture is cooled, made alkaline to pH 11 with 0% aqueous sodium hydroxide and filtered to obtain 15 g of product. By recrystallization from acetonitrile, the desired compound is obtained having a melting point of 150-153 ° ·. Pear analysis C ^ H- ^ NijEg calculated C, 36.3V; H, 5.66; 1.30.27; s, 27.72% found C, 36.29; H, 5.70; K, 30, VO; S, 27.6¼% (D) 1 .l-Dioxide of · 3- {2-Γ (2-Fuanidinothiazol-5- vl) methvlthiolethvlamino} -V-methvlamino-1.2.5-th-i acliazol e

A solution of 2- [(2-guanidinothiazol-5-yl) methylthio] ethylamine (2.0 g, 8.61 * millimoles) [prepared in Stage C] in 60 ml of methanol is added dropwise over 1 minute. a well stirred suspension of 1,1-dioxide of 3, V-dimethoxy-1,2,5-thiadiazole (1.5V g, 8.6V millimoles) in 160 ml of methanol which was cooled to 8 ° at Water and ice bath. Maintaining the temperature at 8 °, anhydrous methylamine is bubbled into the solution for 8 minutes. After 18 hours of stirring at room temperature, the reaction mixture is evaporated under reduced pressure and the residue is deposited on 175 g of silica gel which is chromatographed with gradient elution or by means of acetonitrile and methanol. The appropriate fractions are combined to obtain 1.3 g of product. By recrystallization from methanol, the desired compound is obtained having a melting point of 225-226 ° (with decomposition).

Analysis for ^ oH- ^ NgOgS ^.

calculated C, 31.90; H, V, 28; N, 29.76; S, 25.55% found C, 32.07; H, V, IV; K, 29.91; S, 25.60% EXAMPLE - 1-Oxvde of ^ -amlno-V-i 2-Γ (2-tmanidinothiazol-5-yl) nethvlthio1-ethvlamino) -1.2.5-thiadiazole

A solution of 2- [(2-guanidinothiazol-5-yl) methylthio] ethylamine (3.0 g, 13.0 mmol) [prepared in Example V3, stage C] in 70 is added dropwise in VO minutes. ml of methanol to a well stirred solution of 1-oxide of Bj ^ dimétboxy-l ^ j ^ -thiadiazole (2.1 g, 13.0 millimoles) in 200 ml of methanol which is cooled to 8th and bubbled anhydrous ammonia in the solution for 8 minutes. After 18 hours of stirring at room temperature, the reaction mixture is evaporated under reduced pressure and the residue is deposited on 225 g of silica gel which is chromatographed with gradient elution using acetonitrile and methanol . The appropriate fractions are combined to obtain 3.6 g of the desired compound having a melting point of 85-132 ° and whose nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethyl sulfoxide reveals the presence of about 0 , 3 moles of acetonitrile. Analysis for C ^ n ^ NgOS ^ .0.3 calculated C, 32.24 ·; H, 4.22; N, 32.4-1; S, 26.71% found C, 32.63; H, 4-, 33; N, 32.55; S, 26.62% (correction for 1.84% HgO) EXAMPLE 45 - 1.1-hioxvde of 3-cvclopropy1amino-4- (2- [f5-dîméthv'1am ~ ino "-é-thvl-2-furvl) methvlthio] ethyl amino) -! T 2,5-thia (jiazoT e

The general procedure of Example 8 is repeated, but replacing the 2-propynylamine with an éoui-molar amount of cyclopropylamine and by crystallizing the product in methanol. By recrystallization from isopropanol, 3.5 g of the desired compound is obtained, having a melting point of 194-195 ° (with decomposition) and the presence of the nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethylsulfoxide. of about 1.0 mole of isopropanol.

Analysis for ^ 5 ^ 23 ^ 5¾¾ * ° 3Ε8 ° calculated C, 48.52; H, 7.01; H, 15.72% found C, 48.36; H, 6.95; K, 14.87% _ Q7 - EXAMPLE 46 - 1 .l-Di oxvde de ^ -cyclopropylmétÎr / laTPino-h - ^ - f '^ - diméthTl-amiPométhTl-2-fUTYl,) méth-ylthio] éthTlaffiino} -l .2.5-thiaàiazole

The general procedure of Example 8 is repeated, but replacing the 2-propyhylamine with an equimolar amount of cyclopropylmethylamine and crystallizing the product from methanol. By recrystallization from methanol, 1.6 g of the desired compound are obtained, having a melting point of 86-89 ° (with decomposition) and whose nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethylsulfoxide reveals the presence of about 1.25 moles of methanol.

Analysis for C- ^ Hpi ^ O ^ S2-l, 25 CH ^ O

calculated C, 47.13; H, 6.88; N, 15.93% found C, 47.40; H, 6.49; N, 15.77% (correction for 0.6 g% B ^ O) EXAMPLE 47 - 1.1- 3-Î2-T dioxide (~ 5-dimethvlaminométhvl-2-furvl) méthvl-thiol éthvl amino) -4-m ornholino -l. 2,5-thi adiaz goose

Qn repeats the general procedure of Example 19, but replacing dimethylamine with an equimolar amount of morpholine. After column chromatography, the product is crystallized from isopropanol. Qn dilute the mixture with Skellysolve B and filter it to obtain the desired compound having a melting point of 122-127 °.

Analysis for ci6ï25W5 ° 4S2 calculated C, 46.24; H, 6.06; H, 16.86% found C, 45.82; H, 6.06; li, 16.62% (correction for 0.6l% 1 ^ 0) tnreMPLE 48 - 1.1- Dioxide of 3-Ε2-Γ (5-dimethvlaminomethyl-2-f uryl) methyl- thio1ethvlamino} -l * - (2- methoyvethvlamino) -l .2,5-thiadiazole

The general procedure of Example 8 is repeated, replacing the 2-propynylamine with an equimolar amount of 2-methoxyethylamine. After column chromatography, the residue is taken up "in isopropanol, the solution is evaporated to almost dryness and then cooled to obtain 3.79 g of product. By recrystallization from isopropanol, the desired compound is obtained having a melting point of 56-58 ° and whose nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethyl sulfoxide reveals the presence of about 0.6 moles of isopr opanol.

Analysis for C- ^ HgO

calculated C, 1 * 5.90; H, 6.83; N, 15.93% found 0.1 * 5.50; H, 6.72; 2, 15.63% (correction for 0.7 **% HgO) EXAMPLE 1 * 9 - 1.1- Di-oxide of 3-12-Γ (5-dimethylaminomethyl-2-f uryl) methvl-thiol ethhl amino] -1 * - pvrrolidino-l. 25-thiadiazole

The general procedure of Example 19 is repeated, but replacing the dimethylamine with an equimolar amount of pyrrolidine. The crude reaction mixture is evaporated under reduced pressure, it is taken up in Isopropanol and the whole is filtered to obtain 3, 9 g of the desired compound having a melting point of 15-152 °.

Analysis for c; l6E25K5 ° 3®2 calculated C, 1 * 8.09; H, 6.31; N, 17.53% found C, 1 * 8, OD; H, 6.10; N, 17.71% EXAMPLE 50 - 1.1-3-f 2- h hydroxide (5-dimétfrvlaminométhTl-2-f urrl ^ métîrvl-thiol éthvl amino) -V-pinéridino-l. 2.5-thiadiazol e

The general procedure of Example 19 is repeated, but replacing dimethylamine with an equimolar amount of piperidine. By chromatography, 3.8 g of product are obtained. By recrystallization from hot aqueous ethanol, the desired compound is obtained having a melting point of 106-108 °. -

Analysis for ^ 3 ^ 27 ^ 5¾¾ calculated C, 1 * 9.37; H, 6.58; H, 16.9k% found C, 1 * 9.17; H, 6.52; U, 17.1¼% (correction for 0.2% I ^ O) EZEMPIÆ 5l - 1.1- Dioxide of 3-butylamino-l * -? 2-r (5-dimethvlaminométhvlr-2- · f urYl) meth-vlthio1 ethvlaminol -1.2.5-thiadiazole

The general procedure of Example 8 is repeated, but replacing the 2-propynylamine with an equimolar amount of butylamine. The crude product is chromatographed for three times, then it is dried under high vacuum for 3 hours and 30 minutes to obtain 1.81 g of the desired compound which is a somewhat gummy foam.

Analysis for ^ 0 ^ calculated C, 1 * 7.86; H, 6.78; N, 17, M *% found C, 1 * 7.60; H, 6.81; N, 17.81% (correction for 1.3 **% HgO) EXAMPLE 52 - 1.1- 3 ~ l2-f (5-dimethvlaminoroethvl-2-furvl ') methYl-t> vî o1éthvlamino? -L * - r (2-T3vridvl ') meth-ylamino1-1.2.5-thiadia-xole

The general procedure of Example 8 is repeated, but replacing the 2-propynylamine with an ego-molar amount of 2-aminomethylpyridine. Combine the appropriate fractions from column chromatography to obtain 3.9 g of product. By two recrystallizations from isopropanol, the desired compound is obtained having a melting point of ^ 3-4-5 ° · 011 recrystallizes a sample from absolute ethanol and the resulting solid is heated under vacuum at 60 ° for 6 hours to obtain a fusion product.

This is dissolved in hot isopropanol, the solid is collected by filtration at "room temperature and dried under high vacuum to obtain the desired compound having a melting point of h5-b7 ° and whose resonance spectrum magnetic magnetic (100 MHz) in hexadeuterated dimethyl sulfoxide reveals the presence of approximately 1.25 mole of isopropanol.

Analysis for £ 3¾½¾¾S. 1.2 5 C ^ HgO

calculated C, 51.05; H, 6.70; N, 16.1 * 2 # found C, 51.08; H, 6.32; U, 16.03% (correction for 0.58% I ^ O) EXAMPLE 53 - 1.1- Dioxide of Γ (5-dimethvl aminométhvl-2-furvl) méthvl-thioléthylamino3 -lf-hvdroxvlamino-1.2.5-thiadiazole

The general procedure of Example 8 is repeated, but replacing the 2-propynylamine with an equimolar amount of hydroxylamine. The bruty reaction product, which has deposited the desired product in the form of an oily product, is subjected to reflux heating until the product crystallizes, after which the whole is filtered and the solids are dried to obtain 2.59 g of the compound. sought having a melting point of 203-205 °.

- .Analysis for 0η? ΗΊ qN ^ O ^ Sp calculated C, 39.87; H, 5.30; N, 19.38; S, 17.7¼% found C, 39.53; H, 5.0 *; K, 19.61; S, 17.62% (correction for 1.16% EgO) EXAMPLE% - 1.1- 3-Ϊ2-Γ (5-dimethvlaminoaethvl-2-furvl,) methvl-_thiolethvlaminol-V-dodecylamino-1.2.5-thiadiazole dioxide - 101 -

Qn is added dropwise a solution of 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamine (2.1 * 1 g, 11.2 millimoles) in 25 ml of methanol to a cold well stirred suspension of 1, 1, 3-^ -dioxide-dimethoxy-1,2,5-thiadiazole (2.0 g, 11.2 millimoles) in 200 ml of metha-nol. After 15 minutes of stirring at 2-5 °, a solution of dodecylamine 0 *, 15 g, 22.1 * millimoles) in 25 ml of methanol is added all at once and stirring is continued at room temperature for 18 hours. The reaction mixture is filtered and evaporated under reduced pressure, then the residue is deposited on 60 g of silica gel which is extracted with gradient elution using methylene chloride and methanol. The appropriate fractions are combined, evaporated and the residue is rechromatographed on 60 g of silica gel with gradient elution using acetonitrile and methanol. The suitable fractions from the second chromatography are combined, concentrated under reduced pressure and the crystallized product is collected by filtration and dried to obtain 2.13 g of the desired compound having a melting point of 136-139 °.

Analysis for C2l * El * 5 55 ° 3S2 'calculated C, 55.89; H, 8.79; N, 13.58; S, 12.1 * 3 # found C, 56.163 H, 8.57; K, 13.38; S, 12.61% EXEHPIÆ 55 - 1.1-hioxvde of 3-t2-r (5 ~ dimeth: yiaminomethyl-2-furvl) methvl-tMoleth-ylaainol-V-methoxyainino-1.2.5-thi adï p.vol e

Is the general procedure of Example 8 repeated? but replacing 2-propynylamine with an equimolar amount of methoxyamine. The reaction mixture is stirred at room temperature overnight, during which a crystalline precipitate is formed. The mixture is cooled and filtered, then the solid is dried to obtain 3.8 E of the desired compound having a melting point of 22 ** - 226 (with decomposition).

Analysis for calculated C, 1 * 1.59; H, 5.61 *; K, 18.65; S, 17.08% found C, 1 * 1.25; H, 5.51 *; n, 18.50; S, 17.16% (correction for 0.79% HgO) • RTRÏIPIÆ 56 - Ι.Ί-Dioxide of 3-C2-F (5-dimethvlaminometbvl-2-thienvl ') - methvlthiolethylamino} -l * -nronvlamino-1.2 . 5-thiadiazole

The general procedure of Example 31 is repeated, but replacing the methylamine with an equimolar amount of propylamine. By chromatography, 3.5 g of crystalline product are obtained. By recrystallization from acetonitrile, the desired compound is obtained having a melting point of 191 * -196 ° (with decomposition).

Analysis for calculated C, ¥ +, 61 *; H, 6.21 *; ff, 17.35; S, 23, ¾% found C, ¥ *, 66; H, 6.02; E, 17.88; S, 23.87% EXAMPLE 57 ~ 1-Qyyflp of 3-n ^ no-l4 - {g - [(5-aiméthylaTn-iTiOgéthyl-2-thienyl) -méthylthioléth-vlaminoT-1.2.5-thiadiazole

A solution of 2- [(5-dimethylaminomethyl-2-thienyl) methylthio] -ethylamine (2.8 ** g, 12.3 millimoles) in 25 ml of methanol is added dropwise over 35 minutes to a stirred solution of 3-¥ -dimethoxy-1,2,5-thiadiazole 1-oxide (2.0 g, 12.3 millimoles) in 200 ml of methanol s which is cooled to 3 ° in an ice and water bath . After 15 minutes of stirring, anhydrous ammonia is bubbled through the solution for 5 minutes. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 60 g of silica gel which is chromatographed with gradient elution using methylene chloride and methanol. Combine suitable fractions to obtain 1.73 E of product. By recrystallization from acetonitrile, the desired compound is obtained having a melting point of 1 ^ 9-152 ° (with decomposition).

EXAMPLE 58 - 1.1- Dioxide of 3-Î2-T (5-dimethvlaminométhvl-2-thienvl) mé-tbvlthioléthvlamino ^ -V-r (3-nyridvl3méth, v, lamino'l-1.2.5-thiarb'azol e

The general procedure of Example 31 is repeated; but replacing methylamine with an equimolar amount of 3_aminomethylpyridine. Combine the appropriate fractions from column chromatography to obtain 3.10 g of the desired compound which is an oil. This is dissolved in an excess of 5% hydrochloric acid, the solution is evaporated and the residue is triturated in isopropanol to obtain a solid. By recrystallization from 95% aqueous ethanol, the desired compound is obtained in the form of its dihydrochloride having a melting point of 1 ^ -3-1 ^ 6.5 °.

Analysis for 028 ^ 260½¾¾¾ calculated C, 1 * 1.13; H, k, 99; N, 15.99; S, 18.30% found C, 1 * 1.25; H, **, 90; N, 16.18; S, 18.52% (correction for 2.0 **% HgO) EXEMPIÆ 59 - 1.1- Dioxide of 3-amino-V-i2-Γ (5-dimethylaminométhvl-2-thîé-nvl) méthvlthioléthvlamino3-3 .2.5- thiach 'r? .ol e

A solution of 2 - [(5-dimethylaminomethyl-2-thienyl) methyl-thiojethylamine (2.0 g, 8.68 millimoles) in 25 ml of methanol is added dropwise over 35 minutes to a stirred solution of 1.1 -3.1 * dioxide -di-methoxy-1,2,5-thiadiazole (1.55 g, 8.68 millimoles) in - 104 - 200 ml of methanol which was cooled to 3 ° in a bath of water and ice. After 15 minutes of stirring, anhydrous ammonia is bubbled through the solution for 10 minutes. The reaction mixture is evaporated under reduced pressure to obtain 3.3 B of the desired compound. The nuclear magnetic resonance spectrum (100 KEz) in hexadeuterated dimethyl sulfoxide comprises the following resonances: 6.88 (d, 1H); 6.78 (d, 1H); 4.03 (s, 2H); 3.61 (s, 2H); 3, ¾ (t, 2H); 2.74 (t, 2H); 2.22 (s, 6H) and also reveals the presence of approximately 2/3 mole of methanol.

60 - 1.1- Dioxide of 3-benzvlamino - ^ - Î2-T (5-dimethvlaminométhvl- 2-thi envl ~) m é thvl thi ο 1 é thyl amin ol -1,2.5-thiadiazole

The general procedure of Example 31 is repeated, but replacing the methylamine with an equimolar amount of benzylamine. The reaction mixture is evaporated under reduced pressure to obtain the product. By recrystallization from methanol and treatment with active carbon, 2.63 g of the desired compound is obtained having a melting point of 2Q3-205.5 ° (with decomposition).

Analysis for calculated C, 50.53; H, 5.58; U, 15.5l; S, 21.30% found C, 50.79; H, 5.34; H, 15.78; S, 20.9½% EXAMPLE 61 - 1.1- Dioxide of 3-r3- (3-dimethvlaminomethv3.nhenoyv) nr.QOV.lamino1-4-methylann no-1,2,5-thiadiazole

A solution of 3 “[3“ (dimethylaminomethyl) phenoxy] propylamine · *, (2.73 g, 14.0 millimoles) (prepared according to the method of Belgian patent n ° 867.106) in 50 is added dropwise over 60 minutes. ml of methanol to a stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.5 g, 14.0 millimoles) in $ 2 0 ml of methanol - 105 - that cooled to! f0 in an ice and water bath - After 20 minutes of stirring, milk is bubbled through anhydrous methylamine for 10 minutes in the solution. The reaction mixture is evaporated under reduced pressure and the residue is deposited on 75 g of helix gel which is chromatographed with gradient elution using methylene chloride and methanol. Combine and evaporate the appropriate fractions, then dissolve the solid in n-prqpanol and add 1 equivalent of hydrochloric acid to obtain the hydrochloride. By recrystallization from aqueous ethanol, the desired compound is obtained in the form of its hydrochloride having a melting point of 1U-0- ii * 5 °.

'Analysis for ^ H2lfClNS

calculated 0, Λ6.20; H,; 6.20; .K, .17.96; S, 8.22; Cl, 9.09%. found C, 1 * 6.21; H, 6.06; K, 18.2lf; S, 8.38; Cl, 9.05% (correction for 3.79% E ^ O) EXAMPLE 62 - 1,1-hydroxide of 3- | 2- | ~ (2-dimethylaminométhvlt, hlazol-5-vl) -methylthiol ethylamino JV-methylamino -l.2. 5-thiadiazole A. 5-Carbethoxv — 2— (W— carbophenoxy — N — TnethV) a-nH τιγΛ— methylthiaz ole

Ga mixture of (N-carbophenoxy-N-methylamino) thio- »acetamide 0 * 6.7 g, 0.21 mole) with Ι'α-formylchloroacetate ethyl (30.0 g, 0.20 mole) in 270 ml of 1,2-dichloroethane and the mixture is heated to reflux for * 2 hours. Additional ethyl α-formylchloroacetate (3.00 g, 0.02 mole) was added and heating was continued for 90 minutes. The reaction mixture is extracted twice with 300 ml of cold 5% aqueous sodium carbonate, then washed twice with 300 ml of water and dried over anhydrous sodium sulfate. By evaporation, the product is obtained in the form of a buile which crystallizes slowly. By recrystallization from 2-propanol, 26 g of the desired compound are obtained having a melting point of 81-83 °.

Analysis for calculated C, 56.21 *; s, 5.03; N, 8.7 ^; S, 10.01% found C, 56Λ8; H, 4 ·, 97; N, ß, 54-; S, 10.17% B. 2-Hvdroxymethyl-5-dimetbylami nométlivl tbiazole 5-carbethoxy-2- (N-carbophenoxy-N-methylamino) methylthiazole (19.8 g, 0.62 mole) is added [prepared with Stage A] to a stirred suspension of lithium aluminum hydride (6.12 g, 0.16 mole) in 544 ml of dry tetrahydrofuxan which is cooled to 5 °. The reaction mixture is heated at reflux for 30 minutes / then cooled to room temperature and decomposed, after which it is filtered through Celite and the filtrate is evaporated under reduced pressure. Qu dissolve the residue in 80 ml of 3N hydrochloric acid and extract the solution with ether. The aqueous phase is adjusted to pH 8 and extracted with methylene chloride. The organic phase is dried, filtered and evaporated under vacuum to obtain 6.0 g of the desired compound which is an oil. The nuclear magnetic resonance spectrum (60 MHz) in deuterochloroform includes the following S resonances: 7.50 (s, 1H); 1 *, 85 (s, 2H); 4.15 (s, 1H); 3.75 (s, 2H); 2.35 (s, · 6H).

C. Obi orh-vdrate de 2-chlorométhvl-5-diméthvlami-nométhvl thi az ol e

Qn is added dropwise thionyl chloride (27.1 * g, 0.16 mole) to a solution of 5-hydroxymethyl-2-dimethylaminomethylthiazole (8.9 g, 52.0 millimoles) [prepared in stage B] in 300 ml of methylene chloride which was cooled in an ice and water bath. The mixture is heated to reflux for 2 hours, then cooled and evaporated under reduced pressure to obtain 12.3 g of product. By crystallization from acetonitrile, the desired compound is obtained having a melting point of lltf-lVt0.

Analysis for CyH ^? Cl? KpS

calculated C, 37.01; H, 5.32; N, 12.33; Cl, .31.63% found C, 36.88; H, 5.11; N, 12.11 *; Cl, 31.65% (correction for 0.9l% H ^ O) D. 2-Γ (2-Dimethvlaminométhvltbi azol-5-νΊΛ-méthvlthio 1 ethylamine

Cysteamine hydrochloride (0.2 g, 1.76 mmol) and 5-chloromethyl-2-dimethylaminomethylthiazole hydrochloride (0, ¼ g, 1.76 mmol) [prepared in Stage C] are dissolved in 2.5 ml of concentrated hydrochloric acid and the solution is heated in an oil bath at 100 °. After 2 hours, the mixture is evaporated under reduced pressure and the residue is alealinized with an aqueous solution of sodium hydroxide at 1 * 0%. Or extract the aqueous phase with methyl acetate, then dry the organic phase, filter and evaporate to obtain 0.3 g of the desired compound which is an oil. The nuclear magnetic resonance spectrum (60 MHz) in deuterochloroform includes the following S resonances: 7.50 (s, 1H), 3.95 (s, 2H); 3.76 (s, 2H); 2.85 (m, 1 * H); 2, lfO (s, 6H), 1.85 (ε, 2H).

E. 1,1-3-Î2-T dioxide ('2-dimethylaminomethyl-tMazol-5-vl) methylthio1ethylamino) -l * -methylamino-1,2,5-5' thiadiazole

A solution of 2 - [(2-dimethyl aminomethylthiazol-5-yl) methyl-thio] ethylamine (1.55 g, 6.7 millimoles) (prepared in stage I)] is added dropwise over 1 * 0 minutes. 60 ml of methanol to a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1,19 g, 6,7 millimoles) in 130 ml of cooled methanol at 8 °. At the end of the addition, anhydrous methylamine is bubbled for 8 minutes into the solution which is then stirred at room temperature overnight. The reaction mixture is evaporated under reduced pressure and the residue is chromatographed on 150 g of silica gel with gradient elution using acetonitrile and methanol. Combine suitable fractions to obtain 1.05 g of product. By recrystallization from 2-propanol, the desired compound is obtained having a melting point of 170-172 °.

Analysis for calculated C, 38.28; H, 5.36; N, 22.33; B, 25.56% found C, 38.31; H, 5.32; H, 22.13; S, 25.96% EXAMPLE 63 - 1-Oxide of λ-f 2-Γ (’2-guanidinothiazol-4-vl) methvlthio1ethvl-aminol-V-methylam-iTio-1,2.5-thiadiazole

The general procedure of Example 20 is repeated, but replacing the 3-V-dimethoxy-1,2,5-thiadiazole 1,1-dioyde with an equimolar amount of the corresponding 1-oxide. Combine suitable column chromatography fractions to obtain 4.5 g of product. By crystallization from absolute ethanol, 3.05 S of the desired compound is obtained having a melting point of .175-177 ° · Analysis for ^ 0 ^ 16 ^ 8 ^ ¾ calculated C, 33.32; H, 4.47; N, 31.09; S, 26.68% found c, 33.10; H, 4.42; H, 31.00; S, 26.51% EXAMPLE 64 - l-Qxvde de 3-Ι2-ΓC2-Ruan-id-inotbiazol-4-vl ') méthvlthio1éthyl- aminol -4-hvdr oxv-1.2 "5-thi adiazol e

A solution of 2 - [(2-guanidinothiazol - l <· -yl) methylthio] ethylamine 0f, 15 g, 17.9 millimoles) in 50 ml of methanol is added dropwise over 30 minutes to a solution of 1-Ss ^ -dimethoxy-1 ^^ - thiadiazole oxide (2.9 g, 17.9 mmol) in 350 ml of methanol which is cooled in an "ice and water bath". reaction a solution of sodium hydroxide tablets (3.58 g, 89.5 millimoles) in methanol After stirring overnight at room temperature, the mixture is neutralized with 1 * 9 ml (89, 5 millimoles) of aqueous hydrochloric acid 6, ON and after 10 minutes, the mixture is evaporated under reduced pressure, the solid residue is triturated for 2 hours in 70 ml of water at room temperature, then filtered to isolate the product.

By recrystallization from water, the desired compound is obtained having a melting point of 1 ^ 8-151 °.

Analysis for CqH ^ Nr ^ S ^ calculated C, 31.11; H, 3.77; N, 28.22; S, 27.69? ” found C, 30.95; H, 3.76; N, 28.27; S, 28.11 # (correction for 5.52 # HgO) EXAMPLE 65 - 1-Order of 3-amino-V-t2-r (2-l2-methvlcruanidino) thia2ol - ^ - vl ') méthvlthioléthvlaminot-1.2, 5 -thiadiazole A. 2 - {. r2- (2-Métbvl p-nanidino) thiazol- * l · -vllméthvl-thio} ethyl amine

Cysteamine hydrochloride (1.89 g, 16.6 millimoles) and 2- (2-methylguanidi-no) -J + -chloromethylthiazole Of hydrochloride, 0 g, 16.6 millimoles) are mixed (prepared from (N-methylamidino) thiouxée and 1,3-dichloro-2-propanone] in 20 ml of concentrated hydrochloric acid and the solution is heated in an oil bath at 100 °. After 2 hours, the mixture is evaporated under reduced pressure and the residue is made alkaline with an aqueous solution of sodium hydroxide. The aqueous phase is extracted several times with methyl acetate, then the organic phase is dried, it is filtered and evaporated to obtain 3.35 g of the desired compound5, the nuclear magnetic resonance spectrum (60 MHz) in deuterium oxide comprises the following characteristic resonances S: 6.52 (s, 1H), 3.60 (ε, 2H), 2.70 (m, 7H).

B. 1-Qxvde de 3-amino-lf- {2-Γ (2- ^ 2-methVl tmnni-fl-îno ^ fhT bzoI — V-yl) methylthiolethylamino} -l, 2,5-thiadiazole

A solution of 2 - [(2-j2-methylguanidinojthiazol-1 *: - yl) methyl-thio] ethylamine (2.1 g, 8.56 millimoles) [prepared in Stage A] is added dropwise over 30 minutes. 50 ml of methanol to a solution of 3, ½-dimethoxy-1,2,5-thiadiazole oxide (1.39 g, 8.56 millimoles) in 170 ml of methanol which has been cooled to 7 ° - Anhydrous ammonia is bubbled through the solution for 7 minutes and then stirred at room temperature overnight. The reaction mixture is evaporated under reduced pressure and using 100 g of silica gel (0.062-0.037 mir) the residue is subjected to flash chromatography with gradient elution using acetonitrile and methanol.

The appropriate fractions are combined and evaporated, then the residue is subjected to preparative liquid chromatography under high pressure on silica gel called yU-porasil. The appropriate fractions are combined, concentrated to a small volume and the solution is filtered to collect the desired compound having a melting point of 86-91 ° and whose nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethylsulfoxide reveals the presence of about 0.8 moles of ethanol.

- 111 -

Lice analysis C ^^ H ^ gNgOS ^ .O ^ CpHgO

calculated C, 35.06; H, 5.28; N, 28.20; S, 2> t, 21% t found C, 35.66; H, 5.05; K, 28.33; S, 23.96% * · (lice coxxection 1.6 ^ ·% HpO) EXAMPLE 66 - l-O-rede de ^ -amino-l ^ rW ^ -aiméthTlaminométhvil-phenoyiO'PJO- • PTlaminol-1.2.5-thiadiazole

A solution of 3- [3- (dimethylaminomethyl) phenoxy] pxopylamine (2.5 g, 12.9 millimoles) in 35 ml of methanol is added dropwise over 3 minutes to a stirred solution of 1-oxide of 3, lt-dimethoxy-l, 2,5-thiadiazole fl an π 200 ml of methanol which is heated to 2 ° in an ice and water bath. After 15 minutes of stirring, anhydrous ammonia is baxbotex in the solution for 5 minutes.

We evaporate the reaction mixture under the reduced xed liceession to obtain a cistalline pxoduct. Pax two xecxistalli-sations in the hanoi met, we obtain the compound xechexché having a fusicn point of 165.5-166.5 ° (with decomposition).

Lice analysis calculated C, 51.99; H, 6.55; H, 21.66; S, 9.92% found C, 51.58; H, 6, 1f9; H, 22.03; fi, 10.19% EXAMPLE 67 - 1-Qgvde of l-amino-tf-f 2-Γ (2-methvlaminothiazol-If-vl ') néthvl-tMo1éthvlamino} -1.2. 5-thiadiaz-ole. A. 2 — Γ (2 — Methylaminothiazol-1-yl) methylthiolethvl— amine

Oh dissolves cysteamine chloxhydxate (2.8 g, 2 ^, 6 millimoles) and 2-methylamino-lf-chloxomethylthiazole (4.0 g, 2 ^, 6 millimoles) [pxaxed to paxtix of N-methylthio-uxed and 1,3-dichloxo-2-pxopane] in 20 ml of concentxated chloxhydxic acid and heating the solution in an oil bath to 100 °. After 30 hours of heating, the reaction mixture is evaporated under reduced pressure and the residue is alkalinized with a 4-0% aqueous sodium hydroxide solution. The aqueous phase is extracted with methyl acetate, dried, filtered and evaporated to give 1.75 g of the desired compound which is an oil which is used without further purification in stage B.

B. 3-Oxide of l-amino-4 - i 2-Γ (2-methvlaminothia-zol-y-vl ^ méthvitftn o1étfrviamino) -1.2. 5-thiadiazole_

The product of stage A above is reacted successively with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide and anhydrous ammonia according to the general procedure of Example 17, stage B , after which the chromatography is also carried out as indicated at this point. The appropriate fractions from flash chromatography are mixed and evaporated to give 0.5 B of product in the form of a foam. By crystallization from acetone, the desired compound is obtained having a melting point of 180-183 ° (with decomposition).

Analysis for C ^ H ^ U ^ OS ^ calculated C, 33.9½; H, 4.43; N, 26.39; S, 30.21% found C, 33.96; B, 4.11; N, 26.27; S, 30.44 ·% (correction for 1.4-1% H ^ O) EXAMPLE 68 - 1-Qxvde de 3-amino-4—} 2 ~ Γ (2- [2,3-dimethylguanidino) thiazol- 4 -vl) méthvlthiol éthvlamino} - !. 2 5-thiadiasole A. 2-Γ hydrochloride (2- [2,3-dimethvl: uani-dino3 thiazol-4-yl) methylthi ol éthvlaaine

Cysteamine hydrochloride (2.25 g, 19.6 millimoles) and 4-chloromethyl-2- (2,3-dimethylguani-dino) thiazole (5 g, 19.6 millimoles) (prepared from 1) are dissolved. , 3-dichloro-2-propanone and (N, N'-dimethy 1 amidino) thiourea, itself prepared from cyanodithioiminocar-dimethyl-methylamine] in 17.5 ml of concentrated hydrochloric acid and the solution is heated in an oil bath to 100 °. After 2k hours, the reaction mixture is evaporated under reduced pressure and the residue is crystallized from absolute ethanol to obtain the desired compound having a melting point of 2 ^ 3-2 ^ -5 °.

B. l-Oxvde de 3-amino-V- {2-r (2-l2.3-diméthvlgu-ani dino} thiazol - ^ - vl) méthvlthioléthvlamino} - !, 2.5-thiadia-zole

The product of stage A above is reacted successively with 3, W-dimethoxy-1,2,5-thia-diazole 1-oxide and anhydrous ammonia according to the general procedure of Example 117, stage B. The crude reaction mixture is evaporated under reduced pressure and the residue is crystallized from methanol to obtain the desired compound having a melting point of 201-203 ° (with decomposition).

Analysis for C- ^ H ^ NgOS ^ calculated C, 35.28; H, k, Sk ‘, N, 29.92; S, 25.69% found C, 3k, 93i H, k, 56; N, 30.2 ?; S, 25.92% (correction for 0.88% 11.0) EXAMPLE 69 - 1-Qx ~ yde of 3.H-bis-f2-rr2-guanidinothiazol-l} —vl) méthv1 thîo] -éthvlamino} - 1,2,5-thiadiazole

2 - [(2-guanidino-thiazol-V-y1) methy1thio] ethylamine hydrochloride (6.09 g, 20.0 millimoles) is added to a sodium methylate solution (2.16 g, M3.0 millimoles) ) in 100 ml of methanol which has been cooled to 0 ° in an ice and water bath and, after 20 minutes of stirring, 1-oxide of 3, dimethoxy-1,2,5-thiadiazole ( 1.62 g, 10 millimoles) in solution. The reaction mixture is stirred at room temperature for 65 hours, and then evaporated under reduced pressure. Using 100 g of silica gel (62-37 / u), the residue is subjected to flash chromatography with gradient elution using acetonitrile and methanol. When the appropriate fractions are combined, they are evaporated and the residue is subjected to preparative chromatography under high pressure using silica gel called yu-porasil. Combine the appropriate fractions and evaporate under reduced pressure to obtain the desired compound which is an amorphous solid whose nuclear magnetic resonance spectrum (100 MHz) in dimethyl tallow hexadeuterated oxide reveals the presence of about 0.11 mol of ethanol.

Analysis for cp 6 ^ 24 ^ 12 ^ 5 '0.11 C2H ^ 0 calculated C, 34.42; H, 4.39; B, 29.71; S, 28.33% found C, 34.9 ?; H, 4.41; N, 29.04; S, 27.71% (correction for 1.86% HgO) EXAMPLE 70 - 1 .1 -Di oxide of 3-f 2-Γ (2-aminothiazol-4-vl) methvlthiolethvl-amino) -4-methylamino-1 , 2,5-thiadiazole A. P- [f2-aminot> n agol-h-vl) -Tnethvlthiol ethichlorhvdrate

Cysteamine hydrochloride (5.65 g, 50.0 millimoles) and 2-amino-4-chloro-methylthiazole hydrochloride (9.25 g, 50.0 millimoles) are dissolved in 70 ml of concentrated hydrochloric acid and the solution is heated in an oil bath at 105 ° - After 64 hours of heating, the mixture is evaporated under reduced pressure and the residue is triturated in acetone. The product is collected and triturated in 1 'ethanol, then the solid is collected by filtration and dried to obtain the desired compound having a melting point of 170-200 °.

- 115 -

Analysis for C ^ H- ^ C ^ N ^ Sg calculated C, 27Λ8; H, h, 90'a N, 16.02; S, 21 * Λ6; Cl, 27.0¼% found C, 27.29; E, 5.07; H, 15.91; S, 21 *, 15; Cl, 27.2¼% B. 1.1-Dioxide of 3-12-Γ tëraminothiazol-V-yl'ïmé-fhvlthiol éthvlami'no't ^ -méthylamino-l, 2.5-thiadiazole

Qn is added dropwise in 90 minutes a solution of 2 - [(2-aminothiazol- ^ yl) methylthio] ethylamine (obtained from the dihydrochloride, 3.0 g, 11.1 * millimoles) [prepared in stage A ] in 25 ml of methanol to a stirred partial suspension of 1,1-dioxide of 3, ** “dimethoxy-1,2,5-thiadiazole (2.03 g, 11.1 * millimoles) in 55 ml of methanol qu 'we cooled to 5 °. After 90 minutes, anhydrous methylamine is bubbled for 3 ° minutes into the solution which is then stirred at 5 ° for 19 hours. The reaction mixture is evaporated under reduced pressure and the residue is deposited on ϊ * 00 g of silica gel for chromatography with a mixture (7: 3) of acetone and methylene chloride. Combine the appropriate fractions and evaporate them to obtain the product.

By recrystallization from 9550 ethanol, the desired compound is collected having a melting point of 200-201 °. Analysis for calculated C, 32.32; H, **, 32; N, 25.13; S, 28.76% found C, 32.25; H, 20; E, 25.06; S, 29.1¼% EXAMPLE 71 - 1-Qyvde of 3-amino-1 * -t2-.J '.. f.2-âiméthvlaminométhvlthiazol-5-yl) methylthio * [ethvlaminol -1.2.5-thiadiazole

A solution of 2 - [(2-dimethyl aminomethylthiaz ol-5-yl) methyl thi o] ethyl amine (2.05 g, 8.86 millimoles) is added dropwise [prepared in Example 62, stage L] in 70 ml of methanol to a stirred solution of 3.1 * dimethoxy-1,2,5-thiadiazole 1-oxide (1, ¼¼ g, 8.88 millimoles) in 170 ml of methanol which has been cooled at 8 °. Anhydrous ammonia is bubbled for 8 minutes into the solution which is then stirred at room temperature for 30 minutes. The reaction mixture is evaporated under reduced pressure and the residue is triturated in acetonitrile to give 1.76 g of product. This is purified by flash chromatography on 100 g of silica gel (62-37 yu) using acetonitrile and methanol.

Combine suitable fractions, evaporate and crystallize the residue in acetone to obtain the desired compound having a melting point of 131-133 ° ·

Analysis for CllE17N6OS3 calculated C, 38.13; H, 5.2k-, H, 24 ·, 26; S, 27.76% found C, 37.86; H, 5.06; N, 24 ·, 34-; S, £ 27.6 (correction for 0.4-9% I ^ O) ΕΣΕΚΡΙϊΕ 72 - 1 — Qyydp HP ^ -Bm-ÎTio — 4— [? - [aminothi azo ~ l —4 ~ v1 Wéthvlthiol- éthvlamlno } —I.2.5-thiadiazole

A solution of 2 - [(2-aminothiazol-4-yl) methylthio] ethylamine (obtained from the dihydrochloride, 2.62 g, 10.0 millimoles) is added dropwise over 3 ° minutes. Example 70, Stage A] in 20 ml of methanol in a solution cooled to 5 ° of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.62 g, 10.0 millimoles) in 50 ml of methanol. After 90 minutes of stirring, anhydrous ammonia is bubbled for 3 minutes into the solution which is then stored for 17 hours at 5 °.

The reaction mixture is evaporated under reduced pressure and the residue is subjected to preparative liquid chromatography under high pressure using silica gel called u-porasil. Combine the appropriate fractions and evaporate them under reduced pressure to obtain the desired compound which is an amoiphic solid whose nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethylsulfoxide reveals the presence of about 0.1½ mole d ethanol.

Lice analysis Cgïï ^ Iv. 0, ½ C ^ H ^ O

calculated C, 32.7½; H, ^ 50; M, 26, Q3; S, 29.8CT / found C, 32.39; E, ½, 28; N, 28.39; S, 30.02% (correction for 1.39% HgO) ΈΧΚΚΡΙΈ 73 - 1.1 — Eioxvde de Vméthvlamino ^ -te-r C2-f2.3-dimethylguani-ri ^ nofthi azol ^ -vl'iméthvltMoléthvlamino) -1.2.5 -thiadiazole A solution of 2 - [(2-f2,3-dimethylguanidinojthiazol— ^ yl) methyl-thiojethylamine (2.5 g, 9.6½ millimoles) is added dropwise over M3 minutes [prepared in Example 68, stage A] in methanol to a stirred suspension of 1,1-dioxide, 3, ^ dimethoxy-1,2,5-thiadiazole (1.72 g, 9.6½ millimoles) in 270 ml of methanol which has been cooled at 8 °. Qn bubbled anhydrous methylamine for 7 minuces in the solution which was then evaporated under reduced pressure. The residue is subjected to flash chromatography on 100 g of silica gel (62-37 ÿa) and the appropriate fractions are combined and evaporated to collect 2.5 g of the product which is a foam. By crystallization from aqueous ethanol, the desired compound is obtained having a melting point of 132-137 °.

- Analysis for cp2H20N8C2S3 calculated C, 35.63; H, ^ 98; ii, 27.70; S, 23.70% found C, 35.7%; H, 5, CS *; N, 27.87; S, 23.56% (correction for ^ 78% H2O) EXAMPLE 7½ - 1-Oxide of 2-f f2-âiTnéfhx1 arrï-nothiazol ^ -vl) methylthio1-ethylani-î nol -h-arn-i tio-1, 2.5-thiadiazole A. g - [(2-Mmethylaminothiazol-4 - Tl) methylthio'l- ethvlamine

Cysteamine hydrochloride (5.2b g - 45.9 millimoles) and 2-dimethylamino-4-chloromethylthiazole hydrochloride (9.8 g, 45.9 millimoles) (prepared from N, N-dimethylthiourea) are dissolved and 1.3 ~ dichloro-2-propanone] in 45 ml of concentrated hydrochloric acid and the solution is heated in an oil bath at 100 ° for 96 hours. The mixture is evaporated under reduced pressure and the residue is alkalinized with 40% aqueous sodium hydroxide. The aqueous phase is extracted with methyl acetate, • the extract is dried and evaporated to obtain the desired compound which is an oil which is used without further purification in stage B. The nuclear magnetic resonance spectrum ( 60 MHz) in deuterium oxide includes the following on resonances: 6.97 (s, 1H); 3.94 (s, 2H); 3.67 (s, 3H); 3.15 (s, 3H); 3.05 (m, 4H).

B. 1-Qxvde of 3-12-Γ f2-dimethvlaminothiazol-4-vl) -methvlthiol ethvlamino) -4-aEino-l. 2.5-thiadiazole

A solution of 2- [(2-dimethylaminothiazol-4-yl) methylthio] -ethylamine (3.5 g, 16.1 millimoles) (prepared in stage A) in 70 ml of methanol is added dropwise over 30 minutes. stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.61 g, 16.1 millimoles) in 200 ml of methanol which was cooled to 7 °. Anhydrous ammonia is bubbled for 8 minutes into the solution which is then stirred for 30 minutes before evaporating the mixture under reduced pressure. The residue is triturated in isopropanol, "then it is dissolved in methanol, the solution is filtered and the filtrate is evaporated to obtain the product. The latter is purified by flash chromatography on 100 g of silica gel (of 62-37 dO "using methylene chloride and methanol. Combine the suitable inactions and submit them to high pressure liquid chromatography on a column of silica gel called yu-porasil. Combine the appropriate fractions and evaporates them under reduced pressure to obtain the desired compound having a melting point of 116-122 ° and whose nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethylsulfoxide reveals the presence of approximately 1/3 mole of ethanol.

Analysis for C ^ gH-j ^ NgOS ^. 1/3 CgH ^ O

calculated C, 36.83; H, 5.22; H, 21f, 16% found C, 36.61; H, 06; H, 2 * f, 22% (correction for 11.92% HgO) EXAMPLE 75 -] .1-Lioxvde de 3-f 2-Γ (2-dimethvlaminothiazol - ^ - vl) methyl-thiolethvlamino) -lf-methyl ami no-1.2,5-thiadiazole

A solution of 2- [(2-dimethylaminothiazol-li-yl) methylthio] ethyl & nine (2.5 g, 11.5 millimoles) [prepared in Example 7 ^, stage A] is added dropwise over 30 minutes. stirred suspension of 1,1-dioxide 3, dimethoxy-1,2,5-thiadiazole (2.05 g, 11.5 millimoles) in 200 ml of methanol which has been cooled to 7 ° - bubbled with anhydrous methylamine for 7 minutes in the solution which is then stirred for 30 minutes, after which the mixture is evaporated under reduced pressure. The residue is crystallized from methanol to obtain 1.6 g of product. By two recrystallizations from 2-methoxyetha-nol, the desired compound is obtained having a melting point of 227-229 °.

EXAMPLE 76 - 1,1-Dioxide of 3-Î2-T (2- {2-imidazolidinvil iminothiazol-V-yl) methyl thi ο 1 ethyl amino) -V-methvl amino-1.2. 5-thi ad i a z ol e A. 2-Γ (2-Î2-Imidazolidinylîiminothiazol-l * -yl) -methylthiol ethylamine

Cysteamine hydrochloride (2.22 g,

V

19.5 millimoles) and 2 - [(2-imidazolidi-nyl) imino] -l + -chlorométhylthiâzole hydrochloride (^, 9½ g, l9.5l millimoles) [prepared from 1,3-dichloro-2-propanone and K- (2-imidazolidin-2-yl) thiourea itself prepared from 2- (cyanimino) imidazolidine] in 20 ml of concentrated hydrochloric acid and the solution is heated in the "oil bath at 100 ° for 5 hours and 30 minutes, the reaction mixture is evaporated under reduced pressure and the residue is basified with sodium hydroxide at bo} L The aqueous phase is extracted with methyl acetate, the extract is dried and it is evaporated to obtain 2.02 g of the desired compound which is used without further purification in the following stage.

B. l.l-3-ί2-Γ dioxide (2-C2-ImidazolidinvlHmir nothi azol- ^ · -yl) methylthio1éthvlamino} -if-méthvlanxno ~ l .2.5-_ thi arii'az oüe

A solution of 2 - [(2- {2-imidazolidinyl} iminothiazol-1 * -yl) methyl-thio] ethylamine (2.02 g, 7.85 mmol) (prepared in Stage A) is added dropwise in VO minutes. ] in 85 ml of methanol to a stirred suspension of 1,1-dioxide of 3, ^ - dïméthoxy-l, 2,5-thiadiazole (1, ½ g, 7.85 millimoles) in 190 ml of methanol which one has cooled to 8 °. Anhydrous methylamine is bubbled through the solution for 7 minutes and after 30 minutes at room temperature, the mixture is evaporated under reduced pressure to obtain 3.5 g of product. This is subjected to preparative liquid chromatography under high pressure on silica gel called ^ u-porasil. The suitable fractions are combined, evaporated and the residue is crystallized from methanol to obtain the desired compound having a melting point of 229-231 °. By recrystallization from aqueous ethanol, the desired compound is obtained having a melting point of 136-11 + 0 ° with resolidifi-cation and new fusion at 21-19-22i + ° C.

Analysis for C12H18IÎ8 ° 2S3 calculated C, 35.81; E, l +, 5l; N, 27.81+; S, 23.90¾ found C, 35.51; H, 1 + Λ3; N, 27.98; S, 23.56% (correction for 1 +, 59% H ^ O) • ettctîpiæ 77 - 1.1- 3-ί2-Γ C5-dimethylaininomethyl-2-thienyl) -methylthiol ethylaminoj -1 + -Γ (2- pyridyl) methylamino1-1..2,5-thiadiazole

The general procedure of Example 3¾ is repeated, but replacing the methylamine with an equimolar amount of 2-aminomethylpyridine. By subjecting the crude solid to column chromatography, 3.08 g of product is obtained. By recrystallization from isopropanol, the desired compound is obtained having a melting point of 162-161 + ° (with decomposition).

Analysis for calculated C, 1 * 7.76; H, 5.31 *; N, 18.57% found C, 1 + 7.80; E, 5.32; N, 18.75% ΕΣΕΜΡΕΕ 78 - 1.1- 3-f2-Γ (5-dimethylaminomethyl-2-thienyl) m-thvlthi ο 1 ethyl amino] -1 + - Γ (l + -pyridvl ') methvlamino1-l. 2.5-this-diazole

The general procedure of Example 31 is repeated, but replacing the methylamine with an equimolar amount of 1 + -aminomethylpyridine. After chromatography, the crude product is dissolved in hot isopropanol, the insolubles are decanted and anhydrous hydrogen chloride is added to the solution to obtain the desired product in the form of its hydrochloride. This salt is dissolved in water and the solution is made alkaline with a saturated aqueous solution of sodium bicarbonate to collect, after filtration, the desired compound in the form of its free base, having - a melting point of 88-90 ° . Analysis for C ^ gH ^ li ^ OgBß calculated C, 1 * 7.76; H, 5.31 *; K, 18.57 # found C, 1 * 7.5W; H, 5.32; K, 19.09% (correction for 3.73% I ^ O) EXAMPLE 79 - 1.1-Dioxide of 3-Î2-r (5-dimethylaminométhvl-2-thienvl) -: méthvlthioléthvlaminol -lf-éthvlamino-1.2.5- thiadiazole

The general procedure of Example 31 is repeated; but by replacing the methylamine by an equimolar amount of ethylamine. Qn dissolves the appropriate fractions from column chromatography in 1 ’hot isopropanol and saturates the anhydrous hydrogen chloride solution. The crystalline solid is collected by filtration, which is washed with acetone and dried to collect 2.9 g of the desired compound in the form of its hydrochloride having a melting point of 2 ^ 6-21 * 7® ( with decomposition).

Analysis for C- ^ H ^ CIN ^ O ^ S ^ calculated C, 39, ** 7; H, 5.68; If, 16, ¥ *; Cl, 8.32% found C, 39.81; H, 5.7 **; K, 16.62-, Cl, 8.20% EXAMPLE 80 - 1.1 -meth-ylamino dioxide-U-r3-f ^ -p ~ ipé.rÎdinc> ERthTll1heT jioxy) nropylaminol-l "2" 5- thiadiazole

A solution of 3- (3-piperidinomethylphenoxy) propylamine (2.35 g, 9.1 * 5 millimoles) [prepared as in published British patent application No. 2,023,133] in 30 ml is added dropwise over kO minutes. of methanol> to a stirred partial suspension of 1,1-dioxide of 3 ”^ ~ dimethoxy-1,2,5-thiadiazole (1.68 g, 9.1 * 5 millimoles) which was cooled to 1 ° with water and ice bath - After 15 minutes, anhydrous methylamine is bubbled through the solution for 5 minutes, which is then stirred at room temperature for 30 minutes. The reaction mixture is evaporated under reduced pressure and the residue is subjected to flash chromatography on 100 g of silica gel (62-37 / u) using methanol and acetonitrile. Combine suitable fractions and evaporate to obtain 2.2 g of product. By recrystallization from acetonitrile and treatment with active carbon, the desired compound is obtained having a melting point of 182-10 °.

Analysis for calculated C, 5 **, 91 *; H, 6.92; JJ, 17.80; B, 8, 15%

found C, 5W, 90; H, 7.07; E, 18.11 *; S, 8.29% EXAMPLE 81 -Part I

lsOryde de ^ ~ amino-l * -r ^ -f ^ - 'ni-Deridinoroéthvl, Dhénoyv) urop ~ vlaDi-.nol-1,2,5-thiadiazole

A solution of 3 ~ (3 ~ piperidinomethylphenoxy) propylamine (obtained from the dihydrochloride-, 1 *, 0 g, 12.1 * millimoles) in 1 * 0 ml of methanol is added dropwise over 50 minutes. solution of 3, ¼-dimethoxy-1,2,5-thiadiazole 1-oxide (2.01 g, 12.1 * millimoles) in 200 ml of methanol which was cooled to 0 ° in a water bath and of ice. After 15 minutes, anhydrous ammonia is bubbled through the solution for 5 minutes, which is then stirred at room temperature for 17 hours.

Or the reaction mixture is evaporated under reduced pressure and the residue is subjected to flash chromatography on 100 g of silica gel (62-37y-u) using methanol and acetonitrile. The appropriate fractions are combined and evaporated to obtain U, 18 g of product. By recrystallization from aqueous ethanol at 955 ", the desired compound is obtained having a melting point of 155 ~ 155 ° (with decomposition).

Analysis for calculated C, 56.17; H, 6.93; N, 19.27; S, 8.82% found c, 55.97; H, 7.0 *; N, 19.57; S, 8.63%

Part II

1-3-Amino-4- [3- (3-piperidinomethylphenoxy) propyl-amino] -1,2,5-thiadiazole oxide

A mixture of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (9.16 g, 62.25 mmol) and 3- (3 is stirred at room temperature for 2.5 days. -piperidinomethylphenoxy) propylamine (15.46 g, 62.25 millimoles), [prepared from dihydrochloride J in 500 ml of methanol. The solvent is evaporated off under reduced pressure and the solid residue is recrystallized from methanol to obtain 13.12 g (58%) of the desired compound in the form of a crystalline powder, PF 157-159.5 ”(decomposition) . This product is identical to the compound prepared in Example 81.

ΕΣΕΚΡΙϊΕ 82 - 1.1-Dioxide of 3-amino-tf- [3- (3- · ρΐ · ρéridinométirvlnénoxy ') - • pjopylamino] - !, 2,5-thiadiazole

A solution of 3- (3-piperidinomethylphenoxy) propylamine (obtained from the dihydrochloride, O g, 12, h mil-> »limoles) in 35 ml of methanol is added dropwise over 65 minutes to a stirred partial suspension. of 3, 4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.22 g, 12.4 mmol) in 200 ml of methanol which was cooled to 2 ° in a water and ice. After 15 minutes, anhydrous ammonia is bubbled for 5 minutes into the solution which is then stirred at room temperature for 30 minutes. The reaction mixture is evaporated under reduced pressure and the residue is subjected to flash chromatography on 100 g of silica gel (62-37 ^ u) using methanol and acetonitrile.

Qn combines the appropriate fractions and they are evaporated to obtain 3.2 g of product whose nuclear magnetic resonance spectrum (100 MHz) in hexadeuterated dimethylsulfoxide comprises the following resonances 6: 7.2 (m, 1H); 6.9 (m, 3H); V, 1 (t, 2H); 3.5 (t, 2H); 3.1 * (s, 2H); 2.3 (m, VH); 2.0 (m, 2H); 1.1 * (large s, 6H).

EXAMPLE 83 - T. ~ I-Dioxide of 3 ~ Î2-f (5-dimethylaminométhvl-2-thienvl) mé-tb-ylthi ο 1 éthvl amino3 -U · - (3. V-méthvl enèn oxvbenzvl amino) - 1.2, 5-thiadiazole

A solution of 2- [(5-dimethylaminomethyl ~ 2-thienyl) -methylthio] -ethylamine (2.02 g, 8.8 millimoles) in 30 ml of methanol is added dropwise in VO minutes to a stirred solution of 1 , 3-V-dimethoxy-1,2,5-thiadiazole, 1-dioxide (1.56'g, 8.8 millimoles) in 200 ml of methanol which was cooled to 0 ° in a water bath and of ice. After 20 minutes, piperonylamine (1.1 * 6 g, 9.6 millimoles) is added and the mixture is stirred at room temperature for 3 hours. The reaction mixture is evaporated to almost dryness, ether is added to the residue and the whole is filtered to collect 3.8 to 7 g of product. By recrystallization from methanol, the desired compound is obtained having a melting point of 180-182 °.

Analysis for C20H25N5 <\ S3 calculated C, 1 * 8.1 * 6; H, 5.08; N, IV, 13% found C, V8.92; H, V, 88; N, IV, 52% (correction for 0.38% H2O) - 126 - EXAMPLE fflt - 1 -0> -vrip de ^ -amino-> f-Î2-rf6-diméth'vlaiginoinéth'vl-2-, DVjid- ylV n-ethylthiolethylaminol-1., 2,5-thiadiasole A. 6-fR.N-DiraétbvlcarbamvlV2-c £ rbométhoxvpyridine A solution of 6-carbomethoxy-2- acid is heated for 3 hours at 100 ° with oil. picolinique (22.8 g, 0.13 mol) in 80 ml of thionyl chloride- The solution is evaporated under reduced pressure and the xesidue is dissolved in 200 ml of dioxane / then oh the solution is added dropwise to a solution of dimethylamine (70 g) in dioxane. The reaction mixture is stirred for 2 hours, then allowed to xeposex overnight, filtered and evaporated under reduced pressure. The residue is dissolved in toluene, the solution is diluted with methyl-cyclohexane and filtered to collect 20.7 g of the desired compound having a melting point of 90-92 °.

Analysis for ^ 10 ^ .2¾¾ calculated C, 57.68; H, 5.81; H, 13, MS% found C, 57.61 *; H, 5.85; U, 13.77 # B. 6-Bim ethvl aminométhvl-2-hvdr oxvutéthylnvr idine Add a solution of 6- (R, K-dimethyl 1 carbamy]) - 2-carbométhoxypyridine (20,3 g, 97, 5 millimoles) [prepared in stage A] in 200 ml of tetrahydrofuran to a suspension of lithium aluminum hydride (9.6 g, 0.25 mole) in 500 ml of tetrahydrofuran. The mixture is stirred and heated under reflux in a nitrogen atmosphere for 3 hours, then left to stand at room temperature overnight. The mixture is decomposed with a saturated aqueous solution of sodium sulfate and filtered, then the filtrate is dried and evaporated under reduced pressure. The residue is deposited on 275 g of alumina which is chromatographed with methylene chloride. Combine the appropriate fractions and evaporate to collect 5.2 g of the desired compound, the nuclear magnetic resonance spectrum (60 MHz) in deuterochloroform includes the following resonances: 7.38 (m, 3H); b, 75 (s, 2H); 3.58 (s, 2H); 2.27 (ε, 6H).

'' C. 2-Γ (6-Dimethvlarainomethvl-2-nvridvl) meth, vl- thi ο 1 ethyl am ine

Cysteamine hydrochloride (3.58 g, 31.5 millimoles) and 6-dimethylaminomethyl-2-hydroxy-methylpyridine - (5.0 g, 30.1 millimoles) (prepared in stage B) are dissolved in 50 ml hydrobromic acid at k-8 / ί and the solution is heated to reflux for 12 hours, after which it is left to stand at room temperature for 8 hours.

The reaction mixture is evaporated under reduced pressure to half a volume, it is made basic with aqueous sodium hydroxide to bO / i and it is extracted several times with methylene chloride. The organic extracts are combined and washed with a little water and saturated brine, then they are dried and evaporated under reduced pressure to obtain 3, IV S of the desired compound whose nuclear magnetic resonance spectrum ( 60 MHz) in deuterochloroform includes the following on resonances: 7.5 (m, 3H); 3.83 (s, 2H); 3.56 (s, 2H); 2.7 (m, VH); 2.28 (s, 6Ξ).

D. 3-amino-4- {2 - Oxide {2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino3-1,2,5-thiadiazole

A mixture of 3-amino-4-methoxy-l, 2,5-thiadiazole 1-oxide (1.77 g, o, 012 mole) and 2 - [( 6-dimethylaminomethyl-2- "pyridyl) methylthio] ethylamine (2.71 g, 0.012 mole), [prepared in stage C] in 60 fol of methanol, then the solvent is removed under reduced pressure. The crude oil is purified to twice by rapid chromatography on 70 g of silica gel (Nos. 230 to 400, 63 to 38 μm) while maintaining an elution gradient of methylene chloride-methanol containing 0.5% NH 4 OH. combine the appropriate fractions and evaporate to collect 1.285 g (31.5%) of the desired compound in the form of a brittle foam.

Analysis for (^ 3 ^ 20 ^ 6 ^ 2: calculated C, 45.86; H, 5.92; N, 24.69; S, 18.83% found C, 46.58; H, 6.23; N, 24.00; S, 18.28% (correction for 0.84% H2O): EXAMPLE 85 - 1,1-Dioxide of 3- {2 - [(5-hydroxymethyl-1H-imidazol-4-yl) methylthio] ethylamino) -4-methylamino-1,2,5-thiadiazole

2 - [(5-hydroxymethyl-1H-imi-dazol-4-yl) methylthio] ethylamine [prepared according to the method described in Belgian Patent No. 843,840] is reacted with 1,1-di-oxide 3,4-dimethoxy-1,2,5-thiadiazole and reacting the 3- {2 - [(5-hydroxymethyl-1H-imidazol-4-yl) -methylthio] ethylaminoJ-4- 1,1-dioxide methoxy-1,2,5-thiadiazole with an excess of methylamine according to the general method of Example 2 to obtain the desired compound.

EXAMPLE 86

The general procedure for 11ex-pie 85 is repeated, but replacing the 2 - [(5-hydroxy-methyl-1H-imidazol-4-yl) methylthio] ethylamine with an equimolar amount of 2 - [( 5-bromo-1H-imidazol-4-yl) methylthio] ethylamine, 2- [imidazoI-r.4-ylmethylthio] ethylamine, 2- [imidazol-2-ylmethylthio] ethylamine, 2 - [(l-methyl -imidazol-2-yl) methylthio] ethylamine, from 2 - [(2-methyl-1H-imidazol-4-yl) methylthio] ethylamine, from 2 - [(l-methyl-imidazol-4-yl) methylthio] ethylamine , from 2 - [(1,5-dimethyl-imidazol-4-yl) methylthio] ethylamine, from 2 - [(5-chloro-1-methyl-imidazol-4-yl) methylthio] ethylamine, from 2- [( 5-trifluoromethyl-1H-imidazol-4-yl) methylthio] ethylamine, from 2 - [(5-ethyl-1H-imidazol-4-yl) methylthio] ethylamine and from 2- [(2-amino-1H -imidazol-4-yl) methylthio] ethylamine, respectively (each prepared according to the general methods described in Belgian patent no 779,775) to obtain the 1,1-dioxide of 3- [2- [(5 ~ bromo-1H-imidazol- 4-yl) methylethyl] -ethylaminoj -4-methylamino-1 , 2,5-thiadiazole, 1,1-dioxide of 3- [2 - [imidazol-4-ylmethylthio] ethylaminoj · - 4-methylamino-l, 2,5-thiadiazole, 1,1-dioxide of 3- [2- [imidazol-2-ylmethylthio] ethylaminoj-4-methylamino-1,2,5-thiadiazole, 1,1-dioxide 3— £ 2— [(l-methyl-imidazol-2-yl) methylthio] -ethylaminoj-4-methylamino-1,2,5-thiadiazole, 1,1-dioxide of 3- {2- [(2-methyl-1H-imidazol-4-yl) methyl-thio] ethylamino} -4- methylamino-1,2,5-thiadiazole, 3- {2 - 1,1-dioxide - [(l-methyl-imidazol-4-yl) methylthio] -ethylaminoj -4-methylamino-1,2,5-thiadiazole , 3- {2 - 1,1-dioxide [[(1,5-dimethyl-imidazol-4-yl) methylthio] -ethylamino] -4-methylamino-1,2,5-thiadiazole, 1,1- 3- [2 - [(5-chloro-1-methyl-imidazol-4-yl) methyl-thio] ethylaminoj-4-methylamino-1,2,5-thiadiazole dioxide, 3,1-dioxide ^ 2 - [(5-trifluoromethyl-1H-imidazol-4-yl) - methylthio] ethylaminoj-4-methylamino-1,2,5-thiadiazole, 1,1-dioxide 3- [2 - [(5- ethyl-1H-imidazol-4-yl) methylthio] - ethylaminoj-4-methylamino-1, 2,5-thiadiazole and 1 , 3- (1-dioxide) (2- [(2-amino-1H-imidazol-4-yl) methylthio] - ethylaminoj -4-methylamino-1,2,5-thiadiazole, respectively.

EXAMPLE 87 - 1.1- Dioxide of 3- £ 4- [2-guanidino-1H-imidazol-4-yl] butylamino} - 4-methylamino-1,2,5-thiadiazole

A methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted successively with an equimolar amount of 4- [2-guanidino-1H-imidazol-4-yl] -butylamine [ prepared according to Belgian patent n ° 866.156] and an excess of methylamine according to the general procedure of Example 2, to obtain the desired compound.

EXAMPLE 88 - 1.1- 3- {2 - [(5-methyl-1H-imidazol-4-yl) methylthiojethyl-amino} -4- (2-propynyl) amino-1,2,5-thiadiazole dioxide

By reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 1 equivalent * of 2-propynylamine and by reaction of 3-metho-xy 1,1-dioxide -4-propynylamino-1,2,5-thiadiazole with 1 equivalent of 2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamine, the desired compound is obtained identical to the product of Example 1. EXAMPLE 89 - 1.1- 3- [2 - [(5-methyl-1H-imidazol-4-yl) methylthioj-ethylamino} -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of 3-methylamino-4- (2-mercaptoethyl) -1,2,5-thiadiazole 1,1-dioxide (prepared in Example 17, stage A) with 4-chloromethyl-5-methyl hydrochloride -imidazole and a strong base, the desired compound is obtained identical to the product of Example 2.

EXAMPLE 90 - 1.1- 3-i2 dioxide - [(5-dimethylaminomethyl-2-furyl) methoxy] -ethylamino} -4-methylamino-1,2,5-thiadiazole

By reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 1 equivalent of 2 - [(5-dimethylaminomethyl-2-f uryl) methoxy] ethylamine [prepared according to US Patent No. 4,128,658], then with an excess of methylamine, the desired compound is obtained.

EXAMPLE 91 - 1.1 - 3-f2 dioxide - [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino} -4-ethylamino-1,2,5-thiadiazole

By reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 1 equivalent of ethylamine and by reaction of 3-methoxy-4-ethylamino 1,1-dioxide -1,2,5-thiadiazole resulting with 1 equivalent of> 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamine, the desired compound is obtained identical to the product of Example 7.

EXAMPLE 92 - 3- {2- [(5-Dimethylaminomethyl-2-furyl) methylthio] - ethylamino} -4-methylamino-1,2,5-thiadiazole oxide

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, stage A] with 1 equivalent of methylamine and reaction of 3- 1-oxide methoxy-4-methylamino-1,2,5-thiadiazole resulting with 1 equivalent of 2- [(5-dimethylaminomethyl-2-furyl) -methylthio] ethylamine, the desired compound is obtained identical to the product of Example 13.

EXAMPLE 93 - 3- {3- [(5-Dimethylaminomethyl-2-furyl) methyl-thio] propylamino} -4-ethylamino-1,2,5-thiadiazole dioxide

By reaction of 1-phthalimido-3 - [(5-dimethylamino-methyl-2-furyl) methylthio] propane [prepared according to the process described in Belgian patent n ° 857.388] with hydrazine, then reaction of the resulting substituted propylamine according to the general method of Example 7, the desired compound is obtained.

EXAMPLE 94 -

The general procedure of Example 19 is repeated, but by replacing dimethylamine with thiomorpholine, piperazine, N-acetylpiperazine, N-methylpiperazine, hexamethyleneimine and homopiperazine, respect!, To obtain 1 , 3 ~ 1-dioxide [2- [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino} -4- (4-thiomorpholinyl) -1,2,5-thiadiazole, * 1,1-dioxide of 3- [2- [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino} -4- (1-pipérazinyl) -1,2,5-thiadiazole, 3- [2-dioxide 1,1-dioxide - [(5-dimethylaminomethyl-2 -furyl) methyl-thio] ethylamino} -4- (4-acetyl-1-piperazinyl) -1,2,5-thiadiazole, 1,1-dioxide 3 - (2 - [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino} -4- (4-methyl-1-piperazinyl) -1,2,5-thiadiazole, 1,1-dioxide of 3- {2- [ (5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino} -4- (1-hexamethyleneimino) -1,2,5-thiadiazole and 3- {2- [(5-dimethylaminomethyl- 2-furyl) methyl-thio] ethylamino} -4- (1-homopiperazinyl) -1,2,5-thiadiazole, respectively.

EXAMPLE 95 -

The general procedure of Example 8 is repeated, but replacing the 2-propynylamina with an equimolar amount of cyclobutylamine, aminomethylcyclobutane, ethanolamine, 2-methylthioethylamine, 2,2,2-trifluoroethylamine, 2-fluoroethylamine, ethylenediamine, 2-methylaminoethylamine, 2-dimethylaminoethylamine, 1,1-dimethylhydrazine, cyanamide, 3-aminopropionitrile, guanidine and methylguanidine, respectively, to obtain 1,1-dioxide - (cyclobutylamino) -4- [2- [(5-dimethylamino'-methyl-2-furyl) -methylthio] ethylamino} -1,2,5-thiadiazole, 1,1-dioxide 3 - [(cyclobutyl) methylamino] -4- {2 - [(5-dime-thylaminomethyl-2-furyl) methylthio J ethylamino} -1,2,5-thiadiazole, _ 1,1-dioxide 3- [2 - [(5- dimethylaminomethyl-2-furyl) methyl thio] ethylamino} -4- (2-hydroxyethylamino) -1,2,5-thiadiazole, 1,1-dioxide 3- [2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4- (2 -methylthioethylamino) -1,2,5 -thiadiazole, 1,1-dioxyd e of 3- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino} -4- (2,2,2-trifluoroethylamino) -1,2,5-thiadiazole, 1,1-dioxide 3 - {2- [(5-dimethylaminomethyl-2-furyl) methyl- n ° 3.950.333] with 3,4-dimethoxy-1,2,5-thia-diazole 1,1-dioxide and by reaction of 1 , 3-methoxy-4- 1-dioxide [2 - [(thia-zol-2-yl) methylthio] ethylamino} -1,2,5-thiadiazole resulting with methylamine according to the general procedure of Example 20 , the desired compound is obtained.

EXAMPLE 98 -

By reaction of 2-chloromethyl-4-methyithiazole [prepared by reaction of thionyl chloride on 2-hy-droxymethyl-4-methylthiazole, itself prepared according to the method described in J. Chem. Soc., (Suppl. Issue No. 1), S106 111 (1966) or Acta Chem. Scand., 20, 2649 (1966)] with cysteamine hydrochloride and about 2 equivalents of a strong base, such as sodium methylate, then by reaction of the resulting amine with 1,1-dioxide 3, 4-dimethoxy-1,2,5-thiadiazole, 3-methoxy-4- [2 - [(4-methylthiazol-2 -yl) methylthio] ethyl-amino} -1,2-dioxide is obtained , 5-thiadiazole. By reaction of the latter compound with methylamine according to the general procedure of Example 20, the 1,1-dioxide of 3-methylamino-4- ^ 2- [(4-methylthiazol-2 -yl) methyl thio is obtained ] ethylamino] -1,2,5-thiadiazole.

By repeating the general procedure above, but replacing 2-chloromethyl-4-methylthiazole with an equimolar amount of the chloromethylthiazoles prepared by reaction of thionyl chloride with 2-amino-4-hydroxymethylthiazole1, 2 2-hydroxymethyl -4,5-dimethylthiazole, 3 4-hydroxymethyl-2-methylthiazole, 4 4-hydroxymethyl-2-chlorothiazole, 5-hydroxymethyl-2-methylthiazole5, g 5-hydroxymethyl-4-methylthiazole, 7 = 4 -hydroxymethylthiazole and trg 4-dimethylaminomethyl-2-hydroxymethylthiazole, respectively, there is obtained 3- [2- [(2-aminothiazol-4-yl) methyl thio] ethyl-aminoj-4-methylamino- 1,1-dioxide 1,2,5-thiadiazole, thio] ethylamino] -4- (2-fluoroethylamino) -1,2,5-thiadiazole, 1,1-dioxide of 3- (2-aminoethylamino) -4- {2- [ (5-dimethylami-nomethyl-2-furyl) -methyl thio] ethylamino] -1,2,5-thiadiazole, 1,1-dioxide of 3- {2- [(5-dimethylaminomethyl-2-furyl) methyl thio ] ethylamino] -4- (2-methylaminoethylamino) -1,2,5-thiadiazole, l e 3- {2- [dioxide (5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino] -4- (2-dimethylaminoethylamino) -1,2,5-thiadiazole, 1,1- 3- [2 - [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino] -4- (2, 2-dimethylhydrazino) -l, 2, 5-thiadiazole, 1,1-dioxide 3 -cyanoamino-4- [2 - [(5-dimethylaminomethyl- 2-furyl) methyl thio] ethylamino] -1,2,5-thiadiazole, 3- (3-cyanopropylamino) 1,1-dioxide -4-] 2 - [(5-dimethylami-nomethyl-2-furyl) methyl thio] ethylamino] -1,2,5-thiadiazole, 3- [1,1-dioxide 2 - [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino] · -4-guanidino-1,2,5-thiadiazole and 3- [2-C (5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino] -4,4-dioxide - (N1 -methyl) guanidino-1,2, 5-thiadiazole, respectively · EXAMPLE 96 - 1.1- Dioxide of 3- (2,3-dihydroxypropylamino) -4 ~ (2 - [(2-guanidi-nothiazol-4- yl) methylthio] ethylamino} -1, 2,5-thiadiazole

By reaction of a methanolic solution of 2 - [(2-guanidinothiazol-4-yl) methyl thio] ethylamine with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide according to the procedure of Example 31 and by reaction of the 3-methoxy-4- 1,1-dioxide [2- [(2-guanidinothiazol-4-yl) methyl thio] ethylamino] - 1,2,5-thiadiazole with the 3 -amino-l, 2-propanediol, ~ the desired compound is obtained.

EXAMPLE 97 - 1.1- 3-Methylamino-4- (2 - [(thiazol-2-yl) methylthio] -ethylamino} !, 2,5-thiadiazole dioxide

By reaction of a methanolic solution of 2-C (thiazol-2-yl) -methylthio] ethylamine [prepared according to the process described in the patent of the United States of America, 3,1-dioxide-{2- [(4,5-dimethylthiazol-2-yl) methylthio] -ethylamino} -4-methylamino-1,2,5-thiadiazole, 3- ^ 2-C 1,1-dioxide (2-methylthiazol-4- yl) methylthio Jethyl-amino} -4-methylamino-1,2,5-thiadiazole, 3- {2- [(2-chlorothiazol-4-yl) methylthio] ethyl-, amino] - 4-methylamino-1,2,5-thiadiazole, 3- | 2- 1,1-dioxide [(2-methylthiazol-5-yl) methylthio] ethyl-amino] -4-methylamino-1,2,5 -thiadiazole, 3- [2 - [2 - [(4-methylthiazol-5-yl) methylthio] ethyl-amino} -4-methylamino-1,2,5-thiadiazole, 1,1-dioxide of 3- [2- [(thiazol-4-yl) methylthio] ethylaminoj-4-methylamino-1,2,5-thiadiazole and 3- | 2- [(4-dimethylaminomethylthiazol-2-) 1,1-dioxide yl) -methylthio] ethylamino] -4-methylamino-1,2,5-thiadiazole, respectively.

The above starting compounds are prepared according to the methods described in the following documents: (1) J. Am. Chem. Soc., 68, 2155 (1946); (2) Helv. Chim. Acta, 31, 652 (1948); (3) and (5) Zh. Obshch. Khim., 32, 570 (1962) [C. A., 5! 3, 2525b (1963)]; (4) Rev. Romanian Chim., 10, 897 (1965) [C. A., 6 £, 8164b (1966)]; (6) J. Am. Chem. Soc., 67, 400 (1945); (7) Zh. Obshch. Khim., 27, 726 (1957) [C. A., 51, 16436h (1957)]; (8) An ethanolic solution of dimethylamine is reacted with 2-bromo-4-chloromethylthiazole, prepared according to reference (4) above, and the resulting 2-bromo-4-di-methylaminomethylthiazole is reacted with a strong base and formaldehyde according to the general process described in Acta Chan. Scand., 20, 2649 (1966) to obtain the desired 4-dimethylamino-methyl-2-hydroxymethylthiazole.

EXAMPLE 99 - 3- {3- [(2-Dimethylaminomethyl-4-thiazolyl) methyl-thio] propylamino} -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of 2-dimethylaminomethyl-4-hydroxy-methylthiazole [prepared in Example 23, stage D] with 3-mercaptopropylamine hydrochloride [prepared according to the method described in J. Org. Chem., 27, 2846 (1962)] in aqueous hydrobromic acid (at -48%) and by reaction of the resulting amine successively with 3,4-dimethoxy-1,2,5 1,1-dioxide -thiadiazole and an excess of methylamine, according to the general procedure of Example 20, the desired compound is obtained.

EXAMPLE 100 3- 3- {2 - Oxide [(2-guanidinothiazol-4-yl) methylthio] propyl-amino} -4-amino-1,2,5-thiadiazole

By reaction of a methanolic solution of 2 - [(guanidinothiazol-4-yl) methylthio] propylamine with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxy [prepared in Example 4, stage A] and by reaction of the 1-oxide of 3— ^ 2 - [(2— guanidinothiazol-4-yl) methylthio] propylaminoj — 4-methoxy-1,2,5-thiadiazole resulting with an excess of ammonia following the general procedure of Example 24, the desired compound is obtained.

EXAMPLE 101 - 1.1- 3- (2 - [(2-guanidinothiazol-4-yl) methylthio] ethyl-amino) -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 1 equivalent of methylamine and by reaction of 3-methoxy-4-methylamino- 1,1-dioxide 1,2,5-thiadiazole resulting with 1 equivalent of 2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamine, the desired compound is obtained identical to the product of Example 20.

EXAMPLE 102 - 1.1 - 3- {2 - [(2-Guanidinothiazol-4 ~ yl) methylthio] -ethylamino] -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of a solution of 3-methylamino-4- (2-mercaptoethyl) -1,2,5-thiadiazole 1,1-dioxide [prepared in Example 17, stage A] with 4-chloro hydrochloride -methyl-2-guanidinothiazole and a strong base, the desired compound is obtained identical to the product of Example 20.

EXAMPLE 103 - 1.1 - 3-f2 dioxide - [(2-guanidinothiazol-4-yl) methylthio] ethyl-amino} -4-hydroxy-1,2,5-thiadiazole

By reaction of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 1 equivalent of 2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamine and by reaction of 1,1-dioxide of 3- [2- [(2-guanidinothiazol-4-yl) methylthio] ethylamino} -4-metho-xy-1,2,5-thiadiazole with sodium hydroxide according to the general procedure of Example 12 , stage B, the desired compound is obtained.

EXAMPLE 104-1.1 3- [2 - [(2-dimethylaminanethyl-4-thiazolyl) methylthio jethylamino] -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 1 equivalent of methylamine and by reaction of 3-methoxy-4-methylamino- 1,1-dioxide 1,2,5-thiadiazole resulting with 1 equivalent of 2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamine [prepared in example 22, stage E), the desired compound is obtained identical to the product of example 22.

EXAMPLE 105 - 1.1- 3-f2 dioxide - [(2-dimethylaminanethyl-4-thiazolyl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole ^ By reaction of 1,1-3-methylamino dioxide -4- (2-mercaptoethyl) -1,2,5-thiadiazole [prepared in Example 17, stage Â] with about 1 equivalent of 2-dimethylaminomé-thyl-4-hydroxyméthylthiazole [prepared in Example 23, stage D] in concentrated hydrochloric acid, then by alkalization and continuation of the operations, the desired compound is obtained which is identical to the product of Example 22.

EXAMPLE 106-1.1 3- {2 - [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino} -4-hydroxy-1,2,5-thiadiazole dioxide

By reaction of a solution of 1,1-dioxide of 3- [2- [(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylamino] · - 4-methoxy-1,2,5-thiadiazole [prepared according to the procedure procedure described in Example 22, Stage F) with sodium hydroxide according to the procedure of Example 25, Stage B, the desired compound is obtained.

EXAMPLE 107 1-3-Amino-4- [2- [(2-dimethylaminomethyl-4-thiazolyl) -methylthiolethylamino} -1,2,5-thiadiazole oxide

By reaction of a methanolic solution of 3- [2- [U-dirnethylaminomethyl ^ -thiazolylmethylthioj-ethylamino] 1-oxy-de-4-methoxy-1,2,5-thiadiazole [prepared from 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole according to the general procedure of Example 23, stage F] with anhydrous ammonia according to the general procedure of Example 24, the desired compound is obtained.

EXAMPLE 108 1- 3- (2- [(2-dimethylaminomethyl-4-thiazolyl) methylthio3-ethylamino} -4-methylamino-1,2,5-thiadiazole oxide

By reaction of 3-methylamino-4- (2-mer-captoethyl) -1,2,5-thiadiazole-oxide (prepared by reaction of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide with 2-aminoethanethiol and methylamine according to the general procedure of exan-pie 17, stage A] with approximately 1 equivalent of 2-dimethylamino-methyl-4-hydroxymethylthiazole [prepared in example 23, stage D], the desired compound is obtained.

EXAMPLE 109 3-amino-4- [4- (2-guanidinothiazol-4-yl) butylamino3-1,2,5-thiadiazole-1-hydroxide By reaction of a methanolic solution of 3,4-1-oxide -dimethoxy-1,2,5-thiadiazole successively with 4- (2-guanidinothiazol-4-yl) butylamine [prepared according to the method of US Patent No. 4,165,377] and an excess of anhydrous ammonia according to the general procedure of Example 24, the desired compound is obtained.

EXAMPLE 110-1, 1-Dioxide of 3- [2- [(3-chloro-2-pyridyl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide successively with 2 - [(3-chloro-2-pyridyl) methylthio] ethylamine [prepared according to US Patent No. 4,024,260] and methylamine according to the general procedure of Example 27, the compound sought is obtained.

EXAMPLE 111-1.1- 3- (2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of a methanolic solution of 1.1-3,4-dimethoxy-1,2,5-thiadiazole dioxide successively with an equimolar amount of 2- [(6-dimethylami-nomethyl-2-pyridyl) methylthio] ethylamine [prepared in Example 84, stage C] and an excess of methylamine, the desired compound is obtained.

EXAMPLE 112 -

The general procedure of Example 27 is repeated, replacing the 2- [(2-pyridyl) methylthio] ethylamine with an equimolar amount of 2 - [(3 -bromo-2 -pyridyl) methylthio] ethylamine, 2- [(3-cyano-2-pyridyl) methylthio] ethylamine, 2- [(3-hydroxy-2-pyridyl) methylthio] ethylamine, 2 - [(3 -methoxy-2 -pyridyl) methylthio] ethylamine, 2 - [(3-ethoxy-2 -pyridyl) methylthio] ethylamine, 2 - [(3-methyl-2-pyridyl) methylthio] ethylamine and 2 - [(3-amino-2-pyridyl) methylthio] ethylamine, respectively [prepared according to the general methods described in Belgian patents Nos 779,775, 804,144 and 844,504], to obtain 3- [2 - [(3-bromo-2-pyridyl) methylthio] -ethylamino 1,1-dioxide } -4-methylamino-1,2,5-thiadiazole, 3- [2 - [(3-cyano-2-pyridyl) methylthio] -ethylamino j-4-methylamino-1,2,2-dioxide , 5-thiadiazole, 3- {2- [(3-hy3roxy-2-pyridyl) methylthio] -ethylamino} -4-methylamino-1,2,5-thiadiazole 1,1-dioxide 3- [2- [(3-methoxy-2-py) dioxide ridyl) methylthio] -ethylamino} -4 -meth ylamino-1,2,5-thiadiazole, 1,1-dioxide of 3— {2 — C (3-ethoxy-2-pyridyl) methylthio] -ethylamino} -4 -methylamino-1,2; 5 -thiadiazole, 3- {2- [(3-methyl-2-pyridyl) methylthio] dioxide-1-ethylamino} -4-methylamino-1,2,5-thiadiazole and 3- {2- [(3-amino-2-pyridyl) methylthio] -ethylamino} -4-methylamino-1,2,5-thiadiazole t 1,1-dioxide respectively.

EXAMPLE 113-1.1 3- [2- [(3-chloro-2-pyridyl) methylthio] ethyl-amino} -4- {2-C (5-dimethylaminomethyl-2-furyl) methylthio3-ethylamino} -! , 2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide successively with 2 - [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamine and 2 - [(3-chloro-2-pyridyl) methylthio] -ethylamine, the desired compound is obtained.

EXAMPLE 114 3- 3- {2 - Oxide [(6-dimethylaminomethyl-2-pyridyl) methyl-thio] ethylamino} -4-methylamino-1,2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [obtained in Example 4, stage A] successively with an amount. equimolar of 2 - [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamine [prepared in Example 84, stage C] and an excess of methylamine, the desired compound is obtained.

- EXAMPLE 115 - 1.1- Dioxide of 3 - {2 - [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino} -4- [2- [(4-methyl-1,2,5-oxadiazol-3 -yl) m-thyl thio] ethylamino) -1,2., 5 -thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 2— [(4— methyl-1,2,5-oxadiazol-3-yl) methylthio ] ethylamine [prepared in Example 28, stage B] and 2 - [(5-dimethylaminomé-thyl-2-furyl) methylthio] ethylamine, the desired compound is obtained.

EXAMPLE 116 - 1.1- Dioxide of 3- (2 - [(2-dimethylamino-1,3,4-oxadiazol-5-yl) methylthio] ethylamino] -4-methylamino-1,2,5-thiadiazole

By hydrolysis of 2-dimethylamino-5-ethoxycar-bonyl-1,3,4-oxadiazole [prepared according to the method described in Org. Magn. Resonance, 6, 144 (1974)], then reduction using borane as described in example 28, stage A, and finally reaction with cysteamine according to the procedure of example 29, stage A, we obtain the 2 - [(2-dimé-thylamino-1,3,4-oxadiazol-5-yl) methylthio] ethylamine.

By reaction of the above amine with an equimolar amount of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide and reaction of 3- ^ 2- 1,1-dioxide [(2 -dimethylamino-1,3,4-oxadiazol-5-yl) methylthio] ethylamino} -4-methoxy-1,2,5-thiadiazole resulting with an excess of methylamine, the desired compound is obtained.

EXAMPLE 117-1.1 3- (2 - [(3-dimethylaminomethyl phenyl) methyl-thio] ethylamino} -4-amino-1,2,5-thiadiazole dioxide

By reaction of a methanolic suspension of 1,1-3,4-dimethoxy-1,2,5-thiadiazole dioxide successively with an equimolar amount of 2- [(3- [dimethylaminomethyl] -phenyl) methylthio] ethylamine [prepared according to process of. Belgian patent n ° 867.106] and an excess of ammonia according to the general procedure of Example 24, the desired compound is obtained.

* EXAMPLE 118 - 1.1- Dioxide of 3- [3- [3- (dimethylaminomethyl) phenoxyjpropyl- - amino} -4-amino-1,2,5-thiadiazole

By reaction of a methanolic suspension of 1,1-3,4-dimethoxy-1,2,5-thiadiazole dioxide successively with an equimolar amount of 3- [3- (dimethylaminomethyl) -phenoxy jpropylamine [prepared according to the patent process Belgian No. 867.106] and an excess of ammonia according to the general procedure of Example 24, the desired compound is obtained.

EXAMPLE 119 1-3-f2 oxide - [(5-dimethylaminomethyl-2-thienyl) methylthio] -ethylamino} -4-ethylamino-1,2,5-thiadiazole

By reaction of a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, stage A] successively with an equimolar amount of 2 - [(5-di-methylaminomethyl -2-thienyl) methylthio] ethylamine and an excess of ethylamine according to the general procedure of Example 13, the desired compound is obtained.

EXAMPLE 120-1.1 3- [2- [(5-dimethylaminomethyl-2-thienyl) methyl-thio] ethylaminoJ-4-i2- [(4-methyl-1,2,5-oxadiazol-3-yl) dioxide methyl-thio] ethylamino} -1,2,5-thiadiazole

By reaction of a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with an equimolar amount of 2 - [(5-dimethylaminomethyl-2-thienyl) methylthio] ethylamine and reaction of 1,1 -3- {2 - dioxide ([(5-dimethylaminomethyl-2-thienyl) methylthio] ethylaminoj-4-methoxy-1,2,5-thiadiazole resulting with 2 - [(4-methyl-1,2,5- oxadiazol-3-yl) methyl-thiojethylamine [prepared in Example 28, stage B], the desired compound is obtained.

EXAMPLE 121-1.1- 3- {4- ['2-Guanidino-4-oxazolyl] butylamino} -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with an equimolar amount of 4- [2-guanidino-4-oxazolyl] butylamine [prepared according to the process of Belgian patent no 866.155] and reaction of 3- {4- [2-guanidino-4-oxazolyl] butylamino} -4-methoxy-1,2,5-thiadiazole 1,1-dioxide resulting with an excess of methylamine, obtains the desired compound.

EXAMPLE 122 - 1.1- 3- {2- [.2- (2-amino-5-oxazolyl) ethylthio] ethyl- • amino) -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of an equimolar quantity of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide and of 2— [2— (2— amino-5-oxazolyl) ethylthio] ethylamine [prepared according to U.S. Patent No. 3,950,353] and reaction of 3- [2- [2- (2- (2-amino-5-oxazolyl) ethylthio) 1,1-dioxide] -> ethylamino} -4-methoxy -1.2, 2.5-thiadiazole resulting with excess methylamine wine, the desired compound is obtained.

EXAMPLE 123 - 1.1- Dioxide of 3- [2- [3-isoxazolylmethylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole

By reaction of a methanolic suspension of 1,1-3,4-dimethoxy-1,2,5-thiadiazole dioxide with 1 equivalent of 2- [3- isoxazolylmethylthio] ethylamine [prepared according to the process of the patent of the United States of America No. 3,950,353] and reaction of 3- [2- [3-isoxazolylmethylthio] ethylamino} -4-methoxy-1,2,5-thiadiazole 1,1-dioxide with an excess of methylamine, the compound is obtained research. EXAMPLE 124 -

Following the general procedure of Example 123, but replacing 2- [3-isoxazolylmethylthio] -ethylamine with an equimolar amount of 2 - [(5-methyl-3-isoxazolyl) methylthio 3ethylamine, of 2 - [( 3,5-dimethyl-4-isoxazolyl) methylthio] ethylamine and 2- [(2- (5-methyl-4-isoxazolyl) ethylthio] ethylamine, respectively [each prepared according to the general process of the United States patent America n ° 3,950,353], one obtains the 1,1-dioxide of 3- (2 - [(5-methyl-3-isoxazolyl) methylthio] -ethylamino] -4-methylamino-1,2,5-thiadiazole, τ 3- [2 - [(3,5-dimethyl-4-isoxazolyl) methyl-thio | ethylamino-4-methylaminp-1,2,5-thiadiazole 1,1-dioxide and 1,1-dioxide of 3- ^ 2- [2- (5-dimethyl-4-isoxazolyl) ethylthio] -ethylamino] -4-methylamino-1,2,5-thiadiazole, respectively.

EXAMPLE 125 - 1.1- Dioxide of 3- {2 - [(5-dimethylaminomethyl-2-furyl) methyl- _ 1/114 _ thio] ethylamino] -4 ~ [2- [3-isoxazolylmethylthio] ethylamino} - 1,2 , 5-thiadiazole

By reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole r 1,1-dioxide with 1 equivalent of the following 2- [(5-dimethylaminomethyl-2-furyl) methylthio] -ethylamine the procedure of Example 12, stage A, and by reaction of the resulting product with 1 equivalent of 2- [3-isoxazolylmethylthio] ethylamine, the desired compound is obtained.

EXAMPLE 126-1.1 3- [2- [3-Isothiazolylmethylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole dioxide

By reaction of a methanolic suspension of 1,1-3,4-dimethoxy-1,2,5-thiadiazole dioxide with 1 equivalent of 2- [3-isothiazolyImethylthio] ethylamine [prepared according to the process of the United States patent America No. 3,950,353] and reaction of 3- [2- [3-isothia-zolylmethylthio] ethylamino} -4-methoxy-1,2,5-thiadiazole 1,1-dioxide with an excess of methylamine, obtains the desired compound.

EXAMPLE 127 -

The general procedure of Example 126 is repeated, replacing 2- [3-isothiazolylmethylthio] ethylamine with an equimolar amount of 2-t (3-methyl-4-isothiazolyl) methylthio] ethylamine, of 2 - [(4 -bromo-3-methyl-5-isothiazolyl) methylthio] ethylamine and 2 - [(3 -methyl-5 -isothiazolyl) methylthio] ethylamine, respectively [prepared according to the general methods of United States patent No. 3,450,353 and J. Chem. Soc., 2032 (1963)] to obtain the 3- {2 - [(3-methyl-4-isothiazolyl) methylthio] -ethylamino] -4-methylamino-1,2,5-thiadiazole 1,1-dioxide, 3- [2- [1,1-dioxide [(4-bromo-3-methyl-5-isothiazolyl) methylthio] ethylamino) -4-methylamino-1,2,5-thiadiazole and 1,1-dioxide 3- {2- [(3-methyl-5-isothiazolyl) methylthio] -ethylamino} -4-methylamino-1,2,5-thiadiazole, respectively.

EXAMPLE 128 - 1.1- 3-f2- [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino} -4- {2 - [3-isothiazolylmethylthio] ethylamino) - "1,2,5-thiadiazole dioxide

By reaction of a methanolic suspension of 1.1-3,4-dimethoxy-1,2,5-thiadiazole dioxide with 1 equivalent of 2- [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl-amine according to the procedure of example 12, stage A, then reaction of 3- {2- [(S-dimethylaminomé-thyl ^ -furyl) methylthio] ethylamino} -4-methoxy-1,2,5-thiadia 1,1-dioxide -zole with 1 equivalent of 2- [3-isothiazolylmethylthio] ethyl-amine, the desired compound is obtained.

EXAMPLE 129 - 1.1- Dioxide of 3- £ 2 - [(2-amino-1,3,4-thiadiazol-5-yl) methyl-thio 3ethylamino} -4-methylamino-1,2,5-thiadiazole

By reaction of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 1 equivalent of 2 - [(2-amino-1,3,4-thia-diazol-5-yl) methylthio] ethylamine [prepared according to the method of US patent 3,950,353] and reaction of 3- [2 - [(2-amino-1,3,4-thiadiazol-5,1-dioxide) -yl) methylthio] ethylamino} -4-methoxy-1,2,5-thiadiazole resulting with methylamine, the desired compound is obtained. EXAMPLE 130 -

The general procedure of Example 129 is repeated, replacing the 2 - [(2-amino-1,3,4-thiadiazol-5-yl) -methylthio] ethylamine by an equimolar amount of 3— [1,2 , 4-thiadiazol-3-ylthio] propylamine, 2 - [(1,2,3-thiadiazol-4-yl) methylthio] ethylamine, 2- [(3-hydroxy-1,2,5-thiadiazol-4 -yl) methylthio] ethylamine and 2- [(3-amino-1,2,5-thiadiazol-4-yl) methylthio] ethylamine, respectively [prepared according to the general methods described in the patent of the United States of America No. 3,950,353, J. Am. Chem. Soc., 86, 2861 (1964) and J. Org. Chem., 28, 1491 (1963)] to obtain the 3- ^ 3- 1,1-dioxide [1,2,4-thiadiazol-3-ylthio] propylamino] -4-methylamino-1,2, 5-thiadiazole, 3- ^ 2- 1,1-dicKyde [(1,2,3-thiadiazol-4-yl) methylthio] -ethylamino] -4-methylamino-1,2,5-thiadiazole, 1 , 3- [2-dioxide [- ((3-hydroxy-1,2,5-thiadiazol-4-yl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole and the 1, 3- {2- [1-dioxide [(3-amino-1,2,5-thiadiazol-4-yl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole, respectively.

EXAMPLE 131-1.1 3- [2- [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino3-4- [2- [(3-hydroxy-1,2,5-thiadiazol-4-yl) dioxide ) m-thylthio] ethylamino} -l, 2,5-thiadiazole

By reaction of a methanolic suspension of 1.1-3,4-dimethoxy-1,2,5-thiadiazole dioxide with an equimolar amount of 2- [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamine according to the mode Example 12, stage A, and an equimolar amount of 2 - [(3-hydroxy-1,2,5-thiadiazol-4-yl) methylthio] ethylamine, the desired compound is obtained.

EXAMPLE 132 - 1.1- Dioxide of 3— {2— [(2-amino-1,2,4-triazol-4-yl) methylthio] ~ ethylamino} -4-methylamino-1,2,5-thiadiazole

By reaction of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with 1 equivalent of 2 - [(2-amino-1,2,4-tri-azol-5-yl) methylthio] ethylamine [prepared according to the general methods of United States patent * 3,950,353] and an excess of methylamine according to the general procedure of Example 2, the desired compound is obtained.

EXAMPLE 133 -

The general procedure of Example 132 is repeated, but replacing the 2- [(2-amino-1,2,4-triazol-5-yl) -methylthiojethylamine by an equimolar amount of 2- [(4- methyl-1,2,4-triazol-3-yl) methylthio] ethylamine of 2- [(5-methyl-1,2,3-triazol-4-yl) methylthio] ethylamine and 2- [1,2 , 4-triazol-3-yl) methylthio] ethylamine, respectively [each prepared according to the general methods of United States patent no. 3,950,353] to obtain the 1,1-dioxide 3— £ 2— [(4-methyl-1,2,4-triazol-3-yl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole, * 1,1-dioxide 3— {2— [(5-methyl-1,2,3-triazol-4-yl) methylthio] ethylamino} -4-methylamino-1,2,5-thiadiazole and 3-methylamino-4,1-dioxide {2- [1,2,4-triazol-3-ylmé-thylthio] ethylamino} -1,2,5-thiadiazole, respectively.

EXAMPLE 134 - 1.1- 3- [2 - [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamino] -4- [2- [(5-methyl-1,2,3-triazol-4-) dioxide yl) methyl-thiolethylamino] -1,2,5-thiadiazole

By reaction of a methanolic suspension of 1.1-3,4-dimethoxy-1,2,5-thiadiazole dioxide with an equimolar amount of 2 - [(5-dimethylaminomethyl-2-furyl) methyl-thio] ethylamine according to the mode Example 12, stage A, and an equimolar amount of 2 - [(5-methyl-1,2,3-triazol-4-yl) methylthio] ethylamine, the desired compound is obtained.

EXAMPLE 135 3- 3- {2 - Oxide [(2-dimethylaminomethyl-4-thiazolyl) methyl-thiolethylamino} -4-dimethylamino-1,2,5-thiadiazole

By reaction of a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, stage A] with 1 equivalent of 2- [(2-dimethylaminomethyl-4-thiazo -lyl) methylthio] ethylamine [prepared in Example 22, stage E] and by reaction of 3- £ 1-oxide 2- [(2-dimethylaminomé-thyl-4-thiazolyl) methylthio] ethylamino} -4-methoxy -1.2, 2.5-thiadiazole resulting with an excess of dimethylamine according to the procedure of Example 19, the compound sought is obtained.

EXAMPLE 136 -

The general procedure of Example 135 is repeated, but by replacing dimethylamine with pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, * N-acetylpiperazine, N-methylpiperazine, hexamethyleneimine and homopiperazine, respectively, - to obtain 3- {2 - 1-oxide - [(2-dimethylaminomethyl-4-thiazolyl) m-thylthio] ethylamino} -4- (1-pyrrolidinyl) -1,2,5- thiadiazole, 3- [2 - [(2-dimethylaminomethyl-4-thiazolyl) m-thylthio] ethylamino} -4- (1-piperidinyl) -1,2,5-thiadiazole 1-oxide, 3- {2 - [(2-dimethylaminomethyl-4-thiazolyl) me-thylthio] ethylamino} -4- (morpholinyl) -1,2,5-thiadiazole, 1 - oxide of 3 - {2 - [(2 - dimethylaminometh yl-4-thiazolyl) mes-thylthio] ethylamino} -4- (4-thiomorpholinyl) -1,2, -5-thiadiazole, 3 - {1-oxide. 2 - [(2-dimethylaminanethyl-4- thiazolyl) m-thylthio] ethylamino} -4- (l-piperazinyl) -1,2,5-thiadiazole, 3- {2- [(2-dimethylaminomethyl-4-thiazolyl) m-thylthio] ethylamino oxide } -4- (4-acetyl-1-pipera zinyl) -1,2,5-thia-diazole, 3- {2 - [(2-dimethylaminomethyl-4-thiazolyl) m-thylthio] ethylamino} -4- (4-methyl-1-piperazinyl oxide) ) -1,2,5-thiadiazole, 3- {2- [(2-dimethylaminomethyl-4-thiazolyl) methyl- = thylthio] ethylaminoJ-4- (1-hexamethyleneimino) -1,2-oxide, 5-thiadia zole and 3— {2— 1-oxide [[(2-dimethylaminomethyl-4-thiazolyl) methylthio] ethylaminoJ -4- (1-homopiperazinyl) -1,2,5-thiadiazole f.

EXAMPLE 137 3-amino-4- (2-Ç (6-dimethylaminomethyl-2-pyridyl) -methylthio] ethylamino} -1,2,5-thiadiazole 1,1-dioxide

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide successively with the equimolar amount of 2- [(6-dimethylaminomethyl-2-pyridyl) methylthio] ethylamine [prepared in Example 84, stage C] and an excess of ammonia, the desired compound is obtained.

EXAMPLE 138 - 1.1- Dioxide of 3— {2— [(5-guanidino-1,2,4-thiadiazol-3-yl) m ^ -thylthio3ethylamino] -4-methylamino-1,2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-1,2-thiadiazole 1,1-dioxide successively with the equimolar amount of 2 - [(5-guanidino-1,2,4-thia-diazol -3-yl) methylthio] ethylamine [prepared according to the process described in European patent application 6679] and an excess of methylamine, the desired compound is obtained.

EXAMPLE 139 - 1.1- 3-Amino-4- {2 - dioxide ([(5-guanidino-1,2,4-thiadiazol-3-yl) methylthio] ethylamino3 -1,2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-1,2-thiadiazole 1,1-dioxide successively with the equimolar amount of 2 - [(5-guanidino-1,2,4-thia-diazol -3-yl) methylthio] ethylamine and m excess of ammonia, the desired compound is obtained.

EXAMPLE 140 1-3-amino-4- (2 - [(5-guanidino-1,2,4-thiadiazol-3-yl) -methylthiojethylamino} -! Oxide -! 2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxyr successively with an equimolar amount of 2- [(5-guanidino-1,2,4-thiadiazol-3- yl) methylthio] ethylamine and m excess ammonia, the desired compound is obtained.

EXAMPLE 141-1.1-Dioxide of 3-Î2 - [(5-guanidino-1,2,4-oxadiazol-3-yl) mé-thylthiojéthylamino} -4-methylamino-1,2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide successively with an equimolar amount of 2- [(5-guanidino-1,2,4-oxa-diazol -3-yl) methylthio] ethylamine [prepared according to the method described in European patent application 6286] and an excess of methylamine, the desired compound is obtained.

EXAMPLE 142 - 3-Amino-4 - 1,1-dioxide - (2 - [(5-guanidino-1,2,4-oxadiazol-3-yl) methylthio 3 ethylamino] -1,2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide successively with an equimolar amount of 2 - [(5-guanidino-1,2,4-oxa-diazol -3-yl) methylthio] ethylamine and an excess of ammonia, the desired compound is obtained.

EXAMPLE 143 3-amino-4- 1-Oxide {2 - [(5-guanidino-1,2,4-oxadiazol-3-yl) -methylthio] ethylamino} -1,2,5-thiadiazole

By reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxy-successively with an equimolar amount of 2 - [(5-guanidino-1,2,4-oxadiazol-3 -yl) -methylthio] ethylamine and an excess of ammonia, the desired compound is obtained.

EXAMPLE 144 -

The general procedure of Example 80 is repeated, but replacing the 3- (3-piperidinomethylphenoxy) pro-pylamine with an equimolar amount of 3- (3-pyrrolidinomethylphenoxy) propylamine, of 3- [3- (4- methylpiperidino) methylphenoxy] propylamine, 3- (3-homopiperidinomethylphenoxy) propylamine, 3- (3-morpholinomethylphenoxy) propylamine ^ and 2 of 3- [3- (N-methylpiperazino) methylphenoxy] propylamine, respectively, to obtain 1, 3-methylamino-4- [3- (3-pyrrolidinomethylphenoxy) propylaminoli, 2,5-thiadiazole, PF 156-157 “1-dioxide, 3-methylamino 1,1-dioxide ~ 4- [3- [3 - (4-methylpiperidino) -methylphenoxy] propylamino} -1,2,5-thiadiazole, mp 186-189 °, 3-methylamino-1,1-dioxide 4- [3- (3-homopiperidinomethyl-phenoxy) propylamino ] -l, 2,5-thiadiazole, mp 174-176 ° in the form of the hydrochloride, 3-methylamino-4,1-dioxide [3- (3-morpholinomethyl-phenoxy) propylamino] -l, 2 , 5-thiadiazole, mp 162-163 ° and 3-methylamino-4- {3- [3- (N-methylpiperaz-no) met 1,1-dioxide hylphenoxy] propylamino} -1,2,5-thiadiazole, respectively.

The starting compounds (1) and (2) above are obtained by hydrogenation of a mixture of N- [3- (3-formylpheno-xy) propyl] phthalimide and the corresponding morpholine or N-methylpiperazin on carbon palladium 10% catalytic, then by elimination by means of hydrazine of the phthali-mido protective radical. The other starting compounds are prepared according to the published application for English patent No. 2,023,133. EXAMPLE 145 -

The general procedure of the exa-pie 81 is repeated, but replacing the 3- (3-piperidinomethylphenoxy ·) -propylamine with the equimolar amount of 3- (3-pyrrolidinomethylphenoxy) propylamine, of 3— [3— ( 4-methylpiperidino) methylphenoxy] propylamine, 3 - (3 -homopiperidinometh ylphenox y) propylamine, 3- (3-morpholinomethylphenoxy) propylamine and 3 - [3- (N-methylpiperazino) methylphenoxy] propylamine, respectively,. 3-amino-4- 1-oxide [3- (3-pyrrolidinomethylphenoxy) pro-pylamino] -1, 2,5-thiadiazole, mp 168-170 ° (dec.), 3-amino 1-oxide -4- £ 3- [3- (4-methylpiperidino) methylphenoxy] propylaminoJ-1,2,5-thiadiazole, mp 157-159 °, 3-amino-4-1-oxide [3- (3-homopiperidinomethylphenoxy) ) -propylamino] -l, 2,5-thiadiazole, mp 167-169 °, - 3-amino-4- [3- (3-morpholinomethylphenoxy) pro-pylamino] 1-oxide] -l, 2,5- thiadiazole and - 3-amino-4- [3- [3- (N-methylpiperazino) methylphenoxy] propylamino} -1,2-thiadiazole 1-oxide, mp 139-143 °, respe ctively.

EXAMPLE 146 -

We repeat the general procedure of example-_ ις? - pie 82 by replacing 3- (3-piperidinomethylphenoxy) pro-pylamine by an equimolar amount of 3- (3-pyrrolidinomé-thylphenox y) propylamine, 3- [3- (4-methylpiperidino) methylphenoxy] propylamine, 3- (3-homopiperidinomethylphenoxy) propylamine, 3- (3-morpholinomethylphenoxÿ) propylamine and 3- [3- (N-methylpiperazino) methylphenoxy] propylamine, respectively to obtain 3-amino-4- 1,1-dioxide [3- (3-pyrrolidinomethylphenoxy) -propylamino] -1,2,5-thiadiazole, PF 160-163eC (dec.), 3-amino-4- 1,1-dioxide [3- [3- (4 -methylpiperidino) methylphenoxy Ipropylamino] -1,2,5-thiadiazole, 3-amino-4- [3- (3-homopiperidinomethylpheno-xy) propylamino] -1,2-thiadiazole 3-amino-4,1-dioxide ~ [3- (3-morpholinomethylphenoxy) -propylamino] -l, 2,5-thiadiazole, mp 172-174 ° C and 3-amino-1,1-dioxide- 4- ^ 3- [3- (N-methylpiperazino) methylphenoxy Ipropylamino ^ -1,2,5-thiadiazole, respectively.

EXAMPLE 147 -

The general procedure of Example 80 is repeated, but replacing the methylamine with an equimolar amount of ethylamine, propylamine, n-butylamine, • allylamine, 2-propynylamine, cyclopropylamine, aminomethylcyclopropane, d1 ethanolamine, - 2-methoxyethylamine, 2,2,2-trifluoroethylamine, 2-fluoroethylamine, d1 hydroxylamine, 3-aminopropionitrile, benzylamine, 3-methoxybenzylamine,, 4-methoxybenzylamine,; 3,4-dimethoxybenzylamine, piperonylamine, 4-chlorobenzylamine, 2-aminomethylpyridine, 3-aminomethylpyridine and 4-aminomethylpyridine s, respectively to obtain 3-ethylamino-4- 1,1-dioxide [3- (3-piperidinomethylphé-noxy) propylamino] -l, 2,5-thiadiazole, 3-propylamino-4- 1,1-dioxide [3- (3-pipéridinométhylphé-noxy) propylamino] -l, 2,5- thiadiazole, 3-butylamino-4,1-dioxide [3- (3-piperidinomethylphé-noxy) propylamino] -1, 2,5-thiadiazole, 3-allylamino-4- 1,1-dioxide [ 3- (3-piperidinomethylphé-noxy) propylamino] -1, 2,5-thiadiazole, 3- (2-propynyl) amino-4- 1,1-dioxide [3- (3-piperidinomé-thylphenoxy) propylamina] -1,2,5-thiadiazole, 3- (cyclopropylamino) -1,4-dioxide-4- [3- (3-piperidino-methylphenoXy) propylamino] -1,5-thiadiazole, 1,1- 3 - [(cyclopropyl) methylarnino] -4- [3- (3-pipé-ridinomethylphenoxy) propylamino] -l, 2,5-thiadiazole dioxide, 3- (2-hydroxyethylamino) -1,1-dioxide - [3- (3-piperidino-methylphenoxy) propylamino] -1,2,5-thiadiazole, 3- (2-methoxyethylamino) -4- [3- (3-piperidino-methylphenoxy) propylamino] -1,2-2,5-thiadiazole, 1,1-dioxide 3- (2 , 2,2-trifluoroethylamino) 4-C3- (3-pipé-1 ridinomethylphenoxy) propylamino] -1,2,5-thiadiazole, 3- (2-fluoroethylamino) 1,1-dioxide -4- [3- (3-piperidino-- methylphenoxy) propylamino] -1,2,5-thiadiazole, 3-hydroxyamino-4- 1,1-dioxide [3- (3-piperidinomethylphé-noxy) propylamino] -1,5 -thiadiazole, 3- (3-cyanopropylamino) -4- [3- (3-piperidino-methylphenoxy) propylamino] -1,2 dioxide, 2,5-thiadiazole,

Ί CA

3-benzylamino-4- [3- (3-piperidinomethylphé-noxy) propylamino3-1,2,5-thiadiazole-1,1-dioxide-3- (3-methoxÿbenzylamino) -4- [3- (3-piperidi-nomethylphenoxy) propylamino] -1, 2,5-thiadiazole, 3- (4-methoxybenzylamino) 1,1-dioxide -4- [3- (3-piperidi-nomethylphenoxy) propylamino] -ï, 2, 5-thiadiazole, 3- (3,4-dimethoxybenzylamino) -1,1-dioxide -4- [3- (3-pipé-ridinomethylphenoxy) propylamino] ~ 1, 2,5-thiadiazole 3- (3,4-methylenedioxybenzylamino) -1,4-dioxide [3- (3-piperidinomethylphenoxy) propylamino3-1, 2,5-thiadiazole, 3- (4-chlorobenzylamino) 1,1-dioxide -4- [3- (3-piperidino-methylphenoxy) propylamino] -1, 2,5-thiadiazole, 1,1-dioxide 3 - [(2-pyridyl) methylamino3-4- [3- (3-pipé -ridinomethylphenoxy) propylamino] -1,2,5-thiadiazole, 1,1-dioxide 3 - [(3-pyridyl) methylamino] -4- [3- (3-piperi-dinomethylphenoxy) propylamino3-1,2, 5-thiadiazole and 3-C (4-pyridyl) methylamino3,4- [3- (3-piperi-dinomethylphenoxy) propylamino] -1,2,5-thiadiazole, respectively ent.

EXAMPLE 148 -

The general procedure of Example 147 is repeated, but replacing the 3,4-dimetho-xy-1,2,5-thiadiazole 1,1-dioxide therein with an equimolar amount of 3,4-1-oxide. -dimethoxy-1,2,5-thiadiazole so as to obtain 3-ethylamino-4- [3- (3-piperidinomethylphenoxy) -propylamino] -1-oxide, 2,5-thiadiazole, 1-oxide 3-propylamino-4- [3- (3-piperidinomethylphenoxy) -propylamino] -1, 2,5-thiadiazole, 3-butylamino-lr-oxide 4- [3- (3-piperidinomethylphenoxy) -: propylamino] - 1,2,5-thiadiazole, 3-allylamino-4- [3- (3-piperidinomethylphenoxy) -propylamino] -1-oxide, 2,5-thiadiazole, 3- (2-propynyl 1-oxide) ) amino-4- [3- (3-piperidinomethyl-phenoxy) propylamino 3-1,2,5-thiadiazole, 3- (cyclopropylamino) -1-oxide -4- [3- (3-piperidinomethyl-phenoxy) propylamino3 -1,2,5-thiadiazole, _ 1RÇ - 3 - [(cyclopropyl) methylamino] -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2-oxide, 1,2,2-thiadiazole 3- (2-hydroxyethylamino) -4- [3- (3-piperidinomethylthoxyoxy) propy 1-oxide lamino] -1,2,5-thiadiazole, 3- (2-methoxyethylamino) -4- [3- (3-piperidinomethylphenoxy) propylamino] -1-oxide -1,2,5-thiadiazole 1-oxide 3— (2,2,2-trifluoroethylamino) -4- [3- (3-piperi-dinomethylphenoxy) propylamino] -1,2,5-thiadiazole, 3- (2-fluoroethylamino) 1-oxide -4- [3- (3-piperidinome-thylphenoxy) propylamino] -1, 2,5-thiadiazole, 3-hydroxyamino-1-oxide [4- (3-piperidinomethylphenoxy) -propylamino] -1, 2,5- thiadiazole, 3- (3-cÿanopropylamino) -4- [3- (3-piperidinome-thylphenoxy) propylamino] -1-oxide, 2,5-thiadiazole, 3-benzylamino-4- [1-oxide 3- (3-piperidinomethylphenoxy) -propylamino] -1,2,5-thiadiazole, 3- (3-methoxybenzylamino) -1-oxide -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,5 -thiadiazole, 3- (4-methoxÿbenzylamino) -4- [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5-thiadiazole, 3- (3,4-dimethoxybenzylamino) 1-oxide ) -4- [3- (3-piperidi-nomethylphenoxy) propylamino J-1,2,5-thiadiazole, 3- (3,4-methylenedioxybenzylamino) 1-oxide -4- [3 - (3-pi-peridinomethylphenoxy) propylamino] -1,2,5-thiadiazole, 3- (4-chlorobenzylamino) -4-1-oxide [3- (3-piperidinomethylphenoxy) propylamino] -1,2,5 -thiadiazole, 3 - [(2-pyridyl) methylamino] 1-oxide -4- [3- (3-piperidi-nomethylphenoxy) propylamino3-1,2,5-thiadiazole, 3 - [1-oxide ( 3-pyridyl) methylamino] -4- [3- (3-piperidi-nomethylphenoxy) propylamino] -1, 2,5-thiadiazole, mp 139.5-143 ° and the 1-oxide of 3 - [(4-pyridyl ) methylamino] -4- [3- (3-piperidino-methylphenoxy) propylamino] -1,2,5-thiadiazole, respectively.

EXAMPLE 149 1-Oxide of 3 - [(3-pyridyl) methylamino3-4- [3- (3-piperidinome-

n cC

thylphenoxy) propylamino] -! , 2,5-thiadiazole

A solution of 3- (3-piperidinomethylphenoxy) propylamine (from the dihydrochloride, 3.21 g; 10.0 millimoles) in 30 ml of methanol is added dropwise over 60 minutes to a partial solution of 1-oxide. 3,4-dimetho-xy-1,2,5-thiadiazole (1.62 g; 10.0 millimoles) which was cooled. at 5-7 ° in an ice and water bath. After 3 hours at room temperature, a solution of 3-aminomethyl-pyridine (1.14 g; 10.5 millimoles) in 10 ml of methanol is added and the solution is then stirred for 18 hours. The reaction mixture is evaporated under reduced pressure and the residue is subjected to rapid chromatography on 100 g of silica gel (No. 230-400, 63-38 µm) using a methylene chloride-methanol-ammonia mixture. The appropriate fractions are combined, evaporated and triturated with acetonitrile to obtain 4.05 g of product. By recrystallization from isopropanol, the desired compound is obtained, m.p. 139.5-143 °.

Analysis for C ^ H ^ NgQ ^ S: calculated, 60.77; H, 6.65; N, 18.49; S, 7.04% found C, 60.66; H, 6.64; N, 18.22; S, 7.02% EXAMPLE 150 - 1- 3-amino-4- [3- (3-guanidinophenoxy) propylamino] - 1,2,5-thiadiazole A oxide 2- [3- (3-Nitrophenoxy) propyl ] -lH-isoindole-1,3 (-2H) -dione A partial suspension of m-nitrophenol (6.0 g; 43.0 millimoles), N- (3-bromopropyl) phthalimide is stirred at room temperature for 70 hours. (10.0 g; 37.0 millimoles) and potassium carbonate (0.8 g; 58.0 millimoles) in 50 ml of dimethylformamide. The reaction mixture is diluted with 80 ml of water and filtered to obtain the product. By recrystallization from 2-methoxyethanol, 9.15 g of the desired compound are obtained, mp 149-152 °.

Analysis for C] _7Hi4N205: calculated C, 62.57; H, 4.32; N, 8.59% - 157 - found C, 62.49; H, 4.30; N, 8.71% B. 2- [3- (3-Am inophenoxy) propyll-1H-isoindole-1,3 (2H) dione a A suspension of 2- [3- (3-nitrophenoxy) - - is subjected propyl] -1H-isoindole-1,3 (2H) dione (1.0 g; 3.1 millimoles) [prepared in stage A] and 10% palladium on carbon (0.2 g) ^ in 100 ml of 2 -methoxyethanol at hydrogenation in a Parr apparatus at room temperature for 45 minutes. The reaction mixture is filtered and the filtrate is evaporated to dryness to collect 0.91 g of crude product.

An analytical sample is prepared by rapid chromatography on silica gel (No. 230 - 400, 63-38 ^ / μm) using the methylene chloride-methanol system and by recrystallization from absolute ethanol, the compound is obtained sought, PP 157-162 °.

Analysis -for ci7Hi6N2 ° 3: calculated C, 68.91; H, 5.44; N, 9.45% found C, 69.00; H, 5.54; N, 9.52% C. 2— [3— (3-Guanidinophenoxy) propyl] -1H-isoindole-1,3 (2H) - dione

A mixture of 2- [3- (3-aminophenoxy) propyl] -1H-isoindole-1,3 (2H)-crude dione (13.27 g; 45.0 millimoles) is heated at reflux for 2.25 hours. prepared in Stage B] of 50% aqueous cyanamide (7.9 ml) and 12N hydrochloric acid (3.78 ml; 45.0 millimoles) in 39.4 ml of absolute ethanol. An additional 7.9 ml of 50% aqueous cyanamide is added and heating is continued for 15 hours. The reaction mixture is evaporated under reduced pressure and the residue is subjected to rapid chromatography on 120 g of silica gel (No. 230-400, 63-38 μm) using the methylene chloride-methanol system. The appropriate fractions are combined, evaporated and the residue is triturated in cold acetonitrile to obtain 5.85 g of product. By recrystallization from absolute ethanol, the desired compound is obtained which is in the form of a hydrochloride, mp 185-187 °.

- 158 -

Analysis for C ^ gH ^ gN ^ O ^ .HCl calculated C, 57.68; H, 5.11; N, 14.95; Cl, 9.46% found C, 57.65; H, 5.55; N, 15.08; Cl, 9.16% D. 3-Amino-4- [3- (3-guanidinophenoxy) propylamino3-1,2,5-thiadiazole

Hydrazine hydrate (0.962 g; 19.76 millimoles) is added to a suspension of 2- [3- (3-guanidinophenoxy) propyl] -lH-isoindole-1, 3 (2H) -dione hydrochloride 3.7 g; 9.9 millimoles) [prepared in stage C] in 37 ml of 95% ethanol and the mixture is stirred at room temperature for 17 hours, then it is heated to 50 ° (bath temperature 'oil) for 2 hours. The ethanol is replaced by 37 ml of methanol, 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.18 g; 14.81 millimoles) is added and the resulting suspension is heated. at 50 ° for 4 hours. The mixture is filtered, evaporated to dryness and the residual gum is purified by rapid chromatography on 120 g of silica gel (No. 230 - 400, 63 - 38 µm) using the methylene chloride system (85) : methanol (15) as eluent. After combining the appropriate fractions, the semi-solid product is chromatographed a second time on 70 g of silica gel (No. 230-400, 63-38 μm) while maintaining an elution gradient of methylene chloride-methanol.

The isolated product is subjected to crystallization in the methanol / acetone system to collect 0.27 g of the desired compound containing 1.1 mole of HCl, m.p. 207-209 ° (decomposition).

Analysis for c; p2 ^ 7N7S ° 2 * ^, ^ HC '*':: calculated C, 39.66; H, 5.02; N, 26.98; Cl, 10.73% found C, 39.50; H, 4.91; N, 26.43; Cl, 11.09% (correction for 1.17% H 2 O) EXAMPLE 151 - 3-Amino-4- (2 - [(5-piperidinomethyl-2-furyl) methyl-thio] ethylamino} -l oxide , 2,5-thiadiazole A. 1-3-Amino-4-methoxy-1,2-2,5-thiadiazole - 159 -

A 2f75N solution of ammonia (56.0 ml; 0.154 millimole) in methanol is added dropwise over 1 hour. to a well-stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (24.3 g; 0.15 mole) in 725 ml of methanol at 20 °. The resulting solution is stirred at room temperature for 3 hours, then concentrated to about 125 ml under reduced pressure. After 16 hours at 0 °, the mixture is filtered and dried to obtain 19.9 g of product.

An analytical sample is prepared by recrystallization from methanol to obtain the desired compound, m.p. 182-184 ° (decomposition).

Analysis for C ^ H ^ N ^ O ^ S: calculated C, 24.49; H, 3.43; N, 28.56; S, 21.79% found C, 24.22; H, 3.63; N, 28.60; S, 21.92% B. 1-3-Amino-4- (2 - [(5-piperidinomethyl-2-furyl) m-thylthio] ethylamino} -1,2,5-thiadiazole oxide

A solution of 2 - [(5-pi-peridinomethyl-2-furyl) methylthio] ethylamine (4.0 g; 15.5 millimoles) [prepared according to the method of Belgian patent n ° 857.388 (patent of United States of America No. 4,128,658) 1 in 25 ml of methanol to a stirred suspension of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.31 g; 15, 7 millimoles) [prepared in stage A] in 25 ml of methanol, at room temperature. After 16 hours of stirring, the solution is evaporated under reduced pressure and the residue is subjected to rapid chromatography on 100 g of silica gel (No. 230-400, 63 - 38 µm) using the methanol-ac system -tonitrile. The appropriate fractions are combined and evaporated to obtain 3.71 g of product. By recrystallization from 95% aqueous ethanol with charcoal treatment, the desired compound is obtained, mp 161-163 °.

Analysis for ci5H23N5 ° 2S2: calculated, 48.76; H, 6.27; N, 18.96; S, 17.36% found C, 48.86; H, 6.16; N, 19.66; S, 17.63% EXAMPLE 152 -1-3-amino-4- {2 - Oxide - [(5-methyl-1H-imidazol-4-yl) methylthio-j- _ 1 KO _ ethylamino] -1, 2 , 5-thiadiazole

Stirred at room temperature for 16 hours and evaporate to dryness a mixture of 3- oxide; amino-4-methoxy-1,2,5-thiadiazole (2.5 g; 17 millimoles) and 2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamine (from dihydrochloride, 4 ', 15 g; 17 millimoles) in 90 ml of methanol. The product is deposited on 100 g of silica gel and chromatographed while maintaining an acetonitrile-methanol elution gradient. The appropriate fractions are combined and evaporated to obtain a gum.

By rigorous drying under high vacuum, the desired compound is obtained in the form of an amorphous solid solvated with about 0.07 mole of isopropanol-ether.

Analysis for calculated C, 37.75; H, 4.93; N, 29.35% found C, 37.97; H, 5.22; Or; 26.61% (correction for 1.81% of ^ 0) EXAMPLE 153 - 3-amino-4- [3- (6-piperidinomethyl-2-pyridyloxy) pro-pylamino] -l oxide 2.5 -thiadiazole A. 2-Chloro-6-piperidinomethylpyrjdine

N-bromosuccinimde (87.2 g, 0.49 mole) and 1.0 g benzoyl peroxide are added to 2-chloro-6-methylpy-ridine (50.0 g, 0.392 mole) in 393 ml carbon tetrachloride. The mixture is stirred at reflux for 22 hours, cooled to 10 ° and filtered. To the cooled filtrate, piperidine (83.5 g, 0.98 mole) is added slowly and stirring is continued at room temperature for 18 hours. After separating the piperidine hydrobromide by filtration, the filtrate is concentrated to approximately half volume and extracted with 6N HCl (65 ml) and 3N HCl (40 ml).

The acid extracts are made alkaline with 40% sodium hydroxide and the product is extracted into methylene chloride. The solvent is evaporated and the residue is distilled to obtain 41% of a colorless oil, P.:Eb. 101-103 ° / 0.45 mm Hg (60 Pa).

- 161 -

Analysis for C] _] _ hj_5C ^ N2: calculated C, 62.71; H, 7.18; N, 13.29; Cl, 16.82%. found C, 61.71; H, 7.31; N, 13.63; Cl, 17.20% B. N- [3- (6-Piperidinomethyl-2 -pyridyloxy) propyl] f ormamide

3-Aminopropanol (12.84 g, 0.171 mole) is added to a suspension of 50% sodium hydride in mineral oil (7.96 g, 0.166 mole) in 180 ml of dry dimethylformamide and heats the mixture to 80-83 °. A solution of 2-chloro-6-piperidi-nomethylpyridine (34.0 g, 0.161 mole) [prepared in stage A] in 180 ml of dry dimethylformamide is then added dropwise, and the solution is brought to the end. temperature at 125-128 ° for a period of 3 hours, then the mixture is left to stand for 17 hours at room temperature. The precipitated salts are filtered off, and the solvent is removed in vacuo. The oily residue is dissolved in methylene chloride, the solution is washed with water, dried and the solvent is evaporated. The residue is redissolved in acetonitrile and extracted * with Skelly B solvent. After removing the solvent, the crude oil is purified by rapid chromatography on 270 g of silica gel (N ° 230 - 400, 63 - 38yiim) by maintaining a methanol-methylene chloride elution gradient containing 0.5% NH ^ OH. The appropriate fractions are combined and evaporated to obtain 21.63 g of the desired compound (48.4%) which is in the form of a yellow oil.

C. 3- (6-Piperidinomethyl-2 -pyridyloxy) propylamine

N- [3- (6-piperidinomethyl-2-pyridyloxy) propyl] f oramide (19.6 g, 70.7 millimoles) [prepared in Step B] is added to a 85% potassium hydroxide solution as pellets (18.63 g, 0.332 mole) in 180 ml of methanol and the solution is heated at moderate reflux for 20 hours.

The solvent is removed in vacuo and the residue is partially purified by redissolving it in approximately 180 ml of the 20% methanol-methylene chloride system and passing it over a mass of 38 g of silica gel. The silica is washed with an additional 120 ml of eluent and the combined filtrates are evaporated to obtain an amber oil. The final purification is carried out by rapid chromatography on 120 g of silica gel (No. 230 - 400, 63 - 38 µm) while maintaining a methanol-methylene chloride elution gradient containing 0.5% NH 2 OH. The desired compound is obtained in the form of an oil with a yield of 63%.

D. 1-3-Amino-4- [3- (piperidinomethyl-2-pyridyloxy) -propylamino] - !, 2,5-thiadiazole oxide

The mixture is stirred at room temperature for 20 hours and a mixture of 3- (6-piperidi-nomethyl-2-pyridyloxy) propylamine (3.12 g; 11.9 millimoles) [prepared in Stage C] is evaporated to dryness. 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (1.75 g; 11.9 millimoles) in 40 ml of methanol. The residue is subjected to rapid chromatography on 60 g of silica gel (No. 230 - 400, 63 - 38 µm) while maintaining an elution gradient of methylene chloride-methanol containing 0.5% NH ^ OH . The appropriate fractions are combined and evaporated to dryness to obtain a solid which is triturated in acetonitrile. By recrystallization from acetonitrile containing methanol, 1.24 g of the desired compound is obtained, which is in the form of a white solid, m.p. 145-147 °.

Analysis for c ^ gH24N6 ° 2S: calculated C, 52.73; H, 6.64; N, 23.06; S, 8.80% found C, 52.75; H, 6.50; N, 23.23; S, 9.06% EXAMPLE 154 - 3-Amino-4- [3- (6-dimethylaminomethyl-2-pyridyloxy) -propylamino-1,2,5-thiadiazole oxide

The general procedure of Example 153 is repeated, but replacing in stage A piperidine with an excess of gaseous dimethylamine. After rapid chromatography, then recrystallization from acetonitrile containing methanol, the desired compound is obtained with a yield of 44%, m.p. 141-144 °.

Analysis for -c ^ 3H2oN6 ° 2S: calculated C, 48.13; H, 6.21; N, 25.91; S, 9.88% found C, 47.91; H, 5.96; N, 26.36; S, 9.90% EXAMPLE 155 - 1-Oxide of 3 - {. 2 — C (5-dimethylaminomethyl-2-furyl) methylthio] -ethylamino} -4- (3-pyridyl) methylamino-1,2,5- thiadiazole

A solution of 3-aminomethylpyridine (2.02 g; 18.7 millimoles) in 80 ml of methanol is added dropwise over 40 minutes to a partial suspension of 3,4-dimethoxy-1,2,5-1-oxyea. -thiadiazole (3.03 g; 18.7 millimoles) in 150 ml of methanol, after which a solution of 2-C (5-dimethylaminomethyl-2-furyl) methylthio] ethylamine (4.0 g; 18.7) is added millimoles) in 30 ml of methanol. The reaction mixture is stirred at room temperature for 18 hours and the solvent is removed in vacuo. The residue is deposited on 500 g of silica gel (No. 230-400, 63-38 μm) and it is purified by chromatography while maintaining an elution gradient of acetonitrile-methanol. After combining the appropriate fractions, the desired compound is obtained in the form of an amber oil (4.25 g) containing 1 mole of methanol.

Analysis for ciqH24N6 ° 2S2‘CH30H: calculated, 50.42; H, 6.23; N, 18.57; S, 14.17% found C, 49.86; H, 6.14; N, 18.74; S, 14.77% (correction for 1.82% of H 2 O) EXAMPLE 156 - 3-Amino-4- 1-oxide {2 - [(2-furyl) methyloxy] ethylamino} -1.5 -thiadiazole A. 2 - [(2-Furyl) methyloxy] ethylamine

Little by little 50% sodium hydride in mineral oil (4.8 g; 0.1 mole) is added to a cold solution of furfuryl alcohol (9.8 g; 0.1 mole) in 100 ml of di -.... methylformamide and at the end of the evolution of hydrogen, a mixture of 2-chloroethylamine hydrochloride (11.6 g; 0.1 mole) and sodium hydride is added at once. 50% / mineral oil (4.8 g; 0.1 mole) in approximately 60 ml of dimethylformamide. The reaction mixture is stirred at 0 ° for 30 minutes, then at 20 ° for 4 hours. Dimethylformamide is removed in vacuo and the residue is partitioned between methylene chloride and water. The organic phase is evaporated, the residue is redissolved in acetonitrile and extracted with n-pentane. After removal of the acetonitrile, the resulting brown oil is purified by liquid chromatography under preparative high pressure [10 µm porasil, mobile phase: CH2Cl2 (100): 2-PrOH (5.0): NH40H (0.5)] . The appropriate fractions are combined to obtain 4.2 g (30%) of the desired compound.

B. 1-3-Amino-4- ({2- ((2-furyl) methyloxy] ethylamine) oxide) - 1.2.5- thiadiazole

Stir at room temperature for 2.5 hours and store at 0 ° for 16 hours a mixture of 2 - [(2-furyl) methyloxy] ethylamine (0.564 g; 4 millimoles) [prepared in step A] and 1 -3-amino-4-methoxy-1,2,5-thiadiazole oxide (0.589 g; 4 millimoles). The reaction mixture is filtered to collect 0.525 g of the desired compound, m.p. 178-179 °.

Analysis for CgH ^ N ^ O ^ S: calculated C, 42.17; H, 4.72; N, 21.86% found C, 42.15; H, 4.58; N, 21.71% EXAMPLE 157 - 3-Amino-4- (2 - [-5 (dimethylaminomethyl-2-furyl) methyl-thoxyoxy] ethylamino} -1, 2,5-thiadiazole 1-oxide {2- [(2-Furyl) methyloxy] ethyl} phthalimide

2- [(2-furyl) methyloxy] ethylamine (3.2 g; 22.7 millimoles) [prepared in Example 156, stage A] and phthalic anhydride (3.4 g; 23) millimoles) in 50 ml of toluene and the mixture is heated for 1.5 hours in a flask fitted with a Dean and Stark trap. The mixture is concentrated to an oil which is purified by liquid chromatography under preparative high pressure on silica, using methylene chloride as mobile phase. The appropriate fractions are combined to collect 5.2 g of the desired compound in the form of a light yellow oil.

B. N- {2 - [(5 -Dimethylaminomethyl-2 -furyl) methyloxy 3 ethyl} - - 165 - i! i phthalimide

N, N-dimethylmethylene-immonium chloride (1.4 g; 15 millimoles) is added to a solution of Nf.2 - [(2-furyl) methyloxy] ethyl} phthalimide (2.71 g; 10 millimoles) [ prepared in stage A] in 30 ml of acetonitrile and the mixture is stirred at room temperature for 16 hours, then at reflux for 4.5 hours. The solvent is evaporated off and the residue is subjected to partition between methylene chloride and water and basified with I ^ CO ^ - The organic phase is separated and evaporated to obtain a yellow gum. By liquid chromatography under preparative high pressure on silica by means of CH 4 C 4 dOQ): 2-PrOH (3): NH40H (0.5) as mobile phase, 2.6 g of the desired compound are obtained.

C. N-2 - [(5-Dimethylaminomethyl-2-furyl) methyloxy] ethylamine

0.5 ml of hydrazine hydrate is added to the solution of N- {2- [(5 ~ dimethylaminomethyl-2-furyl) methyloxy] -ethylj phthalimide (2.6 g; 7.92 millimoles) [prepared in stage B] in 25 ml of absolute ethanol and the solution is heated to reflux for 1.5 hours. The resulting mixture is filtered and the solvent is evaporated to obtain approximately 2.3 g of gum.

The desired compound is obtained in the form of purity in the form of a jame oil after liquid chromatography under preparative high pressure on silica by means of Cf ^ d ^ dOO): 95% EtOH (5): NH ^ 0H (0 , 05) as mobile phase, the quantity produced being 1.26 g (80.2%).

D. 1-3-Amino-4- ^ ^ 2- [[(5-dimethylaminomethyl-2-furyl) -methyloxy] ethylamino} -1,2,5-thiadiazole

N-2 [(5-dimethylaminomethyl-2-furyl) methyloxy] ethylamine (1.26 g; 6.36 millimoles) [prepared in Stage C] and 3-amino-4-methoxy 1-oxide are mixed -1.2, 2.5-thiadiazole (0.94 g; 6.36 millimoles) in 25 ml of methanol and the mixture is stirred for 20 hours at room temperature, the solvent is evaporated and the amorphous residue is purified by chromatography liquid under preparative high pressure on silica using Cf ^ C ^ dOO): 95% EtOH (10): NH ^ 0H (0.5).

The appropriate fractions are combined and concentrated to collect 1.6 g of product.

The product is dissolved (1.4 g; 4.47 millimoles) in 20 ml of hot methanol and oxalic acid dihydrate (0.56 g; 4.44 millimoles) is added thereto. The solution is inoculated, kept at 0 ° for 16 hours and the desired compound is isolated therefrom in the form of its hyirogeno-oxalate, mp 132-134 °.

Analysis for C] 2Hi9N503S, C2H2 ° 4: calculated C, 41.68; H, 5.25; N, 17.36% found C, 41.73; H, 5.42; Ni, 17.38% EXAMPLE 158 - 1,1-Dipoxide of 3- [2- [(2-guanidino-4-thiazoyl) methylthio] ethyl-amino} -4- (3-pyridyl) methylamino-1,2, 5-thiadiazole

A solution of 2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamine (from the dihydrochloride, 7.0 g; 23 millimoles) in 180 ml of methanol is added dropwise to a partial suspension of 1.1 -3,4-dimetho-xy-1,2,5-thiadiazole dioxide (4.1 g; 23 millimoles) in 400 ml of methanol at 8 °. 3-picolylamine (2.74 g; 25.3 millimoles) is then added and the reaction mixture is stirred at 8 ° for 15 minutes and at room temperature for 20 hours. The reaction solution is evaporated and the residue is subjected to rapid chromatography on 125 g of silica gel (No. 230 - 400, 63 - 38 µm) using CH3CN (90): CH30H (10): NH ^ 0H (0.5) as eluent. A second purification by preparative high pressure liquid chromatography on silica using CH2Cl2 (85): 95% EtOH (15): NH 4 OH (0.5) as mobile phase gives 0.78 g of the desired compound present under the form of a cream-colored foam containing 0.4 mole of ethanol, mp 128-138 ° (foaming).

Analysis for ^ Q> .0.4 (^ OH: calculated C, 40.20; H, 4.57; N, 26.71; S, 20.38% found C, 40.99; H, 4.17; N , 26.56; S, 20.84% (correction for 4.75% of H2O)

The product (180 mg) is dissolved in 12 ml of methanol, the solution is diluted with 6 ml of ether and acidified with dry HCl. The crystalline precipitate is recrystallized from methanol to obtain the dihydrochloride of the desired compound, which is in the form of an colorless solid, mp 206-209 °.

Analysis for C] _5Hj_9N9 ° 2S3. 2HCl: calculated C, 34.22; H, 4.02 '; N, 23.94; S, 18.27; Cl, 13.47% found C, 34.01; H, 3.91; N, 24.07; S, 18.40; Cl, 13.51% (correction for 4.37% of H 2 O) EXAMPLE 159 - 1-3-Amino-4 oxide ~ {2 - [(2- (2-acetylguanidino) thiazol-4-yl) -methylthio] ethylamino} -1,5,5-thiadiazole

A mixture of 3-amino-4- {{2- [(2-gua-nidinothiazol-4-yl) methyl thio] ethylaminoj -1,2,5- is stirred for 3 days at room temperature. thiadiazole [prepared in Example 88] (1.064 g; 2.8 millimoles), 6 ml of methylene chloride, acetylimidazole (7 ml of an IM solution) and triethylamine (0.305 g; 3 millimoles). The resulting solution is diluted with 15 ml of methylene chloaride, washed with water and evaporated to dryness. The crude residue is purified by liquid chromatography under preparative high pressure on silica using C ^ C ^ (500): 95% EtOH (100): NH ^ OH (3) as mobile phase. The appropriate fractions are combined to obtain 0.418 g of the desired compound, m.p. 180-183 ° (decomposition).

Analysis for cnHx5N3 ° 2S3: calculated C, 34.02; H, 4.15; N, 28.86% found C, 34.03; H, 4.51; N, 27.92% EXAMPLE 160 - 3-Amino-4- {{2- [(5-dimethylaminomethyl-3-thienyl) -methylthiojethylamino} -! , 2,5-thiadiazole

Heated to 60 ° (oil bath temperature) for 2 hours and stirred at room temperature for 18 hours a mixture of 2- [(5-dimethylaminomethyl-3-thienyl) methylthio] ethylamine (1.8 g; 7.81 millimoles) and 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide. The solution is concentrated almost to dryness and the crystal residue is deposited! i lin on 155 g of silica gel (No. 230 - 400, 63 - 38 µm) and subjected to rapid chromatography with an elution gradient of methylene chloride-methanol containing 1% NH ^ OH. The appropriate fractions are combined and evaporated to dryness to give 2.07 g of a colorless solid. By recrystallization from acetonitrile, the desired compound is obtained, mp 141-143 °.

Analysis for c12H19N5OS3: calculated C, 41.71; H, 5.54; N, 20.27; S, 27.84% found C, 41.58; H, 5.41; N, 20.41; S, 28.25% EXAMPLE 161 - 3-amino-4- {2 - Oxide - [(5-piperidinomethyl-3-thienyl) -methylthio] ethylamino} -1,2,5-thiadiazole

The general procedure of Example 160 is repeated, but replacing the 2- [(5-dimethylaminomethyl-3-thienyl) methylthio] ethylamine with an equimolar amount of 2- [(5-piperidinomethyl-3-thienyl) methylthio ] ethylamine. After rapid chromatography, the crude product is recrystallized from acetonitrile to obtain the desired compound which is in the form of a colorless solid, mp 143-145 °.

Analysis for ^ 5 ^ 23 ^ 5 ^ 3 * calculated C, 46.72; H, 6.01; N, 18.16; S, 24.95% found C, 46.60; H, 5.73; N, 18.19; S, 24.83% EXAMPLE 162 1- 1- 3-amino-4- {2- [2- ((5-dimethylaminomethyl-4-methyl-2 ~ thienyl) methylthio] ethylamino) -l, 2,5-thiadiazole oxide

The mixture is stirred at room temperature for 18 hours, then a mixture of 2- [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] -ethylamine (3.0 g; 12.3 millimoles) is evaporated to almost dryness and 3-ami-no-4-methoxy-1,2,5-thiadiazole 1-oxide (1.81 g; 12.3 millimoles).

The residual oil is purified by rapid chromatography on 60 g of silica gel (No. 230 - 400, 63 - 38 µm) with an elution gradient of methylene chloride-methanol.

The appropriate fractions are combined, evaporated under reduced pressure and the resulting gum is slowly crystallized by trituration in acetonitrile. By recrystallization of the product from acetonitrile, 3.0 g of the desired compound are obtained, mp 102-110 °.

Analysis for C] _3H2lN5OS3: calculated, 43.43; H, 5.8 ?; N, 19.48; S, 26.76% found C, 43.11; H, 5.75; N, 19.21; S, 26.90% EXAMPLE 163 - 1-S-amino oxide ^ -te-CtS-piperidinomethyl ^ -methyl ^ -thi-nyl) methylthio] ethylamino} -1,2,5-thiadiazole

The general procedure of Example 162 is repeated, but replacing the 2 - [(5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethylamine by an equimolar amount of 2- [(5-piperidinomethyl-4 -methyl-2-thienyl) methyl-thio] ethylamine. The chromatography product is easily crystallized by trituration from acetonitrile, which is recrystallized. Then from 95% ethanol to obtain the desired compound, m.p. 159-162 ° (decomposition).

Analysis for ci6H25N5S30: calculated C, 48.09; H, 6.30; N, 17.53; S, 24.07% found C, 47.82; H, 6.67; N, 17.74; S, 24.21% EXAMPLE 164 - 3-Amino-4-L2- (benzyloxy) ethylamino3-1,2,5-thiadiazole 1-Oxide A. N— [2— (Benzyloxy) ethylHphthalimide

50% sodium hydride in mineral oil (2.4 g; 50 millimoles) is added at 0 ° under nitrogen to a solution of N- (2-hydroxyethyl) phthalimide (9.6 g ; 50 millimoles) in 125 ml of tetrahydrofuran and after 20 minutes, an excess of benzyl chloride (12.7 g; 0.1 mole) is added. The resulting mixture is stirred at room temperature for 68 hours, the solvent is removed and the residue is partitioned between methylene chloride and water. The organic layer is dried over magnesium sulfate, evaporated to dryness and the solid is redissolved in acetonitrile. By extraction of the solution with n-pentane, then evaporation of the acetonitrile, a yellow oil is obtained. This oil is dissolved in approximately 80 ml of hot absolute ethanol, the solution is filtered and cooled to obtain 8.35 g (59.2%) of the desired compound which is in the form of a crystalline solid, PF 69 -71 °.

Analysis for C ^ H ^ j-NO ^: calculated C, 72.58; H, 5.38; N, 4.99% found C, 72.45; H, 5.40; N, 5.33% B. 2- (Benzyloxy) ethylamine

The product from stage A (8.3 g; 29.5 millimoles) is dissolved in 100 ml of absolute ethanol, hydrazine hydrate (1.65 g; 33 millimoles) is added thereto and the mixture is heated. at reflux for 4 hours. The mixture is filtered and the filtrate is concentrated to collect 1.8 g of a yellow oil. The solids are separated by filtration and dissolved in dilute potassium hydroxide, then the solution is extracted with methylene chloride, the extract is dried and evaporated to give a further 3.0 g of oil. The two residues are combined and purified by liquid chromatography under preparative high pressure on silica using methylene chloride (95.5): 2-propanol (4): NH ^ 0H (0.5) as eluting. The appropriate fractions are combined and evaporated to collect 4.3 g of the desired compound in the form of an almost colorless oil.

C. 1-3-Amino-4- [2- (benzyloxy) ethylaminoj-1,2,5-thia-diazole oxide

The mixture is stirred at ambient temperature for 20 hours, then a mixture of 2- (benzyloxy) ethylamine (4.23 g; 28 millimoles) [prepared in stage B] and of 3-amino-4-methoxy 1-oxide is filtered. -1.5, 2.5-thiadiazole (4.12 g; 28 millimoles) in 100 ml of methanol. The mother liquor is concentrated to obtain a second harvest which is recrystallized from methanol in order to obtain the desired compound, m.p. 200-203 ° (decomposition) in a total amount of 6.37 g (83%).

Analysis for ci2.H14N4 ° 2S * calculated C, 49.61; H, 5.30; N, 21.04% found C, 49.67; H, 5.01; N, 21.37% EXAMPLE 165 - 3 - [3 - (3-1,2-dihydroxy) propylamino] -4- [3- (3-dimethyl-aminomethylphenoxy) propylamino] -1,2,5-thiadiazole oxide

A solution of 3- (3-dimethyl-aminomethylphenoxy) propylamine (3.0 g; 14.4 millimoles) in 30 ml of methanol is slowly added to a cold suspension of 1,2-3,4-dimethoxy-1,2-oxide , 5-thiadiazole (2.34 g; 14.4 millimoles) in 80 ml of methanol and the solution is stirred at room temperature for 70 minutes. The 85% 3-amino-1,2-propanediol / glycerol system (1.54 g; 14.4 millimoles) in 15 ml of methanol is then added and stirring is continued for 20 hours. The solvent is removed under reduced pressure and the residue is triturated in acetonitrile. After filtration, the product is deposited on 100 g of silica gel (No. 230 - 400, 63 - 38 ^, um) and subjected to rapid chromatography with an elution gradient of methylene chloride-methanol containing 1.5% NH ^ OH. The appropriate fractions are combined, evaporated to dryness and the crystalline residue is triturated in acetonitrile to obtain 2.45 g (43%) of the desired compound in the form of a white solid, mp 146-148 °. .

Analysis for C ^^^ NgO ^ S: calculated C, 51.37; H, 6.85; N, 17.62; S, 8.07% found C, 51.04; H, 6.81; N, 17.97; S, 8.36% EXAMPLE 166 - 3-Amino-4- [3- (3-diallylaminomethylphenoxy) propyl-arnino] - hydroxide 2,5,-thiadiazole A. 3- (N, N-diallylaminomethyl) phenol

Sodium borohydride (8.0 g; 0.21 mole) is added to a mixture of 3-hydroxybenzaldehyde (48.85 g; 0.4 mole) and diallylamine (47.22 g; 0.486 mole) and heated gradually mixing up to 100 °. 200 ml of absolute ethanol are then added at a rate which maintains moderate reflux and evolution of hydrogen. The refluxing is continued for 1 hour, then a concentration is carried out under vacuum. The residual oil is partitioned between ether (300 ml), petroleum ether (300 ml) and 1N aqueous NaOH (450 ml). The organic phase is discarded and the aqueous phase is acidified with 70 ml of concentrated HCl.

The aqueous phase is washed several times with ether, then again alkalinized with concentrated NH 4 OH. The product is extracted into several ether fractions, the ethereal solution is washed with water and dried. After evaporation of the solvent, 17.2 g of the desired compound are obtained, which is in the form of an oil.

B. 2 — j3— [3- (N, N-Diallylaminomethyl) phenoxy] propyl} -lH-isoin- dole-1,3 (2H) dione

The crude product from Stage A (17.1 g; 84.2 millimoles) in 20 ml of dimethylformamide is added in several fractions to a suspension of 55% sodium ihydride (3.93 g; 90 millimoles) in 100 ml of dry dimethylformamide and the mixture is stirred until the evolution of gas has ended. N- (3-bromopropyl) phthalimide (24.66 g; 92 millimoles) is then added and stirring is continued for 18 hours. An additional 4.0 g (15 millimoles) of N- (3-bromopropyl) phtaclimide and 435 mg (10 millimoles) of sodium hydride at 55% are added, then the mixture is heated at 40-50 ° for 3 hours. The reaction solution is partitioned between ether (200 ml) and water (400 ml) and the organic phase is extracted with 80 ml IN HCl. The extract is neutralized with ammonium bicarbonate, it is in turn extracted with ether-pentane (3: 2) and the organic solution is filtered through a layer of 12 g of silica gel. By evaporation of the solvent, 23.74 g of the desired compound are obtained, which is in the form of an oil.

Analysis for C24H26N2 ° 3: calculated, 73.82; H, 6.71; N, 7.17% found C, 73.79; H, 6.82; N, 6.97% C. 3- (3-Aminopropoxy) -N, N-diallylbenzenemethanamine

The medium is left to stand for 18 hours at room temperature, then a solution of the phthalimide prepared in Stage B (9.76 g; 25 millimoles) and of hydrazine solution at 64 is heated at 55 ° for 2 hours. % (6.25 g; 125 millimoles) in 50 ml of absolute ethanol. The mixture is filtered and the ethanol is removed under reduced pressure. The residual oil is dissolved in ether and the solution is filtered through a layer of celite-silica gel (5.0 g) to obtain, after concentration under vacuum, 4.92 g of the product in the form of a colorless oil, P.Eb. 120-130 ° / 0.02 mm Hg (2.7 Pa).

Analysis for C] _gH24N2 ° calculated C, 73.80; H, 9.29; N, 10.76% found C, 73.32; H, 9.30; N, 10.27% D. 1-3-Amino-4- [3- (3-diallylaminomethylphenoxy) pro-pylamino] - !, 2,5-thiadiazole oxide

The mixture is stirred at room temperature for 60 hours, then a mixture of 3- (3-aminopropoxy) -N, N-di-allylbenzenemethanamine [prepared in Stage C] (1.3 g; 5 millimoles) and 1- is filtered. 3-amino-4-methoxy-1,2,5-thiadiazole oxide (0.735 g; 5 millimoles) in 10 ml of methanol. The filtrate is concentrated to a syrupy residue which is stirred for 20 minutes with 10 ml of acetonitrile. The solid which has separated is collected by filtration, it is dissolved in methylene chloride (95): methanol (5) and the solution is filtered on a layer of silica gel (25 g). By washing it with additional eluent and evaporating the filtrate, a semi-solid is obtained. The desired compound is collected in the form of a white solid by trituration in acetonitrile, m.p. 134-137 °.

Analysis for ci8H25N5 ° 2S: calculated C, 57.59; H, 6.71; N, 18.65% found C, 57.20; H, 6.46; N, 18.30% EXAMPLE 167 - 3-amino-4- [3- (3-dipropylaminomethylphenoxy) propyl-aminoj-1,2,5-thiadiazole A-3- (3-Aminopropoxy) -N, N-dipropylbenzenemethanamine

A solution of 3- (3-aminopropoxy) -N, N-diallylbenzenemethanamine (2.6 g; 10 millimoles) [prepared in Example 166, Stage C] in 20 ml of ahsolated ethanol is subjected to hydrogenation by means 0.40 g of 5% palladium-on-carbon under a hydrogen pressure of 380 kPa until the end of absorption. The mixture is filtered, concentrated in vacuo and the residue is distilled to obtain 2.1 g (79%) of the desired compound in the form of a colorless oil, P.Eb. 114-11870.02 mm Hg (2.7 Pa).

Analysis for C] _gH28N20: calculated C, 72.68; H, 10.67; N, 10.60% found C, 70.78; H, 10.39; N, 10.07% B. 3-Amino-4- [3- (3-dipropylaminomethylphenoxy) -propylamino] -1,2,5-thiadiazole

The general procedure of Example 166, stage D is repeated, but replacing 3- (3-aminopropo-xy) -N, N-diallylbenzenemethanamine with an equimolar amount of 3-6-aminopropoxy) -N, N-dipropylbenzenemethanamine [prepared in stage A]. The purified product is recrystallized from methylene chloride-acetonitrile to obtain, with a yield of 40%, the desired compound, m.p. 136-138 °.

Analysis for cigH29N5 ° 2S: calculated C, 56.97; H, 7.70; N, 18.46% found C, 56.28; H, 7.69; N, 18.77% EXAMPLE 168 - 3-amino-4- [2- (3-piperidinomethylbenzyloxy) ethyl-amino] -1,2-thiadiazole A. 2- (3-Piperidinomethylbenzyloxy) ethylamine oxide

3-piperidinomethylbenzyl alcohol (6.16 g; 30 millimoles) [prepared according to the general process of Belgian Patent No. 867,106, but replacing di-methylamine with piperidine] is added to the suspension of 50% sodium hydride in mineral oil (3.0 g; 60 millimoles) in 50 ml of dimethylformamide and the mixture is stirred for 30 minutes at room temperature, then cooled to -20 °. 2-chloroethylamine hydrochloride (3.48 g; 30 millimoles) is then added, the cooling bath is removed and stirring is continued for 3 hours. The solvent is removed in vacuo and the residue is subjected to partition between ether and water. The organic phase * is extracted with 30 ml of IN HCl, the aqueous phase is made alkaline with concentrated NH4OH and extracted with ether, to obtain, after drying and evaporation, * 5.1 g of an oil. The crude mixture is purified by liquid chromatography under preparative high pressure on silica using methylene chloride (100): 2-propanol (20) rNH ^ OH (0.5) as mobile phase. The appropriate fractions are combined to obtain 2.12 g of the desired compound after vacuum distillation, P.Eb. 124-126 ° / 0.02 mm Hg (2.7 Pa).

B. 1-3-Amino-4- [2- (3-piperidinomethylbenzyloxy) -ethylamino] - !, 2,5-thiadiazole oxide

The mixture is left to stand at ambient temperature for 20 hours, then a mixture of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (0.441 g; 3 millimoles) is heated at 50 ° for 2 hours and of 2- (3-piperidinomethylbenzyl-oxy) ethylamine (0.744 g; 3 millimoles) [prepared in stage A] in 11 ml of methanol. The solvent is removed in vacuo and the residual amorphous solid is crystallized from dichloromethane-acetonitrile-ether. Finally, the product is washed with water and with acetonitrile to obtain the desired compound in the form of the monohydrate, m.p. 98-103 °.

Analysis for C17H25N5 ° 2S * H2O: calculated C, 53.52; H, 7.14; N, 18.36% found C, 53.69; H, 6.91; N, 18.48% EXAMPLE 169 - 3-Amino-4- [3- (piperidinomethylphenoxy) ethylamino] oxide - 1,2,5-thiadiazole A. 3-Piperidinomethylphenoxy-acetonitrile

The general procedure of exan-pie 168, stage A, is applied, but replacing the 2-chloroethylamine hydrochloride with an equimolar amount of chloroaceous-tonitrile. After continuing operations, the crude product is distilled under vacuum to obtain, with a yield of 85.7%, the desired compound, P.Eb. 87-92 ° / 0.02 mm Hg (2.7 Pa). Analysis for c ^ 4H ^ gN20: calculated C, 73.01; H, 7.88; N, 12.16% found C, 72.95; H, 8.08; N, 12.02% B. 2- (3-Piperidinomethylphenoxy) ethylamine

A solution of 3-piperidinomethylphé-noxy-acetonitrile (3.16 g; 13.6 millimoles) in approximately 15 ml of tetrahydrofuran is added to a suspension of aluminum hydride (prepared from 1.04 g; 27, 4 millimoles of lithium aluminum hydride and 0.76 ml of concentrated f ^ SO ^ in 70 ml of tetrahydrofuran) and the mixture is stirred at room temperature for 2 hours. Then add saturated sodium sulfate (3.1 ml) drop by drop, then add a small amount of IN NaOH, after which the mixture is heated for 2 hours, solid sodium sulfate is added to it and the insolubles are separated by filtration. The tetrahydrofuran is replaced by methylene chloride, the organic phase is washed with dilute NaOH and the solvent is evaporated to obtain the compound. sought which is of high purity. An aliquot is distilled under vacuum to obtain a colorless oil, P.Eb. 120 ° / 0.03 mm Hg (4 kPa).

Analysis for cp4H22N20: calculated, 71.75; H, 9.46; N, 11.96% found C, 70.98; H, 9.53; N, 11.34% C. 1-3-Amino-4- [3- (piperidinomethylphenoxy) ethyl- ^ arnino] - !, 2,5-thiadiazole oxide

It is heated to about 50 ° in an oil bath for 3 hours, then stirred at room temperature for 17 hours a mixture of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (0, 75 g; 5 millimoles) and 2- (3-piperidinome-thylphenoxy) ethylamine (1.17 g; 5 millimoles) [prepared in stage B] in 25 ml of methanol. The precipitated crystals are collected by filtration, which are washed and dried to obtain 1.20 g of the desired compound which is of very high purity, mp 191-192 ° (decomposition)

Analysis for ci6H23N5 ° 2S: calculated C, 54.99; H, 6.63; N, 20.04% found C, 54.69; N, 6.67; N, 19.88% EXAMPLE 170 - 3-amino-4- [3- (3-piperidinomethylthiophenoxy) propyl-amino] -1,2,5-thladiazole A-m-dithiobenzoyl chloride

A mixture of m-dithiobenzoic acid (20.8 g, 67.9 mmol) [prepared according to the method described in J. Chem. Soc., London, 119, 1792 (1921)] and thionyl chloride (200 ml), the mixture is filtered and the excess SOCl ^ is removed in vacuo.

B. Dithio bis-3,31-N, N-di (piperidino) benzenecarboxamide

The crude product from Stage A, dissolved in 100 ml of tetrahydrofuran, is added dropwise at 3 ° to a solution of piperidine (25.1 g; 0.29 mole) in 500 ml of tetrahydrofuran. The mixture is stirred at room temperature for 76 hours and poured into 1500 ml of dilute HCl (about 2N). After 1 hour, the product is extracted into ether and the solution is washed successively with water, 1N aqueous NaOH and water. The solvent is evaporated to obtain 26.4 g of the desired compound.

C. 3- (Piperidinomethyl) thiophenol

A solution of dithio bis-3,3 '-N, N-di (piperidino) benzenecarboxamide (141.5 g; 0.32 mol) [prepared in Stage B] is added dropwise in a nitrogen atmosphere. 2200 ml of ether to a suspension of lithium aluminum hydride (45.3 g; 1.19 mole) in 2200 ml of ether and the mixture is stirred for 20 hours at room temperature. The mixture is decomposed by adding a saturated solution of sodium sulphate, filtered and the filter cake is stirred with 3000 ml of water. A solution of citric acid monohydrate (550 g; 2.62 moles) in 550 ml of water is added and the pH of the solution is adjusted to 2 with 12N HCl, then to 8 with ammonium hydroxide concentrated. The solution is extracted exhaustively with ether to obtain 120 g of solid.

An aliquot of the desired compound is recrystallized from isopropanol to obtain the product melting at 121-123 °; mass spectrum 206 (M +).

Analysis for C ^ Hj ^ NS: calculated C, 69.56; H, 8.21; N, 6.76; S, 15.46% found C, 69.02; H, 8.03; N, 6.67; S, 15.06% D. N- {3- [3- (Piperidinomethyl) thiophenoxy] propyl) phthalimide

A mixture of 3- (piperidinomethyl) thiophenol (1.0 g; 4.82 millimoles) [prepared in step C] and N- (3-bromopropyl) phthalimide (1, 1 g; 4.15 millimoles) in 5 ml of dry dimethylformamide. The solvent is evaporated off under reduced pressure and the crude oil is purified by rapid chromatography on 75 g of silica gel (No. 230 - 400, 63 - 38yUm) while maintaining an elution gradient of methylene chloride-methanol containing 0 , 5% of NH ^ OH as eluent. After combining the appropriate fractions, the product chromatographed in isopropanol is recrystallized to obtain the desired compound in the form of its bromhydra-te, mp 188-192 °.

Analysis for ^ 2 gN2 ° 2 S * HBr calculated C, 58.10; H, 5.72; N, 5.89; Br, 16.81% found C, 57.79; H, 5.41; N, 5.73; Br, 16.80% E. 3- (3 -Piperidinomethylthiophenoxy) propylamine

Hylrazine hydrate (26.9 g; 0.54 mole) is added to a solution of N- {3- [3- (piperidinome-thyl) thiophenoxy] propyl} phthalimide hydrobromide (58.0 g; 0.12 mol) [prepared in Stage D] in 1650 ml of 95% ethanol and the reaction mixture is heated to 45 ° for 4.5 hours. The mixture is diluted with 500 ml of ether, filtered and the filtrate is evaporated to dryness to obtain the desired compound which is in the form of an amber oil (14.1 g). An aliquot is distilled to obtain a colorless oil, m.p. 154-155 ° / 0.15 mm Hg (20 Pa).

Analysis for ci5H24N2S: calculated C, 68.13; H, 9.15; N, 10.59% found C, 67.37; H, 9.07; N, 10.94% F. 1-3-Amino-4- [3- (3-piperidinomethylthiophenoxy) -propylamino] -1,2,5-thiadiazole oxide

A mixture of distilled 3- (3-piperidinomethylthiophenoxy) propylamine (0.855 g; 3.23 millimoles) [prepared in Stage E] and 3-amino 1-oxide is heated for 4 hours in an oil bath at 55 °. 4-methoxy-1,2,5-thiadiazole (0.532 g; 3.6 millimoles) in 12 ml of methanol. The solvent is evaporated in vacuo and the semi-solid residue is recrystallized from α-ketonitrile to obtain 0.83 g of the desired compound in the form of colorless crystals, mp 142-145 °. Analysis for: calculated C, 53.80; H, 6.64; N, 18.45; S, 16.90% found C, 53.63; H, 6.65; N, 18.64; S, 17.03% EXAMPLE 171 - 3-Methylamino-4- [3- (3-piperidinomethylthiophenoxy) -propylamino] - !, 2,5-thiadiazole A 1-oxide suspension of 3,4- dimethoxy-1,2,5-thiadiazole (1.35 g; 7.56 millimoles) in 250 ml of methanol, a solution of 3- (3-piperidinomethylthiophenoxy) propylamine (2.0 g) is slowly added at room temperature. ; 7.56 millimoles) [prepared in Example 170, stage E] in 100 ml of methanol. Gaseous methylamine is bubbled through the solution for 10 minutes and stirring is continued at room temperature for 16 hours. The reaction solution is concentrated almost to dryness and the residue is purified by rapid chromatography on 150 g of silica gel (No. 230 - 400, 63 - 38 ^ um) using the system G ^ Cl ^ OS) ΐΟΗ ^ ΟΗίδ ): NH ^ 0H (0.5) as eluent. The appropriate fractions are combined, evaporated to dryness and the residue is crystallized from absolute ethanol. By recrystallization from methanol, 1.41 g of the desired compound are obtained, which is in the form of a colorless solid, m.p. 137-140 °.

- 180 -

Analysis for cigH27N5OS2 * calculated C, 54.93; H, 6.91; N, 17.80; S, 16.29¾ found C, 55.11; H, 6.63; N, 17.89; S, 16.55%

EXAMPLE AA

1-3-t2-Oxide - [(5-dimethylaminomethyl-2-furyl) methylthio 3-ethylamino} -4- (6-methyl-3-pyridyl) -methylamino-1,2,5-thia-diazole

A methanolic solution of 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethyl laminate (2.14 g; 0.01 mol) is added dropwise over 45 minutes to a cold solution of 1-oxide of 3, 4-dimethoxy-1,2,5-thiadiazole (1.6 g; 0.01 mole) in 75 ml of methanol, then a solution of 6-me-thyl-3-aminomethylpyridine (2.05 g; 0) , 0105 mole) in 35 ml of methanol. The reaction solution is stirred at room temperature for 18 hours, evaporated and the crude product is purified by rapid chromatography on 95 g of silica gel. The resulting solid is triturated with ether to obtain the desired compound in the form of an off-white solid, m.p. 115-121 °.

Claims (36)

1. Compound of formula (s0) p / "D \ URM, A- (CH2) mZ (CH2) I1RH · B1 where p represents 1 or 2; ïP" represents a hydroxyl radical or E2 and each independently represent an atom of hydrogen or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower), cycloalkyl (lower) alkyl (lower), hydroxyalkyl (lower), alkoxy (lower) alkyl (lower), alkylthio radical (lower) -alkyl (lower), aminoalkyl (lower), alkyl (lower) -aminoalkyl (lower), dialkyl (lower) aminoalkyl (lower), pyrrolidinoalkyl (lower), piperidinoalkyl (lower), xnorpholinoalkyl ( lower} piperazinoalkyl (lower), pyridylalkyl (lower), amino, alkyl (lower) amino, dialkyl (lower) amino, 2,2,2-trifluoroethyl, 2-fluoroethyl, hydroxyl, alkoxy (lower), 2,3 -dihydroxypropyle, cyano, cy ano alkyl e (lower), amidino, alkyl (lower) -amidino, Α'-ίΟΗ ^^, Ζ '(CI ^). ^, -, phenyl, phenylalkyl (lower), substituted phenyl o u substituted (lower) phenylalkyl, the phenyl ring of which may carry one or two substituents chosen independently from the alkyl (lower), hy- droxyl, alkoxy (lower) and halogen atoms radicals or a substituent chosen from the methylenedioxy and triluoromethyl radicals and amino (lower) dialkyl, with the restriction that B2 and cannot both represent cycloalkyl (lower), phenyl, substituted phenyl, amino, alkyl (lower) amino, dialkyl (lower) -amino, hydroxyl, alkoxy (lower), cyano, amidino, 2 alkyl (lower) amidino or A'-CCH ^^ "Z '; or B and jß can together represent a radical -CI ^ CH ^ X (CH2) χ-; r represents 1, 2 or 3; X represents a methylene radical, a sulfur or oxygen atom or a ϋ-Ε * radical with the restriction that when r represents 1, X represents a methylene radical; B ** represents a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), alkanoyl (lower) or benzoyl radical; m and m 'each independently represent 0; 1 or 2; a and n 'each independently represent 2, 3 or J *; Z and Z 'each independently represent a sulfur or oxygen atom or a methylene radical; A and A 'each independently represent a phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, fuxyl, thienyl or pyridyl radical, it being understood that A and A' can independently comprise one or two substituents, the first substituent being chosen from halogen atoms and alkyl radicals (lower), hydroxy-le, trifluoromethyl, amino, hydroxymethyl, alkoxy (lower), HER1 * - (CH0) „N = C / and - (CH-) NE ^ E6, 2. Xk 2 Q. ΗΗΙΓ and the second substituent being chosen from halogen atoms and alkyl (lower), hydroxyl, trifluoromethyl, amino, hydroxymethyl and alkoxy (lower) radicals; q represents 0, 1, 2, 3S 5 or 6, each radical IL * being independently as defined above or else the two radicals E ^ together forming an ethylene radical, and B ** and B ^ independently represent an atom d hydrogen or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower) or phenyl radical, 5 6 with the restriction that E and E cannot both represent cycloalkyl (lower) or phenyl radicals; or else B '* and B ^ taken together with the nitrogen atom to which they are united may represent a pyrrolidino, morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino radical; as well as a non-toxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide of such a compound. 2. Compound according to claim 1, in the formula of which E ^ represents an EE ^ E ^ radical. 3. Compound according to claim 1 or 2, in the formula of which p represents 1 or 2 represents an EE2E3 B ** radical and E ^ independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl radical. (lower), cycloalkyl (lower) alkyl (lower), pyridylalkyl (lower), (CHg) ^, -, phenylalky-le (lower) or 3.1 * - methylenedioxybenzyl, with the restriction that E ^ and I? cannot both represent radicals. A'-CCH ^^ iZ '(C ^) ^, -; m and m ’each independently represent O or 1; n and n * each independently represent 2 or 3; Z and Z 'each independently represent an oxygen or sulfur atom or a methylene radical; A and A ′ each independently represent a phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl radical, it being understood that A and A ′ may independently comprise one or two substituents, the first substituent being chosen from (lower) alkyl radicals, ___ 56 -K = C. and -CHpNE? E °, - ^ EHE4 · and the second substituent being chosen from alkyl radicals (lower); s each B ** independently represents a hydrogen atom or an (lower) alkyl radical or else the two E ** together represent an ethylene radical, B '* and E ^ each independently represent a hydrogen atom or a (lower) alkyl radical or else B and E ^ taken together with the nitrogen atom to which they are united may represent a pyrrolidino, morpholino, piperidino, methylpiperidino, 1-methylpiperazino or homopiperidino-1 radical. - Compound according to any one of claims 1 to 3 corresponding to the formula ^ 3 V // ^ ngh2-A A-ÇH2ZCÏÏ2CH2EH ee2e3 ch3 ^ O where p represents 1 or 2, Z represents a sulfur atom or a methylene radical, ï £ and E? each independently represent a hydrogen atom or an alkyl radical (lower) or else when represents a hydrogen atom, E ^ can also represent an alkenyl (lower), alkynyl (lower), phenylalkyl (lower), cycloalkyl (lower) radical ) alkyl (lower), pyridylmethyl or represents a hydrogen atom or a methyl radical. 5. Compound according to any one of claims 1 to 3 corresponding to the formula (0) P STS o ^ ε *> '11' H v H CE2ZCH2CE2I® KITE3 where p represents 1 or 2 »Z represents a sulfur atom or a methylene radical, k each B independently represents a hydrogen atom or methyl radical or "else the two E ^ taken together can represent an ethylene radical, E2 and E ^ each independently represent a hydrogen atom or an alkyl radical (lower ) or when B2 represents a hydrogen atom, can also represent an alkenyl (inferior), alkynyl (lower), pyridylmethyl, H ζ y "= c / 3_" / Vehp -CH2CH SGEf * -CH2CH2SCH2 '-2 radical 6. Compound according to any one of claims 1 to 3 corresponding to the formula ** • 3 s (0) p / 2 \\ Vf NE ch3 CH2ZCH2CH2EH 'EB2 ^ - 186 - where p represents 1 or 2; Z represents a sulfur atom or a methylene radical, E2 and B3 each independently represent a hydrogen atom or an alkyl radical (lower) or "else when E2 represents a hydrogen atom, fi3 can also represent an alkenyl radical (lower ), alkynyl (lower) or rCH2CH2SCH2 "JE" * - 3 represents a hydrogen atom or a methyl radical. 7. Compound according to any one of claims 1 to 3 corresponding to the formula <°> PKN E13 n — y // ^ IÎCH2- ^ CH2ZCH2CH2im ^ ^ NE2®3 çh3 ^ S where p represents 1 or 2, Z represents a sulfur atom or a methylene radical, E2 and E3 each independently represent a hydrogen atom or an (lower) alkyl radical or else when I? represents a hydrogen atom, B3 can also represent an alkenyl (lower), alkynyl (lower), phenyl-alkyl (lower), pyridylmethyl, 3, V-methylenedioxÿben-zyle or CH2N ^ radical; S 3 E13 represents a hydrogen atom or a methyl radical. - 187 - 8. Compound according to any one of claims 1 to 3 having the formula H .0¾ (0) / V 1 N ïï \ J. W ^ CHgSOHgCHgKH ^ Kï ^ B3 where p represents 1 or 2, B2 and B3 each independently represent a hydrogen atom or an (lower) alkyl radical or else when E2 represents a hydrogen atom, B3 can also represent an alkenyl radical (lower), alkynyl (lower) or H GErCji -CBgCEgSCHg ^ N 9. Compound according to any one of claims 1 to 3 corresponding to the formula C °) p B K <XJf ^ BCHg — CHg ZCHgCHgKH ^ ^ BB2 ^ £ where p represents 1 or 2; Z represents a sulfur atom or a methylene radical, E2 and B3 each independently represent a hydrogen atom or an alkyl radical (lower) or else when B2 represents a hydrogen atom, B3 can also represent an alkenyl radical (lower) , alkynyl (lower) or A -ch2ch2 zoh2 - \ ^ J- ch2n ^ ^ 5 6 E and B each independently represent a hydrogen atom or an alkyl radical (lower). 10. Compound according to any one of claims 1 to 3 corresponding to the formula (6% E · fl I ^ _ // ^ NCHg — OCH2CH2CH2HH NB2 !? y where p represents 1 or 2, E2 and each independently represent an atom of hydrogen or an alkyl radical (lower) or hien when P2 represents a hydrogen atom "E? can also represent an alkenyl radical (lower), alkynyl (lower) or y * 5 -ge2ge2ce2o \ ^ Lcs2iî ^ 6 E ^ and E ^ each independently represent a hydrogen atom or an alkyl radical (lower), or hien when B represents a hydrogen atom, B ^ can also represent an alkenyl (lower) or alkynyl radical (lower) ), or also E ** and E ^, taken together with the nitrogen atom to which they are united, can represent a pyrrolidino, morpholino, piperidino or homqpiperidino radical. 11. A compound according to claim 1 which is the 1,1-di oxide of 3 ~ 12 - [(5-dimethyl aminomethyl-2-furyl) -methylthio] ethylaminoj -! * - (n-propyl) amino-1,2 , 5-thiadiazole. 12. A compound according to claim 1 which is 3 ”1,1-dioxide {.2_ [(5-dim ethy1 atninomethyl-2-furyl) -methylthio) ethylaminoj -V-amino-1,2,5-thiadiazole. 13. A compound according to claim 1 which is 3 “1,2-dioxide [2” [(2-guanidinothiazol-1 * -yl) methylthio] ethylamino] -V-amino-1,2,5-thiadiazole. Il * · - Compound according to Claim 1, which is 3- [2 _ [(5-dimethylaminomethyl-2-thienyl) -methylthio] ethylamino) -if-methylamino-1,2,5-thiadiazole 1,1-dioxide. 15. A compound according to claim 1 which is the 1-oxide of 3_a ™ i ^ 0 _ ^ “[2 ~ [(2-Eu ^ iàiBOthiazol-h - yl) - m ethyl t hi o] é thyl amino] -1 , 2,5-thi adi az ol e - 16. A compound according to claim 1 which is 3-amino-1 + -j 2 - / (Z-guanidinc-thiazol - ^ - yl) -methylthio / ethylaminoj-1, 2, 5-thiadiazole monohydrate. 17. The compound of claim 1 which is 3-amino-V- ^ 2 - / (2-guanidino-thiazol-h — yl) -methylthio-ethylamino | -l, 2,5-thiadiazole hydrochloride . 18. A compound according to claim 1 which is 3-amino-3-amino-1 * - £ 2- [(2-dimethylaminomethyl-1-thiazolyl) methylthio] ethylamino) -1,2,5-thiadiazole. 19. A compound according to claim 1 which is 3-amin-V- [3- (3-dimethylaminomethylphenoxy) - 1-oxide; propylamino] -1,2,5-thiadiazole. 20. A compound according to claim 1 which is 3-methylamino-1-1,1-dioxide * · - [3 ”(3_piperidinomethyl-phenoxy) pr opyl amino] -1,2,5-thiadiaz ol e. 21. A compound according to claim 1 which is 3-amino-1 + oxide - [3- (3-piperidinomethylphenoxy) pro-pylamino) -1,2,5-thiadiaz ole. 22. Compound of formula - 190 - ο N Κ \ _II η s where each B 'represents a halogen atom or an alkoxy (lower) or alkylthio (lower) radical or a • phenoxy or phenylthio radical which can carry 1 or 2 substituents chosen from halogen atoms and alkyl (lower), alkoxy (lower) and nitro- radicals 23. I "e 1-oxide of 3 ^" d-imethoxy-1,2,5-thiadiazole. 2 \ - Compound of formula (0) p BH B12 B7 where p represents 1 or 2, η B represents an eliminable radical chosen from halogen atoms and alkoxy (lower), alkyl-thio (lower), phenoxy, phenylthio, substituted phenoxy and phenylthio radicals, the phenyl ring of which can carry 1 or 2 substituents chosen from halogen atoms and radicals alkyl (lower), alkoxy (lower) and nitro, B ^ 2 represents a radical A (CH2) ffiZ (CH2) nÏÏH- »I ^ B ^ B- or HSCCH ^ ÏÏH- where ^ B2 and E? each represent independently a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower), cycloalkyl (lower), alkyl (lower), hydroxy alkyl (lower), alkoxy radical (lower) alkyl (lower), alky 1 thi o (lower) -alkyl (lower), aminoalkyl (lower), alkyl (lower) -aminoalkyl (lower), dialkyl (lower) aminoalkyl (lower) , pyxrolidinoalkyl e (lower), piperoyinoalkyl (lower), moipholinoalkyl (lower), piperazinoalkyl (lower), pyridylalkyl (lower), amino, alkyl (lower) -amino, dialkyl (lower) amino, 2,2,2-trifluoroethyl, '2-fluoroethyl, hydroxyl, aikoxy (lower), 2,3-dihydroxypropyl, cyano, cyanoalkyl (lower), amidino, alkyl- (lower) amidino, A'-iCH ^) ^, Z' (CH2) nt -, phenyl, phenyl-alkyl (lower), substituted phenyl or substituted phenylalkyl (lower) of which the phenyl ring can carry one or two substituents independently chosen from the alkyl (lower), hydroxyl, alkoxy (lower) and halogen atoms radicals or a substituent chosen from the methylenedioxy, trifluoromethyl and dialkyl (lower) amino radicals, with the restriction that B2 and cannot both represent cycloalkyl (lower), phenyl, substituted phenyl, amino, (lower) amino, di- alkyl (lower) amino, hydroxyl, alkoxy (lower), cyano, amidino, alkyl (lower) amidino or Α ' -ίΦ ^^, Ζ * (CHg) ^ -; or B2 and B ^ taken together can represent a radical -CH ^ HgXiCHg) ^ -; r represents 1, 2 or 3, Σ represents a methylene radical, a sulfur L or oxygen atom or an IJ-B radical, η - with the restriction that when p represents 2 and B represents a methoxy radical, B2 and E? taken together with À - the nitrogen atom to which they are united cannot represent a morpholino radical and that when r represents 1, X represents a methylene radical; represents a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), alkanoyl (lower) or benzoyl radical; _ 109 _ π. and a 'each independently represent 0, 1 or 2; n and n 'each independently represent 2, 3 or 4; Z and Z 'each independently represent a sulfur or oxygen atom * or a methylene radical; * t A and A 'each independently represent a phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyie, oxadiazolyl, furyl, thienyl or pyridyl radical, it being understood that A and A' can independently comprise one or two substituents, the first substituent being chosen from halogen atoms and alkyl (lower), hydroxyl, trifluoromethyl, amino, hydroxymethyl, alkoxy (lower) and NHE * - (CH0) N = C ^ and - (CH ~) ÏHeAb6 radicals 2 <1 \ u 2 Q. bhh * and the second substituent being chosen from halogen atoms and alkyl (lower), hydroxyl, trifluoromethyl, amino, hydroxymethyl and alkoxy (lower) radicals; q represents 0, 1, 2, 3, ^ 5 or 6; each independently is as defined above or the two B * 1- together represent an ethylene radical, and B "* and E ^ each independently represent a hydrogen atom or an alkyl (lower), alkenyl (lower) radical , (lower) alkynyl, (lower) cycloalkyl or phenyl, with the restriction that E ^ and E ^ cannot both represent cycloalkyl (lower) or phenyl radicals or else B '* and E ^ taken together with the atom d nitrogen to which they are united can represent a pyrro-lidino, morpholino, piperidino, methylpiperidino, K-methyl-piperazino or homopiperidino radical, as well as a Bel, hydrate, solvate or N-oxide of such a compound 0 · 25. Compound of formula:]; "" n HS (CH2) nNH ^ ^ HE2! ^ Where p represents 1 or 2; n represents 2, 3 or bz E2 and each independently represents a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), cycloalkyl (lower), cycloalkyl (lower) alkyl (lower) radical ), hydroxyalkyl (lower), alkoxy (lower) alkyl (lower), alkylthio (lower) al-kyle (lower), aminoalkyl (lower), alkyl (lower) ami-noalkyl (lower), dialkyl (lower) aminoalkyl (lower ), pyrrolidinoalkyle (lower), piperidinoalkyle (lower), morpholinoalkyle (lower), pipérazinoalkyle (lower), pyridylalkyle (lower), amino, alkyl (lower) amino, dialkyl (lower) amino, 2,2,2-trifluoroethyl, 2 -fluoro-ethyl, hydroxyl, alkoxy (lower), 2,3-dihydroxypropyl, cyano, cyanoalkyl (lower), amidino, lower (alkyl) ami-dino, A '- (CH2) m, Z' (CH2) j1i -, phenyl, pheny3 (lower) alkyl, substituted phenyl or substituted (lower) phenylalkyl in which the phenyl ring can carry one or two: substituents chosen independently from i halogen atoms and alkyl (lower), hydroxyl and alkoxy (lower) radicals or a substituent chosen from methylenedioxy, tri-fluoromethyl and dialkyl (lower) amino radicals, with the restriction that E2 and cannot all represent two of the cycloalkyl (lower), phenyl, substituted phenyl, amino, alkyl (lower) amino, dialkyl (lower) amino, hydroxyl, alkoxy (lower), cyano, amidino, lower (alkyl) amidino or '-ÎCHg radicals 2 '(CH2) n' -, or E2 and taken together can represent a radical -CH ^ CE ^ X (CH2); r represents 1, 2 or 3 "\ X represents a methylene radical, a sulfur or oxygen atom or a K-E ^ radical, with the restriction that when r represents 1, X-represents a methylene radical; B1 * represents a hydrogen atom or an alkyl (lower), alkenyl (lower), alkynyl (lower), alkanoyl (lower) or benzoyl radical; m 'represents 0, 1 or 2; n 'represents 2, 3 or Z' represents a sulfur or oxygen atom or a methylene radical; A 'represents a phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadia-zolyl, oxadiazolyl, furyl, thienyl or pyridyl radical, it being understood that A' may comprise one or two substituents, the first substituent being chosen from halogen atoms and radicals alkyl (lower), hydroxyl, trifluoro-methyl, amino, hydroxymethyl, alkoxy (lower), UHE1 * · - (0 ^) ^ = 0 ^ and - (CH2) qKE5E6,; ^ ÎÎHE1 * · and that the second constituent is chosen from halogen atoms and alkyl (lower), hydroxyl, trifluorethyl, amino, hydroxymethyl and alkoxy (lower) radicals; q represents O, 1, 2, 3, 5 or 6; each E ^ independently is as defined above k or the two E taken together may represent an ethylene radical; TS? and B ^ each independently represent a hydrogen atom or an alkyl (lower), slkenyl (lower), alkynyl (lower), cycloalkyl (lower) or phenyl radical, with the restriction that B 'and B cannot represent v * both have cycloalkyl (lower) or 5 6 phenyl radicals, or By and B taken together with the nitrogen atom to which they are united may represent a pyrrolidino, morpholino, piperidino, methylpiperidino, lî- methyl-piperazino or homopiperidino, as well as a hydrated, solvated or l-oxide salt of such a compound. 26. Pharmaceutical composition, characterized in that it comprises, as main active constituent, a compound according to any one of claims 1 to 21 in the form of the base or in the form of a pharmaceutically acceptable non-toxic acid addition salt, in combination with a pharmaceutically acceptable excipient. 27. Composition according to Claim 26, characterized in that the active constituent is the 1-oxide of 3-ami no-if- [p— [(2-guanidinothiazol-l * -yl) inethylthio] ethyl-amino} -l , 2,5-thiadiazole monohydrate. 28. Composition according to claim 26, characterized in that the active constituent is the chlor- hydrate of 1-oxide of 3 ~ amino ~ V ~ {2- [(2-guanidinothiazol- 1 V-)l) -methylthio) ethylaminoj -1,2,5-thiadiazole. 29. Method for inhibiting gastric secretion in humans and animals, characterized in that a pharmaceutical composition according to any one of claims 26 to 28 is administered in a therapeutically effective amount. 30. A process for the preparation of a compound according to any one of claims 1 to 21, in the formula of which E ^ represents a radical NE2 »3, characterized in that a compound of formula is reacted: (? P NHMB? V where p represents 1 or 2 n each B 'represents a halogen atom or an alkoxy (lower) or alkylthio (lower) radical or phenoxy or phenylthio radical which can carry 1 or 2 substituents chosen from halogen atoms and radicals alkyl (lower), alkoxy (inferror) and nitrp, successively with a compound of formula A (jCH,) Z (CH,) NH9 or A '(CH9) .Z4CH9), NH9 2m 2n2 2m' 2 n1 2 and with a compound of formula 2. HNR R or vice versa, in an inert solvent, and if the thing is desired, the resulting product is converted into a non-toxic pharmaceutically acceptable salt, hydrate, solvated t or N-oxide according to a conventional technique. 31. Process according to claim 30, in case 9 where ES represents a radical AÎCHp ^ ZiCHgXjEHg, characterized in that the reaction is carried out in one stage with two -, equivalents of the compound of formula A (CE9) -Z (CH9) EHQ. b ci Ifl, tL H t— 32. Process for the preparation of a compound according to V * · 4 claim 1 in the formula of which B ^ represents a hydroxyl radical, characterized in that a compound of formula: (0) p NSN M jP V is reacted where p represents 1 or 2, each B 'represents a halogen atom or a radical - alkoxy (lower) or alkylthio (lower ·) or a phenoxy or phenylthio radical which can carry 1 or 2 substituents chosen from halogen atoms and alkyl (lower), alkoxy (lower) and nitro radicals first with 1 equivalent of a compound of formula A (0H2) n2 (0H2) I1MH2 in an inert organic solvent, after which the resulting product is reacted with 1 potassium, lithium or sodium hydroxide and, if desired, the resulting product is conventionally converted to a non-toxic pharmaceutically acceptable salt, hydrate, solvate or K-oxide. 33. Process for the preparation of a compound according to any one of claims 1 to 21, in the formula of which E1 represents a radical -2iE2B ^, characterized in that (l) a compound of formula is reacted: (0) Vp X E7 E7 where p represents 1 or 2, each E7 represents a halogen atom, a radical Λ <· alkoxy (lower) or alkylthio (lower) or a phenoxy or phenylthio radical which can carry 1 or 2 substituents chosen from halogen atoms and the alkyl (lower), alkoxy (lower) and nitro radicals, in two stages and in any order, with compounds of the formulas HS (CHg ^ ïïHg and HNR2R3 where n represents 2 or 3, in a solvent inert organ, and (2) the resulting compound is reacted with a compound of formula Mcs2) ni where 2 represents a fluorine, chlorine, "bromine or iodine atom or a radical B11 represents an alkyl radical (lower) , phenyl or methylated or "brominated phenyl, O ^ SF, acetoxy or 2,1t-dinitro-phenoxy in the presence of a hase and, if desired, the resulting product is conventionally converted to a pharmaceutically acceptable, non-toxic salt, hydrate, solvate or oxide. 34. Process according to claim 30, characterized in that the compound of formula: (O) c P N N M 7 7 j R R is reacted with an approximately -equimolar amount of compound of formula: 2. HNR R then with an approximately equimolar amount of compound of k ζ formula: i '* A (CH „) Z (CH ~) NH- Z m Z η Z 35. Process according to claim 34, characterized in that the intermediate compound is isolated, then reacted with the compound of formula: A (CH-) Z (CH-) NH-2 m 2 n 2