PT98777A - METHOD FOR THE PREPARATION OF 3- (5-TRIFLUOROMETHYL-BENZOTIAZOL-2-YLETHYL) -4-OXO-3H-FTALAZIN-1-ILACETATE MONOHYDRATE - Google Patents

Description

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The present invention relates to 3- (5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl acetate (hereinafter referred to as the monohydrate) with pharmaceutical compositions containing the monohydrate, with methods of using the monohydrate in the treatment of chronic complications caused by diabetes mellitus, and with methods for the preparation of the monohydrate.

The corresponding anhydrous form forming 3- (5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl acetate is disclosed in U.S. Patent No. 4,868,301, the disclosure of which is incorporated herein by reference as reference. Both the anhydrous and monohydrate forms are useful in the treatment of certain chronic complications caused by diabetes mellitus, such as diabetic cataracts, retinopathy and neuropathy. Accordingly, the monohydrate has a specific lower volume than the anhydride allowing administration of smaller dosage forms which are generally easier to swallow and which may be more easily produced.

Summary of the Invention

The present invention relates to 3- (5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl-acetate monohydrate. The present invention also relates to a pharmaceutical composition for the treatment of complications associated with diabetes comprising an effective amount of the monohydrate and a pharmaceutically acceptable carrier. The present invention also relates to a method of treating a diabetic mammal (e.g. a human) directed to complications associated with diabetes comprising administering to said mammal an effective amount of the monohydrate. The present invention also relates to a method for preparing the monohydrate comprising dissolving the anhydrous form in an aqueous solution having a pH of about 7.0 to about 8.0, adjusting the pH to between about 5.5 and about 5.8, and separation of the resulting crystals from the solution.

DESCRIPTION OF THE DRAWINGS Fig. 1 of the drawings shows the thermogram of the monohydrate by differential scanning calorimetry. Fig. 2 of the drawings indicates the thermal gravimetric analysis (TGA) of the monohydrate. Fig. 3 of the drawings indicates the X-ray powder diffractogram of the monohydrate. FIG. 4 of the drawings indicates the X-ray powder diffractogram of the anhydrous form.

Detailed Description of the Invention The monohydrate can be isolated by dissolving the anhydrous form in an aqueous solution having a pH of about 7.0 to about 8.0, preferably about 7.5. The solution is preferably 0.3 M sodium phosphate buffer and the concentration of the anhydrous form is 4

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P

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of about 3 mg / ml. The pH is then adjusted to between 5.5 and 5.8 with an acid, for example a mineral acid such as hydrochloric acid. The concentration of the acid is usually about 1 N. When the anhydrous form is solubilized and the pH adjusted as described above, the temperature of the buffer solution is preferably in the range of about 30 to about 40øC, more preferably about 37øC. The solution is then cooled to room temperature and allowed to remain undisturbed until crystallization is complete (for example overnight). The resulting crystals are removed by filtration. The novel monohydrate of the invention has a rhomboidal crystalline structure. The anhydrous form crystallizes in the form of long needles. As the rhomboid monohydrate is more compact than the anhydrous form, the monohydrate has a significantly smaller volume than the anhydrous form taking into account the lower specific volume of the monohydrate. The lower specific volume of the monohydrate is important for the present compound since it is expected that the compound will be administered to a container at a relatively high dose of about 0.5 to 25 mg / kg. With the higher specific volume of the anhydrous form, the dosage form may have to be large to accommodate the large volume of the anhydrous form. The larger dosage form may be difficult to swallow to at least some containers. In addition, the production of a smaller dosage form of the monohydrate may be simpler, since certain production steps, such as densification or compactness, may be omitted.

Differential Scanning Calorimetry

Samples were analyzed on a Perkin-Elmer DSC-4 analyzer at a scan rate of 20 ° per minute. The DSC thermogram for the anhydrous form did not reveal an endothermic peak at 100 ° to 130 ° and suggesting no water or hydration in the sample. The DSC thermogram of the hydrate (Fig. 1) indicates an endotherm at about 125 ° C which is consistent with the hydrate form.

Thermal Gravimetric Analysis

TGA thermograms were obtained on a Perkin-Elmer TGA-2 thermal-gravimetric analyzer. The TGA thermogram of an anhydrous sample did not show weight loss by heating from 40ø to about 170øC. The material did not appear to contain water of hydration, since the release of water from a crystalline hydrate generally shows an accompanying weight loss at temperatures of about 100 ° C. The TGA thermogram of a sample of the monohydrate (Fig. 2) showed weight loss between about 90ø and 140øC as the temperature was raised over this temperature range at a rate of 20ø per minute. The weight loss of about 4% corresponds to the loss of one mole of water. The temperature above which weight loss occurred and the amount of weight loss suggested that one mole of water was lost, and thus the sample is a monohydrate. 6

X-Ray Diffractometry X-ray powder diffraction was obtained on a Siemens powder diffractometer. The beam intensity as a function of angle 2 - was recorded at a scan rate of Io per minute.

Characteristic diffractograms for the monohydrate and anhydrous forms are shown in Figures 3 and 4, respectively. Peaks in degrees 2 - (2T) and their corresponding intensities (I) are given in the following tables I (monohydrate) and II (anhydrous).

Table I (monohydrate) 2T I 2T I 7,068 2 24,393 5 10,592 3 24,879 2 10,743 6 25,448 4 10,948 12 26,064 7 12,122 6 27,635 8 13,474 1 28,464 9 14,146 6 29,211 1 15,705 35 30,356 4 16,980 11 31,048 8 17,050 8 31,808 6 17,791 2 32,065 3 18,777 6 32,417 2 19,028 14 32,813 2 20,318 13 33,302 1 21,061 100 33,963 1 21,435 17 35,675 2 21,823 6 36,008 2 22,218 1 36,935 1 23,210 7 37,613 4 23,971 12 39,271 1 8

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Table II (anhydrous) 2T I 2T I 5,946 100 28,716 21 6,973 39 29,241 19 8,133 10 29,923 21 10,206 4 30,729 42 12,087 27 31,090 18 12,552 42 32,479 10 14,110 80 33,453 5 15,301 14 34,740 5 16,570 56 35,094 6 18,162 76 36,027 7 18,758 18 36,688 8 20,658 36 38,607 19 21,320 19 40,516 5 22,151 32 42,287 6 23,395 70 43,576 7 23,694 12 44,124 7 25,195 50 46,359 8 26,329 29 47,838 5 27,540 27 27,759 14 The novel monohydrate of the present invention is useful as an inhibitor of the enzyme aldose reductase in the treatment of chronic complications of diabetes, such as diabetic cataracts, retinopathy and neuropathy. As used in the claims and detailed disclosure about this, the treatment is intended to include both the prevention and treatment of those conditions. The compound may be administered by a series of conventional routes of administration, including the oral, parenteral and topical routes. In general, the 9

compound will be administered orally or parenterally at doses ranging from about 0.5 to 25 mg / kg body weight of the subject to be treated per day, preferably from about 1.0 to 10 mg / kg. However, a certain variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any case, determine the appropriate dose for a given individual.

the novel compound of the invention may be administered alone or in combination with pharmaceutically acceptable carriers in single or multiple doses. Pharmaceutically acceptable carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Pharmaceutical compositions formed by combining the monohydrate and the pharmaceutically acceptable carrier are then rapidly administered in a series of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions, etc. These pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binding agents, excipients, etc. Thus, for the purpose of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be used together with various disintegrating agents such as starch, alginic acid and certain complex silicates together with binding agents such as polyvinyl pyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules. Preferred materials for this purpose include lactose or milk sugar and high molecular weight polyethylene glycols. When it is desired to obtain suspensions 10

aqueous or elixirs for oral administration, the essential active ingredient contemplated herein may be combined with various sweetening or flavoring agents, coloring matter or pigments and, if desired, emulsifying or suspending agents together with diluents such as water, ethanol, propylene glycol , glycerin and combinations thereof.

For parenteral administration, solutions of the monohydrate in sesame or peanut oil, aqueous porplyethylene glycol, or in sterile aqueous solution may be used. Such aqueous solutions should be appropriately buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this aspect, the sterile aqueous media used is readily available by standard techniques known to those skilled in the art.

The monohydrate may not only be advantageously used for the preparation of aqueous pharmaceutical compositions for parenteral administration, as previously described, but more particularly for the preparation of pharmaceutical compositions suitable for use as ophthalmic solutions. Such ophthalmic solutions are of particular interest for the treatment of diabetic cataracts by topical administration and treatment of such conditions in this way constitutes a preferred embodiment of the present invention. Thus, for the treatment of diabetic cataracts the monohydrate is administered to the eye in the form of an ophthalmic preparation prepared according to standard pharmaceutical practice, see for example " Remington's Pharmaceutical Sciences " 15th Edition, pages 1488 to 1501 (Mack Publishing Co., Easton, Pa). The ophthalmic preparation will contain 11

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monohydrate in a concentration of about 0.01 to about 1% by weight, preferably about 0.05 to about 0.5%, in a pharmaceutically acceptable solution, suspension or ointment. There will necessarily be some variation in concentration depending on the condition of the individual being treated and the person in charge of the treatment will determine the most appropriate concentration for a particular individual. The ophthalmic preparation will preferably be in the form of a sterile aqueous solution containing, if desired, additional ingredients, for example preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents viscosity-increasing agents, etc. Suitable preservatives include benzalkonium chloride, chlorobutanol, thimerosal, etc. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borate, sodium and potassium carbonate, sodium acetate, sodium biphosphate, etc., in amounts sufficient to maintain the pH between 6 and 8, preferably between 7 and 7.5. Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, etc., so that the equivalent of sodium chloride of the ophthalmic solution has a value of about 0.7 to about 0.11, preferably about 0.9%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea, etc. The wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282, and tyloxac-pol. Suitable viscosity enhancing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petroleum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, and the like. The ophthalmic preparation will be administered topically to the eye of the subject in need thereof.

treatment by conventional methods, for example in the form of drops or by bathing the eye in the ophthalmic solution. The following example illustrates the preparation and properties of the monohydrate. Example

3- (5-TRIFLUOROMETHYLBENZOTIZOL-2-YLETHYL) -4-OXO-3H-FATALAZIN-1-YLETHETATE MONOHYDRATE 1.87 g of 3- (5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-3H (anhydrous form) were added to 600 ml of 0.29M sodium phosphate composed of 0.152 mol of Na2HPO4 and 0.022 mol of NaH2 PO4 (dissolved in distilled water) at 37Â ° C. The pH was adjusted over a period of about 5 minutes with 1N HCl to a pH of about 5.17. The solution was allowed to stand at room temperature for about four days.

The crystals were collected by filtration and dried overnight under vacuum at room temperature.

Both DSC and TGA thermograms (Figures 1 and 2) revealed that the material had a volatile component which was lost after heating through a temperature range of 76 to 153 ° C, suggesting that the component was water. The percentage of water lost was indicated by TGA to be 4.12% which is in agreement with the amount of water expected for a monohydrate (4.12%). Karl Fisher analysis verified the presence of water in the crystal with values varying between 3.3 and 4.4%. The aspect of the 13

Monohydrate crystals were very different from those of the anhydrous crystals isolated from organic solvents being of romb instead of having the needle-like shape. The crystalline system revealed by powder diffraction by single crystal X-rays to be triclinic with two molecules per unit cell. The X-ray powder diffraction pattern was shown in Fig. 3.

It was found that the specific volume of the monohydrate was 1.6 cc / g. This can be compared to a volume specific for the anhydrous form (prepared as described in Example 16 of U.S. Patent No. 4,868,301) of 6.8 cc / g. #

Claims (1)

Claims ia. A method for preparing 3- (5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl acetate monohydrate, characterized in that it comprises dissolving 3- (5-trifluoromethylbenzothiazole -2-ylmethyl) -4-oxo-3H-phthalyn-2-ylacetate in an aqueous solution having a pH of about 7.0 to about 8.0, adjusting the pH between about 5.5 and about 5, 8, and the separation of the resulting crystals from the solution. 2 -. A method according to claim 1, wherein said monohydrate has a specific volume of less than about 2 cm / g. Lisbon, August 26, 1991 J. PEREIRA DA CRUZ Official Property Agent Industry! RUA VICTOR CORDON, 10-A 3. · 1200 USBOA