HU201245B - Process for production of medical compositions containing as active substance dimethil-1-(dimetoxi-phosphonile)-4-chlor-benzil-phosphate (clanicloit) - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of a pharmaceutical composition comprising dimethyl 1- (dlmethoxylphosphonyl) -4-chlorobenzylphosphate (Claniclort), such that the Claniclor produced by the known method is a carrier, carrier and / or carrier. mixed with other excipients, it can be used as microscopic zinc inducer or converted into antithetic drug products. EN 201 245 Scope of the description: 4 pages without drawing -1-

Description

The present invention relates to a process for the preparation of pharmaceutical compositions containing dimethyl 1- (dimethoxyphosphonyl) -4-chlorobenzyl phosphate (Claniclor) as an active ingredient. The process is characterized in that the Claniclor prepared in the known manner can be used in admixture with conventional carriers, vehicles and / or other excipients, for use as a microsomal enzyme inducer or as an antithyroid drug.

Claniclor has been reported in the literature as an active ingredient of antiatherogenic agents for the treatment of human cardiovascular diseases as lipid metabolism regulators (Drugs of Fut. 7 (4) 271 1982). In addition, U.S. Pat. No. 4,067,971 has been found to be useful in the treatment of ischemic diseases, U.S. Pat. No. 4,133,861 to treat diabetes, and U.S. Patent 4,337,809 to treat sickle cell anemia.

Clanlclor can be prepared according to European Patent Nos. 15,370, English Patent 2,079,285 and US Patent 4,416,887.

The two most important risk factors in the pathogenesis of arteriosclerosis are the increased importance of low (LDL) and very low-density lipoproteins (VLDL) in the blood and high-density lipoproteins (HD), rather than high blood cholesterol and

VLDL + LDL

HDL ratio is the so-called. atherogenic factor increase of ^1's. Claniclor lowers blood triglyceride levels and LDL cholesterol, while increasing phospholipid levels, HLD cholesterol and osse cholesterol. Thus, it is significantly reduced by atherogenic factor and is therefore suitable for arteriosclerosis (diabetes, cardiovascular) of various origins and locations. for the treatment of hyperlipidemic, cholesterolemic conditions.

It acts primarily by inhibiting lipid synthesis as it significantly reduces the total lipid and cholesterol content of liver tissue. Some researchers suggest that increasing the rate of partial cholesterol degradation may also be responsible for the effect.

In addition to the above effects, ischemic heart disease has a beneficial effect on increasing the rate of deoxygenation of the blood, i.e., it increases the rate of O ₂ release from the blood in the ischemic areas.

Sickle cell anemia is a genetically determined disease of unknown aetiology characterized by irreversible deformity of erythrocytes by making the erythrocyte membrane more permeable to Ca ²⁺ . (U.S. Patent No. 4,337,309)

Organic phosphate compounds inhibit the pathological accumulation of calcium phosphate salts in erythrocytes of patients with sickle cell anemia. This effect is related to the effect of diphosphates on calcium metabolism, which is also present in hypercalcaemic states.

Claniclor has not been marketed as a medicine for the treatment of the aforementioned disorders, which may be due to the adverse side effects during prolonged treatment (about 4-6 weeks) required to produce the appropriate effect.

From the effects of Claniclor discussed so far, III. the structure of the molecule does not result in the enzyme inducer III described by us. antithyroid effect. Through the action of the enzyme reducing agent, biotransformation I and II. increases the activity (quantity-dependent) of the enzymes involved in phase II. This is a protein synthesis stimulating effect.

The antithyroid effect, which occurs within a narrow dose response, can be explained by shifting the peripheral metabolism of tlroxin towards the reverse triiodotronron (rT ₃ ). It is not thought to have a direct effect on the thyroid gland.

It is an object of the present invention to provide a process for the preparation of a pharmaceutical composition containing Claniclor as an active ingredient, which can be used as a microsomal enzyme inducer or as an antherlloid preparation.

The invention is based on the one hand on the discovery that ClanClCl induces a microsomal enzyme system at therapeutic doses.

Treatments were performed with male Wistar rats at oral doses of 200 mg / kg / day and 400 mg / kg / day for 5 days. Increases in enzyme activity were measured, with biotransformation enzymes I and II. phase. ClanClCl produced a 70% increase in the anllln-hydroxylating capacity of the microsomal monooxygen gas system, and a 90% increase in the demethylation of ethyl morphine. The amount of cytochrome P-450 increased by 20-50%.

Biotransformation II. Phase I Induction of Phase I was shown to be a dose dependent increase in uridine diphospho-glucuronyl transferase activity. Conventional microsomes from untreated rats using p-nitrophenol as a substrate exhibited activity of 30 nM / min / mg. ClanClCl treatment at 200 mg / kg / day increased the enzyme activity to 55 nmol / ml / mg, and treatment with 400 mg / kg / day to 77 nmol / min / mg.

Hexobarblturate sleep study in mice clearly demonstrated its ability to induce enzymes. Sleep time decreased by 30-40%.

The results of the above studies indicate that Claniclor is a potent microsomal enzyme inducer. In human use it may be suitable for preventing various chemical intoxication in newborn babies! jaundice and to normalize these metabolic pathways in genetically determined 'las-2HU 201 245 A san metabolizing' individuals.

A further basis of the present invention is the discovery that ClanClCl also affects the peripheral metabolism of the thyroxine (T4) hormone in addition to its enzyme inducer effect.

ClanclCl 200 mg / kg once daily for 5 days was orally administered to Wistar rats with an average weight of 200-220 g. In male rats, serum T4 levels (nmol / l ± S.E.) Increased significantly from 35.9 ± 4.22 to 65.4 ± 3.76, 81.8%, with a modest change in T3. In the female groups, the T4 level (nmol / 1 + SE) increased from 28.7 ± 2.73 to 35.0 + 3.87 significantly by 22%, and the T3 level (nmol / 1 + SE) increased by 9.7 ± It significantly decreased from 1.61 to 6.3 ± 1.28 by 34.8%. Reverse T3 (rT3) showed a tangential increase in both groups.

Experimental data indicate that Clanlclor has been shown to significantly inhibit peripheral monodejodination after short-term treatment (5 days), which may be effective in treating patients with overactive thyroid gland.

Clanlclor decreases the T3 concentration of the biologically most active thyroid hormone by shifting the T4 conversion to the ineffective rT3 and is therefore primarily used as an adjuvant to shorten or for the rapid reduction of hyperthyroidism. As antithyroid drugs containing the active ingredient 1-methylimidazole-2-thiol do not have the above peripheral effect (Klára Megyeri; Shielding Disease Medicina Bp. 1986.36), Clanlclor supplements and positively influences their therapeutic effect.

In addition to the above areas of application, Clanclochlor may be used as a stand alone medication in patients with central hyperthyroidism, when TSH levels are unchanged.

Its use as an enzyme inducer and its use as an antithyroid agent has no or beneficial effect on the metabolism of fatty acids.

Based on the toxicity, therapeutic efficacy and pharmacokinetic properties of ClanClCl, it is recommended to administer 100 mg twice daily (tablets, capsules, dragees, etc.) as an enzyme inducer (based on experimental animal studies). For neonatal jaundice, a dose of 50-100 mg / kg body weight is recommended.

The antithyroid effect requires a dose of 100 mg three times a day for an adult weighing 70 kg.

Example 1

Preparation of the active ingredient (according to Example 4 of European Patent No. 15,370)

To a solution of 4.4 g (40 mmol) of dimethyl phosphonate and 5.17 g (40 mmol) of di-n-butylamine at 0 ° C

Dimethyl 4-chlorobenzoylphosphonate (9.96 g, 40 mmol) was added dropwise. After stirring for 1 hour at 0 ° C, the precipitate was filtered off and recrystallized from dichloromethane: 1: 3.

Yield: 10 g, mp .: 81-82 ° C ^f H NMR (CDCl3): 7.5-7.3 (m, 4H); 5.58-5.4 (m-1H);

3.95-3.5 (m, 12H).

Example 2

Each 100 mg tablet contains:

Clanllor 100 mg microcrystalline cellulose 100 mg polyvinylpyrrolidone 10 mg calcium phosphate 30 mg talc 8 mg magnesium stearate 2 mg

250 mg

1000 g of crystalline active substance, 1000 g of anhydrous crystalline cellulose, 300 g of calcium phosphate are homogenized in a machine homogenizing with 100 g of polyvinylpyrrolidone. The granules are then dried, 80 g of talc and 20 g of magnesium stearate are added to the dried material and, after homogenization, pressed to a 250 mg tablet in the usual manner on a tabletting machine.

Example 3

Composition of capsule containing 100 mg of active substance per capsule:

Claniclor 100 mg polyvinylpyrrolidone 2 mg potato starch 27 mg magnesium stearate 1 mg

130 mg

Depending on the size of the batch, the active ingredient is homogenized with the premixed excipients and the finished granules are filled into hard gelatin capsules in a suitable device.

Claims (1)

Process as active ingredient dimethyl-1- (dimethoxyphosphonyl) -4-chlorobenzylphosphate (Clanlclort) 55, characterized in that the Clanlclor, prepared in a known manner, is formulated with a conventional carrier, vehicle and / or other excipients to be used as microsomal enzyme inducers or antithyroid drugs.