CS246052B2 - Method of 3,4-disubstituted 1,2,5-thiadiazole-1-oxides and-1,1-dioxides production - Google Patents

Abstract

The title compds. of formula (I) and their non-toxic salts or hydrates are prepd. by treating compds. of formula (II); in the presence of an inactive solvent, with compds. of formulas (A) and (B) , successively. In the formulas, P is 1 or 2; R1 is -NR2R3; R2 and R3 are H, (lower)alkyl, (lower) alkenyl, etc.; m is 0 or 1; n is 2 or 3; Z is S, O or methylene; A is phenyl, imidazolyl, pyridyl, etc; and R7 is halo, (lower)alkyl, (lower) alkylthio, phenoxy, etc. The prods. are useful as antiulcer agents.

Description

A represents a phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl group, which optionally contain one or two substituents, the first substituent being selected from the group consisting of alkyl with 1 to 12, preferably 1 to 8, carbon atoms, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, alkoxy of 1 to 12, preferably 1 to 8 carbon atoms and a group of the formula

NHR ⁴ from - (C ^ CHJgN \ NHR ⁴ or - (CH _{2) q} NR5R6 wherein p is 1 or 2,

R ¹ is a hydroxyl group, m is an integer from 0 to 2 inclusive, n is an integer from 2 to 4 inclusive,

Z is sulfur, oxygen or methylene, and the second substituent is selected from the group consisting of alkyl having 1 to 12, preferably 1 to 8 carbon atoms, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, 246052, and alkoxy 1 to 12 , preferably 1 to 8 carbon atoms, q is an integer from 0 to 6 inclusive, each of R ⁴ is hydrogen, alkyl of 1 to 12, preferably 1 to 8 carbon atoms, alkenyl of 2 to 12, preferably 2 to 8 carbon atoms, an alkynyl group having 2 to 12, preferably 2 to 8 carbon atoms, an alkanoyl group having 1 to 12, preferably 1 to 8 carbon atoms or a benzoyl group, or both R ⁴ together represent an ethylene group, and each of R ⁵ and R ^e independently of the other is hydrogen, alkyl of 1 to 12, preferably 1 to 8 carbon atoms, alkenyl of 2 to 12, preferably 2 to 8 carbon atoms, alkynyl an alkyl group having from 2 to 12, preferably from 2 to 8 carbon atoms, a cycloalkyl group having from 3 to 12, preferably 3 to 8 carbon atoms, or a phenyl group, wherein R ⁵ and R ^{6 are} not both simultaneously cycloalkyl having 3 to 12, preferably 3 or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached represent a pyrrolidine, morpholine, piperidine, methylpiperidine, N-methylpiperidine or homopiperidine group.

The term "non-toxic, pharmaceutically acceptable salts" includes not only acid addition salts but also alkali and alkaline earth metal salts. The compounds of formula I have been found to form salts with metals such as potassium, sodium and calcium. These salts are probably formed by displacement of the proton from one of the nitrogen atoms adjacent to the thiadiazole ring, but this is merely a theoretical consideration, and is not intended to limit the invention in any way.

The invention also provides a process for the preparation of intermediates of the compounds of formula I.

The first clinically active H 2 -receptor antagonist was burimamide of formula XXXa. It inhibits gastric secretion in animals and humans, but oral absorption is low.

C - NHCH ₃ (X XX I

XXXa: R2 = H, Z = CH, X = S burimamide XXXb R ² = СНз, Z = S, X = S metiamide XXXc R ² = СНз, Z = S, X = NCN cimetldin.

Metiamide (XXXb), another H2-receptor antagonist used, is stronger than burimamide and is effective in humans for oral administration. However, its clinical applicability is limited due to its toxicity (agranulocytosin. Cimetidine (XXXc) is as potent an H 2 -antagonist as metiamide without inducing agranulocytosis, and has recently been commercially available as an anti-ulcer drug. The half-life of cimetidine is relatively short, which is relatively short results in the need for a treatment regimen comprising several daily doses of 200 to 300 mg tablets, and there is therefore a need for anti-ulcer drugs that have a longer duration of action and / or are more potent than cimetldine.

The invention also encompasses a process for the preparation of all possible tautomeric forms, geometric isomers, optical isomers of the compounds of the formula I as well as the compounds of the formula I present in the form of zwitterions and also the compounds of these forms.

The compounds of formula (I) according to the invention are prepared by the preparation of a compound of formula (II)

Ю If, n ' ^s ' n

R ⁷ R ⁷

Wherein p is 1 or 2 and each of R ⁷ is halogen, alkoxy of 1 to 12, preferably 1 to 8 carbon atoms, alkylthio of 1 to 12, preferably 1 to 8 carbon atoms, phenoxy or phenylthio, which optionally contains one or two substituents from the group consisting of halogen, alkyl of 1 to 12, preferably 1 to 8 carbon atoms, alkoxy of 1 to 12, preferably 1 to 8 carbon atoms and nitro, is left in an inert organic solvent with one equivalent of a compound of formula XXIII

A (CH ₂ ) _m Z (CH ₂ ) _n NH ₂ (XXIII) wherein

A, Z, m and n are as defined above, and the product obtained is then reacted with potassium, lithium or sodium hydroxide, whereupon the resulting product is optionally converted into a non-toxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide.

The starting compounds of formula II wherein p is 2 and each of R ⁷ is chloro, methoxy or ethoxy are known; their preparation is described in J. Org. Chem. 40, p. 2743 (1975). The starting compounds of formula II wherein p is 2 and each of R ⁷ is alkoxy, alkylthio, phenoxy, optionally substituted phenylthio or substi

246052 5 6

a fatty phenoxy group (compounds of formulas IV and V) may be prepared by reacting a dichloro compound of formula III with an appropriate alkanol, alkylthiol, phenol, thiophenol, substituted phenol or substituted thiophenol to give the corresponding compound of formula IV or V wherein R ³ is alkyl, phenyl or substituted phenyl moiety, according to the scheme:

(IV)

The reaction is carried out in an inert organic solvent such as ether, dimethylformamide and the like. If the reactant of formula R ⁸ O ^or H or R ⁸ SH is liquid, such as methanol, ethanol, ethyl mercaptan or thiophenol, the reaction may be reactants as solvent. Appropriate starting materials of formula II wherein p is 1 (compounds of formulas VII and VIII) can be prepared in the same manner from a compound of formula II wherein each of R ⁷ is chlorine (compound of formula VI).

(VIlD

The compound of formula (VI) is a novel compound, but may be prepared from the known compound 3,4-dihydroxy-1,2,5-thiadiazole-1-oxide (which is again prepared as described in Org. Prep. 255 [1969]) by the same procedure used for the preparation of the compound of formula III from 3,4-dihydroxy-1,2,5-liadiazole-11-dioxide (see J. Org. Chem. 40, p. 2,743 [1975]). The starting compounds of formulas VII and VIII are novel compounds not previously described in the literature.

Alternatively, the starting compounds of formulas (IV) and (VII) may be prepared by reacting an appropriately substituted oxalic acid diimide ester of formula (IX) with sulfur trioxide SC12 or sulfur trichloride S2Cl2 in an inert solvent such as dimethylformamide to give the appropriately 3,4-disubstituted 1,2,5- The compound of formula (X) is then oxidized to the corresponding 1-oxide of formula (VII) or 1,1-dioxide of formula (IV).

R ⁸ O OR 9 SCI 2 c ---- c ---- ZX or S 2 Cl 2

NH (IX)

R ⁸ O OR ⁸ 2 [0] compound i -----> general Yi of formula VII ^N Y ^N [0] compound ---> General (X) of formula IV

Diimidestery formula IX wherein R ⁸ is methyl, ethyl, n-propyl, isopropyl, n-butyl and n-pentyl group, are known and their preparation is described in the periodical Chem. Ber. 107, page 3, 121 (1974). In a similar manner, the corresponding compounds may be prepared wherein R 8 is a phenyl radical optionally substituted by an alkyl, alkoxy, halogen or nitro group. Compounds of formula X wherein R 8 is methyl or ethyl are described in J. Org. Chem. 40, p. 2749 (1975).

It is reported in the literature that the 1,2,5-thiadiazole ring is sensitive to oxidation, that oxidation of thiadiazoles with peracids is usually accompanied by ring disruption and sulfate ion formation, and that attempts to prepare 1,2,5-thiadiazole-1,1-dioxide oxidation of the base ring with peracetic acid resulted in ring cleavage.

Surprisingly, it has been found that 3,4-disubstituted 1,2,5-thiadiazole-1-oxides of formula VII and 1,1-dioxides of formula

IV can be readily prepared in good yield by oxidation of the appropriately 3,4-disubstituted 24605 2 1,2,5-thiadiazole X with a peracid. such as m-chloroperbenzoic acid, in an inert solvent such as chloroform.

By way of example, the preparation of 3,4-methoxy-1,2,2-thiadiazole-1-oxide:

To a solution of 50.7 g (25.0 mmol) (85% content) of m-chloroperbenzoic acid in 900 ml of chloroform, a solution of 35.2 g (24.1 g) of (24.1 g) was added over 3 minutes at 20 ° C. mmol) of 3,4-dimethoxy-1,2,5-thiadiazole [prepared by the method described in J. Org. Chem. 40, p. 2749 (1975)] in 100 ml of chloroform while cooling the reaction mixture so that its temperature does not exceed 32 ° C due to the exothermic reaction. After stirring the reaction mixture at room temperature for 3 hours, excess peracid was treated with an additional 2.0 g of 3,4-dimethoxy-1,2,5-thiadiazole, and the reaction mixture was stirred for 1 hour.

The organic solution was extracted twice with 300 ml of 1% sodium bicarbonate solution each time, washed with 250 ml of water, dried and evaporated under reduced pressure to give 47.0 g of product. Recrystallization from isopropyl alcohol gave 34.0 g of the title compound. Further recrystallization from isopropyl alcohol gave an analytical sample with a melting point of 135-137 ° C.

Analysis for C4H6N2O5S:

calculated:

H, 3.72; N, 7.27; S, 19.77. Found:

H, N, 17.26; S, 19.83%.

The preparation of the appropriate 1,1-dloxide is described below in Illustrative Procedure No. 1.

Illustrative Procedure · No. 1

3,4-dimethox2-1,2,5-thiaziazole-d, 1-dioxide

A solution of 1.48 g (10.1 mmol) of 3,4-dimethoxy-1,2,1-thladlazole (prepared as described in J. Org. Chem. 40, 2749 [1975]) in 20 ml of chloroform was added with stirring to a solution of 4.11 g (20.3 mmol) of m-chloroperbenzoic acid (containing 85%) in 60 ml of chloroform over 1 minute. The mixture was stirred at room temperature for 1 hour, then heated at reflux for 8 hours and then stirred again at room temperature for 1 hour. Then, the reaction mixture is extracted with aqueous sodium bicarbonate solution and water, and the resulting organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was treated with methanol and filtered to give 1.03 g of product. Recrystallization from methanol gave the title compound, m.p. 200 DEG-202 DEG.

Analysis for C 18 H 18 N 2 O 3 S:

calculated:

% H, 3.39;% N, 15.72;% S, 18.00. Found:

% C, 26.82;% H, 3.18;% N, 16.09.

A particularly advantageous process has now been found which can be used in one step to prepare a compound of formula (VII) directly from a compound of formula (IX) by reacting a compound of formula (IX) with thionyl chloride. This reaction proceeds according to the reaction scheme

R8OOR \ ZSOCI2

G-C --- Z \ S

HN NHn (IX) (vin

248952

1) 0 and is carried out in an inert organic solvent such as methylene chloride, chloroform, etc., At a temperature ranging from about -20 ^-?, · C to about 25 C, preferably in the range of CD about 0 ° C to about 1 ' ) ° C. Although this reaction may be carried out without the addition of an acid-reactive base, it is preferred to add about two equivalents of base to remove the hydrochloric acid formed in the reaction. This results in higher projections of the compound of formula (VII). Suitable bases are inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, and organic bases such as triethylamine, pyridine and the like. This process not only removes one step but is much more economical by not expensive oxidizing agents such as m-chloroperbenzoic acid must be used. Illustrative Process # 2 describes the preparation of a compound of formula (VII) wherein R 3 is methyl by this method.

Illustrative Procedure 2

3 ·, 4 - Дtπ ^ t ^ tУ <l) C ^^ - 5, -Jh> · 1 ^ hiα ^ (^ 1-2 ^ -ЯxLoxid)

A solution of 4.0 · g (34.5 mmol) of diimethyl oxalate dimethyl ester and 5.71 ml (5.58 g; 70.6 mmol) of pyridine in 8 ml of methylene chloride CH2Cl2 was added dropwise to a cold solution of 2.61 ml. (4.25 g; 34.7 mmol) of thiopropyl chloride in 18 ml of methylene chloride CH 2 Cl 2 under a stream of nitrogen at a rate such that the reaction temperature is maintained between 0 ° C and 15 ° C. The reaction mixture is then stirred at room temperature for 20 minutes and then washed twice with 11 ml of aq. N hydrochloric acid. The aqueous phase is extracted twice with 20 ml of methylene chloride CH2Cl2 each time and the combined organic phases are dried and evaporated to dryness under reduced pressure. The solid residue was recrystallized from isopropanol to give 3.0 g · · · title compound o> ^ tep tlo ^ T ^ i- point ranging from 137 · ^Q to 139 ° C.

The compounds of formula (I) are prepared by the method of the invention from the starting compound of formula (II) according to the following reaction scheme:

(O) _p e compound A (CH ₂ ) _and Z (OH) 2 NH 2 common ------ _- ---------. of formula II (Com. vz. XXIII) ^{And (} Щ1 _п ын ъ / юн (ХИ

^{A! C} U '''2 ¹ · ^Η 2.'η ^ΝΗ

Р> _р

AA

OH (I b)

In this reaction scheme, M is a metal cation, which is preferably K +, L 'or Na +. The reactions are carried out in an inert organic solvent, for example methanol, which is a suitable and readily available solvent. The reaction temperature is not a critical parameter. Most of the starting compounds are sufficiently reactive and the reaction is preferably carried out at a temperature below room temperature, for example at a temperature in the range of 0 to 10 ° C. For somewhat less reactive compounds, it is convenient to carry out the reaction at room temperature. Sometimes it is desirable to subsequently raise the temperature of the reaction mixture (e.g. to 30 to 60 T) to complete the reaction. All intermediates of formula XI are novel compounds.

The invention further provides novel starting compounds of formula (IIa) wherein each R ⁷ is a leaving group selected from the group consisting of halogen, alkoxy, alkylthio, and phenoxy or phenylthio, optionally containing one or two substituents selected from the group consisting of halogen , alkyl, alkoxy and nitro.

In a preferred embodiment of the compounds of formula IIa, each R ^{7 is} alkoxy, phenoxy or substituted phenoxy, and in particular each R ^{7 is} methoxy.

The term "non-toxic, pharmaceutically acceptable salt" as used herein refers to a salt of a compound of Formula I with a non-toxic, pharmaceutically acceptable organic or inorganic acid. Such acids are known and include hydrochloric, hydrobromic, sulfuric, amidosulfonic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, ethanedisulfonic, benzenesulsulfonic, acetic, propionic, tartaric, citric, tartaric, citric, tartaric, citric, tartaric, citric, tartaric acids. by known procedures. Some of the compounds of formula (I) and some of the intermediates listed above form di-salts, tri-salts, etc. It should be noted that salts of intermediates are not limited to salts with nontoxic, pharmaceutically acceptable acids, unless such intermediates are used alone as pharmaceuticals.

It has been found that many of the compounds of formula (I) are firmly attached to the solvents from which they are recrystallized. In some cases, these products appear to be true solvates, while in other cases these products only retain a foreign solvent or are a mixture of a solvate with a foreign solvent. Although the solvent can be removed by drying at elevated temperature, this process often converts the nicely crystalline product into a gummy solid. Since the solvated products generally had completely sharp melting points, it was common practice to dry these products at room temperature. Where products retained the solvent even after prolonged drying, the amount of solvent was determined, for example, by nuclear magnetic resonance analysis. In some of the examples below, the amount of crystal solvent (where appropriate) is given, and the analysis and melting points refer to solvated products unless otherwise indicated.

For therapeutic use, the pharmacologically active compounds produced by the process of the invention will generally be administered in the form of a pharmaceutical composition comprising, as the main active ingredient, at least one of the compounds in base or non-toxic pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable carrier. .

These pharmaceutical products can be administered orally, parenterally or rectally in the form of suppositories. These products can be used in a wide variety of pharmaceutical forms. For example, when a solid carrier is used, the composition may be tableted or optionally powdered or pelleted into a hard gelatin capsule, or made into a lozenge. When a liquid carrier is used, the composition may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or an aqueous suspension or suspension in a non-aqueous liquid. The pharmaceutical compositions are prepared by conventional techniques appropriate to obtain the desired composition.

Preferably, each dosage unit contains the active ingredient in an amount of from about 0.5 mg to about 150 mg, and in particular in an amount of from about 2 mg to about 50 mg. The active ingredient is preferably administered, in equal doses, two to four times daily. The daily dosage regimen preferably comprises from 1 mg to about 660 mg, especially from about 4 mg to about 200 milligrams of active ingredient.

Compounds acting on the H2-receptors opposite histamine have been shown to be potent inhibitors of gastric secretion in animals and humans [Brimblecomble et al., J. Int. Copper. Res., 3, p. 86 [1975]). Clinical evaluation of cimetidine as a compound acting on the H 2 -receptors opposite to histamine has shown that it is an effective drug in the treatment of ulcer diseases of the gastrointestinal tract (Gray et al., Lancet, 1, p. 8 001 [1977]). One of the standard animal models for determining the gastric anti-mixing efficacy of histamine H 2 -antagonists is a ligated duodenum rat. Table I shows the magnitude of the gastric anti-shuffling dose ED.50 (in gmoles / kg) of some of the compounds produced by the method of the invention in the ligand-ligated rats. Determination of gastric anti-mixing efficacy in a rat which has been ligated with the duodenum for 2 hours.

The rat duodenum ligation method was proposed by Shay et al. (Gastroentorology, 5, p. 53 [1945]) for studying ulcer perforation on the gastrointestinal tract; however, once known, this method was also used to study gastric secretion in rats (Shay et al., Gastroentorology, 26, p. 906 [1954], AD Brodie, Am. J. Dig. Dis., 11, p. 231 [1966]). This modified procedure was used to evaluate the efficacy of the compounds produced by the method of the invention against gastric secretion.

Male rats of the species Long are used

Evans weighing from 280 to 300 grams. The test animals are housed individually in cages and kept free of food for 24 hours, but with free access to water. Under ether anesthesia with central incision to? 1 β 9 5 2 reaches the stomach and binds the duodenum with cotton thread. After wound closure, ether is discontinued and the test compound or control vehicle is administered either intraperitoneally or subcutaneously in a volume of 1 ml / kg. All compounds are solubilized with one equivalent of hydrochloric acid and made up to volume with water. The test animals are again placed in cages from which the water bottles have been removed, and after two hours they are sacrificed with ether. The stomach is removed and the contents of the stomach accumulated during the two hours are transferred to a volume tube. The titratable acidity was determined by filtering a 1 ml sample to pH 7.0 with a 0.02 N solution. sodium hydroxide · using an automatic burette and electrometric pM-meter (Radiorneter). The amount of titratable acid excreted in microequivalents is calculated by multiplying the volume, in milliliters, of the acid concentration in milliequivalents in 1 liter. Acid secretion inhibition (in%) is calculated according to the acid secretion inhibition relationship (in ° / o) amount of acid excreted (in control) amount of acid excreted [after test compound application] x 100 amount of acid excreted (in control)

In single dose experiments, at least five rats were used, and at least three different dose sizes were used to construct a dose-response curve. Initially, the test compound and control in the hiculum were administered by the intraperitoneal injection in this test. Later, however, the test was found to be more sensitive when used with subcutaneous injections, and all subsequent tests were performed by subcutaneous administration. The method of application of the individual compounds is shown in Table I.

TABLE I

The effect of the compounds produced by the method of the invention on secretion of gastric acid in a rat that was on time. two hcdin ligated the duodenum

Example Compound No. Route of administration of ED 50 *) / pitch / kg

i. p. 31.1 (11.1— 82.8)

pp 33 (8,7 - 141)

Some of the compounds produced by the method of the invention have also been tested and demonstrated efficacy in guinea pigs (isolated atrial right ventricular atrial test), and in dogs (gastric tube test, intravenous administration) and Heidenhein oral administration test. The first two tests were performed according to the procedures described in U.S. Pat. No. 4,112,234. Heidenhein's dog test was carried out according to the procedure of Grossman and Konturk described in Gastroenterology, 66, 512 (1974).

"Cdite" is a registered trademark of Johns-Manville Products Corporation for diatomaceous earth. "Skellysolve B" is a registered trademark of the Skelly Oil Company for a petroleumethers fraction boiling in the range of 60 to 68 ^° C, consisting mainly of n-henane.

The term "flash chromatography" refers to the relatively new chromatographic technique described by W. C. Styll et al. in J. Org. Chem., 43, pp. 2,923-2,925 (1978). It uses finer powder chromatographic media and pressures slightly higher than atmospheric pressure to achieve faster chromatographic separation.

In the examples below, all temperature data are given in degrees Celsius, and the term "de-β-β (β-tyl) ulfoxide" refers to deuterated dimethylsulfoside.

Example 1

3-hydroxy-4- [2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamino-1,2,5-thiadiazole-1,1-dioxide

A. 3- [2 - [[5-Methyl-1H-imidazol-4-yl] methylthio] ethylbenzomethoxy. .alpha., .alpha.-Ammoniumzol-yudiol

Stirring is continued with vigorous stirring

2.9 g (U, 2 mmol) of 3-dimethoxy-1,2,5-thiadiazole-1,1,1-dimethyl-oxide [prepared according to the procedure described above, in J. Org. Chem.

p. 2,743 (1975) in 200 mL methanol at room temperature add a solution of 2.73 g of [11.2 rom-ol] 2 - [(5-methyl-1H-imidazol-4'-yl) methylthiojethylaminulum (from dihydrochloride) (prepared according to the procedure of Belgian Patent No. 779 775) vs 25 ml of methanol. The mixture was stirred for 30 minutes to give a methanolic solution of the title compound.

4 0 5 2

R ₍ = - 0.44 according to thin-layer chromatographic analysis (silica / / 1Л1ХИ2: СНзОН [90: 10]).

В. 3-hydroxy-4'2 - [(5-methyl-1H-imidazol-4-yl) methylthio] ethylamino; -1,2,5-thiadiazole-1,1-dioxide

To a methanolic solution of the product of paragraph A., cooled to 0 ° C in an ice water bath, was added a solution of 2.10 g (52.5 mmol) of sodium hydroxide pellets in 25 mL of anhydrous methanol. After stirring at 0 ° C for 2 hours, then at room temperature for 68 hours, the reaction mixture was neutralized by the addition of 8.75 mL (52.2 mmol) of aqueous 6.0 N hydrochloric acid and evaporated after 10 minutes of stirring. under reduced pressure. The residue was recrystallized with 95% ethanol to give the crude product, which was dissolved in methanol, filtered to remove sodium chloride, and chromatographed on 60 g of silica gel, eluting with a graduated mixture of methylene chloride and methanol. The appropriate fractions were combined and evaporated under reduced pressure to give the title compound, m.p. 263-265 ° C (dec.).

Analysis for C9H13N5S21O3:

calculated:

% C, 35.64;% H, 4.32;% N, 23.09;% S, 21.13;

% C, 35.56;% H, 4.38;% N, 23.01;

Example 2

3- (2 - ((5-dimethylaminomethyl-2-furyl) methylthio) ethylamino; -4-hydroxy-1,2,5-thiadiazole-1,1-dioxide

A. 3- (2 - ((5-dimethylaminomethyl-2-furyl) methylthio] ethylamino) -4-methoxy-1,2,5-thiadiazole-1,1-dioxide

Under vigorous stirring, to a suspension of 1.78 g (10.0 mmol) of 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide in 180 ml of anhydrous methanol, which was cooled to 1 ° in an ice-water bath. C, a solution of 2.14 g (10.0 mmol) of 2- [5-dimethylaminomethyl-2-furyl) methylthio] ethylamine in 25 ml of anhydrous methanol was added dropwise over 35 minutes. After 15 minutes at 0 ° C, a methanolic solution of the title compound is formed.

R _f = 0.48 by chromatographic analysis TLC [silica / / CH2Cl2: СНэОН (9: 1)].

2.0 ml of this solution was acidified by addition of 6.0 N hydrochloric acid solution and evaporated under reduced pressure without heating to give the title compound as the hydrochloride.

The NMR spectrum (100 MHz) in D2O gives the following resonances δ:

6.45 (d, IH);

6.19 (d, IH);

4.14 (s, 2H); 4.0 (s, 3H);

3.64 (s, 2H).

3.37 (t, 2H).

2.65 (s, 6H); 2.61 (t, 2H).

B. 3-: 2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino-4-hydroxy-1,2,5-thiadiazole-1,1-dioxide

To a methanolic solution of the product of paragraph A, cooled to 0 ^DEG C. in an ice water bath, was added a solution of 2.10 g (52.5 mmol) of sodium hydroxide pellets in 25 mL of anhydrous methanol. The mixture was stirred at 0 ^° C for 2 hours and then at room temperature for 68 hours. The reaction mixture was neutralized by the addition of 8.75 ml (52.5 mmol) of aqueous 6.0 N hydrochloric acid solution and evaporated after 10 minutes of stirring. under reduced pressure. The residue was recrystallized with 95% ethanol to give the crude product, which was dissolved in methanol, filtered to remove sodium chloride, and chromatographed on 60 g of silica gel, eluting with a graduated mixture of methylene chloride and methanol. Appropriate fractions were combined and evaporated under reduced pressure to give 3.19 g of product. Recrystallization from aqueous methanol gave the title compound, m.p. 109-122 ° C.

Analysis for C12H18N4O4S2:

calculated:

H, 5.24; N, 16.17; S, 18.51. Found:

% C, 41.59;% N, 5.32;% S, 18.81%.

(Corrected to 1.15% H2O.)

Example 3

3- {2 - [(2-guanidothiazol-4-yl) methylthio] ethylamino-4-hydroxy-1,2,5-thiadiazole-1-oxide

A solution of 2.91 g (17.9 mmol) of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide in 350 ml of methanol, which had been pre-cooled with an ice-water bath, was added dropwise over 30 minutes. 4.15 g (17.9 mmol) of 2 - [(2-guanidinothiazol-4-yl) methylthio] ethylamine in 50 ml of methanol. A solution of 3.58 g (89.5 mmol) of sodium hydroxide pellets in methanol was then added to the reaction mixture. The reaction mixture was stirred overnight at room temperature and then neutralized by the addition of 14.9 ml (89.5 mmol) of aqueous 6.0 N acid solution.

π hydrochloric acid and, after 10 minutes, evaporate under reduced pressure. The solid residue is rubbed with 70 ml of water at ambient temperature for 2 hours and then filtered to give the product. Recrystallization from water gave the title compound, m.p. 148-151 ° C.

calculated:

% C, 31.11;% H, 3.77;% N, 27.22;

% C, 30.95;% H, 3.73;% N, 28.27.

(Corrected due to 5.52% H? O.)

Analysis for C ^ HHnsNyChSs:

Claims (1)

A process for the preparation of 3,4-disubstituted 1,2,5-thiazam-u-i-oxide and 1,1-dioxides of the formula I wherein p is 1 or 2, R ¹ represents a hydroxyl group. m represents an integer from 0 to 2 inclusive, n represents an integer from 2 to 4 inclusive, Z is sulfur, oxygen or methylene, and A represents a phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolvyl, isooxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl group optionally having one or two substituents, the first substituent being selected from the group consisting of 1 to 12 alkyl preferably 1 to 8 carbon atoms, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, alkoxy of 1 to 12, preferably 1 to 8, carbon atoms and a group of the formula NHR ⁴ Z - (CH ₂ ) _q N = C \ NHR ⁴ or - (CH ₂ ) _q NR ⁵ R ⁶ and the second substituent is selected from the group consisting of alkyl of 1 to 12, preferably 1 to 8 carbon atoms, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and alkoxy with 1 to 12, preferably 1 to 8, carbon atoms, q is an integer from 0 to 6 inclusive, each of R ⁴ is hydrogen, an alkyl group of 1 to 12, preferably 1 to 8 OF THE INVENTION C 8 alkenyl, C 2 -C 12, preferably C 2 -C 8 alkenyl, C 2 -C 12, preferably C 2 -C 8 alkynyl, C 1 -C 12, preferably C 1 -C 8 alkanoyl, or benzoyl, or both R ⁴ together represent ethylene, and each of R ⁵ and R ⁶ independently of the other is hydrogen, alkyl of 1 to 12, preferably 1 to 8 carbon atoms, alkenyl of 2 to 12 , preferably 2 to 8 carbon atoms, an alkynyl group having 2 to 12, preferably 2 to 8 carbon atoms, a cycloalkyl group having 3 to 12, preferably 3 to 8 carbon atoms, or a phenyl group, wherein F? and R ^{6 are} not both cycloalkyl having 3 to 12, preferably 3 to 8, carbon atoms or phenyl. or R ⁵ and R ^G together with the nitrogen atom to which they are attached represent a pyrzolidine, a morphine, a piperidine, a methylpiperidine, an N-methylpiperazine or a homopiperidine group, as well as their non-toxic, pharmaceutically acceptable salts, hydrates, solvates or N-oxides, characterized in that the compound of the general formula II N N Π Π Wherein p is 1 or 2 and each of R ⁷ is halogen, alkoxy of 1 to 12, preferably 1 to 8 carbon atoms, alkylthio of 1 to 12, preferably 1 to 8 carbon atoms, phenoxy or phenylthio which optionally contains one or two substituents from the group consisting of halogen, an alkyl group of 1 to 12, preferably 1 to 8 carbon atoms, an alkoxy group of 1 to 12, preferably 1 to 8 carbon atoms and a nitro group, is left in an inert organic the solvent is reacted with one equivalent of a compound of Formula XXIII A (CH ₂ ) _m Z (CH ₂ ) _n NH ₂ (XXIII) wherein A, Z, m and o are as defined above, and the product is then reacted with potassium, lithium or sodium hydroxide, whereupon the resulting product is optionally converted to a non-toxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide.