CS246095B2 - Method of n-iminopyridinium's betaines production - Google Patents

Abstract

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of N-iminopyridinium betaines and inert aminopyridinium hydroxide salts which have pharmaceutical properties for  R1 is hydrogen or 2-furylmethylamino;

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

R1 is hydrogen or 2-furylmethylamino,

R 2, R 4 and R 6 are C 1 -C 4 alkyl, phenyl or hydrogen;

X 'anion of a pharmaceutically acceptable acid As preferred examples of pharmaceutical anions at 246095

Examples of suitable acids are mineral acid anions such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acids and organic acid anions such as acetic, citric, oxalic, lactic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic and cyclohexylsulfamic acids.

The compounds of the formula I are prepared by the process according to the invention by reacting the N-aminopyridinium salt of the formula V

with an acid chloride of formula VI

Joint formula VI under basic conditions gives the corresponding betaines of the general formula I by reaction with an acid of the formula H ^{+ _} X in a suitable solvent such as an alcohol or ketone, transferred to the corresponding N-aminopyridinium salt of formula II.

Due to their good diuretic activity and very low toxicity, compounds of formulas I and II are used as medicaments administered in both human and veterinary therapy.

The following examples illustrate the process according to the invention without limiting it.

Example 1

Preparation of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] -2,6-dimethylpyridinium hydroxide as an inert salt

1-Amino-2,6-dimethylpyridinium iodide (2.5 g, 0.01 mol) dissolved in water (20 ml) and acetone (10 ml) was treated with potassium carbonate (2.8 g, 0.02 mol). . 4-Chloro-3-sulfamoylbenzoyl chloride (2.54 g, 0.01 mol) dissolved in acetone (10 mL) was added over 15 minutes. The mixture was stirred at room temperature for three hours and then concentrated by evaporating acetone at a temperature below 40 ° C. The reaction mixture was extracted with chloroform, dried (sodium sulfate), filtered and the solvent was evaporated. Recrystallization of the residue from ethanol yields

2.1 g (62% of theory) of the inert salt of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] 2,6-dimethylpyridinium hydroxide of the formula wherein each symbol is as defined above and wherein Z is a chloride, iodide and anion

and the resulting salt is converted in the basic medium to the corresponding betaine of formula I.

The N-aminopyridinium salts of formula (V) are obtained, for example, by the procedure of R. Gosl and A. Meuwsen, Org. Synt., 1963, 43, 1, using aqueous solutions of the corresponding pyridines and hydroxylamino-O-sulfonic acid; or may be prepared according to the procedure of Y. Tamura, J. Minamikawa and M. Ikeda, Synthesis, 1977, 1, by reacting the respective pyridines with an amination agent which is O-mesitylenesulfonylhydroxylamine.

By reacting the N-aminopyridinium salts of the general formula V with

Melting point 266-267 ° C.

Spectroscopic data:

IC (KBr):

1632, 1590, 1540, 1360, 1330, 1165 cm ^-1 ;

¹ H NMR, δ, (DMSO / d 6):

2.47 (s, 6H);

7.25 - 8.50 (m, 8H).

Example 2

Preparation of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] -2,4,6-trimethylpyridinium chloride

248095

To a solution of the inert salt of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] 2,4,6-trimethylpyridinium hydroxide (3.5 g, 0.01 mol) in ethanol (80 mL) was added with stirring 10 mL of saturated ethanol with hydrogen chloride. After stirring for one hour, the resulting precipitate was filtered off and washed with ethanol. 3.6 g (92%) of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] -2,4,6-trimethylpyridinium chloride of the formula are obtained.

Melting point 272-274 ° C.

Spectroscopic data:

IR (KBr):

1705, 1642, 1348, 1165 ^cm-1;

¹ H NMR, δ, (DMSO / d 6):

2.6 (s. 3H);

2.6 (s. 3H);

2.7 (b, 6H);

4.85 (e, 2 H);

7.7 - 8.05 (m, 4H);

8.35 to 8.65 (m, 2H).

Example 3

Preparation of 1 - [(4-chloro-2- / 2-furylmethylamino-4-sulfamoylbenzoyl) amino] -2,4,6-trimethylpyridinium chloride hydrochloride

To a suspension of the inert salt of 1 - [(4-chloro-2- (2-furylmethylamino) -5-sulfamoylbenzoyl) amino] -2,4,6-trimethylpyridinium hydroxide (4.6 g, 0.01 mol) in ethanol (40 mL). 20 ml of ethanol saturated with hydrogen chloride were added with stirring, and after a few seconds a clear solution was obtained which immediately began to precipitate, and the precipitate was filtered off, washed with ethanol to give 4.9 g (98%) of hydrochloride 1. -f (4-chloro-2- (2-furylmethylamino) -5-sulfamoylbenzoyl) amino] -2,4,6-trimethylpyridinium chloride of formula

Melting point: 257-258 ° C.

Spectroscopic data:

IR (KBr):

1668, 1635, 1565, 1355, 1165 cm ^-1 ;

@ 1 H NMR .delta. (DMSO / d6):

2.6 (s, 3H);

2.7 (s. 6H);

4.6 (s. 2H);

to 6 (e, 5H);

6.4 (d, 2 H);

7.1 (s, 1H);

7.6 (s, 1H);

7.95 (s, 2H);

8.73 (s, 1H).

Example 4

Preparation of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] -2,4,6-triphenylpyridinium chloride

To a solution of the inert salt of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] -2,4,6-triphenylpyridinium hydroxide (5.4 g, 0.01 mol) in ethanol (25 mL) was added with stirring 10 mL of ethanol. After stirring for half an hour, the resulting precipitate was filtered off to give 5.2 g (90% of theory) of 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] -2,4,6-triphenylpyridinium chloride of formula

Melting point: 290-292 ° C.

Spectroscopic data:

IR (KBr):

1700, 1628, 1340, 1170 cm ^-1;

1 H NMR, δ S, (DMSO / d 6):

4.5 (s, 3H);

7.25 to 7.73 (m, 11H);

7.73 to 8.3 (m, 7H);

8.53 (s, 2 H).

Example 5

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

1-Aminopyridinium iodide (2.2 g, 0.01 mo246095 µl) dissolved in water (20 mL) and acetone (10 mL) was treated with potassium carbonate (2.8 g, 0.02 mol). 4-Chloro-3-sulfamoylbenzoyl chloride (2.54 g, 0.01 mol) dissolved in acetone (10 mL) was added over 15 minutes. Stir for 3 hours at room temperature and concentrate by evaporating acetone at less than 40 ° C. Extract with chloroform, dry (Na 2 SO 4), filter and evaporate the solvent. Recrystallization of the residue in ethanol gave 2.3 g (74% of theory) of the 1 - [(4-chloro-3-sulfamoylbenzoyl) amino] pyridinium hydroxide inner salt of formula

SO ^ N

Melting point: 225 to 22 ° C.

Spectroscopic data:

IC (KBr):

1625, 1600, 1550, 1355, 1335, 1160 cm ^-1 ;

@ ¹ H NMR, .delta. (DMSO / d6):

7.25 to 8.30 (m, 7H);

8.60-8.95 (m, 3H).

Diuretic activity

The method of R. M. Taylor, J. G. 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. The products are administered in a 0.5% carboxymethylcellulose suspension 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 (mg / kg); sodium, potassium (meq / kg / 8h) (flame photometer); chloride (meq / kg / 8h) (chloride meter); pH / 8 hours (pH meter) and osmotic pressure (mosmol / 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 static test “t” according to the Student for Independent Values, the values of the above parameters are compared with the proportions applied at 40 mg / kg and the control. The product is considered to have diuretic activity when the difference between the control and the seed is significant (P <0.05) (Blin, C.I. 1970, "Statistics in Biology, Vol. II, Mc Graw-Hill, New York)."

In the following Table I, urine excretion volumes are given 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 eight hours after administration of 40 mg / kg of some of the compounds prepared by the method of the invention.

Table 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 8,4 N 22.9+ 31.9 ++ 36.7+ + + 45.2+ + + 50.7+ + + Example 2 6,2 N 18.6 + + 28.4+ + + 36.1+ + + 47.3+ + + 52.4+ + + Example 3 0.0 n. 11.9 N 19.6 N 28,5 N 34.4+ 39.2+ + Example 4 5,2 h. 12.6 N 16.8 N 19.0 N 21,5 N 25,3 N Chlortalidone 8.7+ + + 21.0+ + + 30.9+ + + 37.6 + + + 45.6+ + + 49.8 + + + nv: bland (P>0.05); ⁺ : significant (P <0.05); ++: 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 9.5+ + + 1.8+ ++ 11.7+ + + 6,1 N 34.2+ + + Example 2 8.9+ ++ 1.6+ + 9.3 + + + 6,3 N 31.0+ + + Example 3 5,9 N 1,2 n. 7.2 n. 6,7+ + 23.4 N Example 4 6.0 N 1,2 n. 7,5 + 6,2 N 25.1+ + Chlortalidone 9.3+ + + 1.9 + + + 10.8+ ++ 6,6+ 29.9+ + +

4 E 0 9 Π

As a non-limiting example, the effective doses (ED 50) of the corresponding with chlorotalidone are shown in the table of valuables prepared according to Example 1 in cf. III.

urine volume and osmotic pressure Table III

Product ED 50 (mg / kg) ¹¹¹ Osmotic pressure

Urine volume mosmol / kg / 8 h ml / kg / 8 h

Example 1 4.6 2.1

Chlortalidone 6.9 7.7% The ED 50 value was calculated from the curve showing the decrease in the decimal log of the dose, relative to the percentage of effect obtained.

Acute toxicity

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 and 10 ml / kg in rats in addition to the maximum dose of 12,800 mg / kg given in a volume of 30 ml / kg.

The lethal dose of 50 cannot be determined because mortality does not occur. In human therapy, the anticipated dose of the compounds of formula I produced 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:

Example of pastilles:

Due to their salidiuretic properties, pharmaceutical compositions containing the compound of the formula I as active ingredient can be used with good results in the treatment of cardiac, renal and hepatic edema, 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 in the treatment of hypertension.

Folder grams

1 - [(4-chloro-3-sulfamoylbenzo-) yl) amino] -2,4,6-trimethylpyri- dinium hydroxide in the form of an inert- salts 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

Claims (1)

A process for the preparation of N-iminopyridinium betaines of the general formula (I) ## STR3 ## wherein R1 is hydrogen or 2-furylmethylamino, R 2, R 4 and R 6 are C 1 -C 4 alkyl, phenyl or hydrogen, and pharmaceutically acceptable salts thereof, characterized in that the N-aminopyridinium salt of formula V is reacted wherein: R 2, R 4 and R 6 are as defined above and wherein Z ^- represents the anion Cl ^- J - and the acid chloride of formula VI wherein R 1 is as defined above in an alkaline environment and, optionally, reacted with an acid to convert the obtained betaines into pharmaceutically acceptable salts.