CH632763A5 - Triazolothiadiazine derivatives and processes for preparing them - Google Patents

Description

The present invention relates to new therapeutically active compounds derived from triazolothiadiazine as well as processes for the preparation of these compounds and their use as active substances of therapeutic compositions.

The compounds according to the invention correspond to the general formula

^ 3s

> n I II

in which:

R! represents a hydrogen atom, a trifluoromethyl radical, a saturated or unsaturated alkyl radical, linear or branched in Q to C16, a C3 to C7 cycloalkyl radical, an alkyl (Cj-Cg) cyclo-5 (C3-C7) alkyl radical ), an aryloxyalkyl radical (QQ), an aryl radical, an arylalkyl radical (Cx-C6), a saturated or unsaturated heterocyclic radical such as thienyl or furyl, a radical of formula

—CH — Rs, io |

R7

in which R7 is a hydroxy, cyano or Q-C6 alkoxy radical and Rs is a CVQ or aryl alkyl radical,

R2 and R3, independently of each other, represent a hydrogen atom, an aryl radical, a Q-Cg alkyl radical, a C3-C7 cycloalkyl radical, an (Ci-C6) oxycarbonyl alkyl radical , alkyl (Ca-C6) carbamoyl, carboxy or cyano,

n is equal to 0.1, 2 or 3,

20

R4 represents a hydrogen atom, a C1-C6 alkyl radical, an aryl radical, a hydroxyl radical or an alkyl (Q-Cg) oxy radical,

R5 represents hydrogen, and

R6 represents a hydrogen atom, an alkyl radical in Q-Cg, alkyl (Cj-Cg) carbonyl, arylcarbonyl or arylalkyl (QQ) carbo-nyl or, when n = 0, R5 and R6 together represent a single bond . In addition to the compounds of formula I, the invention also relates to their addition salts with pharmaceutically acceptable acids.

30

In the preceding definition, the term aryl denotes a phenyl radical substituted by one, two or three radicals chosen independent of one another from hydrogen, halogens, C 1 -C 6 alkyl radicals, (CrC 6) alkyl oxy , alkenyl (C2-Cs) oxy, alkynyl (C2-C6) oxy, alkyl (Cj-Cg) thio, trifluoromethyl, alkylene (C [-C4) dioxy and the nitro group.

The addition salts may be in particular those formed with hydrohalic, sulfuric, nitric, phosphoric, formic, acetic, maleic, fumaric, methanesulphonic, lactic, succinic, tartaric acids and acidic metal salts such as disodium orthophosphate. and monopotassium sulfate. In addition, the free bases can exist in hydrated or practically anhydrous form.

(I)

45

The compounds of formula I can be prepared by reaction of a 4-amino 4H-triazole-1,2,4 thiol-3 of formula II with an α-halogenated ketone derivative of formula III (method A), or a dihalogenated derivative of formula IV (method B), according to the following diagrams

Method A

12 #

X - 0 - c I \

R3

(III)

Method B

FU

H

x,

h2N /

N R-v Q M

Y (-> n4 TJ

—V r4-Sj - n— "•

(i "

not.

x - ç - (cn2) n - Ç - X -!

R.

I

Rr

(IV)

h

NOT-

HgN

/

r,

(he)

R2

(Crë) n I "If r5 f h

* 1

(Ib)

5

632,763

Rt, R2, R3j R4 and R5 having the meanings given above and X denoting a halogen. This reaction is advantageously carried out in an anhydrous inert solvent or without solvent by heating under reflux, for approximately 4 to 24 h.

The compounds of formula II can be prepared: 1) by cyclization of a potassium dithiocarbazinate in the presence of hot hydrazine in an aqueous medium, according to the following scheme:

koh r, -c-nh-nh2 ►

o cs2

ri - c — nh —nh —c — s © k®

He II

o s nh2-nh,

H, 0

2) by cyclization of a methyl dithiocarbazinate in the presence of hydrazine in ethyl alcohol at reflux, according to the following scheme:

r, -c-nh-nh2

O

koh

CS2, IMe ri - c — nh — nh — c — s — Me

At 11

O s

NH2-NH2

C, H, OH

1

O

H - S ^ (\ K \

a) The 4-amino-5-benzyl 4H-triazole-1,2,4 thiol-3 intermediate can be prepared as follows:

Method 1:

5 To a solution containing 84 g (1.5 mol) of potassium hydroxide and 150 g (1 mol) of phenylacetoohydrazide in 11 of absolute alcohol, 114 g (1.5 mol) are added, with cooling and stirring. ) of carbon disulfide. After 3 h, the reaction mixture is poured onto 11 of ethyl ether. The precipitate is drained, washed three times with 100 ml of ethyl ether, then dried.

221 g of 3-benzyl potassium dithiocarbazinate (0.95 mol), 48 g of hydrazine in 500 ml of water are heated to reflux with stirring for 1 h. The reaction mixture is poured onto ice, then acidified with concentrated hydrochloric acid. The white precipitate formed is washed with water and then recrystallized from aqueous ethyl alcohol. 4-Benzyl-5 4H-triazole-1,2,4 thiol-3 is obtained, which melts at 172 ° C.

NMR (DMSO d6) s5H at 7.4ppm s IH (S-H) at 13.6 ppm 20 s 2H at 4.15 ppm s 2H (NH2) at 5.65 ppm

Method 2:

To a solution containing 8.4 g (0.15 mol) of potassium hydroxide and 15 g (0.1 mol) of phenylacetoohydrazide in 100 ml of absolute alcohol, is added, with cooling and stirring, 11, 4 g (0.15 mol) of carbon disulfide. After 3 h, 30 ml of water are added and then, drop by drop, 14.2 g of methyl iodide. The methyl ester precipitates after 30 min and adding 100 ml of water.

24 g (0.1 mol) of 3-benzyl methyl dithiocarbazinate obtained above and 5 g of hydrazine in 100 ml of ethyl alcohol are heated at reflux for 12 h. The reaction mixture is poured onto ice, then acidified with concentrated hydrochloric acid. After recrystallization, a compound identical to that obtained by method 1 is obtained.

35

40

3) by condensation of a carboxylic acid with 3-thiocarbo-hydrazide at temperatures varying between 90 and 150 ° C in the presence or not of a solvent, according to the following scheme:

R! -C-OH + NH2-NH-C-NH-NH2 ►

45

R

The compounds of formula I in which Rs is other than hydrogen can be obtained by the action of an alkylating or acylating agent on a compound of formula Ib, according to conventional methods.

In addition, certain compounds of formula Ib can be obtained by reduction of a compound of formula la according to conventional methods.

60

Example 1:

Benzyl-3-methyl-6 7H hydrochloride (1,2,4) triazolo (3,4b) (1,3,4) thiadiazine

R, = -CH2 - <^ \; n = 0; R2 = R3 = H; R4 = CH3;

~~ I I

- C — N— = —C = N -

I I R5 Re

Method 3:

10.6 g of 3-thiocarbohydrazide and 13.6 g of phenylacetic acid are heated for 3 h at 150 ° C. After cooling, 200 ml of anhydrous ether are added. The precipitate is drained, then recrystallized from aqueous alcohol.

b) 15 g (0.073 mol) of 4-amino-5-benzyl 4H-triazole-1,2,4 thiol-3, prepared according to method 1, 2 or 3, and 6.75 g of chloroacetone are heated to reflux for 12 h. It is left to crystallize by cooling, then the crystals formed are wrung out. After recrystallization from absolute alcohol, a compound is obtained which melts at 252 ° C. NMR (DMSO d6) s 5H at 7.4 ppm s 2H at 4 ppm s (H +) 11.8 ppm s 2H 4.3 ppm s 3H (CH3) 2.35 ppm

Example 2:

Benzyl-3-methyl-6,6-dihydro-hydrochloride 5,6 7H (1,2,4) triazolo (3,4b) (1,3,4) thiadiazine

R1 = CH2 - <^ 0 ^>; n = 0; R2 = R3 = H; R4 = CH3;

R5 = H; R6 = H

Maintaining the temperature between 0 and 5 ° C., 6.2 g of potassium tetrahydruroborate are added in portions to a solution of 3 g of sodium hydroxide, 21.8 g of the compound obtained in Example 1 in 150 ml methanol. After addition, stirring is continued for 20 h at room temperature. The solvent is evaporated off and the residue is dissolved in 100 ml of methylene chloride, then washed with water. The hydrochloride is extracted according to the conventional method. A compound is obtained which melts at 170 ° C.

632763

Example 3:

Benzyl-3 dihydro-5,6 7H hydrobromide (1,2,4) triazolo (3,4b)> 1,3,4) thiadiazepine

R1 = CH2 - <^^>; R2 = R3 = R4 = Rs = H; R6 = H; n = l

15 g of 4-amino-5-benzyl 4H-triazole-1,2,4 thiol-3 and 8 ml of 1-bromo-3-chloro propane in 100 ml of absolute alcohol are heated at reflux for 4 h. The solvent is evaporated and the residue is recrystallized from aqueous alcohol. The compound obtained melts at 230 ° C.

Analysis:

Calculated: C 44.04 H 4.67 N 17.12%

Found: C 43.91 H 4.59 N 17.13%

The following compounds were prepared by operating as in Example 1.

Example 4:

Phenyl-3-ethoxy-6 7H 1,2,4-triazolo hydrobromide (3,4b) (1,3,4) thiadiazine. F = 146C.

Example 5:

3-methyl-6-ethoxy hydrochloride 7H 1,2,4-triazolo (3,4b) (1,3,4) thiadiazine. M = 130 ° C.

Example 6:

Orthomethoxyphenyl-3 methyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. Mp 170 ° C.

Example 7:

Paramethoxybenzyl-3-methyl-6 7H 1,2,4-triazolo hydrochloride 13,4b) (1,3,4) thiadiazine. Mp 137 ° C.

Example 8:

3-Parachlorophenyl hydrochloride 6-methyl 7H 1,2,4-triazolo (3,4b) (1,3,4) thiadiazine. F = 155: C.

Example 9:

Parachlorobenzyl-3-methyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. M = 140 ° C.

Example 10:

Propyl-3 methyl-6phenyl-7 7H 1,2,4-triazolo hydrochloride (3,4 b) (1,3,4) thiadiazine. F = 116 C.

Example 11:

Benzyl-3-phenyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. F = 155 = C.

Example 12:

Benzyl-3-diphenyl-6,7 7H1,2,4-triazolo hydrochloride (3,4b)! 1,3,4) thiadiazine. Mp 165 ° C.

Example 13:

Deparanitrobenzyl-3 methyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. Mp 210 ° C.

Example 14:

X-methylbenzyl-3-methyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) 11.3.4 / thiadiazine. F = 106 C.

Example 15:

(Phenyl-3-propyl) -3methyl-6 7H1,2,4-triazolo (3,4b) (1,3,4) thiadiazine hydrochloride. F = 130 C.

Example 16:

Parahydroxybenzyl-3 methyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. M = 172 ° C.

Example 17:

Benzyl-3-ethoxy-6 7H1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. Mp 95 ° C.

Example 18:

Cyclopropane-3 methyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. M = 152 ° C.

Example 19:

Parachlorophenoxymethyl-3 methyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. M = 136 ° C.

Example 20:

Parafluorobenzyl-3methyl-6 7H 1,2,4-triazolo hydrochloride (3,4b) (1,3,4) thiadiazine. M = 120 ° C.

Example 21:

Benzyl-3 ethyl-6phenyl-7 hydrochloride 7H1,2,4-triazolo (3,4b) (1,3,4) thiadiazine. Mp 156 ° C.

The licensee has found that the compounds of formula I and their addition salts with pharmaceutically acceptable acids have the property of decreasing gastric secretions and can be used in therapy, in particular for reducing acid gastric secretions and for treating gastric ulcers and duodenals.

The results of the pharmacological study demonstrating this property will be given below.

The action of the derivatives on the inhibition of gastric acid secretion has been studied by proceeding as indicated below. The technique is based on a test consisting in determining the capacity of a compound to modify the gastric secretion (volume and total acidity) caused in the rat by a ligation of the pylorus [Method of Shay 1945 modified by Kim and Shore ("J. Pharmacol. Exp. Ther. ", 141, 321, 1963)].

The study relates to batches of 10 female SPF rats (Sprague Dawley strain) of approximately 150 g fasted with food 48 h before the test and receiving for food only a mixed solution of glucose and sodium chloride. On the day of the experiment, the pylorus is ligated under ether anesthesia and, 4 h later, the rats are sacrificed. After collection of the secretion and centrifugation, the volume and the total acidity are measured (assay with NaOH N / 100 at the pH meter).

All these products are studied at a dose of 100 mg / kg per os. The results are shown in the table below. The activities are expressed relative to the controls in percentage of inhibition for the volume of gastric secretion and for the total production of acid.

Example

Activity on gastric secretion volume (%)

Activity on total acidity (%)

1

-53

-37

2

-30

-20

7

-57

-20

8

-65

-31

14

-49

- 7

15

-67

-39

18

-52

-38.5

6

5

10

15

20

25

30

35

40

45

50

55

60

65

A subject of the invention is therefore also the use of a compound of formula I or one of its addition salts with pharmaceutically acceptable acids, as active substance in therapeutic compositions, in particular in admixture with a pharmaceutically acceptable excipient. s

These therapeutic compositions can be administered orally or parenterally.

632,763

These compositions can in particular be in the form of capsules, tablets or injectable solutions.

They can contain from 1 to 60% by weight of active principle depending on the mode of administration.

The daily dose in adults can be 0.1 to 3 g of active ingredient by oral route and 0.05 to 1.5 g of active ingredient by parenteral route.

R

Claims (10)

632763 1. Therapeutically active compounds of formula r- (vs: 3 N. not 'A I II u \ Rc "NOT' i r, wherein R2, R3 and R4 have the meanings given in claim 1, and X denotes a halogen. 3. Process for the preparation of compounds according to claim 1 of formula (I) (the) r4 <^ n '^ L1 in which: Ri represents a hydrogen atom, a trifluoromethyl radical, a saturated or unsaturated alkyl radical, linear or branched at C, at CI6, a cycloalkyl radical at C3 to C7, an alkyl (Cj-C6) cycloalkyl radical (C3- C7), an aryloxyalkyl radical (C ^ Q), an aryl radical, an arylalkyl radical (C, -C6), a saturated or unsaturated heterocyclic radical, a heterocyclic alkyl radical, a radical of formula -CH-RS, R, in which R, is a hydroxy, cyano or C 1 -C 6 alkoxy radical, and Rs is a C 1 -C 6 alkyl or aryl radical, R, and R3, independently of one another, represent a hydrogen atom, an aryl radical, an alkyl radical in Q-Cj, a cycloalkyl radical in C3-C7, an alkyl radical (QQ) oxycarbonyl, alkyl (Cj-C6) carbamoyl, carboxy or cyano, n is equal to 0.1,2 or 3, R4 represents a hydrogen atom, a Cj-C6 alkyl radical, an aryl radical, a hydroxyl radical or an alkyl radical (Q-Cg) oxy, R5 represents a hydrogen, and R6 represents a hydrogen atom, an alkyl radical in Q-Q, alkyl (Cj-Cg) carbonyl, arylcarbonyl or arylalkyl (Q-Cg) carbo-nyl or, when n = 0, R5 and R0 together represent a single bond, as well as their addition salts with pharmaceutically acceptable acids. 2. Process for the preparation of compounds according to claim 1 of formula (the) in which R ,, R2, R3 and R4 have the meanings given in claim 1, characterized in that a compound of formula h is prepared I h2N ^ will) L1 wherein Rt has the meaning given in claim 1, by cyclization of a potassium dithiocarbazinate of formula Ri- -SK 30 C-NH-NH-C- II II o S in the presence of hot hydrazine in an aqueous medium and this compound is reacted as indicated in claim 2. 4. Process for the preparation of compounds according to claim 1 of formula (the) in which Rx, R2, R3 and R4 have the meanings given in claim 1, characterized in that a compound of formula is prepared h Ns in which Rt, R2, R3 and R4 have the meanings given in claim 1, characterized in that a compound of formula h2N / 'is reacted fiai) r 1 h s ". Ì h2N / d n- (ii) L1 in which R; has the meaning given in claim 1, with a halogenated derivative of formula x - c - c // in which Rj has the meaning given to claim 1, by cyclization of a methyl dithiocarbazinate of formula R! —C — NH — NH — C — SCH3 He li O S in the presence of hydrazine in ethyl alcohol at reflux and this compound is reacted as indicated in claim 2. 5. Process for the preparation of compounds according to claim 1 of formula 5 \ M- \ (III) r- (Ia) R, 3 632,763 in which Rt, R2, R3 and R4 have the meanings given in claim 1, characterized in that a compound of formula is prepared 7. Process for the preparation of compounds according to claim 1 of formula h Ì H2N- / ' •not- (ii) (Ib) in which Rj has the meaning given in claim 1, by condensation of a carboxylic acid of formula 15 rj - c —oh II O with the 3-thiocarbohydrazide of formula 20 nh2-nh-c-nh-nh2 s at a temperature of 90 to 150 ° C with or without the presence of solvent, and this compound is reacted as indicated in claim 2. 25 6. Process for the preparation of compounds according to claim 1 of the formula in which R1; R2, R3 and R4 have the meaning given to claim 1, and Rs represents a hydrogen atom, characterized in that a compound of formula h is prepared s k, Ì h2N / ridi) \ r 1 NOT db) in which R! has the meaning given in claim 1, by cyclization of a potassium dithiocarbazinate of formula R ^ C-NH-NH-C-SK He II O S in the presence of hot hydrazine in an aqueous medium and this compound is reacted as indicated in claim 6. 8. A process for the preparation of compounds according to claim 1 of the formula in which R1, R2, R3 and R4 have the meaning given to claim 1, and R5 represents a hydrogen atom, characterized in that a compound of formula h h2n r not (he) (Ib) in which R1; R2, R3 and R4 have the meaning given in claim 1, and Rs represents a hydrogen atom, characterized in that a compound of formula i is prepared h in which Rt has the meaning given in claim 1, with 55 a dihalogenated derivative of formula s n. r, r4 I I x - ç - (ch2) n - ç - x + ì ? r, (IV) 60 h2n n- (II) \ r 1 rc in which Rj, R2. R3 and R4 have the meaning given in claim 1, R5 represents a hydrogen atom and X a halogen. in which Ri has the meaning given to claim 1, by cyclization of a methyl dithiocarbazinate of formula R, -c-nh-nh-c-sch3 He II O s in the presence of hydrazine in ethyl alcohol at reflux and this compound is reacted as indicated in claim 6. 632,763 4 9. Process for the preparation of compounds according to claim 1 of formula (Ib) in which R ,, R2, R3 and R4 have the meaning given to claim 1, and R5 represents a hydrogen atom, characterized in that a compound of formula is prepared H sS "ì NOT* h2n n- "n if (ii) i in which R! has the meaning given in claim 1, by condensation of a carboxylic acid of formula rj-c-oh it O with the 3-thiocarbohydrazide of formula NH2-NH-C-NH-NH2 II S at a temperature of 90 to 150 ° C in the presence or absence of a solvent, and this compound is reacted as indicated in claim 6. 10. Use of a compound of formula I according to claim 1 or one of its addition salts with pharmaceutically acceptable acids as active substance of a therapeutic composition.