CS246096B2 - Method of n-iminopyridinium's betaines production - Google Patents

Description

The invention relates to a process for the preparation of N-iminopyridinium betaines and inert aminopyridinium hydroxide salts having a pharmaceutical action. These novel derivatives correspond to the general formula I and in the form of salts to the general formula II

where it means

R2 is a carbamoyl group or hydrogen; and the X ^- anion of a pharmaceutically acceptable acid.

Representative examples of anions of pharmaceutically acceptable acids include mineral acid anions such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric, and organic acid anions such as acetic, citric, oxalic, lactic, tartaric methanesulonic, benzenesulfonic, p. -toluenesulfone and cyclohexylsulfamine.

The present invention provides a process for the preparation of compounds of formula (I) wherein R 2 is as defined above, characterized in that N- (2,4-dinitrophenyl) pyridinium chloride (VII) is reacted

(vn) where

R2 is as defined above, with the monosubstituted hydrazine of formula IV

NH

(IV) in the presence of a tertiary amine, such as triethylamine, to bind protons.

The N- (2,4-nitro-enyl) pyridinium chloride (Zinc salt) of formula VII is obtained, for example, by reacting 1-chloro-2,4-dinitrobenzene with the corresponding pyridine (see Z. Zincke, G. Henser and W. Moller, Ann. 1904, 333, 296).

Reaction of N- (2,4-dinitrophenyl) pyridinium chloride of formula VII with a monosubstituted hydrazine of formula IV and a tertiary amine that binds protons affords the corresponding betaines of formula I. These betaines of formula I can then be reacted with a pharmaceutically acceptable acid (H ⁺ X in a suitable solvent such as an alcohol or a ketone can be converted to the corresponding N-aminopyridinium salts of the general formula (II).

Because of the good diuretic activity and very low toxicity, the compounds of the formula I prepared according to the invention and the compounds of the formula II are used as medicaments administered in both human and veterinary therapy.

The following non-limiting examples illustrate the preparation of compounds of formulas I and II.

Example 1

Preparation of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] pyridinium hydroxide as an inert salt

A solution of N- (2,4-dinitrophenyl) pyridinium chloride (8.4 g, 0.03 mol), 4-chloro-3-sulfamoylbenzoyl hydrazide (7.5 g, 0.03 mol) is maintained at reflux for two hours: and triethylamine (3.2 g, 0.032 mol) in ethanol (250 mL).

The mixture is allowed to cool, the precipitate formed is filtered off and washed successively with ethanol, water, again with ethanol and finally with ethyl ether. The precipitate thus obtained is heated to reflux in 250 ml of dioxane / water (4: 1) at reflux for 24 hours and then the dioxane is evaporated under reduced pressure. The residue was treated with dilute hydrochloric acid and the reaction mixture was then filtered. The aqueous solution was neutralized with sodium hydroxide with stirring for two hours. The reaction mixture was cooled on standing to give a precipitate which was recrystallized from aqueous ethanol.

6.2 g (66% of theory) of the inert salt of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] pyridinium hydroxide of the formula I are obtained.

Melting point: 225-226 ° C.

Spectroscopic data:

IC (KBr):

1625, 1600, 1550, 1355, 1335, 1160 ^{cm-1; 1} H NMR, δ, [DMSO (de)]:

7.27 - 8.30 (n, 7H);

8.60-8.95 (m, 3H).

Example 2

Preparation of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] -3-carbamoylpyridinium hydroxide as an inert salt

A solution of 3-carbamoyl-1- (2,4-dinitrophenyl) pyridinium chloride (6.5 g, 0.02 mol), 4-chloro-3-sulfamoylbenzoyl hydrazide (5 g, 0.02) was stirred at room temperature for six hours. mole) and triethylamine (2.15 g, 0.021 mole) in methanol (50 mL), the precipitate formed is filtered off and washed successively with methanol, water and again methanol and finally ethyl ether. : (1) (100 ml) and heated to reflux for 15 hours, then the dioxane is evaporated under reduced pressure, the residue acidified with dilute hydrochloric acid and then filtered and washed with water. The precipitate is stirred with dilute sodium hydroxide solution for one hour, filtered and washed with water to give 4.1 g (57% of theory) of the inert salt of 1 - [(4-chloro-3-). sulfamoylbenzoyl jamino] -3-carbamoylpyridinium hydroxide of formula:

246996

Mp 273-274 ° C.

Spectroscopic data:

IR (KBr):

1700, 1638, 1595, 1545, 1355, 1335,

1175 cm ^-1 ;

1 H NMR, δ, [DMSO / d]:

7.5 - 8.75 (m, 9H);

8.9 (d, IH);

9.18 (s, 1 H).

Example 3

Preparation of 1 - [(4-chloro-3-sulfamoylbenzoyl jamino) pyridinium chloride

While stirring, 10 ml of a saturated solution of hydrochloric acid in ethanol is added to a solution of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] pyridinium hydroxide inner salt (3.1 g, 0.01 mol) in ethanol (80 ml). After stirring for one hour, the precipitate formed is filtered off and washed with ethanol to give 3.2 g (91% of theory) of Li [(4-chloro-3-sulfamoyl-benzoyl-amino) -pyridinium chloride of formula:

Melting point: 247-249 ° C. Spectroscopic data:

IC (KBr):

1680, 1348, 1162 cm ^-1 ;

1 H NMR, δ (DMSO / d 6):

7.84 (d, IH);

8.24-8.48 (m, 3H);

8.69 - 8.82 (m, 2H);

9.28 (d, 2H);

11.2 (s, 3H).

Diuretic efficacy

The method of R. M. Taylor, JG Topliss, J. Med. Pharm. Chem. 1962, 4, 312: Male Sprague-Dawley rats (HC / CFY) weighing 150-200 g are used. Feed and drink are discontinued for 16 hours prior to the test; products are administered in a suspension of 0.5% carboxymethylcellulose in 0.9% sodium chloride solution using a feeding probe at 50 ml / kg body weight. Animals are placed in individual metabolic cages and the total urine excreted after 1, 2, 3, 4, 6 and 8 hours is collected.

The following parameters are determined in the urine: volume (ml / kg); sodium and potassium (meq / kg / 8 hours) (flame photometer); chloride (meq / / kg / 8 h) (chloride meter; pH / 8 hours (pH meter) and osmotic pressure (mc> pitch / kg / 8 h) (osmometer).

Control animals receive a suspension of 0.5% carboxymethylcellulose in 0.9% sodium chloride solution at 50 ml / kg body weight.

Using the statistical test “t” according to the Student for Independent Values, the values of the above parameters are compared with the proportions applied at a dose of 40 mg / kg and the control. The product is considered to have diuretic efficacy when the difference between control and seed is significant (P <0.05) (Blin, CI, 1970, "Statistics in Biology" Vol. II, Mc Graw-Hill, New York ).

The following Table I shows urine excretion volumes at various intervals of time after administration of 40 mg / kg of various compounds prepared by the method of the invention.

The following Table II lists the various parameters (sodium, potassium, chlorine, pH, osmotic pressure) measured in total urine excreted over 8 hours after administration of 40 mg / kg of some of the compounds prepared by the method of the invention.

Ta b u 1 k and I

Product Urine excretion (ml / kg) 1 hour 2 hours 3 hours •4 o'clock 6 hours 8 hours Control 4.4 12.3 17.2 21.3 25.0 27.6 Example 1 7.3 + 15.2 N 27.6+ + + 35.4+ ++ 40.5+ + + 44.5+ + + Example 2 5.8 n. 8.6 n. 19,5 N 24.2 N 31.1 N 37,5+ Chlortalidone 8.7+ + + 21.0+ + + 30.9+ ++ 37.6 + + + 45.6+ + + 49.8+ + +

nv: bland (P>0.05); ⁺ : significant (P < C, 05); ⁺⁺ highly pronounced (P <0.01); ^{+ + +} : very high (P <0.001).

Table II Product Urine excretion (8 hours) On TO Cl PH Osmotic pressure Control 5.6 1,2 6.4 6.1 20.7 Example 1 8.3 + + + 1.5+ + 9.2+ ++ 6.6 + 25.5 + + + Example 2 6,6 N 1,1 N 7.0 N 6,2 N 20.8 N Chlortalidone 9.3+ + + 1.9+ ++ 10.8+ ++ 6.6 + 29.9 + + +

By way of non-limiting example, Table III lists the effective doses of fifty (ED 50) corresponding to the urine volume and osmotic pressure of the compounds prepared according to Example 1 as compared to chlortalidone.

Table III

Product

ED50 mg / kg ¹¹¹ urine volume ml / kg / 8 hours osmotic pressure mosmol / kg / 8 hours

Example 1 4.1 1.9

Chlortalidone 6.9 7.7 '' The ED 50 value was calculated from the curve showing the decrease in the decimal logarithm of the dose to the percentage of effect obtained.

Acute toxicity Example of pastilles:

Albino CFLP-RE mice weighing 20-25 g and Sprague-Dawley CFY-RE rats weighing 125-175 g were orally administered the product in a 5% gum arabic suspension. The volume administered is 25 ml / kg in mice next to a maximum dose of 12,800 mg / kg given in a volume of 50 ml / kg and 10 ml / kg in rats next to a maximum dose of 12,800 mg / kg given in a volume of 30 ml / kg.

Lethal dose cannot be determined because no mortality occurs. In human therapy, the anticipated dose of the compounds of formula I prepared by the method of the invention is about 20 to 60 mg / day, administered, for example, in the form of lozenges.

Pastilles, as an exemplary pharmaceutical form of the compounds of Formula I, are prepared as follows:

Folder grams

1 - [(4-chloro-3-sulfamoylbenzo-) yl) amino] -2,4,6-trimethylpyridinium hydroxide in the form of an inert salt 0,0200 lactose 0.1015 starch 0,0270 microcrystalline cellulose 0.0180 pregelatinized starch 0.0054 polyvinylpyrrolidone 0.0054 magnesium stearate 0.0018 colloidal silica 0.0009

total 0.1800 g

Because of their salidiuretic properties, pharmaceutical compositions containing as active ingredient a compound of the formula I according to the invention can be used with good results in the treatment of cardiac, renal and hepatic edema, in the treatment of cardiac insufficiency and arterial hypertension and to ensure lactation blocking.

It goes without saying that pharmaceutical compositions containing the compounds of formula (I) produced by the process of the invention may contain as active ingredient one or more compounds of the formula (I) produced by the process of the invention together with other active substances having a different or complementary action , such as a beta-blocking agent used to treat hypertension.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of N-iminopyridine-betaine betaines of formula (I) R2 is as defined above, with the monosubstituted hydrazine of formula IV R, Ν ’ NH $ i fiv; where R2 is a carbamoyl group or hydrogen, and pharmaceutically acceptable salts thereof, characterized in that N- (2,4-dinitrophenyl) pyridinium chloride (VII) is reacted in the presence of a tertiary amine such as triethylamine to bind the protons, optionally leaving the betaine obtained reacting with an acid to a pharmaceutically acceptable salt.