HU215392B - Pharmaceutical compositions containing pyridine carboxamide derivatives as active component and process for producing them - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising a pyridine derivative of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, or to the preparation thereof. In the formula (I), X is halogen, R is hydrogen, Z is pyridyl. The compounds of formula (I) have anti-ischemic activity and are primarily used to treat forms of ischemia that are characterized by increased vascular and platelet aggregation. C ^ NOR (I) HU 215 392 B The scope of the description is 6 pages (including 1 page figure)

Description

FIELD OF THE INVENTION The present invention relates to novel pharmaceutical compositions containing a pyridine derivative of the Formula I, or pharmaceutically acceptable acid addition salts thereof, or to their preparation.

In the general formula (I)

X is halogen,

R is hydrogen,

Z represents a pyridyl group.

The compounds of formula (I) are described in M. Kocevar et al., Synth. Comm., 181427-32 (1988).

Compounds of formula (I) have been found to have anti-ischemic activity and primarily to cure forms of ischemia characterized by increased vascular tone and platelet aggregation. The compounds were tested in vitro for vasorelaxant activity in a thoracic aorta isolated from rabbit. [Am. J. Physiol. 257: 1327-1333 (1989)] and tested for inhibition of platelet aggregation in human plasma.

In the latter case, venous blood was collected from healthy human subjects, and the samples were treated with sodium citrate and centrifuged after 10 minutes at 1000 rpm for 10 minutes. This resulted in platelet-rich plasma on which ADP aggregation was induced (control), and after addition of various concentrations of test compounds, we attempted to induce ADP aggregation.

We took a dose-response curve of the test compound at various concentrations, and read about the EC ₅₀ value. The mean of 6 replicates is reported.

Molsidomine (Takeda) was used as reference under the same conditions. The results are summarized in the table below (compounds have the same serial number as the examples).

Compound EC ₅₀ (M) on isolated rabbit aorta EC ₅₀ (M) human plasma 1 2,5-10-5 2.0, KH 2 2.6-10 ^-4 3.01 (H 3 4,0-10-5 1.210 to 3 Ref. Material 10-3 1,5-10-3

It can be seen from the table that each of the test compounds is less effective than the reference substance in both vasodilator and platelet aggregation inhibitory activity.

The active compounds and their pharmaceutically acceptable acid addition salts are suitable for both oral and parenteral administration, but preferably parenterally, especially i.v. administered by injection.

For the preparation of oral preparations, for example, lactose or starch may be used as fillers. Gelatin, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or starch gelling agents may be used as binding or granulating agents.

Potato starch or microcrystalline cellulose is preferably added as a disintegrant, but ultra-amylopectin or formaldehyde casein and the like can be used. too. Talc, collodial silicic acid, stearin, calcium and magnesium stearate, etc. as antiadhesive and lubricant. It can be used. For example, tablets may be prepared by wet granulation followed by compression. The mixed active and excipients, and optionally a portion of the disintegrant, are granulated with an aqueous, alcoholic or aqueous alcoholic binder solution in a suitable apparatus and then dried. Next, other disintegrants, glidants and anti-adhesives are added to the dried granulate and compressed into tablets. Optionally, the tablet may be provided with a score line for ease of administration. Tablets may also be prepared directly from the mixture of the active ingredient and suitable excipients by direct compression. The tablets may optionally be formulated with protective, flavoring or coloring agents commonly used in the preparation of pharmaceuticals, such as sugar, cellulose derivatives (methyl or ethyl cellulose, sodium carboxymethyl cellulose, etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food colorings, food colorants, flavorings, iron oxide pigments, etc. using pellets.

When preparing a capsule, the mixture of active ingredients and excipients is filled into a capsule.

For parenteral administration, the composition is prepared by injection. In preparing a solution for injection, the active compounds are optionally in the presence of solution mediators such as polyoxyethylene sorbitan monolaurate, monooleate or monostearate (Tween 20, Tween 60, Tween 80) in distilled water and / or various organic solvents such as glycol. dissolved in ethers. The solution for injection also contains a variety of excipients, such as preservatives such as benzyl alcohol, methyl or propyl p-oxybenzoic acid, benzalkonium chloride or phenylmercuroborate, etc., and antioxidants such as ascorbic acid, tocopherol, sodium pyrosulfate and optionally complexing agents such as ethylenediaminetetraacetate to bind metal traces and pH adjusting and buffering agents and optionally a local anesthetic such as lidocaine. The solution for injection containing the pharmaceutical composition of the invention is filtered before filling into the ampoule and then sterilized after filling.

For example, the compounds of formula (I) may be prepared as follows:

Example 1 (3-Pyridinecarbohydroximidoyl chloride) hydrochloride g (109 mmol) of 3-pyridinecarboxamidoxime was dissolved in a mixture of 300 ml of water and 113 ml of concentrated hydrochloric acid. The solution was cooled to 0 ° C and a solution of sodium nitrite (9.38 g, 136 mmol) in water (53 mL) was added dropwise with stirring at this temperature for 1 hour. After stirring for a further 2 hours at 0 ° C, sodium hydrogen carbonate was added in small portions to the pH of the reaction mixture. The precipitated solid was filtered, washed with cold water and dried at room temperature in vacuo. Quantity of raw product

392 2 g, dissolved in 400 mL of ethyl acetate, the insoluble material is filtered off hot and the product crystallizes immediately from the filtrate.

Yield: 8.5 g (50%)

133-137 ° C.

IR (KBr): 3400 (s), 2500 (s), 1525, 1255, 1240, 1030, 955.810, 700, 640 cm ^-1 .

1 H-NMR (DMSO-d 6): 12.7 s, 1H (OH); 8.96 d, 1H; 8.67 dd: 1H; 8.14 m, 1H; 7.52 m, 1H (pyridine 2-6-4-5) ppm.

¹³ C NMR (DMSO-d ₆ ): 150.7, 146.8, 134.1, 128.6,

123.6 (pyridine 2-6-4-3-5), 134.1 [C (Cl) = NO-]. Analysis calculated for C ₆ H ₅ N ₂ OC ₁ -HCl:

calculated found

C 46.0% 46.1%

H 3.22% 3.23%

N 17.9% 17.5%

Cl 22.6% 22.2%

Example 2 (2-Pyridinecarbohydroxymidoyl chloride) Hydrochloride The procedure described in Example 1 was followed except that 2-pyridine carboxamidoxime was used as starting material.

Yield: 40%. 124-127 ° C.

IR (KBr): 3000 (s), 2830 (s), 1490, 1430, 1270, 1030, 1005, 1000, 960,780, 745, 700, 625 cm ^-1 .

1 H-NMR (DMSO-d ₆ ): 12.7 s, 1H (OH); 8.66 d, 1H; 7.87 m, 2H; 7.48 m, 1H (pyridine 6-3.4-5) ppm. ¹³ C-NMR (DMSO-d ₆ ): 149.6, 149.1, 136.9, 124.8, 121.4 (pyridine), 136.5 [C (Cl) = NO-] ppm.

Analysis calculated for C ₆ H ₅ N ₂ OC ₁ -HCl:

calculated found

C 46.0% 45.9%

H 3.22% 3.27%

N 17.9% 17.5%

Cl 22.6% 23.0%

Example 3 (4-Pyridinecarbohydroximidoyl chloride) Hydrochloride The procedure described in Example 1 was followed except that 4-pyridinecarboxamidoxime was used as starting material.

Yield: 26%. 142-145 ° C.

IR (KBr): 2500 (s), 1800 (s), 1600.1415, 1260.1220, 1035, 1015, 950, 825, 865, 580 cm ^-1 .

1 H-NMR (DMSO-d ₆ ): 13.0 s, 1H (OH); 8.70: s: 2H; 7.74 m, 2H (pyridine 2.6-3.5).

¹³ C-NMR (DMSO-d ₆ ): 149.8, 140.0, 120.3 (pyridine),

133.6 [C (Cl) = NO].

Analysis calculated for C ₆ H ₅ N ₂ OC ₁ -HCl:

calculated found

C 46.0% 46.1%

H 3.22% 3.26%

N 17.9% 17.5%

Cl 22.6% 22.5%

Example 4

Active ingredient (product of Example 1) 10% propylene glycol 40% ethyl alcohol 10% benzyl alcohol 1.5% benzoic acid 2.2% sodium benzoate 2.8% distilled water pro. inj. gives 100%

The above components are prepared as follows for injection. Propylene glycol, ethanol and benzyl alcohol are mixed. Benzoic acid and sodium benzoate are dissolved in distilled water. The two solutions are combined, filtered and the active ingredient is dissolved and the pH is adjusted to 7. Portions of 1 ml / vial were prepared by sterilization at 100 ° C for 40 minutes.

Example 5 Active ingredient (product of Example 2) 20% propylene glycol 40% ethyl alcohol 10% benzyl alcohol 1.5% benzoic acid 2.2% Sodium benzoate 2.8% ethylenediaminetetraacetic acid sodium 0.1% distilled water pro. inj. give 100% From the above components as described in Example 4

prepare an injection solution analogously.

Example 6

In all cases, the procedure of Example 5 was followed except that the product of Example 3 was used in an amount of 10%.

Example 7 Active ingredient (product of Example 1) 1.0 g lactose 100.0 g wheat starch 100.0 g saccharose 68.5 g polyvinylpyrrolidone 10.0 g 90% ethanol 90.0 g talc 9.0 g magnesium stearate 1.5 g The above components are known per se wet

granulation to form tablets.

Example 8 Active ingredient (product of Example 2) 2.0 g lactose 100.0 g wheat starch 100.0 g saccharose 67.0 g polyvinylpyrrolidone 10.0 g 90% ethanol 90.0 g talc 9.5 g magnesium stearate 1.5 g The above components are known per se wet

tablets are prepared by the granulation process.

Example 9

All were treated according to Example 8, except that 4.0 g of the product of Example 3 were used as the active ingredient.

Claims (2)

PATENT CLAIMS CLAIMS 1. A process for the preparation of a pharmaceutical composition, wherein the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, prepared in a manner known per se, is X in the formula X, halogen, R, hydrogen and Z, pyridyl. and / or mixed with other excipients in a customary dosage form. (Priority: 06/06/1994) A pharmaceutical composition comprising as active ingredient a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, wherein X is halogen, R is hydrogen and Z is pyridyl, in association with customary carriers and / or other excipients. (Priority of Amendment: 07/07/1994)