KR810001776B1 - Process for preparing hydrazinopyridazine derivatives - Google Patents

Abstract

Anti-hypertensive agent, hydrazinopyridazine deriv. I[R = C1-4 alkyl or hydroxy substd. C1-4 alkyl; R1 = H, C1-4 alkyl, phenyl or 3-pyridyl group and its non-toxic salts were prepd. by acylating compd. II with pyridine in the presence of acetylchloride.

Description

Method for preparing hydrazinopyridazine derivatives

The present invention relates to a method for preparing a hydrazino pyridazine derivative effective as an antihypertensive agent, in particular, a novel compound formulated by the method of the present invention is substituted with a N (2'-hydroxypropyl) amino group at position 3 -(2'acylhydrazino) pyridazine is the following general formula (I):

In the above structural formula

R is alkyl containing 1 to 4 carbon atoms, optionally substituted with hydroxy groups,

R ₁ is a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, phenyl or 3-pyridyl group.

The invention also relates to compounds of general formula (I) which are pharmaceutically harmless inorganic or non-toxic salts. The alkyl group containing 1 to 4 carbon atoms used above is a straight or branched saturated alkyl group, in particular methyl, ethyl, propyl, butyl, isobutyl, t-butyl, 2-hydroxyethyl and 2-hydroxypropyl.

The inorganic acids used above are hydrochloric acid, minimal acid, sulfuric acid and phosphoric acid. Organic acids used above are acetic acid, succinic acid, benzoic acid and P-toluenesulfonic acid.

Of particular interest among the hydrazino pyridazines having antihypertensive action in the art are the 3- (2'-hydroxypropyl) alkylamino-6-hydrazino pyridazines claimed in US Pat. No. 3,769,278. Comparing the compound most structurally similar to the compound according to the present invention as a comparative material, the general formula (I) compound has substantially no palpitation, slow progression, and has a more persistent antihypertensive action. The action of the compound of formula (I) is tested by oral administration to the side with renal hypertension according to the A. Grollman method Proc. Soc. Exptl. Biol. And Med., 57, 102, 1944. The compound is administered at least three doses to a group of four animals. Blood pressure and heart rate are measured immediately before and after 1,3,5,7,24,30 hours.

3- (2'-hydroxypropyl) methylamino-6- (2'-acetylhydrazino) pyridazine compound of the general formula (I) was substituted with hydralazine and 3- (2'-hydroxypropyl) methylamino- The results of the experiments in comparison with 6-hydrazinopyridazine are recorded in the following table (1).

TABLE 1

DE 25 denotes a dose (blood pressure DE 25) and an increase in heart rate of 25% (heart rate DE 25) that causes a 25% drop in blood pressure relative to baseline. Half-life time means the interval between acquaintances in which blood pressure drop is reduced by half compared to the minimum effect.

Although the compound has a high blood pressure action of the same strength as the compound-3- (2'-hydroxypropyl) -methylamino-6-hydrazinopyridazine according to the present invention, the compound has a significantly long duration of action (6 times). Longer) In Table 1, it can be seen that palpitations do not occur at doses that can treat hypertension.

This is expressed as the ratio of heart rate DE 25 / blood pressure DE 25 as recorded in the following table (2).

TABLE 2

Since palpitations do not occur at therapeutic doses, the compounds according to the invention are effectively applied to all cases of hypertension, in particular hypertension with renal insufficiency.

According to the preparation method of the present invention, the above general formula (I) compound is a 3- (2'-hydroxypropyl) -alkylamino-6-hydrazinopyridazine according to the preparation method described in US Patent No. 3,769,279. It is prepared by acylating as a starting material at a temperature of -10 to 10 DEG C under anhydrous conditions in a suitable solvent.

Organic bases, preferably pyridine, are usually used as solvent. The acylation reaction is carried out in the presence of a fruity acylating agent containing chloride or the desired acid anhydride. The starting material is preferably used in the form of salts and the final product (I) is obtained as a free base from the corresponding compound which is chlorinated according to known methods.

The following examples are described for the purpose of illustrating the invention and are not intended to limit the invention.

Example 1

3- (2'-hydroxypropyl) methylamino-6- (2'-acetylhydrazino) pyridazine

27 g of 3- (2'-hydroxypropyl) methylamino-6-hydrazino pyridazine dibasic salt obtained according to the method described in U.S. Patent No. 3,769,278 was dissolved in 200 ml of anhydrous pyridine and in this solution at 0 ° C. 7 ml of acetyl chloride is slowly added dropwise. After complete dropwise addition the reaction mixture is stirred at 0-5 ° C. for 2 hours and at 0 ° C. overnight. Distillation on a rotary evaporator at about 10 ° C. under vacuum removes pyridine to give an oily residue which is placed in sodium methylate solution and stirred at 0 ° C. for treatment. The resulting product was dried at 10 ° C., the residue was taken up in isopropyl alcohol, filtered through a Celite cake and the filtrate was dried under vacuum and recrystallized from ethyl alcohol to give 3- (2′-hydride with a melting point of 168 ° C. Oxypropyl) methylamino-6- (2'-acetylhydrazino) pyridazine is obtained.

Example 2

3- (2'-hydroxypropyl) ethylamino-6- (2'-acetylhydrazino) pyridazine

Reaction was carried out according to the method described above using 3- (2'-hydroxypropyl) ethylamino-6-hydrazino pyridazine dihydrochloride as starting material, and the 3- (2'- having a melting point of 156 to 158 ° C. Hydroxypropyl) -ethylamino-6- (2'-acetylhydrazino) pyridazine is obtained.

Example 3

3- (2'-hydroxypropyl) ethylamino-6- (2'-propionylhydrazino) pyridazine

Reacting according to the method described in Example 1 above using propionyl chloride as the acylating agent to have 3- (2'-hydroxypropyl) methylamino-6- (2'-propionylhi) having a melting point of 155 to 157 ° C. Obtains Drazino) Pyridazine.

Example 4

3- [bis- (2'-hydroxypropyl) amino] -6- (2'-acetylhydrazino) pyridazine

3- [bis (2'-hydroxypropyl) -amino] -6-hydrazinopyridazine as a starting material was reacted according to the method described in Example 1 above, and the melting point was 150 to 155 캜. [Bis (2'-hydroxypropyl) amino] -6- (2'-acetylhydrazino) pyridazine is obtained.

Example 5

3- (2'-hydroxypropyl) methylamino-6- (2'-pivaloylhydrazino) pyridazine

Reaction according to the method described above using pivaloyl chloride as the acylating agent to give 3- (2'-hydroxypropyl) methylamino-6- (2'-pivaloylhydra having a melting point of 170 to 172 캜. Gino) Pyridazine.

Example 6

3- (2'-hydroxypropyl) methylamino-6- (2'-nicotinoylhydrazino) pyridazine

Reacting according to the method described above using nicotinoyl chloride as the acylating agent, 3- (2'-hydroxypropyl) methylamino-6- (2'-nicotinoyl having a melting point of 75 ° C. (decomposed) Obtain hydrazino) pyridazine.

Example 7

3- (2'-hydroxypropyl) methylamino-6- (2'-formylhydrazino) pyridazine

Dissolve 13.5 g of 3- (2'-hydroxypropyl) methylamino-6- (2'-hydrazino) pyridazine dihydrochloride in 25 ml of formic acid, and successively add 6 ml of acetic anhydride at 0 ° C. After 30 minutes, 8.4 g of sodium bicarbonate was added. The mixture is stirred at 0 ° C. for 30 minutes and allowed to stand overnight at room temperature. The solvent was removed and recrystallized from acetone / ethanol (8: 2) to give 3- (2'-hydroxypropyl) methylamino-6- (2'-proylhydrazino) pyridazine having a melting point of 130 to 132 캜. Get

Claims (1)

A compound produced by the following formula (II), wherein the corresponding free hydrazino compound or salt thereof is acylated using a solvent such as a free base in the presence of acylated acid at a temperature between -10 and 10 ° C. A method for preparing non-toxic salts with hydrazinopyridazine derivatives of the following general formula (I) or pharmaceutically toxic inorganic or organic acids by isolating in the form of a free base or in the form of a corresponding salt.

In the above structure, R is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, and R ₁ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, phenyl or 3-pyridyl group.