WO1992003432A1 - 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3h-phythalazin-1-ylacetic acid monohydrate - Google Patents
3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3h-phythalazin-1-ylacetic acid monohydrate Download PDFInfo
- Publication number
- WO1992003432A1 WO1992003432A1 PCT/US1991/003391 US9103391W WO9203432A1 WO 1992003432 A1 WO1992003432 A1 WO 1992003432A1 US 9103391 W US9103391 W US 9103391W WO 9203432 A1 WO9203432 A1 WO 9203432A1
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- compound
- monohydrate
- ylmethyl
- oxo
- ylacetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to 3- (5-trifluoro- methylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-l-yl- acetate monohydrate (hereinafter referred to as the mono- hydrate) to pharmaceutical compositions containing the monohydrate, to methods of using the monohydrate in the treatment of chronic complications arising from diabetes mellitus, and to methods of preparing the monohydrate.
- the present invention relates to 3- (5-trifluorororcethyl- benzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-l-ylacetate monohydrate.
- the present invention also relates to a pharmaceutical composition for treating diabetes-associated complications 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) for diabetes- associated complications which comprises administering to said mammal an effective amount of the monohydrate.
- a diabetic mammal e.g. a human
- the present invention also relates to a method of treating a diabetic mammal (e.g. a human) for diabetes- associated complications which comprises administering to said mammal an effective amount of the monohydrate.
- the present invention also relates to a method of preparing the monohydrate comprising dissolving the anhdyrous form in an aqueous solution at a pH of about 7.0 to about 8.0, adjusting the pH to between about 5.5 -to about 5.8, and separating the resulting crystals from the solution.
- Fig. 1 of the drawings depicts the differential scanning calorimetry (DSC) thermogram of the monohydrate.
- Fig. 2 of the drawings depicts the thermal gravimetric analysis (TGA) thermogram of the monohydrate.
- Fig. 3 of the drawings depicts the x-ray powder diffractogram of the monohydrate.
- Fig. 4 of the drawings depicts the x-ray powder diffractogram of the anhydrous form.
- the monohydrate may be isolated by dissolving the anhydrous form in an aqueous solution at a pH of about 7.0 to about 8.0, preferably about 7.5.
- the solution is preferably 0.3 sodium phosphate buffer and the concentra ⁇ tion of the anhydrous form is about 3 mg/ml.
- the pH is then adjusted to between about 5.5 and 5.8 with an acid, e.g. a mineral acid such as hydrochloric acid.
- the concen ⁇ tration of the acid is usually about IN.
- the temperature of the buffer solution is preferably about 30 to about 40°C, more preferably about 37°C.
- the solution is then cooled to room temperature and allowed to remain undisturbed until crystallization is complete (e.g., overnight) .
- the resulting crystals are removed by filtra ⁇ tion.
- the novel monohydrate of the invention has a rhom- boidal crystalline structure.
- the anhydrous form crystal ⁇ lizes in the form of long needles. Since the rhomboidal monohydrate is more compact than the anhydrous form, the monohydrate takes up a significantly smaller volume than the anhydrous form accounting for the lower specific volume of the monohydrate.
- the lower specific volume of the nonohydrate is important to the present compound since the compound is expected to be administered to a recipient at a relatively high dose of about 0.5 to 25 mg/kg.
- the dosage form may have to be large to accomodate the large volume of the anhydrous form.
- the larger dosage form may be difficult to swallow for at least some recipients.
- the manufacture of a smaller dosage form of the monohydrate may be simpler, since certain steps in the manufacture may be omitted, such as densification or compaction.
- the DSC thermogram of the hydrate (Fig. 1) shows an endotherm at about 125°C which is consistent with a hydrate form.
- TGA thermograms were obtained on a Perkin-Elmer TGA-2 thermogravimetric analyzer.
- the TGA thermogram of a sample of the anhydrous form showed no weight loss on heating from 40° to about 170°C.
- the material was not likely to contain water of hydration, since 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 90° and 140°C as the temperature of the sample was increased through this temperature range at a rate of 20° per minute.
- the weight loss of about 4% corresponds to the loss of one mole of water.
- the temperatures over which the weight loss occurred and the amount of weight lost suggest that one mole of water is lost, and therefore that the sample is a monohydrate.
- X-ray powder diffraction patterns were obtained on a Siemens powder diffractometer. Beam intensity as a func ⁇ tion of the angle 2 - was recorded at a scanning rate of 1° per minute.
- 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.
- treatment is meant to include both the prevention and alleviation of such condi ⁇ tions.
- the compound may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, parenterally and topically.
- the compound will be administered orally or parenterally at dosages between about 0.5 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 1.0 to 10 mg/kg.
- some variation in dci ⁇ age will necessarily occur depending on the condition of the subject being treated.
- the person respon- sible for administration will, in any event, determine the appropriate dose for the individual subject.
- the novel compound of the invention may be admin ⁇ istered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses.
- suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
- the pharmaceutical compositions formed by combining the monohydrate and the pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
- These pharma ⁇ ceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
- tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
- binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
- lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
- Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
- Vlhen aqueous suspensions or' elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
- solutions of the monohydrate in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed.
- aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitioneal adminis ⁇ tration.
- the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
- the monohydrate may not only be advantageously em ⁇ ployed for the preparation of aqueous pharmaceutical compositions for parenteral administration, as described above, but more particularly for the preparation of pharma ⁇ ceutical compositions suitable for use as ophthalmic solutions.
- ophthalmic solutions are of principal interest for the treatment of diabetic cataracts by topical administration and the treatment of such conditions in this manner is a preferred embodiment of the present invention.
- the mono ⁇ hydrate is administered to the eye in the form of an ophthalmic preparation prepared in accordance with con ⁇ ventional 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 the monohydrate in a concentration from about 0.01 to about 1% by weight, preferably from about 0.05 to about 0.5%, in a pharma ⁇ ceutically acceptable solution, suspension or ointment. Some variation in concentration will necessarily occur, depending on the condition of the subject to be treated and the person responsible for treatment will determine the most suitable concentration for the individual subject.
- the ophthalmic preparation v/ill 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 and the like.
- Suitable preservatives include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like.
- Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borate, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about 6 to 8, preferably between about 7 and 7.5.
- Suitable tonicity agents are dextran 40., dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic solution is about 0.7 to about 0.11 preferably about 0.9%.
- Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabi- sulfite, sodium thiosulfite, thiourea and the like.
- Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
- Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethyl- propylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrroli- done, carboxymethylcellulose and the like.
- the ophthalmic preparation will be administered topically to the eye of the subject in need of treatment by conventional methods, for example in the form of drops or by bathing the eye in the ophthalmic solution.
- the specific volume of the monohydrate was found to be 1.6 cc/gm. This may be compared to a specific volume for the anhydrous form (prepared as described in Example 16 of U.S. Patent No. 4,868,301) of 6.8 cc/gm.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
3-(-5-Trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate monohydrate is useful in the treatment of certain chronic complications arising from diabetes mellitus. The compound has a lower specific volume than the corresponding anhydrous form.
Description
3-(5-TRIFLU0R0METHYLBENZ0THIAZ0L-2-YLMETHYL)-4-0X0-3H-PHYTHALAZIN-l-YLACETIC ACID MONOHYDRATE.
Background of the Invention The present invention relates to 3- (5-trifluoro- methylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-l-yl- acetate monohydrate (hereinafter referred to as the mono- hydrate) to pharmaceutical compositions containing the monohydrate, to methods of using the monohydrate in the treatment of chronic complications arising from diabetes mellitus, and to methods of preparing the monohydrate.
The corresponding anhydrous form, 3-(5-trifluoro- methylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-l- yl-acetate, is disclosed in United States Patent No. 4,868,301 the disclosure of which is incorporated by reference. Both the anhydrous and monohydrate forms are useful in the treatment of certain chronic complications arising from diabetes mellitus, such as diabetic cataracts, retinopathy and neuropathy. The monohydrate, however, has a lower specific volume than the anhydride allowing for the administration of smaller dosage forms which are generally easier to swallow and which may be easier to manufacture.
Summary of the Invention The present invention relates to 3- (5-trifluororcethyl- benzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-l-ylacetate monohydrate.
The present invention also relates to a pharmaceutical composition for treating diabetes-associated complications 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) for diabetes- associated complications which comprises administering to said mammal an effective amount of the monohydrate.
The present invention also relates to a method of preparing the monohydrate comprising dissolving the anhdyrous form in an aqueous solution at a pH of about 7.0
to about 8.0, adjusting the pH to between about 5.5 -to about 5.8, and separating the resulting crystals from the solution.
Description Of The Drawings
Fig. 1 of the drawings depicts the differential scanning calorimetry (DSC) thermogram of the monohydrate.
Fig. 2 of the drawings depicts the thermal gravimetric analysis (TGA) thermogram of the monohydrate.
Fig. 3 of the drawings depicts the x-ray powder diffractogram of the monohydrate.
Fig. 4 of the drawings depicts the x-ray powder diffractogram of the anhydrous form.
Detailed Description of the Invention
The monohydrate may be isolated by dissolving the anhydrous form in an aqueous solution at a pH of about 7.0 to about 8.0, preferably about 7.5. The solution is preferably 0.3 sodium phosphate buffer and the concentra¬ tion of the anhydrous form is about 3 mg/ml. The pH is then adjusted to between about 5.5 and 5.8 with an acid, e.g. a mineral acid such as hydrochloric acid. The concen¬ tration of the acid is usually about IN. When solubilizing the anhydrous form and adjusting the pH as described above, the temperature of the buffer solution is preferably about 30 to about 40°C, more preferably about 37°C. The solution is then cooled to room temperature and allowed to remain undisturbed until crystallization is complete (e.g., overnight) . The resulting crystals are removed by filtra¬ tion.
The novel monohydrate of the invention has a rhom- boidal crystalline structure. The anhydrous form crystal¬ lizes in the form of long needles. Since the rhomboidal monohydrate is more compact than the anhydrous form, the monohydrate takes up a significantly smaller volume than the anhydrous form accounting for the lower specific volume of the monohydrate.
The lower specific volume of the nonohydrate is important to the present compound since the compound is expected to be administered to a recipient at a relatively high dose of about 0.5 to 25 mg/kg. At the higher specific volume of the anhydrous form, the dosage form may have to be large to accomodate the large volume of the anhydrous form. The larger dosage form may be difficult to swallow for at least some recipients. In addition, the manufacture of a smaller dosage form of the monohydrate may be simpler, since certain steps in the manufacture may be omitted, such as densification or compaction.
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 show an endothermic peak at 100c to 130°C suggesting that there was no water of hydration on the sample.
The DSC thermogram of the hydrate (Fig. 1) shows an endotherm at about 125°C which is consistent with a hydrate form.
Thermal Gravimetric Analysis
TGA thermograms were obtained on a Perkin-Elmer TGA-2 thermogravimetric analyzer. The TGA thermogram of a sample of the anhydrous form showed no weight loss on heating from 40° to about 170°C. The material was not likely to contain water of hydration, since 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 90° and 140°C as the temperature of the sample was increased through this temperature range at a rate of 20° per minute. The weight loss of about 4% corresponds to the loss of one mole of water. The temperatures over which the weight loss occurred and the amount of weight lost suggest that one
mole of water is lost, and therefore that the sample is a monohydrate.
X-ray Diffractometry
X-ray powder diffraction patterns were obtained on a Siemens powder diffractometer. Beam intensity as a func¬ tion of the angle 2 - was recorded at a scanning rate of 1° per minute.
The characteristic diffractograms for the monohydrate and the anhydrous forms are depicted in Figures 3 and 4, respectively. The peaks in degrees 2 - (2T) and their corresponding intensities (I) are set out in the following tables I (monohydrate) and II (anhydrous) .
Table I (monohydrate)
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 specification hereof, treatment is meant to include both the prevention and alleviation of such condi¬ tions. The compound may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, parenterally and topically. In general, the compound will be administered orally or parenterally at dosages between about 0.5 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 1.0 to 10 mg/kg. However, some variation in dciϊage will necessarily occur depending on the condition of the subject being treated. The person respon-
sible for administration will, in any event, determine the appropriate dose for the individual subject.
The novel compound of the invention may be admin¬ istered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. The pharmaceutical compositions formed by combining the monohydrate and the pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharma¬ ceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. Vlhen aqueous suspensions or' elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes 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 propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably 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 intraperitioneal adminis¬ tration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
The monohydrate may not only be advantageously em¬ ployed for the preparation of aqueous pharmaceutical compositions for parenteral administration, as described above, but more particularly for the preparation of pharma¬ ceutical compositions suitable for use as ophthalmic solutions. Such ophthalmic solutions are of principal interest for the treatment of diabetic cataracts by topical administration and the treatment of such conditions in this manner is a preferred embodiment of the present invention. Thus, for the treatment of diabetic cataracts the mono¬ hydrate is administered to the eye in the form of an ophthalmic preparation prepared in accordance with con¬ ventional 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 the monohydrate in a concentration from about 0.01 to about 1% by weight, preferably from about 0.05 to about 0.5%, in a pharma¬ ceutically acceptable solution, suspension or ointment. Some variation in concentration will necessarily occur, depending on the condition of the subject to be treated and the person responsible for treatment will determine the most suitable concentration for the individual subject. The ophthalmic preparation v/ill 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 and the like. Suitable preservatives include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal
and the like. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borate, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about 6 to 8, preferably between about 7 and 7.5. Suitable tonicity agents are dextran 40., dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic solution is about 0.7 to about 0.11 preferably about 0.9%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabi- sulfite, sodium thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethyl- propylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrroli- done, carboxymethylcellulose and the like. The ophthalmic preparation will be administered topically to the eye of the subject in need of 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-Trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-l-ylacetate Monohydrate 1.87 g of 3- (5-trifluoro ethylbenzothiazol-2-ylmethyl) - 4-oxo-3H-phthalazin-l-ylacetate (anhydrous form) were added to 600 ml of 0.29M sodium phosphate composed of 0.152 mole Na2HP0. and 0.022 mole NaH2P04 (dissolved in distilled water) at 37°C. The pH was adjusted, over a period of about 5 minutes with 1 N HC1 to about pH 5.17. The solution was allowed to remain 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) showed that the material has a volatile component which was lost upon heating through the temperature range 76 to 153°C, suggesting that the component was water. The percent water loss was shown by TGA to be 4.12% which agrees with the amount of water to be expected for a monohydrate (4.12%) .
Karl Fisher analysis verified the presence of water in the crystal with values varying from 3.3 to 4.4%. The habit of the monohydrate crystals was much different from that of crystals of the anhydrous form isolated from organic solvents being rhombic in nature rather than needle-like. The crystal system was by single crystal x-ray powder diffraction shown to be triclinic with two molecules per unit cell. The powder x-ray diffraction pattern was as shown in Fig. 3.
The specific volume of the monohydrate was found to be 1.6 cc/gm. This may be compared to a specific volume for the anhydrous form (prepared as described in Example 16 of U.S. Patent No. 4,868,301) of 6.8 cc/gm.
Claims
1. The compound 3-(5-trifluoromethylbenzothiazol-
2-ylmethyl) -4-oxo-3H-phthalazin-l-ylacetate monohydrate.
2. The crystalline form of the compound of claim 1, characterized by the x-ray powder diffractogram having the following absorption bands:
the compound of claim 1 effective in treating such compli¬ cations and a pharmaceutically acceptable carrier.
6. A composition according to claim 5, wherein said compound is characterized by the x-ray powder diffractogram having the following absorption bands:
0
5
0
5
8. A composition according to claim 5, wherein said compound is characterized by a specific volume of less than 5 about 2 cc/gm.
9. A method of treating diabetes-associated compli¬ cations in a mammal comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1 that is effective in treating such complications.
10. A method according to claim 9, wherein said compound is characterized by the x-ray powder diffractogram having the following absorption bands:
11. A method according to claim 10, wherein said compound is characterized by a specific volume of less than about 2 cc/gm.
12. A method according to claim 9, wherein said compound is characterized by a specific volume of less than about 2 cc/gm.
13. A method of preparing 3-(5-trifluoromethyl- benzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-l-ylacetate monohydrate comprising dissolving 3-(5-trifluoromethyl- benzothiazol-2-ylmethyl)-4-oxo-3H-phthalin-2-ylacetate in an aqueous solution at about pH 7.0 to about 8.0, adjusting the pH to between bout 5.5 to about 5.8, and separating the resulting crystals from the solution.
14. The compound 3- (4-trifluoromethylbenzothiazol-
2-ylmethyl) -4-oxo-3H-phthalazin-l-ylacetate monohydrate prepared by the process of claim 13.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57397390A | 1990-08-28 | 1990-08-28 | |
| US573,973 | 1990-08-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992003432A1 true WO1992003432A1 (en) | 1992-03-05 |
Family
ID=24294150
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1991/003391 Ceased WO1992003432A1 (en) | 1990-08-28 | 1991-05-15 | 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3h-phythalazin-1-ylacetic acid monohydrate |
Country Status (3)
| Country | Link |
|---|---|
| IE (1) | IE913011A1 (en) |
| PT (1) | PT98777A (en) |
| WO (1) | WO1992003432A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0982306A3 (en) * | 1998-08-21 | 2000-07-05 | Pfizer Products Inc. | Polymorph of zopolrestat monohydrate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0222576A2 (en) * | 1985-11-07 | 1987-05-20 | Pfizer Inc. | Heterocyclic oxophthalazinyl acetic acids |
| EP0295051A2 (en) * | 1987-06-09 | 1988-12-14 | Pfizer Inc. | Preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains |
-
1991
- 1991-05-15 WO PCT/US1991/003391 patent/WO1992003432A1/en not_active Ceased
- 1991-08-26 PT PT9877791A patent/PT98777A/en not_active Application Discontinuation
- 1991-08-27 IE IE301191A patent/IE913011A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0222576A2 (en) * | 1985-11-07 | 1987-05-20 | Pfizer Inc. | Heterocyclic oxophthalazinyl acetic acids |
| EP0295051A2 (en) * | 1987-06-09 | 1988-12-14 | Pfizer Inc. | Preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains |
Non-Patent Citations (1)
| Title |
|---|
| Journal of Medicinal Chemistry, vol. 34, no. 1, January 1991, American Chemical Society, (Washington, DC, US), B.L. Mylari et al.: "Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-Ä[5-(trifluoromethyl)-2-benzothiazolylÜmethylÜ-1-phthalazine-acetic acid (Zopolrestat) and congeners", pages 108-122, see pages 108-122 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0982306A3 (en) * | 1998-08-21 | 2000-07-05 | Pfizer Products Inc. | Polymorph of zopolrestat monohydrate |
| US6159976A (en) * | 1998-08-21 | 2000-12-12 | Pfizer Inc. | Polymorph of zopolrestat monohydrate |
Also Published As
| Publication number | Publication date |
|---|---|
| IE913011A1 (en) | 1992-03-11 |
| PT98777A (en) | 1992-07-31 |
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