CS244411B2 - 3,4-diamino-1,2,5-thiadizole derivatives preparation method - Google Patents

Description

(54) A process for pH preparation of 3,4-diamino-1,2,5-thiadiazole derivatives

A process for the preparation of 3,4-diamino-1,2,5-thiadiazole derivatives of the general formula I

R-A-W-N

(IV) (I) or in any order and optionally converting the obtained compounds to a physiologically acceptable salt.

The compounds of formula I exert an antisecretory effect.

wherein W is - (CH ₂ ) -X- (CH ₂ ) _f - or - or a physiologically acceptable salt thereof comprising reacting a compound of formula II (ol '

with an amine of formula III R-AW-NH ₂ (II) (III) and in reaction of the resulting compound with an amine of formula V IV

24441,

The invention relates to a process for the preparation of 3,4-diamino-1,2,5-thiadiazole derivatives.

Acidic gastric secretion inhibitors, acting through histamine H2-receptor antagonism, are effective anti-ulcer agents. Structurally, these compounds are considered to have 3 substituents or groups, i.e., A-B-C, each of which can independently affect the entisecretory efficacy. Part A may be a substituted or unsubstituted aromatic or heteroarometric group, as disclosed, for example, in US Patent 3,950,333, Durant et al, US Patent 4,128,658, Price et al, and Belgian Patent 867,106 (Derwent Abstract 84065A / 47).

The central or B moiety may be a linker attached to the group A as A-CH 3 Cl 2 CH 2 -, AOCH 3 Cl 2 CH 3 or A- (m-phenylene) as disclosed in the aforementioned patents and European Patent 3,640, Jones et al (Derwent Abstract 61827 B (34)).

The remaining terminal substituent C is structurally different from the A and B moieties and may be, for example, substituted guanidine, substituted 1,1-diaminoethylene, or 3,5-diamino-1-alkyltriazole, as disclosed in the aforementioned US patents, Durant et al. et al and in Belgian patent 87 5 846 (Derwent. Abstract 79110 B (44)).

The invention is directed to a part C which produces antisecretory activity when coupled to A-3 molecular moieties. These new structural V elements are the 3,4-diamino-1,2,5-thiadiazole-1-oxide and 3,4-diamino-1,2,5-thiadiazole-1,1-dioxide group, by incorporating these groups into the AB The molecular moiety yields compounds which exhibit substantially greater potency. than known prior art compounds such as those described in the US, Belgian and European patents as described above.

The invention relates to a process for the preparation of 3,4-diamino-1,2,5-thiadiazole compounds having one of the amino groups attached to a substituted or unsubstituted phenyl or heterocyclic moiety by a linear or cyclic linking group.

The present invention provides a process for the preparation of 3,4-diamino-1,2,5-thiadiazole derivatives of the formula I

NN _n .

RAWN - ¹ - L N < ¹

R ₂ (I) wherein W is - (CH ₂ ) _n -X- (CH ₂ ) - or and P is hydrogen, alkyl of 1 to 5 carbon atoms,

wherein R 1 and R 2 are independently hydrogen, C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl or C 1 -C 5 phenylalkyl in the alkyl moiety or R 1 and R 2 together with the nitrogen to which they are attached form attached, a 5- or 6-membered heterocycle which optionally contains an additional oxygen, sulfur or Ν-Ηγ group, where R? is hydrogen, alkyl of 1 to 3 carbon atoms or benzyl,

R 6 and R 8 are independently hydrogen or alkyl of 1 to 5 carbon atoms, n is 0 or 1,

24441) na is 2 to 4, k is 1 to 4,

X is oxygen, sulfur or methylene, p is 1 or 2,

E ₁ and R ₂ independently of one another denote hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, alkynyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, pyridyl or substituted alkyl of (C 1 -C 5) wherein the substituent is phenyl, C 3 -C 7 cycloalkyl, pyridyl, imidazolyl, morpholino, hydroxy, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio or C 1 -C 5 dialkylamino the carbon atoms in each alkyl moiety, or R 1 and R ₂ , together with the nitrogen to which they are attached, form a 5- or 6-membered heterocycle, which optionally also contains an oxygen, sulfur or NR? group, where Ry is as defined above, benzofuranyl, phenylene or a five-membered or six-membered heterocycle containing 1 to 3 oxygen, sulfur or nitrogen atoms, which is optionally condensed with a benzene ring, provided that when A is a five-membered heterocycle or benzofuranyl, n is 1, and physiologically acceptable salts thereof, characterized in that a compound of formula II (ol) is reacted

P

(ii) wherein p is 1 or 2 and L, and Lg are terminal groups such as C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, phenoxy or phenylthio, in an aprotic solvent at a temperature in the range of -78 to 50 ° C, with an amine of general formula III wherein W is

RA W-NH ₂

- (III) or

- (CH ₂ ) _n - X - (CH ₂ ) _{m and} R, A, n, Xamme as defined above, and the resulting compound is reacted at 0 to 100 ° C with an amine of formula IV

H-N

(IV) wherein R 1 and R 1 are as defined above, or the compound obtained in any order is optionally converted into a physiologically acceptable hall.

The term alkyl of 1 to 5 carbon atoms includes a straight or branched configuration. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl or the like.

Examples of C 3-7 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

C 3 -C 5 alkenyl has in its straight or branched configuration one unsaturated bond. Examples of such alkenyl groups are propenyl, butenyl, pentenyl, and the like.

The term C 3 -C 5 alkynyl encompasses straight or branched chain configurations with one triple bond. Examples of such alkynyl groups are propargyl, butynyl, pentynyl and the like.

Preferred compounds of formula I are those wherein R 1 and R 8 are independently hydrogen, alkyl of 1 to 5 carbon atoms, alkynyl of 3 to 5 carbon atoms, or substituted alkyl of 1 to 5 carbon atoms, wherein the substituent is phenyl, pyridyl, or imidazolyl, and R 1 and R 2 are independently hydrogen, C 1 -C 5 alkyl or P 1 and R 2 are joined to form a piperidine, morpholine or a C 1-6 alkyl-piperazine heterocyclic ring.

Other preferred compounds are those wherein R, 5 carbon atoms and p are 1 or 2.

and R 1 is independently hydrogen or alkyl of 1 to 5 carbon atoms

Other preferred compounds are those wherein the A ring as above, n is 0, X is oxygen, m is 3, and is m-phenylene or a six-membered heteroarr R is

-CCH _{2) k} -N

wherein k is 1 and R 1 and R 1 is alkyl of 1 to 5 carbon atoms, preferably methyl, or are linked to form a morpholine, piperidine or N-methylpiperazine ring.

Another preferred value of Substituent A is furan, imidazole, thiazole, oxazole, thiophene, triazole, thiadiazole, oxadiazole or benzofuran.

When A is a heterocycle, it is preferred that n = 1, X is sulfur and r-2.

Preferred values of R depend on and vary ae as defined in A.

When A is benzofuran, R is preferably

- (CH

2'k

Wherein k = 1 and R1 and R2 are hydrogen, or alkyl of 1 to 5 carbon atoms, preferably hydrogen, or methyl, or are linked to form a morpholine, piperadine or N-methylpiperazin ring.

When A is imidazole ,. Preferably R is alkyl of 1 to 5 carbon atoms, more preferably methyl.

When A is thiazole, R is preferably:

^NHR 5

-N = Cnhr ₆ wherein Rej and Rg are most preferably hydrogen.

It is further preferred that the phenyl ring of Formula I, is to the adjacent group in the metha-position.

is connected

Specific examples of preferred compounds of the invention are:

3-N- (2 - ((5-diethylethylaminoethyl-2-furanyl) (ii) ethylthio) -ethyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- (2- (η 5 -diethylaainofflethyl-2-furanyl / methylthio) -methyl) amino-4-methylamino-1,2,5-thiadiazole-1,1-dioxide

3-N- (2 - ((2-furanyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2- (2-guanidino-4-thiazolyl / methylthio) ethyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- (2 - ((5-dimethylaminomethyl-2-furanyl / ethylthio) -ethylaaino) -4-dimethylaaino-1,2,5-thia diazole-1-oxide

3-N- (3- (2-guanidino-4-thiazolyl) phenyl) aaino-4-methyl-aaino-1,2,5-thiadiazole-1-oxide

3-N- (3- (2-guanidino-4-thiazolyl) phenyl) amino-4-methylamino-1,2,5-thiadiazole-1,1-dioxide

3-N- (2- (5-diaethylaainomethyl-2-furanyl / methylthiolethyl) aaino-4- (2-propynyl) aaino-1,2,5-thiadiazole-1-oxide

3-N- (2- (5-dimethylaainomethyl-2-furanyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2- (2-guanidino-4-thiazolyl) methylthio) ethyl) amino-4-aethylamino-1,2,5-thiadiazole-1,1-dioxide

3-N- (3- (3- (dimethylaminomethyl) phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2 - ((3- (diaethylaainomethyl / phenyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N-13- (3- (dimethylaminomethyl / phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- (3- (3- (1-piperldinylmethyl) phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- (3- (3- (4-methyl-1-piperazinyl / methyl) phenoxy) propyl) amino-4-methylaraino-1,2,5-thiadiazole-1-oxide

3-N- (3- (3- (4-morpholinomethyl / phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- (3- (3- (4-morpholinomethyl / phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3_N_ (2- (4-Methyl-5-ifflidazolyl / methylthio) ethyl) araino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- (2- (4-methyl-5-imidazolyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N-C 2 - ((5- (1-piperidinylmethyl) -2-furanyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-K- (2 - ((5- (4-morpholinylmethyl) -2-furanyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (3- (3- (dimethylaminomethyl / phenoxy) propyl) amino-4-amino-1,2,5-thiazole-1-oxide

3-N- (3- (3- (1-piperidinylraethyl / phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

2444.1

3-11- (3- (3- (4-morpholinylaethyl / phenoxy) propyl) amino-4-amino-, 2,5-thiadiazole-1-oxide

3-N- (2 - ((6- (4-morpholinylmethyl) -2-benzofuranyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2- (2-guanidino-4-thiazolyl / methylthio) ethyl) amino-4-1,2,5-thiadiazole-1-oxide

3-14- (3- (2-guanidino-4-thiazolyl) phenyl) amino-4-amino-1,2,5-thladiazole-1-oxide

3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) araino-4-amino-2,5-thiadiazole-1,1-dioxide

3-H- (3- (3- (dimethylaminomethyl) phenoxy) propyl) amino-4-amino-, 2,5-thiadiazole-1,1-dioxide

3-N- (2- ((6- / 4-Mor morpholinyl / ^{-2-benzofuranyl,} furanyl) methylthio) ethyl) and n! Amino-4-awino-, 3,5-thiadiazole-1,1- dioxide

3-N- (3- (2-guanidino-4-thiazolyl) phenyl) amino-4-amino-1,2,5-thiadiazole-1,1-dioxide

3-N- (2 - ((6- (4-morpholinyl) -2-benzofuranyl) methylthio) ethyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- [3- (3- (dimethylaminomethyl) phenoxy) propyl] amino-4-methylamino-1,2,5-thiadiazole-1,1-dioxide

3-N- (2 - ((2-guanidino-4-thiazolyl / methylthio) ethyl) -araino-4-cyclohexylamino-1,2,5-thiadiazole-1-oxide

3-N- (2- (η 5 -dimethylaminomethyl-2-furanylmethylthio) ethyl) amino-4-phenylamino-1 *: 2,5-thiadiazole-1 --dioxide

3-N- (2 - ((6- (4-morpholinyl) -2-benzofuranyl) methylthio) ethyl) amino-4- (2-pyridylamino) -1,2,5-thiadiazole-1-oxide

3-N- (2- (4-methyl-5-imidazolyl / methylthio) ethyl) araino-4-: phenylethylamino-1,2,5-thiadiazole-1-oxide

3-N- (3- (3- (4-morpholinylraethyl / phenoxy) propyl) amino-4-cyclohexylmethylamino-1,2,5-thiadiazole-1,1-dioxide

3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) -ethyl) amino-4- ((2-pyridylmethyl) amino) -1,2,5-thiadiazole-1,1-dioxide

3-N- (3- (3-diraethylaminomethyl / phenoxy) propyl) amino-4- (2- (3-pyridyl) ethyl) amino-1,2,5-thiadiazole-1-oxide

3-N- (3- / 2-guanidino-4-thiazolyl / phenyl) amino-4- (2/1 -imidazolyl / ethyl) amino-1,2,5-thiadiazole-1,1-dioxide

3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4- (2-methoxyethyl) amino-1,2,5-thiadiazole-1-oxide

3_M_ (2 (η 2 -Glididin-4-thiazolyl / methylthio) ethyl) amino-4-dimethylaminoethyl-1,2,5-thiadiazole-1,1-dioxide

3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4- (1-piperidino) -1,2,57

-thiadiazole-1-oxide

3-N- (2- (η 5 -dimethylaminomethyl ^- 2-furanyl / methylthio) ethyl) amino-4-ethoxy-1,2,5-thiadiazole-1-oxide

3-N- (2- (η 5 -diethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-ethoxy-1,2,5-thiadiazole-1,1-dioxide

3-N- (3- (5-dimethylaminomethyl-2-furahyl / methylthio) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (4 - ((5-dihylethylaminoethyl) -2-furanyl / -ethylthiobutyl) amino-4-methylamino-1,2,5-thiadiazole-1,1-dioxide

3-N- (3- (3- (dierathylarainowethyl) phenylthio) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2- (3- (4-morpholinyl-methylphenyl / methylthio) -ethyl) araino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- (4- (3-dimethylaminophenyl) butyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide

3-N- (2 - ((5- (2-N-methylaminoethyl) -2-thienyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (3- (6-aorfolinylmethyl-2-pyridinyloxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2 - ((5- / 2-methylguanidino (-1,2,4-thiadiazol-3-yl) methylthio) ethyl) amino-4-araino-1,2,5-thiadiazole-1,1 -dioxide

3-N- (2- (5-guanidino-1,2,4-oxadiazol-3-yl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2 - ((6- (dimethylaminomethyl) -2-pyrazinyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1,1-dioxide

3-N- (2- (5-methyl-4-oxazolyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2- (6- (dimethylaminonethyl) -2-benzo (b) thienylmethylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1,1-dioxide

3-N- (3- (5- (N-ethylamino) methyl-3-pyridyloxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

The compound of formula II is reacted with the compound of formula III preferably in an aprotic solvent such as tetrahydrofuran, acetonitrile, ethyl acetate, ether and the like in the range of -78 to 50 ° C, preferably -78 to 0 ° C. The reaction proceeds rapidly and is completed rapidly. Generally, the gaseous amine is bubbled into the reaction mixture for sufficient time to complete the reaction, preferably 1 equivalent of amino is added over 5 minutes to two hours. The solid or liquid amine is added in portions over the same time. The progress of the reaction can be monitored by removing aliquots of the reaction mixture and analyzing them by thin layer chromatography. After completion of the reaction, the reaction mixture is allowed to warm and the product is obtained using a technique known in the literature.

The reaction with the second amine is generally slower than with the first amine. In each case, the reactivity is determined but depends on the individual thiadiazole substrate and the nature of the reacting amine.

The reaction with the second amine is carried out in a protic or non-protic solvent such as methanol, ethanol, ether, ethyl acetate, tetrahydrofuran and the like. The reaction is generally carried out in the range of 0-100 ° C and is completed in 5 minutes to 6 days. If the desired reaction temperature is higher than the boiling point of the reaction mixture, the reaction can be carried out in a pressure vessel. Reactions with thiadiazole sulfones are generally faster than those with the corresponding sulfoxide, and reactions with sulfones are generally completed in a shorter time and at a lower temperature than sulfoxides. The product is isolated using a technique known in the literature.

Thiadiazole starting materials, wherein p is 2, with two end groups, are compounds generally known in the art. E.g. viz. Carmack et al. J. Org. Chem. 30, 2743 (1975).

Complex amines which react with thiadiazole as starting material are also known in the art. See, e.g., Durant et al., Price et al. And Jones et al., Which references have been incorporated in the introduction to the invention.

It is understood, however, that other amines as starting materials similar to those in the above references can be prepared using the procedures described in these references.

Thiadiazole starting materials, wherein p is 1, with two terminal groups are unknown compounds of the prior art. These compounds are prepared by reacting a suitably substituted oxalimidate or oxalthioimidate with ε thionyl chloride.

wherein L, and X > ₂ are as previously defined.

Suitably the disubstituted oxalimidate or oxalthicimidate is reacted with thionyl chloride in the presence of a base to neutralize the hydrogen chloride released during the reaction. The base may be any organic or inorganic base which does not react with any starting material or product. Generally, tertiary amines such as triethylamine and pyridine or inorganic bases such as alkali metal carbonate or bicarbonate are used. The reaction of the component is generally dissolved in a suitable solvent such as methylene chloride, chloroform, toluene, ether, tetrahydrofuran, acetonitrile or the like or any other solvent that is not reactive. The reaction is conducted at a temperature between -78 ⁰ / dry ice bath / 100 ° C or the reflux temperature of the reaction mixture. The reaction is preferably carried out at a temperature in the range of 0 ° C to room temperature and is generally complete within 1/2 to 10 hours. Thionyl chloride is generally used in a slight excess, although larger amounts of the reactant are not detrimental.

The intermediates obtained from these major thiadiazole starting materials, where p is 1, are also novel and can be expressed by the following formula V

wherein a / R, and Rg are the same and are C1 -C5 alkoxy, C1 -C5 alkylthio, phenoxy or phenylthio, or b / R6 and R8 are different and one of Rj or Rg is amino or alkylamino. having 1 to 5 carbon atoms and the other is a halogen or alkylthio group having 1 to 5 carbon atoms, or c / R, and R g are different and one of R 1 and R g is as defined in (a) and the other is

R.

wherein R 3 and R 6 are independently hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, alkynyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, pyridyl, substituted alkyl of 1 to 5 C 5 -C 5 -alkyl, wherein the substituent is phenyl, C 3 -C 7 cycloalkyl, pyridyl, imidazolyl, morpholino, hydroxy, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio or C 1 -C 5 dialkylamino Or R and together with the nitrogen to which they are attached form a five-membered or 5-carbon atom;

Six-membered heterocyclue, which may also contain as heteroatom oxygen, sulfur or N-Rg, such as morpholine, thiomorpholine, piperidine, piperazine, N-alkyl piperazine of 1 to 5 carbon atoms

O (VI) wherein R j, R g, R j and R 6 may independently be hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, alkynyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, pyridyl, or substituted alkyl of 1 to 5 carbon atoms, wherein the substituent is amino, phenyl, substituted phenyl, cycloalkyl of 3 to 7 carbon atoms, pyridyl, alkoxy of 1 to 5 carbon atoms, imidazolyl, morpholino, hydroxy, a C 1-5 dialkylamino group in each alkyl moiety or R 6 and R 6 together with the nitrogen to which they are attached form a five-membered or six-membered heterocycle, which may also contain, as heteroatom, oxygen, sulfur or N-R 3, such as morpholine, thiomorpholine , piperidine, piperazine, N-C 1 -C 5 alkylpiperazine, and pyrrolidine, wherein R 8 is hydrogen or C 1 -C 3 alkyl.

The compounds of the invention readily form physiologically acceptable salts. Such salts include salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, nitrates and phosphonates. Particularly useful organic acid salts are formed with aliphatic mono- or dicarboxylic or sulfonic acids. Examples of such salts are acetates, maleicates, fumarates, tartrates, citrates, benzoates, succinates, methanesulfonates, and isothionates. The compounds and their salts may also form hydrates and solvates. In addition, it can also form a nitrogen atom in the groups R, k, R, and Rg of quaternary salts and N-oxides.

The compounds of the invention may form tautomeric isomers of the nitrogen atoms adjacent to the thladlazole ring. When one or both adjacent nitrogen atoms have a hydrogen atom, an exo-imino structure may be formed on one or both of these nitrogen atoms, as shown in the following structure:

In addition, when p is 1, there is a possibility of stereoisomerism corresponding to the absolute R or S configuration of the thiadiazole ring sulfur atom in these compounds.

As noted above, the compounds of Formula I have been found to exhibit pharmacological activity in animals as antagonists of a particular histamine activity that is not blocked by antihistamines such as mepyramine. E.g. it was found to selectively inhibit histamine-stimulated gastric acid secretion in the stomach of dogs by chronic fistula at a dose of 0.001 to 5 mg per kg intravenously or orally at a dose of 0.01 to 10 mg per kg. Similarly, the effect of these compounds is demonstrated by their antagonism on the effect of histamine on other tissues not affected by histamine H1 antagonists. An example of such tissue is the isolated right atrium of the guinea pig.

These compounds were found to be up to 200 times more potent in experimental animals than commonly used gastric antisecretory H2 antihistamines.

The pharmaceutical carrier used may be, for example, a solid or a liquid. Examples of solid carriers are lactose, kaolin, sucrose, calf, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water, and the like.

Various pharmaceutical forms can be used. If a solid carrier is used, the preparations may be tabletted, placed in a hard gelatin capsule as a powder or in the form of a pill, or in the form of a lozenge. The amount of solid carrier may vary within wide limits, but the preferred range is 15 mg to 0.4 g. When a liquid carrier is used, the compositions may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution as ampoules or aqueous or nonaqueous liquid suspensions.

The pharmaceutical preparations are prepared in a conventional manner, such as by mixing, granulating and compressing or dissolving the ingredients, according to the desired preparation.

The active ingredient is in the composition in an effective amount to inhibit histamine-induced gastric acid secretion. The route of administration may be oral or parenteral.

Preferably, each daily dose contains the active ingredient in an amount of 1 mg to 500 mg, most preferably in the range 20 mg to 200 mg, to be administered in a single dose or in several divided doses.

For therapeutic use, the pharmacologically active compounds of the invention are normally administered as pharmaceutical preparations containing as an active ingredient at least one of this compound in the elderly form or in the form of an addition salt with a pharmaceutical carrier.

Other pharmacologically active compounds may be. included in the product in certain cases. It may be desirable to combine the compound or compounds of the invention with anticholinergic agents such as propanthelinera, H, antihistamines such as mepyramine, pyribenzamine chlorpheniramine and the like, or prostanoids.

Preferably, the composition is formulated in a unit dosage form suitable for the desired mode of administration, for example, as a tablet, capsule, or injectable solution.

The following examples illustrate the process of the invention without limitation.

Example 1

3-N- (2- (5-dimethyl-9-fluoroethyl-2-furanyl / methylthio) -ethyl) amino-4-methylaraino-1,2,5-thiadiazole-1-oxide hydrochloride

And 3-ethoxy-4-methylamino-1,2,5-thiadiazole-1-oxide

Anhydrous methylamine (7.7 g, 0.25 mol) was dissolved in 100 mL of tetrahydrofuran while cooling with dry ice acetone. The cold solution was added dropwise to the 3,4-diethoxy-1,2,5-thiadiazole-1-oxide in 250 mL of tetrahydrofuran with stirring at -15 ° C over 1 1/2 hours. Stir for an additional hour at -15 ° C and remove the solvent in the bag. · The beige solid residue is purified by chromatography on silica gel (100 g): using chloroform * Almost white substance (39.6 g) melts at 91-92 Deň: 32 ° C.

Infrared valence vibrations - 1 095 cc for the S »O n -checked magnetic rasonance spectrum for thiadiazole-1-oxide carbons: delta = 163.34,

157.36

B 3-N- (2- (η 5 -diethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-aethylamino-1,2,5-thiadiaaol-1-oxide hydrochloride

To a stirred solution of 1.76 g (10.0 mmol) of 3-ethoxy-4-methylamino-1,2,5-thiadiazole-1-oxide in 25 mL of methylene chloride and added 2.14 g (10.0 amoles) of 2- (Η 5 -diethylamino-ethyl-2-furanyl) methylthio) ethyl amine. The mixture was stirred for 3 days at room temperature under nitrogen and concentrated in vacuo. The residue is redissolved in a minimum amount of methylene chloride and the residue is chromatographed on a dry aluminum oxide activity III column. 1-2 * Merge mixtures methane - CH ₂ C1 ₂ to give the free base of the title compound, which was dissolved in 1 equivalent 1N aqueous hydrochloric acid and the solution filtered through a filter with an additive, and the filtrate aa lyofillzuje. The residue is dissolved in a mixture of 4 parts of tetrahydrofuran with one part of absolute ethanol and cooled to give a hygroscopic white substance which is filtered and dried under vacuum at 60 ° C to give 3-M- (2- (η 5 -dimethyl-aalnomethyl) 2-furanyl (methylthio) ethyl) amino-4-methyl-amino-1,2,5-thiadiazole-1-oxide hydrochloride as the tetrahydrofuran solvate. (amorphous). The sample exhibits a correction nuclear magnetic rasonance spectrum (DgO) and my Infrared Valence Vibration (KB _f ) of 1,050 cm -1 for S 0 O.

Example 2

3-N- (2- ([5-dimethylaminomethyl-2-furanyl / methylthlo) -thyl) -a aloo-4-methylaaino-1,2,5-thiadlazole 1,1-dioxide hydrochloride

1. 3-Oethoxy-4-mothylamino-1,2,5-thiadlasol-1,1-dloxal

X of a solution of 20.06 g (10.0 amoles) of 3,4-dlothoxy-1,2,5-thiadlasol-1,1-dioxld in 25 [mu] l of additions and add 0.8 g of a 40% solution of aothylalanine in water. The resulting clear colorless solution α was allowed to stand for 16 hours at room temperature and concentrated in vacuo. The residue was stirred in 25 L of methylene chloride and filtered to give 0.35 g of a mixture of the title compound and 3,4-bia-aethylamino-1,2-5-thiadlazole-1,1-dioxide. The filtrate is chromatographed on alumina III and the desired compound is eluted with 29% asthanol-a-alala-chloro mixture to give 0.65 g (34%) of pure 3-ethoxy-4-aylamino-1,2,5-thiadiazole. -1,1-dioxide, m.p.

Mp 160-161 ° C.

B 3-N- (2- (η 5 -methylaminomethyl-2-furanyl / asthylthio) ethyl) aaino-4-methylaalno-1,2,5-thiadiasol-1,1-dloxide hydrochloride hydrate

X stirring a suspension of 3-ethoxy-4-asthylaaino-1,2,5-thiadiazole-1,1'-dloxide (0.65 g,

3.4 amol) in 10 [mu] l methylene chloride was added 0.73 g (3.4 amol) of 2- (5-diaothylaainoasthyl-2-furanyl) methylthio) athylaine. The suspension was stirred under nitrogen at room temperature and clarified after 2.5 hours. After 1.5 days, the mixture was concentrated in vacuo and the residue chromatographed on alumina activity III as in Example 2A. The free bee of the desired compound is dissolved in 1 equivalent of 1N hydrochloric acid, and the residue is filtered by filtration additive and lyophilized and attracted to 3-N- (2- (5-diaethylaminomethyl-2-furanyl / ethylthlo) ethyl) aaino-4-methyl-alano -1,2,5-thiadiazole-1,1-dioxide hydrochloride as a hydrate, which is dried under vacuum at 60 ° C (amorphous). The hygroscopic substance exhibits a corrective nuclear magnetic roaonance spectrum (O ₂ O) and my infrared valence vibration (XBr) of 1 155 and 1 305 cm ^-1 for SO ₂ ·

Example 3

3-N- (2-guanldino-4-thiazolyl / methylthio) ethyl) -aaino-4-methyl-amino-1,2,5-thiadiazole-1-oxide

To a stirred solution of 3.3 g (14 mole) of 2- ((2-guanidin-4-thiazolyl) methylthio) ethylamine in 25 L of ethyl acetate and 5 L of absolute ethanol was added 2.5 g (14 mmol) of 3-ethoxy- 4-methylamino-1,2,5-thiadiazole-1-oxide. The resulting suspension was stirred under nitrogen at room temperature for 16 hours at which time the gum gradually solidified to a solid which was filtered off to give 5.1 g (100%) of the crude title compound. Recrystallization from water containing small amounts of ethanol gave a white solid, mp 169-171 ° C (dec.) Identified as 3-N- (2 - ((2-guanidino-4-thiazolyl) methylthio) ethyl) amino-4-methylamino- l, 2,5-thiadiazol-t-oxide which exhibits the correction reaonanční nuclear magnetic spectrum (D ₂ °> DC1) and an infrared stretching vibration (KBr) I ca 030 ^'1 to S> 0th

Example 4

3-N- (2- (N-dimethylaminomethyl-2-fluoro / methylthio) -ethyl) amino-4-dimethylamino-1,2,5-thiadiazole-1-oxide

A. 3-N- (2- (η 5 -methylaninomethyl-2-furenyl) ethylthio) ethyl) amino-4-ethoxy-1,2,5-thiadiazole-1-oxide

Dissolve 3,4-diethoxy-1,2,5-thiadiazole-1-oxide (1.9 g, 1.0 aaol) in 10 mL of tetrahydrofuran and add dropwise a solution of 2 - ([5- (5- dimethylaminomethyl-2-furanyl / methylthio) ethylemine (2.14 g, 10 aaol) in 10 [mu] l tetrahydrofuran. The solution is stirred overnight at room temperature. Removal of the solvent in vacuo affords a viscous amber oil. Chromatography on silica gel (50 g) using 5% ethanol in chloroform provided 3) 6 g.

3-H- (2- (η 5 -dimethylaminomethyl-2-furanyl / methylthio) ethyl) aaino-4-ethoxy-1,2,5-thiadiazole-1-oxide as a viscous oil. Analysis of nuclear magnetic resonance confirms the presence of 1/2 of chloroform.

B. 3-N- (2- (5-dimethylaainoaethyl-2-furanyl / methylthio) -ethyl) amino-4-dimethylamino-1,2,5-thiadiazole-1-oxide

3-H- (2- (5-dimethylaainomethyl-2-furamyl / methylthio) ethyl) amino-4-ethoxy-1,2,5-thiadiazole-t-oxide (3.05 g, 8.5 aaol) was added with Dissolve in 10 [mu] l tetrahydrofuran and dimethylamine (0.38 g, 8.5 mmol) is bubbled into the solution at ice bath temperature6. The reaction is carried out in a sealed flask at room temperature with stirring overnight. Excess dimethylamine is then added to complete the reaction. Removal of the solvent in vacuo gave 2.7 g of a viscous amber oil which was purified by silica gel chromatography. The chromatographed oil solidifies on a standstill and melts at 55-58 ° C in petroleum ether. It was recrystallized from n-butyl chloride to give 3-N- (2 (- [(5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) emino-4-dimethylamino-1,2,5-thiadiazole-1-oxide).

Example 5

3-N- (3- (2-guanidino-4-thiazolyl) phenyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide

A. 3-N- (3- (2-guanidino-4-thiazolyl) phenyl) amino-4-methoxy-1,2,5-thiadiazole-1-oxide

A solution of 3.33 g (0.010 mol) of 3- (2-guanidino-4-thiazolyl) benzenamine in 50 ml of methanol is added to a suspension of 1.94 g (0.010 mol) of 3,4-bia (methylthio) -1,2, Of 5-thiadiazole-1-oxide in 20 ml of methanol with stirring. All solid dissolved and the solution was stirred for 120 hours. Behea for the last 24 hours, no change in βαδβί has been observed in thin layer chroatography. The reaction mixture was filtered to give 0.71 g of an orange substance, which gave only the initial spot in thin layer chromatography, the filtrate was evaporated to dryness in vacuo and attracted to 3.30 g of a yellow substance. Nuclear magnetic resonance of the material indicates the presence of the product. The substance is purified on a neutral alumina column of activity III. Elution with chloroform and 1% methanol (chloroform and 5% methanol) chloroform gave the thia diazole starting material.

Boys with mixtures of 10 *, 20% and 50 * aethanol (chloroform gave 2.32 g (14%) of yellow product-containing material. Recrystallized from aeetonitrile to give 1.20 g; mp 217-221 DEG C .; N- (3'-2-guanidino-4-thiazolyl-phenyl) -a-amino-4-methoxy-1,2,5-thiadiazole-1-oxide, proton nuclear nagnetic resonance agrees with the structure.

It is observed that during the course of this reaction, the solvent (aethanol) exchanges the residual ethylthio group and the formation of the 4-methoxy compound. This does not affect the reaction because the second aainadia reacts with either the 4-methoxy compound or the 4-methylthio compound.

B. 3-N- (3- (2-guanldino-4-thiazolyl) phenyl) alno-4-aathylamino-1,2,5-thiadiazole-1-oxide

0.37 g of 33% acetyl amine / ethanol (0.12, 0.0040 mol) was added to the suspension.

1.27 g (0.0039 aol) of 3-N- (3-Z2-guanidino-4-thiazolyl / phenyl) -aauro-4-aethoxy-1,2,5-thiadiazole-1-oxide in 30 [mu] l aathanol for nícháni. The solid dissolved and after 30 minutes a precipitate began to form. According to thin-layer chromatography, the reaction was complete in two hours and the precipitate was filtered off and dried to yield 0.76 g (70% of the crude product). The product was dissolved in 5 [mu] l of ethylsulfoxide and filtered. Aethanol was added to the solution and a precipitate was obtained which was aa filtered and dried to give es0.97 g. 160-161 ° C (r) product; proton nuclear magnetic resonance with the structure of 3-N- (3- (2-guanidino-4-thiazolyl) phenyl) amino-4-ethylsalno-1,2,5-thiadiazole-1-oxide.

Example 1 and d 6

3-N- (3- (2-guanidino-4-thiazolyl) phenyl) alno-4-methyl-aaino-1,2,5-thiadiazole-1,1-dioxide

4. 3-N- (3- (2-guanidino-4-thiazolyl) phenyl) amino-4-ethoxy-1,2,5-thiadiazole-1,1-dioxide

A solution of 1.17 g (0.005 mol) of 3- (2-guanidino-4-thiazolyl) benzenaine in 30 ml of ethanol and added to the slurry 1.03 g (0.005 aol) of 3,4-diethoxy-1,2,5-thiadiazole -1, t-dioxide in 30 [mu] l ethanol was stirred. Dry solid o and dissolve within 1 minute and in two minutes with the formation of a precipitate. The reaction mixture is stirred for 5 hours at which time the reaction is complete by thin layer reaction. The precipitate was filtered, succinated and recrystallized from ethanol to give 1.35 g of 3-N- (3- (2-guanidino-4-thlazolyl) phenyl) aino-4-ethoxy-1,2,5-thiadiazole-1. 1-dioxide mp 237 DEG-239 DEG.

B. 3-N- (3- (2-guanidino-4-thiazolyl) phenyl) amino-4-methylamino-1,2,5-thiadiazole-1,1-dioxide.

0.70 g of a 33 * solution of aethylaine / aathanoi (0.23 g, 0.0075 mol) and added to the suspension 2.91 g (0.0075 aol) of 3-N- (3- / 2-guanidino-5-thiazolyl) (phenyl) amino-4-ethoxy-1,2,5-thiadiazole-1,1-dioxide from Part A of this Example in 75 [alpha] -ethanol. The mixture is stirred for 3 hours at alatnoate temperature, when the thin layer reaction is complete. The reaction mixture was filtered to give aa 1.30 g of a yellow substance which gave only the initial spot in thin-layer chromatography. The filtrate was evaporated to dryness in vacuo to give 2.00 g (70%) of a yellow solid. Recrystallization from water yielded 0.72 g of a melting point of 263 DEG-265 DEG C. The proton nuclear aagnotic resonance confirms the structure of 3-N- (3- (2-guanidino-4-thiazolyl) phenyl) aaino-4-mathylamino-1, 2,5-thiadiazole-1,1-dioxide.

Example 7

3-N- (2 - ([5-palethylaminomethyl-2-furanyl / methylthio) -ethyl) -amino-4- (2-propynyl) amino-1,2,5-thiadiaxole-1-oxide

3-H- (2 - ((5-diaethylaninone-ethyl-2-furanyl / ethylthio) -ethyl) aa-4-ethoxy-2,5,5-thia

2444 U Diazole-1-oxide (5.37 g, 0.015 mol) was dissolved in 30 ml of tetrahydrofuran and a solution of 2-propynylamine (0.91 g, 0.065 mol) in 5 ml of tetrahydrofuran was added dropwise over a few minutes. The reaction mixture was stirred at room temperature for 72 hours. Removal of the solvent in vacuo gave a dark amber oil. Chromatography on silica gel using 53 > methanol / chloroform gave 3.2 g of a light amber oil. Proton nuclear magnetic resonance agrees with the assumed structure.

Example 8

3-N- (2- (η 5 -dimethylaminomethyl-2-furanyl / ethylthio) ethyl) emino-4-amino-1,2,5-thiadiazole-1-oxide

3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-ethoxy-1,2,5-thiadiazole-1-oxide (5.37 g, 0.015 mol) ) was dissolved in 10 ml of tetrahydrofuran and a solution of anhydrous ammonia (1.7 g, 0.10 mol) in 10 ml of cold tetrahydrofuran was added at an ice bath temperature. The reaction mixture was stirred on an ice bath for several hours and then overnight at room temperature. Removal of the solvent in vacuo gave a viscous oil, which solidified upon elution in petroleum ether, yielding 4.8 g of a light beige solid. Recrystallization from nitromethane gave 2.7 g of a light yellow-brown solid, m.p. 132-136 ° C (dec.).

Example 9

3-N- (2- (2-guanidino-4-thiazolyl / methylthio) ethyl) amino-4-methylamino-1,2,5-thiadiazole-1,1-dioxide

Using the same procedure as in Example 3, using 1.16 g (5.0 mmol) of amine and 0.96 g (5.0 mmol) of 3-ethoxy-4-methylamino-1,2,5-thiadiazole-1,1 of dioxide, 0.65 g of 3-N- (2-guanidino-4-thiazolyl / methylthio) ethyl) aaino-4-methylamino-1,2,5-thladiazole-1,1-dioxide is obtained, m.p. M.p. 182-184 ° C, dec. after recrystallization from water; infrared valence vibrations for SO ₂ , 1350, 1150 cm -1 (KBr); proton magnetic resonance is consistent with structure. He did

3-N- (3- (3- (dimethylaminomethyl) phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

To a solution of 3- (3- (dimethylaminomethyl) phenoxy) propylamine (2.9 g, 0.0139 mmol) in acetonitrile (9 mL) was added 3-ethoxy-4-amino-1,2,5-thiadiazole-1- oxide (2.25 g, 0.014 mol). Almost immediately, complete dissolution occurs and after 1/4 hour precipitation begins. The reaction mixture was stirred at ambient temperature for 16 hours and the crude product was filtered off. The white material was washed with acetonitrile, ether, and air dried to give 4.35 g of 3-N- (3- (3-dimethylaminomethyl / phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole- 1-oxide, mp Mp 158-162 ° C.

Example 11

3-N- (2 - ((3- (dimethylaminomethyl / phenyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

To a solution of 2 - ((3- (dimethylaminomethyl) phenyl) methylthio) ethylamine (3.36 g, 0.015 mol) in acetonitrile (10 mL) at room temperature was added 3-ethoxy-4-amino-1,2,5- thiadiazole-1-oxide (2.42 g, 0.015 mol). At 15 minutes complete dissolution occurred and the product started to precipitate after 1/2 hour. The reaction mixture was stirred at ambient temperature for 16 hours and the product was filtered off, washed with acetonitrile, ether, and air dried to give 3.7 g of crude product. Crystallization from acetonitrile gave pure 3-N- (2 - ((3- (dimethylaminomethyl) phenyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide as a yellow-brown rose, m.p. Mp 120-123 ° C.

244 * 11

Example 12

3-N- (3- (3- (dimethylaminomethyl / phenoxy) propyl) aaine-4-methylamino-1,2,5-thiadiazole-1-oxide hydrochloride

3- (3- (dimethylaminomethyl) phenoxy) propylamine (1.716 g, 0.00823 M) dissolved in tetrahydrofuran (7 a1) and added to 3-ethoxy-4-methylamino-1,2,5-thiadiazole-1- of oxide (1.443 g, 0.00823 M) suspended in tetrahydrofuran (7 [mu] l). The resulting solution was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with 10% methanol-chloroform to give a gum (2.5 g). The product is dissolved in ethanol (10 ml), acidified with 6N ethanolic hydrochloric acid, precipitated with diethyl ether, filtered ee and dried in vacuo at 55 ° C to give 3-N- (3- (3- (dimethylaminomethyl) phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide hydrochloride, m.p. 95 ° C (dec) as diethyl ether solvate.

Example 1

3-N- (3- (3- (1-piperadinylmethyl) phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide hydrochloride

3- (3- (1-piperidinylmethyl) phenoxy) propanamine (2.48 g, 0.01 M) in tetrahydrofuran (4 mL) was treated with 3-ethoxy-4-methylamino-1,2,5- thiadiazole-1-oxide (1.87 g _t 0.0107 M) in tetrahydrofuran (35 ml) according to the method of Example 12 to give 3-N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide hydrochloride as a non-crystalline substance solvated with ethanol.

Example *

3-N- (3- (3- (4-methyl-1-piperazinyl / methyl) phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide hydrochloride

A. 3- (3- (4-Methyl-1-piperazinyl) methyl) phenoxy) propanamine

To 2- (3- (3-formylphenoxy) propyl) -1H-isoindole-1,3-dione (20 g, 0.064 U) suspended in 50 mL of ethyl acetate was added 1-methylpiperazine (19.53 g, 0.195 M) and the mixture was stirred at ambient temperature for 45 minutes longer than required to form a solution. Acetic acid (23.1 g, 0.385 M) in a mixture of ethyl acetate (40 mL) and ethanol (80 mL) was added along with 10% palladium on carbon (3 g). The mixture was hydrogenated (0.35 MPa), filtered and the filtrate was concentrated in vacuo. The residue was dissolved in dilute hydrochloric acid and extracted with a. Methylene chloride. The aqueous phase was basified with solid sodium carbonate and extracted with methylene chloride. The organic extracts were dried over sodium sulfate and concentrated in vacuo. The residual oil (21 g) was stirred in a mixture of ethanol (250 ml) and 64% hydrazine (100 ml) for 90 hours at ambient temperature. The mixture was diluted with diethyl ether, filtered, and the filtrate was concentrated in vacuo and the residue distilled. The product is obtained by collecting a fraction distilling at 215 DEG-223 DEG C./0.9 mbar, weight 9.7 g.

B. 3-N- (3- (3- (4-Methyl-1-piperazinyl / methyl / phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiazole-1-oxide hydrochloride

Reaction of 3- (3- ((4-methyl-1-piperazinyl) -methyl) phenoxy) propanamine (3.1 g, 0.0118 M) in tetrahydrofuran (3 mL) with 3-ethoxy-4-methylamino-1, 2,5-thiadiazole-1-oxide as described in Example 12 affords 3-N- (3- (3- (3 - ((4-methyl-1-piperazinyl) methyl) phenoxy) propyl) amino-4-methyl amino-1); 2,5-thiadiazole-1-oxide hydrochloride, mp 78 ° C with decomposition.

Example 15

3-N- (3- (3- (4-morpholinomethyl / phenoxy) propyl) amino-4-methylamino-1,2,5-thiadiezol-1-oxide hydrochloride

A. 3- (3- (4-Morpholinoethyl) phenoxy) propanamine

Reaction of 2- (3- (3-foraylphenoxy) propyl) -1H-isoindole-1,3-dione (20 g, 0.0647 M) with morpholine (16.9 g, 0.194 M) and the conditions described in Example 14A, and isolating the product in the same manner gave 11.6 g of 3- (3- (4-aorfolinoaethyl) phenoxy) propanamine, m.p. 188-196 ° C at 20 mm Hg.

B. 3-K- (3- (4-Morpholito-ethyl / phenoxy) propyl) amino-4-aethylamino-1,2,5-thiadiazole-1-oxide hydrochloride

Reaction of 3- (3- (4-Borfolinoethyl) phenoxy) propanaain (3.0 g, 0.012.8) in tetrahydrofuran (4 m) with 3-ethoxy-4-methylamino-1,2,5-thiadiezol-1-oxide (2.27 g, 0.01298) in tetrahydrofuran (4 ml) as described in Example 12 affords 3-N- (3- (4-aorfolinomethyl) phenoxy) propyl) amino-4-aethylamino-1,2 5-thiadiazole-1-oxide hydrochloride, m.p. 90 DEG-95 DEG C. with decomposition.

Example 1 a d 16

3-8- (3- (3- (4-norfolinoaethyl / phenoxy) propyl) aaino-4-aaino-1,2,5-thiadiasol-1-oxide

3- (3- (4-aorfolinoaethyl) phenoxy) propenaline (2.856 g, 0.01142 8) in acetonitrile (4 α1) was reacted with β 3-ethoxy-4-amino-1,2,5-thiadiezol-1- oxide (1.933 g, 0.012 δ) suspended in 5 mL of acetonitrile. After stirring at ambient temperature for 20 hours, the crystalline product was filtered, washed with acetonitrile, and dried under vacuum at 65 ° C to give 3-8- (3- (3- (4-morpholinoaethyl / phenoxy) propyl) amino-4-aaino). -1,2,5-thiadiazole-1-oxide; m.p. 185 DEG-186.5 DEG C. with decomposition.

Example 17

3-8- (2- (4-Methyl-5-imidazolyl / methylthio) ethyl) amino-4-aethylamino-1,2,5-thiadiazole-1-oxide hydrochloride

2 - ((4-methyl-5-iidazolyl) methylthio) ethylamine (1.836 g, 0.01073 8) dissolved in a mixture of tetrahydrofuran and methylene chloride (3 mL) and added to 3-ethoxy-4-methylamino-1,2,5 -thiadiazole-1-oxide (1.8604 g, 0.10738) and stirred ee for 20 hours at ambient temperature. The reaction mixture is concentrated in vacuo, the residue is dissolved in 10 ml of isopropanol, acidified with ethanolic hydrochloric acid and diluted with diethyl ether. The crude product was filtered, redissolved in isopropanol (15 ml) and diluted with acetonitrile to 500 ml. Filter the mixture, remove the solid, concentrate the filtrate in vacuo. The residue (2.6 g) was dissolved in isopropanol (12 ml) and the product was precipitated with diethyl ether and attracted to 3-N- (2- ((4-methyl-5-imidazolyl) aethilthio) ethyl) emino-4-methylamino- 1,2,5-thiadiazole-1-oxide hydrochloride, m.p. 118 ° C (dec.)

Example 16

3-N- (2- (η 5 -diethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiezole-1,1-dioxide

To a filtered solution of 2- ((5-dimethyl-aeinomethyl-2-furanyl) methylthio) ethylamine (8.35 g, 39.0 pitch) in 70 mL of methanol ee was added 6.9 g (38.9 pitch). -ethoxy-4-amino-1,2,5-thiadiezol-1,1-dioxide. The clear solution was stirred at room temperature for 2 hours, during which time a white precipitate separated. The precipitate was collected, boiled and 125 mL of ethyl acetate and again filtered and splashed to give 10.4 g of the pure title compound; m.p. 159 DEG-160 DEG C. with decomposition.

, 7

Example 19

3-N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

A solution of 13.66 g (0.055 mol) of 3- (3- (1-piperidinylmethyl) phenoxy propane amine in 5 ml of CH 2 CN) was added to 8.87 g (0.055 mol) of 3-ethoxy-4-amino-1,2 5-thiadiazole-1-oxide in 200 ml of CH 2 CN The mixture was stirred under nitrogen at room temperature and a colorless product began to precipitate over 15 minutes, after 24 hours the reaction mixture was filtered and the product was washed with CH 2 CN. slurry in 75 mL of CH 2 CN and stirred for 24 hours in a sealed vessel The solid was filtered off and again stirred with CH 2 CN for 48 hours The solid was then filtered and dried at 78 ° C for 4 hours under vacuum to give 16.0 g (80%) of pure product, mp 152.5-154.5 ° C.

Example 20

3-N- (2- ([6- (4-Apholinylmethyl) -2-benzofuranyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

A. Ethyl 6-methylbenzofuran-2-carboxylate

A solution of 6-methylbenzofuran-2-carboxylic acid (111.0 g (0.636 mol) and concentrated sulfuric acid (4 ml) in 1 L of ethanol was refluxed for 16 hours. About 2/3 of the solvent was distilled off under reduced pressure. The residue was poured into 1 liter of ice water and the oily ester was added to ether, washed with saturated sodium bicarbonate solution and water and dried over sodium sulfate to give 90.5 g (70%) of ethyl 6-methylbenzofuran-2 by distillation under reduced pressure. The product crystallizes in a receiver, mp 35-42 ° C.

B. Ethyl 6- (bromoethyl) benzofuran-2-carboxylate

N-bromosuccinimide (37.4 g, 0.21 mol) was added to a solution of ethyl 6-methylbenzofuran-2-carboxylate (40.8 g, 0.2 mol) and α, α'-azobis-isobutyronitrile (500 mg) in carbon tetrachloride (300 mL). The suspension was refluxed for 3 hours. It is then cooled and the succinimide is removed by filtration. The carbon tetrachloride solution was washed with water and dried with sodium sulfate. The solution was then evaporated under reduced pressure. The solid residue was recrystallized from hexane to give 47.4 g (60%) of crystalline ethyl 6- (bromomethyl) benzofuran-2-carboxylate, mp 95-102 ° C. Magnetic resonance spectrum (CDCl @): delta 1.40 (3Η, ΐ, 0Η ₃₎ 4.40 (2H, q, _CH2 O), 4.58 (2H, s, CH ₂ hr).

C. Ethyl 6- (4-morpholinylmethyl) benzofuran-2-carboxylate

To a solution of 10.0 g (0.035 mol) of ethyl 6- (bromomethyl) benzofuran-2-carboxylate in 100 ml of ether was added dropwise at 0-4 ° C a solution of 7.7 g (0.088 mol) of morpholine in 100 ml of ether. . The mixture was stirred for 18 hours, water was added and the layers were separated. The organic layer was extracted with 3N hydrochloric acid. The acidic extract was basified with 10N sodium hydroxide and extracted with ethyl acetate. The extract was dried and concentrated to give 8.4 g (86%) of ethyl 6- (4-morpholinylmethyl) bencofiiran-2-carboxylate.

D. 2-Hydroxymethyl-6- (4-morpholinylmethyl) benzofuran

To a suspension of lithium aluminum hydride (2.1 g, 0.03 mol) in ether (50 ml) was added dropwise a solution of 8.4 g (0.03 mol) of ethyl 6- (4-morpholinylmethyl) benzofuran-2-ol at room temperature. of carboxylate in 25 ml of ether. The mixture was stirred for 18 hours, saturated sodium sulfate was added until a white suspension formed and the solid was filtered. The material was washed with chloroform and the filtrate was extracted with water. The chloroform-ether solution was concentrated to give 4.7 g (63%) of β-hydroxymethyl-6- (4-morpholinomethyl) benzofuran, m.p. Mp 103-107 ° C.

2444 Π

Β. 2 - ((5- / 4-morpholinylmethyl / 2-benzofuranyl) methylthio) ethane amine

2-hydroxymethyl-6- (4-iaorfolinylinethyl) benzofuran, 4.7 β (0.02 mol) was added portionwise to an ice-cooled solution of 2.4 g (0.02 mol) cyateamine hydrochloride in 10 ml of 12K HCl under nitrogen. The ice bath was removed and the solution was stirred at room temperature for 17 hours. It is cooled, the pH is adjusted to 10 with 40% sodium hydroxide and extracted with methylene chloride. The extract was concentrated to give 6 g of 2 - ((6- (4-morpholinylmethyl) -2-benzofuran-4) methylthio) ethane amine.

F. 3-N- (2 - ((6- / 4-Morpholinylmethyl / 2-benzofuranyl) methylthlo) ethyl) amino-4-amino-1,2,5-thiadiazole -, - oxide

Using the procedure of Example 11, using 2 - ((6- (4-morpholinylmethyl) -2-benzofuranyl) methylthlo) ethanamine gave the title compound as a white solid, m.p. Mp 143-146 ° C.

Example 21

3-N- (2 - ((6- (4-morpholinylmethyl) -2-benzofuranyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1,1-dioxide

Using the method of Example 18 and 2 - ((6- (4-morpholinylmethyl) -2-benzofuranyl) methylthio) ethanamine as the amine reactant and acetonitrile as the solvent, the desired product was obtained as a pale yellow solid, m.p. Mp 164-167 ° C.

Example 22

3-N- (2 - ((6- (4-morpholinylmethyl) -4-benzofuranyl) methylthio) ethyl) amino »4-methylamino-1,2,5-thiadiazole-1-oxide

Using the procedure of Example 1B using 2 - ((6- (4-morpholinylmethyl) -2-benzofuranyl) methylthlo) ethane amine as the amine reactant and acetonitrile as solvent at a weekly reaction time, a crude product was obtained. Silica gel chromatography gave the pure title compound; mp 139 143 ^o C.

Example 23

3-N- (2 - ((5- (4-morpholinylmethyl) -2-furanyl) methylthlo) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide,

Using the procedure of Example 11 using 2 - ((5- (4-morpholinylmethyl) -2-furanyl) methylthio) ethane amine as the amine reagent ee, the title compound is obtained as a crystalline solid, m.p. Mp 42-44 ° C.

Example 24

3-N- (2 - ((5 - [(piperidinylmethyl) -2-furanyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-, oxide

Using the method of Example 1 using 2 - ((5- (1-piperidinylmethyl) -2-furanyl) methylthio) ethanamine as the amine reagent, the title compound was obtained as a solid, m.p.

, 50 ° C.

Example 25

3-N- (2- (4-methyl-5-imidazolyl / methylthlo) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

Following the procedure of Example 11, using 2r ([4-methyl-5-imidazolyl] methylthio) ethanamine as the amine reactant, the desired product is obtained in the impure state. Chromatography on silica gel and precipitation from isopropyl alcohol-ether gave the pure title compound containing 0.31 molar equivalent of laopropyl alcohol; m.p. Mp 98-126 ° C.

Example 26

3-N- (2- (4-methyl-5-imidazolyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1,1-dioxide

Essentially according to the method of Example 18, using 2- (4-methyl-5-imidazolyl) methylthio) ethanamine as the amine reagent and acetonitrile as the solvent gave the desired product. Purification by silica gel chromatography and precipitation from ethanol-ether gave pure title compound containing 0.5 molar equivalent of ethanol; m.p. 78-92 ° C.

Example 27

3-N- (2- (2-guanidino-4-thiazolyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

Using the 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide in place of the 3-ethoxy-4-methylamino-1,2,5-thiadiazole-1-oxide of Example 3 and purifying the product by silica gel chromatography and crystallization to give the title compound; m.p. Mp 186-188 ° C.

Example 28

3-N- (3- / 2-guanidino-4-thiazolyl / phenyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

Using the procedure of Example 5 and using a solution of ammonia in alcohol instead of the methylamine solution in Part 5B, a crystalline product is obtained which is recrystallized from dimethylsulfloxide-acetonitrile to give the pure desired compound containing the crystal. dimethylsulfoxide molecule; m.p. Mp 219-220 ° C.

Example 29

3-N- (2- (6-dimethylaminomethyl-2-pyridyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide hydrochloride hemihydrate

Using 2- (6-dimethylaminoethyl-2-pyrldyl (methylthio) ethanamine) published in British Pat. 2,038,804 / instead of 2 - ((3- (dimethylaminomethyl / phenyl) methylthio) ethylamine according to example 11 and carrying out the reaction and working up in a similar manner to give 3-N- (2 - ((6-dimethylaminomethyl-2-pyridyl) methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide. This base is dissolved in an equivalent amount of aqueous hydrochloric acid and the solution is lyophilized to give the hydrochloride salt of the pure title compound as a hemihydrate in a glassy solid form.

Example 30

3-N- (3- (3- (dimethylaminomethyl) phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-1-dioxide

Using the 3-ethoxy-4-amino-1,2,5-thiadiazole-1,1-dioxide in place of the 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide according to Example 10 and carrying out the reaction in the same manner. in acetonitrile to give a crystalline product. Recrystallization from nitromethane gave the title compound; m.p. Mp 173-175 ° C.

Example 1 a d 31

3-N- (2- (5-dimethylaminomethyl-2-thienyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

2- ([5-dimethylaminomethyl-2-thienyl / methylthio) ethanamine and 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide were reacted in acetonitrile solution according to the method described in Example 1 1 . The reaction product is purified by chromatography and then crystallized from acetonitrile / methanol to give the pure title compound, m.p. Mp 143-147 ° C.

Example 32

3-N- (2- (5-methylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-amino-2,5-thladiazole-1-oxide

Reaction of 2- (5-methylaminoaethyl-2-furanyl / methylthio) ethaneane with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide in acetonitrile was carried out as described in Example 11. The crude product was chromatographed It is chromatographed on silica gel and then crystallized from ethanol to give the pure desired compound; 153 DEG-56 DEG.

Example 33

3-H- (3- (3- (4-methyl-1-piperazinyl / methyl) phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

Using the method of Example 0 using 3- (3- ((4-methyl-, 1-piperazinyl) methyl) phenoxy) propanamine (prepared as in Example 14) as the propanarain reactant, a product was obtained which crystallized with chloroform- ether to give pure desired compound; m.p.

, 33 ° C with decomposition.

Example 34

3-K- (2- (4-Methyl-5-oxazolyl / methylthio) ethyl) emino-4-amino-1,2,5-thladiazole oxide

Reaction of 2- (4-methyl-5-oxazolyl / methylthio) ethanamine with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide in acetonitrile solvent by the procedure of Example 11 affords the title compound; m.p. Mp 48-150 ° C.

Example 35

3-N- (3- (6-Dimethylmororaethyl-2-pyridylthio) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

A. 3- (6-Dimethylaminomethyl-2-pyridylthio) propanamine

A mixture of 3-mercaptopropylamine (4.8 g, 0.053 mol) and 60% sodium hydride in mineral oil (2.18 g, 0.054 mol) in dry dimethylformamide (50 ml) was heated to 80 ° C and a solution was added dropwise. 6-dimethylaminomethyl-2-chloropyridine (8.7 g, 0.051 mol) in 50 mL of dry dimethylformemide. The mixture is heated at 125 ° C for 3 hours, then cooled, diluted with 70 ml of ethanol and evaporated to dryness after filtration to remove the precipitated substance. This residue was dissolved in water and the product was extracted with chloroform, then with dilute hydrochloric acid, and the acidic extract was neutralized with sodium carbonate and the product was extracted with chloroform, dried and evaporated to give 9.5 g. This residual oil was distilled to give with 5.64 g of pure product; mp 129-133 ° C 66.6610 Pa.

B. 3-N- (3- (6-dimethylaminomethyl-2-pyridylthio) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide hydrochloride

The amine product of Part A is reacted with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide essentially according to Example 0. The reaction product is chromatographed, dissolved in methanol and an equivalent amount of alcoholic hydrochloric acid is added. Acetonitrile was added to give pure desired compound, m.p. Mp 174-176 ° C.

Example 36

3-N- (2- / 6-dimethylaminomethyl-2-pyridylthio / ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

A. 2- (6-Dimethylanalomethyl-2-pyridylthio) ethanamine

2,

Cysteamine hydrochloride (3.43 g, 0.030 mol) was added to a suspension of 60% sodium hydride in mineral oil (2.5 g, 0.0625 mol) in dry dimethylformamide (30 mL) and heated to 80 ° C. A solution of 6-dimethylaminomethyl-2-chloropyridine (5.0 g,

0.284 mol) in 30 ml of dry dimethylformamide and then the reaction temperature is raised to 125 ° C for 2 hours. The reaction mixture was then cooled, diluted with ethanol (60 mL) and the salts were removed by filtration before evaporating to dryness. This residue was dissolved in chloroform, washed with water and extracted ^with dilute ky ⁱⁿ electrical degrees in hydrochloric acid. The acidic extract was neutralized with sodium carbonate and the product extracted with chloroform was dried and evaporated to give 4.4 g. This residual oil was distilled to give 2.74 g of pure product; mp 109-114 ° C / 33,330 Pa.

B. 3-N- (2- (6-Dimethyl-aminomethyl-2-pyridylthio) -ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

The amine product of Part A is reacted with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide essentially by the method of Example 10. The pure desired compound, m.p. 172 DEG-175 DEG C., crystallized from the reaction mixture.

Example 37

3-N- (3- (6-dimethylaminomethyl-2-pyridyloxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

A. N- (3- (6-Dimethylaminomethyl-2-pyridyloxy) propyl) formamide

3-Aminopropanol (2.55 g, 0.034 mol) was added to a suspension of 60% sodium hydride in mineral oil (1.29 g, 0.033 mol) in dry dimethylformamide (30 mL) and the mixture was heated to 80 ° C and then add dropwise a solution of 6-dimethylaminomethyl-2-chloropyridine (5.45 Si 0.032 mol) in 30 mL of dry dimethylphenamide. The reaction temperature was raised to 125 ° C for 3 hours, then the reaction mixture was cooled, diluted with ethanol and the precipitated salts were filtered off. The solvent was removed in vacuo. The residue was dissolved in chloroform, washed with water, extracted with dilute hydrochloric acid, and the acidic extract was neutralized with sodium carbonate. The crude product was extracted with chloroform, dried and evaporated (7.6 g). This residue was chromatographed on silica gel (200 g), eluting with 3 to 8% methanol / chloroform to give 3.2 g of pure desired product as an oil.

B. 3- (6-Dimethyleminomethyl-2-pyridyloxy) propylamine

N- (3- / 6-dimethylaminomethyl-2-pyridyloxy / propyl) formamide (2.7 g 0.013 mol) was added to a solution of 85% potassium hydroxide as pellets (3.0 g) dissolved in methanol (30 ml) and heated with gentle reflux for 21 hours. The reaction mixture was cooled, diluted with diethyl ether (30 mL), the precipitated salts were filtered, and the solvent was removed in vacuo. The residue was dissolved in water and the product was extracted with ethanol / chloroform, dried and evaporated to give 2.1 g of pure product.

C. 3-N- (3- (6-dimethylaminomethyl-2-pyridyloxy) propyl) araino-4-amino-1,2,5-thiadiazole-1-oxide

The amine product of Part B is reacted with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide essentially as described in Example 10. The reaction product is purified by chromatography and crystallization from methylalkolacetonitrile to give the desired product. compound; m.p. Mp 139-142 ° C

Example 38e 3-N- (3- (2-pyridylthio) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

The 3- (2-pyridylthio) propylamine is reacted with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide as described in Example 10. The reaction product is recrystallized from a mixture of chloroform and methanol to give the pure desired product. compound; m.p. Mp 177-179 ° C.

Example 39

3-N- (2 - ((2-pyridyl) methylthio) ethyl) amino-4-amino-1,2,5 thiadiazole-1-oxide

Reaction of 2 - ((2-pyridyl) methylthio) ethanamine with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide is carried out essentially as described in Example 11. The reaction product is purified by chromatography and crystallization from methylalkolacetonitrile to give the title compound; m.p. 102-104 ° C.

Example 40

3-N- (2- (2-pyrazinyl) methylthio (ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

Reaction of 2 - ((2-pyrazinyl) methylthio) ethanine with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide under the conditions described in Example 11 and purification of the product by chromatography and crystallization from acetonitrile- methanol to give pure desired compound; m.p. M.p. 148-150 ° C.

Example 41

3-N- (2- (4-methyl-5-thiezolyl / methylthio) ethyl) amino-4-amino-2,5-thiadiazole-1-oxide

A. 2- (4-Methyl-5-thiazolyl / methylthlo) ethanamine

To 95 ml of 49% HBr cooled in an ice bath is added cysteamine hydrochloride (7.96 g,

0.07 M) and the mixture is stirred until a solution is formed. To this solution was slowly added 4-methyl-5-thiazolylmethanol (9.05 g, 0.07 M). After stirring at 25 ° C for 1/2 hour, the mixture was refluxed for 5 hours and then made alkaline with 10 N sodium hydroxide solution while cooling in an ice bath. The solution was extracted several times with methylene chloride. The methylene chloride extracts were diluted with an equal volume of ether, washed once with brine and dried with sodium sulfate. The solution was filtered and concentrated in vacuo and the residue distilled to give a colorless oil of the desired product (10.05 g, 76%); b.v. 121.5-125 ° C / 92.22 Pa.

B. 3-N- (2- (4-Methyl-5-thiazolyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

The amine from Part A was reacted with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide as described in Example 11 using tetrahydrofuran as the non-reaction solvent. Recrystallization of the product from methanol gives the pure desired compound; m.p. Mp 157-159 ° C.

Example 42.3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-N- (2-phenylethyl) amino-1;

2,5-thiadiazole-1-oxide

A. 3-ethoxy-4-N- (2-phenylethyl) amino-1,2,5-thiadiazole -, - oxide

To a solution of 9.51 g (0.05 mL) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide in 20 mL of tetrahydrofuran was added a solution of 6.6 g (0.05 mol) at -10 ° C. Of 2-phenylethanamine in 50 ml of tetrahydrofuran over 2 hours. The mixture was stirred in an ice bath for 18 hours and then concentrated in vacuo. The residue was washed with ether and then recrystallized from acetonitrile to give 10.8 g of 3-ethoxy-4-N- (2-phenylethyl) amino-1,2,5-thiadiazole-1-oxide; m.p. 1.6-1.8 ° C.

B. 3-N- (2 - ((5-dimethylaminomethyl-2-furanyl) ethylthio) ethyl) amino-4-N- (2-phenylethyl) araino-1,2,5-thiadiazole -, - oxide

The product of Part A and an equimolar amount of 2- (5-diaethylaminomethyl-2-furanyl / methylthio) ethylamine were stirred in tetrahydrofuran essentially as described in Example 2. The crystalline reaction product is recrystallized from acetonitrile-ether to give the title compound; m.p. 92.5-94.5 ° C.

Example 43

3-N- (3- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-N- (2- / 4-pyridyl / ethyl) amino-1,2,5-thiadiazole-1 - oxide

A. 3-Ethoxy-4-N- (2- (4-pyridyl) ethyl) amino-1,2,5-thiadiazole-1-oxide

Using an equimolar amount of 2- (4-pyridyl) ethanamine instead of the 2-phenylethanamine obtained in Part A of Example 42 and using the same procedure, 3-ethoxy-4-N- (2- (4-pyridyl) ethyl) was obtained. amino-1,2,5-thiadiazol-1-oxld by recrystallization from acetonitrile-ether, m.p. 101-103 ° C.

B. 3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-N- (2- (4-pyridyl) ethyl) amino-1,2,5-thiadiazole -1-oxide

The product of Part A of this Example 43 and an equimolar amount of 2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethylamine were stirred in acetonitrile for 48 hours at room temperature. The reaction product crystallizes from ethyl acetate to give the title compound; m.p. Mp 88-91 ° C.

Example 44

3-N- (2- (2-furanyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-oxide

Reaction of 2 - ((2-furanyl) methylthio) ethanamine with 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide in acetonitrile under the conditions described in Example 11 and recrystallization of the solid product from acetonitrile yields the pure desired product. compound, mp 164 DEG C. with decomposition.

Example 45

Comparison of compounds exhibiting gastric antisecretory activity

The study is conducted in female small chasing dogs with a chronic stomach fistula. Test compounds are administered i.v. in 0 minutes. Gastric secretion is stimulated by administration of a maximum secretory dose of histamine dihydrochloride (64 µg / kg, base, sc) at 0 minutes, gastric secretion is collected by gravity drainage for 3 thirty minute intervals (0-30, 30-60 and 60-90 minutes) . The volume in ml is measured and the aliquot is titrated to pH 7 to determine the acid concentration (titratable acid mEq / l / j total acidity (m Eq) is calculated as the product of volume and acid concentration. Percent inhibition of volume, acid concentration and total The acidity is calculated with respect to the blank test in the same animals, and the ED50 values are determined by linear regression analysis.

The results obtained with the test compounds are shown in Table 1, wherein A and B are thiadiazole-1-oxide and thiadiazole-1,1-dioxide of the invention and C and D are prior art compounds.

Table 1

Inhibition of gastric secretion induced by histamine in dogs with chronic gastric fistula (1)

Test compounds Number of doses Number of animals / dose (3) IV ED / / mg / kg

Total acidity

AND

(B)

C

D

4 0.007

3 0.005

3 1,1

4 1.8 (1) itistamine dihydrochloride (64 g / kg / base s.c.), the most effective secretory stimulant.

(.2) ED 50 calculated at the time of maximum secretion in the blank (0-30 min after histamine).

(3) (N) minimum number of dogs per dose level.

A. 3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-amino-1,2,5-thiadiazole-1-ox. (Example 8).

B. 3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-4-aaino-1,2,5-thiadiazole-1,1-dioxide. (Example 18)

C. 3-N- (2- (5-dimethylaminomethyl-2-furanyl / methylthio) ethyl) amino-5-amino-1,2,4-trlazole, published in Belgian patent 875,846 (Example 5) (Derwent 79110 B (44).

D. N-Cyano-N-methyl-N- (2- [4-methyl-5-imidazolyl / methylthio / ethyl) guanidine, U.S. Pat. No. 3,950,333 (Examples 24 and 36; paragraph 8); in clinical use under the common name of Cimetidine.

The results of the above table show that compounds A and B of the invention have 150 to 350 times greater potency than compounds C and D of the prior art.

The following preparations are provided to illustrate the processes that can be used to obtain the novel intermediates of the invention.

Preparation

4,3-diethoxy-1,2,5-thiadiazole-1-oxide

To a solution of 441 g (3.06 mol) of diethyloxididate in 300 ml of methylene chloride and 780 ml (9.63 mol) of pyridine was added dropwise with cooling at 0 ° -? Thionyl chloride. The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between dilute hydrochloric acid and methylene chloride. The methylene chloride was washed once with dilute hydrochloric acid, twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution.

Dry the organic layer with magnesium sulfate, concentrate to a small volume and dilute with hexane. The crystals were filtered off, washed with water and dried in vacuo to give 410 g of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide, m.p. M.p. = 74-78 ° C.

The sample was recrystallized from cyclohexane to give white crystals, mp 75-78 ° C. Spekrum Mass 190 (M ⁺ CGH, 0N2OS), 161 (M ⁺ - C 2 H ₅₎

Infrared (CHCl3) 1625 (C = N), 1060 cm &lt; -1 & gt ^; (SO). Proton Nuclear Magnetic Resonance Spectrum (CDCl-j), delta 4.5 (q, J = 7Hz, 4H), delta 1.5 (t, J = 7Hz, 6H)

Preparation 2

3,4-bis-methylthio-1,2,5-thiadiazole-1-oxide

To the solution, 353 g (2.39 mol) of bismethylthiooximidate in 1500 ml of methylene chloride and 580 ml of pyridine (7.2 mol) were added dropwise at 0-5 ° C 188 ml (2.59 mol) of thionyl chloride. The temperature of the mixture was raised to room temperature and stirred for an additional 2 hours. The mixture was partitioned between methylene chloride and dilute hydrochloric acid. The organic layer was washed once with dilute hydrochloric acid, twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. Dry the organic layer with magnesium sulfate and concentrate to a small volume and dilute with ether.

The crystals were filtered, washed with ether and dried to give 401 g of 3,4-bis-methylthio-1,2,5-thiadiazole-1-oxide, m.p. 109-112 ° C Mass Spec 194 (M + C CH ^OS)

Infrared (CHCl3) 1625 (C = 14), 1050 cm @ -1 (SO)

Proton Nuclear Magnetic Resonance Spectrum (CDCl3) 2.7 ppm s.

Preparation 3

3-9-methoxy-4-methylamino-1,2,5-thiadiazole-1-oxide

Anhydrous methylamine (7.7 g, 0.25 mol) was dissolved in 300 mL of tetrahydrofunane while cooling with dry ice-acetone. This cold solution was added dropwise with stirring over 1-1 / 2 hours, at -15 ° C, to 3,4-diethoxy-1,2,5-thiadiazole-1-oxide (47.5 g, 0.25 mol). in 250 ml of tetrahydrofuran. Stir another hour at -15 ° C and remove the solvent in vacuo. The beige solid residue was purified by silica gel chromatography (100 g) using chloroform. The off-white solid (39.6 g) melts at 91-92 ° C.

Infrared spectrum S = 0 valence vibration 1,095 cm -1, 30 nuclear magnetic resonance for thiadiazole-1-oxide carbon: 163.34, 157.36.

Preparation 4

3-Ethoxy-4- (1-pyrrolidinyl) -1,2,5-thiadiazole-1-oxide

To 50.0 g (263 mmol) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide in 250 ml of ethanol was added 18.7 g (263 mmol) of pyrrolidine. The mixture was stirred at room temperature for 30 minutes, then concentrated to 1/4 volume and diluted with an equal amount of ether. The reaction mixture was filtered and the filtrate was concentrated in vacuo, dissolved in methylene chloride and washed 3 times with dilute hydrochloric acid and 2 times with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oil crystallized upon trituration in ethyl acetate. The solid was filtered to give 23.5 g of white crystals, m.p. Mp 59-62 ° C, identified as 3-ethoxy-4- (pyrrolidinyl) -1,2,5-thiadiazole-1-oxide.

Mass Spectrum 215 (M ⁺ ), 186 (M ⁺ -C ₂ H ₅ ), 170 (M ⁺ -C ₄ H ₈ N), 119 (M ⁺ -C ₅ H ₈ N ₂ ), 70 (C 1 H 6) 1 Infrared Spectrum (CHCl ₃ ) 1625 (C = N), 1.25 cm ”(SO)

Proton Nuclear Magnetic Resonance Spectrum (CDCl3) 4.5 (t, J = 7 Hz, 2H) 3.7 (m, 4H) 2.0) (M, 4H) 1.5 (t, J = 7 Hz 3H) .

Preparation 5

3-methylthio-4- (4-morpholino) -1,2,5-thiadiazole-1-oxide

1.9 g (10 mmol) of 3,4-dithiomethyl-1,2,5-ihiadiazole-1-oxide and 0.9 ml (10 mmol) of morpholine are dissolved in 25 ml of acetonitrile and stirred at room temperature for 30 minutes. Reaction mixture 3e is filtered to give 500 mg of crystals whose proton nuclear magnetic resonance points to a 3-morpholine adduct. 200 mg of this material were redissolved in 5 ml of acetonitrile and heated at reflux for 1 hour. The reaction mixture was evaporated to sgcha and the residue was dissolved in ether and filtered. The solid fly has a melting point of 142-48 ° C and nuclear magnetic resonance confirms the structure of 3-thiomethyl-4- (4-morpholino) -1,2,5-thiadiazole-1-oxide.

Preparation 6

3-Ethoxy-4-amino-2,5-thiadiazole-1,1-dioxide

To a suspension of 3,4-diethoxy-1,2,5-thiadiazole-1'-dioxide (5.15 g, 25 mmol) in 25 mL of dry methylene chloride was added 4.05 g (25 mmol) of hexamethyldisilazane. The mixture was stirred, under nitrogen at room temperature for 8 hours, and the resulting clear solution was filtered through a short silica gel column. Elution with 1-4% ethanol-CH 2 Cl 2 gave fractions containing 3.8 g of pure 3-etho-2,444,411 xy-4-amino-1,2,5-thiadiazole-1,1-dioxide, m.p. M.p. 176-177 ° C.

Preparation 7

3-thoxy-4-amino-1,2,5-thiadiazole-1-oxide

To a partial suspension of 28.5 g (0.15 mol) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide in 75 ml of ethanol is added dropwise a solution of 114 ml of ca. 4 M ammonia in ethanol. The progress of the reaction was monitored by thin layer chromatography. When the reaction is half complete, the product begins to crystallize. The precipitated product was filtered and washed with ethanol to give a white crystalline product, 12.4 g, m.p. 130-134 ° C. The ethanol mother liquor was concentrated to give an additional yield.

Preparation 8

3,4-diamino-1,2,5-thi adiazole-1-oxide

In a reaction vessel containing ethane, ol (300 mL) immersed in a cooling ice bath, 40.0 g (210 mmol) of 3,4-diethoxy-1,2,5-thiadiazole-1-ol was added with stirring until 3e formed. of ammonia from Preparation 1. An excess of ammonia gas was bubbled through the solution slowly for about 5 minutes until a clear solution was obtained. The ice bath was then removed with a clear solution and an excess of ammonia gas was bubbled through for another 20 minutes, the bubbling rate was moderate for the first 5 minutes, and the rate increased for the remaining 15 minutes until copious crystals formed. Additional ethanol (200 mL) was added and ammonia gas was bubbled through the solution for a further 5 minutes. The crystals were then filtered off, washed with ethanol and dried (133.32 Pa) overnight to give 98.0% 3,4-amino-1,2,5-thiadiazole-1-1-oxide; m.p. 300 [deg.] C.

The magnetic resonance spectrum agrees with the structure.

The procedures described in the foregoing Preparations are used to obtain the following intermediates of Formula XX

^K , ^R 2 Point thaw C ₂ HgO- ' r ~ \ -N_O 123 to 125 Noc: 2 ° C C ₃ H _r O- -N ~ N-CH, 130 Noc: 2 ° C 2 5 C ₂ HgO- NHg 130 to 133 Noc: 2 ° C ch ₃ s- -C 119 to 120 Noc: 2 ° C C _o H _r 0  N N — H 218 Noc: 2 ° C 2 9 \ _t CH ₃ S- -NH-CH / CH _3/2 135 to 136 ° c

The foregoing preparations are used to obtain the following intermediates of formula XXI:

3-amino-4- »methylamino-1,2,5-thiadiazole-1-oxide,

3-amino-4- (2-dimethylaminoethyl) amino-1,2,5-thiadiazole-1-oxide, 3-amino-4-dodecylamino-1,2,5-thiadiazole-1-oxide,

3-amino-4- (4-fluoroanilino) -1,2,5-thiadiazel-1-oxide,

3-amino-4-morpholino-1,2,5-thiadiazole-1-oxide,

3-Morpholino-4- (2-pyridinomethyl) amino-1,2,5-thiadiazole-1-oxide 3,4-diamino-1,2,5-thiadiazole-1-oxide.

Claims (3)

I of the invention Preparation of 3,4-diamino-1,2,5-thiadiazole derivatives of general formula I <0) _P AND N (I) wherein W is - (CH ₂ ) _n - X - (CH ₂ ) _B - or - and R is hydrogen, alkyl of 1 to 5 carbon ethers, K, 5 or -N = C NH-R, wherein R1 and R1 are independently hydrogen, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or. C 1 -C 5 phenylalkyl or R 1 and R 2 together with the nitrogen to which they are attached form a 5- or 6-membered heterocycle which optionally contains an additional oxygen, sulfur or N-R 6, where R 5 is C 1 -C 5; is hydrogen, alkyl of 1 to 3 carbon atoms or benzyl, R 6 and R 8 are independently hydrogen or alkyl of 1 to 5 carbon atoms, n is 0 or 1, n is 2 to 4, k is 1 to 4, X is oxygen, III or methylene, p is 1 or 2, R 1 and R ₂ independently of one another denote hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, alkynyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, pyridyl or substituted alkyl of 1 to 5 carbon atoms; C 1 -C 5 -alkyl, wherein the substituent is phenyl, C 3 -C 7 -cycloalkyl, pyridyl, imidazolyl, morpholino, hydroxy, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio or C 1 -C 5 dialkylamino carbon atoms in each alkyl part, or Ri and _R2 together with the nitrogen to which they are attached, a five- or six-membered heterocycle which may also contain oxygen, sulfur or NR? where R? is as defined above, A is benzofuranyl, phenylene or a 5- or 6-membered heterocyclic containing from 1 to 3 oxygen, sulfur or nitrogen atoms, optionally condensed with a benzene ring, with the proviso that when A is a 5-membered heterocycle or benzofuranyl, n is 1 , and physiologically acceptable salts thereof, wherein p is 1 or 2 and L, and L ₂ are terminal groups such as (C 1 -C 5) alkoxy, (C 1 -C 5) alkylthio. 5-carbon atoms, phenoxy or phenylthio, in an aprotic solvent at a temperature ranging from -78 to 50 ° C, with an amine of formula III raw-hh _{2 (} III) wherein R, A, and W are as defined above, and at 0 to 100 ° C with an amine of formula XV. R (IV) wherein R, and Rg are as defined above, in any order, and the compound obtained is optionally converted to a physiologically acceptable salt. 2. The method of item 1 of the preparation 3-N (3- (3-piperidinylmethyl / phenoxy) propyl) amino-4-amino-1,2,5-thiadiazole-1-oxide and physiologically acceptable salts, characterized by reacting with 3-ethoxy-4- aaino-1,2,5-thiadiazole-1-oxide with 3- (3- (1-piperidinyl-methyl) phenoxy) -propanaminene in methyl cyanide at room temperature and the resulting compound optionally converted to a physiologically acceptable salt. ‘Severography, n. P., MOST Price 2,40 Kčs