Pharmaceutical formulations containing 3-(4-cinnamyl-l-piperazinyl) amino derivatives of 3-formylrifamycin SV and 3-formylrifamycin S and a process of their preparation

Abstract

The present invention related to a process of preparation of pharmaceutically acceptable formulations containing as active substance 3-(4-cinnamyl-1-piperazinyl)-amino derivatives of 3-formylrifamycine SV and 3-formylrifamycine S, which possess high activity against Gram-positive and Gram-negative microorganisms, as well as against tuberculous micobacteria (including atypical and rifamycin resistant), and to a method for the preparation of 3-(4-cinnamyl-1-piperazinyl)-amino derivatives of 3-formylrifamycine SV and 3-formylrifamycine S. The method for the preparation of pharmaceutical compositions is readily feasible, and does not require special equipment for its implementation. The process for preparing the compounds is characterized by high yield and purity, using an environmental clean solventethanol and water in the preparation and isolation of substances, and the absence of residual organic solvents in the final product.

Claims

1. A pharmaceutical formulation comprising a mixture of an active substance and excipient, wherein the active substance has the structure ##STR00005## wherein R is H or Na, and R is COCH3 or H, and wherein the amount of active ingredient per dosage unit is from 100 to 600 mg, and the excipients are present in an amount from 1 to 25% based on the total weight of the mixture.

2. The pharmaceutical formulation according to claim 1 wherein the excipients comprise microcrystalline cellulose and starch.

3. The pharmaceutical formulation according to claim 1 wherein the excipients comprise sliding excipients selected from the group consisting of sodium stearyl fumarate and magnesium stearate.

4. A compound of a formula ##STR00006## wherein R is H or Na, and R is COCH3 or H.

5. The compound according to claim 4 wherein RH and RCOCH.sub.3.

6. The compound according to claim 4 wherein RNa and RCOCH.sub.3.

7. The compound according to claim 4 wherein RH and RH.

8. The compound according to claim 4 wherein RNa and RH.

9. The pharmaceutical formulation according to claim 1, wherein RH and RCOCH.sub.3.

10. The pharmaceutical formulation according to claim 1, wherein RNa and RCOCH.sub.3.

11. The pharmaceutical formulation according to claim 1, wherein RH and RH.

12. The pharmaceutical formulation according to claim 1, wherein RNa and RH.

13. A method of treating a person of diseases and conditions caused by Gram-positive or Gram-negative bacteria, the method comprising: providing a dosage of an active substance and excipient, wherein the active substance has the structure ##STR00007## wherein R is H or Na, and R is COCH3 or H, and wherein the amount of active ingredient per dosage unit is from 100 to 600 mg, and the excipients are present in an amount from 1 to 25% based on the total weight of the mixture.

14. The method of claim 13 and wherein the ailment is caused by tuberculous mycobacterium.

15. The method of claim 13 and wherein the ailment is atypical and rifamycin resistant forms of tuberculosis.

16. The method of claim 13 and wherein RH and RCOCH.sub.3.

17. The method of claim 13 and wherein RNa and RCOCH.sub.3.

18. The method of claim 13 and wherein RH and RH.

19. The method of claim 13 and wherein RNa and RH.

Description

PREFERRED EMBODIMENT OF THE INVENTION

(1) Further, the description will be presented examples of the embodiment of the pharmaceutical formulations, and examples of obtaining the active compounds of formulas I and II, and pharmaceutical formulations are not limited to the examples described and may also be applied such embodiments, within the parameters outlined above and ratios.

Example 1

(2) Microcrystalline cellulose (5.60 g) and sodium stearyl fumarate (1.40 g) are sieved and dry-mixed with a pre-weighed amount (30.0 g) of the active ingredient-sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin SV (compound Ib). After a homogenization, mixture comprising 15.1% of microcrystalline cellulose, 3.8% sodium stearyl fumarate and 81.1% of active substance, is filled into a capsule and then be packaged in a suitable manner, e.g. in aluminum/aluminum blisters. Obtained are 1805 capsules with an average weight of the contents 1859 mg.

Example 2

(3) Prior sieved starch (6.00 g) and sodium stearyl fumarate (1.00 g) are dry-mixed with a pre-weighed amount (30.0 g) of sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl rifamycin S (Compound IIb). After a homogenization mixture is obtained with content-16.2% starch, sodium stearyl fumarate 2.7% and 81.1% of the above-described active agent. The mixture is filled into a capsule and then be packaged in a suitable manner in aluminum/aluminum blisters. Obtained are 1805 capsules with an average weight of the contents 1859 mg.

Example 3

(4) Microcrystalline cellulose (3.0 g) and sodium stearyl fumarate (1.0 g) are sieved and dry mixed well with a pre-weighed amount (60.0 g) of sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl-25-desacetoxy rifamycin SV (Compound Id). The resulting homogeneous mixture containing microcrystalline cellulose 4.7%, 1.6% sodium stearyl fumarate and as an active ingredient the sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl-25-desacetoxy rifamycin SV-93.8%, is filled into capsules, which are packaged in a suitable way in aluminum/aluminum blisters. Obtained are 1805 capsules with an average weight of the contents 320 mg16 mg.

Example 4

(5) Starch (12.50 g) and magnesium stearate (0.75 g) are sieved and dry-mixed well with a pre-weighed amount (37.0 g) of sodium salt of 3-(4-cinnamyl-1-piperazinyl)-iminomethyl-25-desacetoxy rifamycin S (Compound IId). The resulting homogeneous mixture consisting of 12.5% starch, magnesium stearate 1.5% and 74% of active substance is filled into capsules, which are packaged in an appropriate manner. Obtained are 1805 capsules with an average weight of the contents 320 mg16 mg.

(6) Similarly, compositions were prepared with all other derivatives disclosed already in this patent specification.

Example 5

(7) To a solution of 6.3 g (0.0289 gM) N1-cinnamyl-N4-amino piperazine in 200 ml of ethanol is added 1.2 ml of glacial acetic acid. Under stirring and at 20-30 C. to the ethanol solution are added portion wise 20 g (0.0276 gM) 3-formylrifamycin SV after each batch waiting to dissolve. Addition takes about 30 min and depletion of the starting rifamycin SV is monitored by thin layer chromatography. Stirring is continued for 2 h wherein there is a formation of a dark red crystalline precipitate. The reaction mixture is diluted with 200 ml water, stirred for 15 min and cooled to 5 C. The resulting precipitate of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV is filtered and washed with 20 ml water. After drying under vacuum at 70 C. 25 g of a dark red precipitate are obtained, representing 98% of the theoretical yield. The product has purity greater than 98%.

Example 6

(8) To a suspension of 25 g (24.7 g as 100%) of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV (0.0264 gM) in 200 ml of ethanol with stirring 4.88 ml of 30% solution of sodium methoxide (0.0264 gM) is added, wherein the suspension almost immediately pass into solution. The reaction mixture is filtered and the solvent is distilled under vacuum till complete elimination. To the resulting gummy residue 200 ml of water and 1 g of sodium ascorbate is added. The mixture is stirred until complete dissolving, and subjected to lyophilization. Obtained are 25.2 g (99.2% of theory) of the sodium salt of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV in 98% purity.

Example 7

(9) To a solution of 5 g of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV in 150 ml of ethanol, 3 g of manganese dioxide is added, the reaction mixture was stirred for 4 hours, and by thin layer chromatography is monitored the passage of the hydroquinone into a quinone form. The reaction mixture is heated to 50-60 C., and filtered, and the precipitate of Mn02 is washed thoroughly with warmed ethanol. The resulting solution is distilled under vacuum to near dryness. The precipitate is dried in a vacuum oven at 50 C. Obtained are 4.9 g (98.2% of theory) of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin S. The product is a dark violet crystalline precipitate.

Example 8

(10) To a solution of 5 g of the sodium salt of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV in 150 ml of ethanol 5 g Mn02 is added and the mixture is stirred for 4 hours to complete switching into the quinone form (TLC). The mixture is heated to 50-60 C., filtered and the precipitate of Mn02 is washed thoroughly with hot ethanol. The solution is distilled to about of the original volume. The residue is dried in a vacuum oven at 50 C. Obtained are dark violet crystals of the sodium salt of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin S. Yield 5 g (97.6 of theory).

Example 9

(11) To a solution of 5 g of sodium hydroxide in 100 ml of a 50% aqueous ethanol 5 g of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV is added. Almost immediately, the mixture passes into the solution, in which after 10 min begins to fall bright red precipitate. The mixture is cooled to 10 C., filtered and the precipitate is dried in a vacuum oven at 50 C. Obtained are 4.5 g (92% of theory) of the sodium salt of 25-desacetyl-3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV.

Example 10

(12) To a solution of 3.5 g of sodium salt of 25-desacetyl-3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV in 100 ml of ethanol under heating to 40 C., 2 ml of hydrochloric acid diluted in 10 ml water are added. Orange-red solution is obtained, which crystallized upon cooling. The received bright orange precipitate of 25-desacetyl-3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV is filtered and dried in a vacuum oven at 50 C. Yield 3.3 g (96.5% of theory).

Example 11

(13) The procedure is as in Example 5 but instead of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin SV is used 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin S. Obtained is sodium salt of 3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin S in 90% yield of theory.

Example 12

(14) The product of Example 7 was subjected to the procedure described in Example 6. Prepared is 25-desacetyl-3-(4-cinnamyl-1-piperazinyl) iminomethyl rifamycin S in 95% yield