CS246095B2 - A method for producing N-iminopyridinium betaine - Google Patents

Abstract

The invention relates to a process for the preparation of N-iminopyridinium betaines and inert aminopyridinium hydroxide salts having pharmaceutical properties, wherein R1 represents a hydrogen atom or a 2-furylmethylamino group,

Description

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

where means

R1 is a hydrogen atom or a 2-furylmethylamino group,

R2, R4 and R6 are C1-4 alkyl, phenyl or hydrogen and

X" anion of a pharmaceutically acceptable acid As preferred examples of anions pharmaceu246095

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

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

with acid chloride of general formula VI

of the general formula VI in a basic medium, the corresponding betaines of the general formula I are obtained, which, by reaction with an acid of the general formula H ⁺ X ^_ in a suitable solvent, such as an alcohol or ketone, are converted into the corresponding N-aminopyridinium salts of the general formula II.

Due to their good diuretic efficacy and very low toxicity, compounds of general formula I and II are used as drugs administered in both human and veterinary therapy.

The following practical examples illustrate the method according to the invention, but do not limit it in any way.

Example 1

Preparation of l-[(4-chloro-3-sulfamoylbenzoyl)amino]-2,6-dimethylpyridinium hydroxide in the form of 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 for 3 hours at room temperature and then concentrated by evaporation of the acetone at a temperature below 40 °C. The reaction mixture was extracted with chloroform, dried (sodium sulfate), filtered and the solvent was evaporated. The residue obtained was recrystallized from ethanol to give

2.1 g (62% of theory) of the inert salt of 1-[(4-chloro-3-sulfamoylbenzoyl)amino]2,6-dimethylpyridinium hydroxide of the formula where the individual symbols have the meanings given above and where Z represents the chloride and iodide anions and the anion of the formula

and the resulting salt is converted into the corresponding betaine of general formula I in an alkaline medium.

N-Aminopyridinium salts of the general formula V are obtained, for example, by the method of R. Gosl and A. Meuwsen, Org. Synt., 1963, 43, 1, using aqueous solutions of the corresponding pyridines and hydroxylamino-O-sulfonic acid; or they can be prepared by the method of Y. Tamura, J. Minamikawa and M. Ikeda, Synthesis, 1977, 1, by reacting the corresponding pyridines with the aminating agent O-mesitylenesulfonylhydroxylamine.

By reacting N-aminopyridinium salts of general formula V with acid chloride of general formula

Melting point 266 to 267 °C.

Spectroscopic data:

IC (KBr):

1632, 1590, 1540, 1360, 1330, 1165 cnr ¹ ;

^X H NMR, δ, (DMSO/de/):

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 1-[(4-chloro-3-sulfamoylbenzoyl)amino]2,4,6-trimethylpyridinium hydroxide (3.5 g, 0.01 mol) in ethanol (80 ml) was added 10 ml of ethanol saturated with hydrogen chloride while stirring. After stirring for one hour, the precipitate formed 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

The melting point is 272 to 274 °C.

Spectroscopic data:

IR (KBr):

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

^] H NMR, δ, (DMSO /de/):

2.6 (s, 3H);

2.6 (s, 3H);

2.7 (b, 6H);

4.85 (e, 2H);

7.7 - 8.05 (m, 4H);

8.35 to 8.65 (m, 2H).

Example 3

Preparation of l-[(4-chloro-2-(2-furylmethylamino-N-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 grams, 0.01 mole) in ethanol (40 ml) was added 20 ml of ethanol saturated with hydrogen chloride with stirring. After a few seconds a clear solution was obtained which immediately began to precipitate. The precipitate was filtered off, washed with ethanol and 4.9 g (98% of theory) of 1-[(4-chloro-2-(2-furylmethylamino)-5-sulfamoylbenzoyl amino]-2,4,6-trimethylpyridinium chloride hydrochloride of the formula

The melting point is 257 to 258 °C.

Spectroscopic data:

IR (KBr):

1668, 1635, 1565, 1355, 1165 cm” ¹ ;

*H NMR, á, (DMSO /de/}:

2.6 (s, 3H);

2.7 (s, 6H);

4.6 (s, 2H);

to 6 (e, 5H);

6.4 (d, 2H);

7.1 (s, 1H);

7.6 (s, 1H);

7.95 (s, 2HJ;

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 l-[(4-chloro-3-sulfamoylbenzoyl)amino]-2,4,6-triphenylpyridinium hydroxide (5.4 g, 0.01 mol) in ethanol (25 ml) was added 10 ml of ethanol saturated with hydrogen chloride with stirring. After half an hour of stirring, the precipitate formed was filtered off; 5.2 g (90% of theory) of l-[(4-chloro-3-sulfamoylbenzoyl)amino]-2,4,6-triphenylpyridinium chloride of the formula was obtained.

The melting point is 290 to 292 °C.

Spectroscopic data:

IR (KBr):

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

*H NMR, <S, (DMSO /de/):

4.5 (s, 3H);

7.25 to 7.73 (m, 11H);

7.73 to 8.3 (m, 7H);

8.53 (s, 2H).

Example 5

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

1-Aminopyridinium iodide (2.2 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 for 3 hours at room temperature and concentrated by evaporation of acetone at a temperature below 40 °C. It was extracted with chloroform, dried (Na2SO4), filtered and the solvent was evaporated. Recrystallization of the residue obtained in ethanol gave 2.3 g (74% of theory) of the inner salt of 1-[(4-chloro-3-sulfamoylbenzoyl]amino]pyridinium hydroxide of the formula

SO^N

The melting point is 225 to 22Θ °C.

Spectroscopic data:

IC (KBr):

1625, 1600, 1550, 1355, 1335, 1160 cm"¹;

⁴ H NMR, 5, (DMSO /de/):

7.25 to 8.30 (m, 7H);

8.60 to 8.95 (m, 3H).

Diuretic activity

Method according to R. M. Taylor, J. G. Topliss: J. Med. Pharm. Chem. 1962, 4, p. 312.

Male Sprague-Dawley rats (HC/CFY) weighing 150 to 200 g are used. The animals are fasted for 16 hours before the start of the test. The products are administered in a suspension of 0.5% carboxymethylcellulose in 0.9% sodium chloride solution by gavage at a rate of 50 ml/kg body weight. The animals are placed in individual metabolic cages and the total amount of urine excreted is collected after 1, 2, 3, 4, 6 and 8 hours.

The following parameters are determined in urine: volume (mg/kg); sodium, potassium (mEq/kg/8 h) (flame photometer); chloride (mEq/kg/8 h) (chloridometer); 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 in an amount of 50 ml/kg body weight.

Using a Student's t-test for independent values, the values of the previously mentioned parameters are compared with the 40 mg/kg seeded portion and the control portion. The product is considered to have diuretic activity when the difference between the control portion and the seeded portion is significant (P < 0.05) (Blin, C. I. 1970, "Statistics in Biology, Vol. II, Mc Graw-Hill, New York).

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

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

Table I

Product Urine output (ml/kg) 1 hour 2 hours 3 hours 4 hours 6 hours 8 hours Check 4.4 12.3 17.2 21.3 25.0 27.6 Example 1 8.4 AD 22.9+ 31.9 + + 36.7+ + + 45.2+ + + 50.7+ + + Example 2 6.2 a.d. 18.6 + + 28.4+ + + 36.1+ + + 47.3+ + + 52.4+ + + Example 3 0.0 n. v. 11.9 AD 19.6 AD 28.5 a.m. 34.4+ 39.2+ + Example 4 5.2 a.m. 12.6 AD 16.8 AD 19.0 a.d. 21.5 a.m. 25.3 a.m. Chlorthalidone 8.7+ + + 21.0+ + + 30.9+ + + 37.6 + + + 45.6+ + + 49.8 + + + nv: not significant (P >0.05); ⁺ : pronounced (P < 0.05); + + : highly significant (P < 0.01); + ++: very highly pronounced (P < 0.001). Table II Product Urine output (8 hours) On To Cl PH Osmotic pressure Check 5.6 1.2 6.4 6.1 20.7 Example 1 9.5+ + + 1.8+ + + 11.7+ + + 6.1 a.d. 34.2+ + + Example 2 8.9+ + + 1.6+ + 9.3 + + + 6.3 a.m. 31.0+ + + Example 3 5.9 a.m. 1.2 AD 7.2 a.d. 6.7+ + 23.4 AD Example 4 6.0 a.m. 1.2 AD 7.5 + 6.2 a.d. 25.1+ + Chlorthalidone 9.3+ + + 1.9 + + + 10.8+ + + 6.6+ 29.9+ + +

4 S 0 9 Π

As a non-limiting example, the table of values prepared according to Example 1 in ref. III shows the effective doses (ED50) corresponding to chlorthalidone.

The volume of urine and the osmotic pressure of the urine depend on the Table III

Product EDso (mg/kg) ¹¹¹ Osmotic pressure

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

Example 1 4.6 2.1

Chlorthalidone 6.9 7.7 '^The ED50 value was calculated from a curve showing the decrease in the decimal logarithm of the dose, relative to the percentage of effect obtained.

Acute toxicity

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

A lethal dose of 50 cannot be determined because death does not occur. In human therapy, the expected dose of the compounds of general formula I, produced by the process according to the invention, is approximately 20 to 60 mg/day, administered, for example, in the form of lozenges.

Lozenges, as an exemplary pharmaceutical form of compounds of general formula I, are prepared in the following manner:

Example of lozenge composition:

Pharmaceutical compositions containing as an active ingredient a compound of general formula I, produced by the method according to the invention, can be used with good results, due to their salidiuretic properties, for the treatment of cardiac, renal and hepatic edema, for the treatment of cardiac insufficiency and arterial hypertension and for ensuring the blocking of lactation.

It is understood that pharmaceutical compositions containing compounds of general formula I, produced by the process according to the invention, may contain as active ingredient one or more compounds of general formula I, produced by the process according to the invention, together with other active ingredients having different or complementary effects, such as, for example, a substance with beta-blocking activity, which is used in the treatment of hypertension.

Ingredient grams

l-[(4-chloro-3-sulfamoylbenzo- yl)amino]-2,4,6-trimethylpyri- dinium hydroxide in inert form 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 silicon dioxide 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.