Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-02-13
2003-05-27
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C514S233500, C514S235500, C514S248000, C544S111000, C544S114000, C544S115000, C544S116000
Reexamination Certificate
active
06570013
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to [4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine salt, diethanolamine salt and triethanolamine salt, pharmaceutical compositions thereof and methods of treating diabetic complications in mammals comprising administering to said mammals said salts or said compositions. This invention is also directed to combinations of said salts with sodium hydrogen ion exchange (NHE-1) inhibitors, selective serotonin retuptake inhibitors (SSRIs), glycogen phosphorylase inhibitors (GPIs), sorbitol dehydrogenase inhibitors (SDIs) and antihypertensive agents. Said combinations are also useful in treating diabetic complications in mammals.
Zopolrestat, also known as [4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid, is disclosed in U.S. Pat. No. 4,939,140, which is incorporated herein by reference.
It is well known in the art that highly water soluble medicinal preparations, when administered orally, result in efficient absorption of such preparations from the gastrointestinal tract into systemic circulation. Another hallmark of such preparations is the rapid rate at which they are absorbed into the systemic circulation resulting in a high concentration of the active agent in the blood. Also, water soluble preparations are especially suitable for parenteral administration, for example, intravenous adminstration. The instant ethanolamine salt of this invention exhibits a surprising degree of water solubility.
SUMMARY OF THE INVENTION
This invention is directed to a salt form of zopolrestat selected from [4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine salt, also known as zopolrestat ethanolamine; [4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid diethanolamine salt, also known as zopolrestat diethanolamine; and [4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid triethanolamine salt, also known as zopolrestat triethanolamine. These compounds are salt forms of zopolrestat, which is the compound of the formula I
Zopolrestat ethanolamine has a water solubility of 40 mg/mL, zopolrestat diethanolamine has a water solubility of 100 mg/mL and zopolrestat triethanolamine has a water solubility of 6.6 mg/mL. As such, these salt forms of zopolrestat are highly water soluble forms of zopolrestat. Accordingly, these compounds are each advantageous salt forms of zopolrestat.
This invention is also directed to pharmaceutical compositions comprising zopolrestat ethanolamine, zopoirestat diethanolamine or zopolrestat triethanolamine and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to a pharmaceutical composition comprising zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat triethanolamine and a second pharmaceutical agent. Said second pharmaceutical agents include NHE-1 inhibitors, SSRIs, GPIs, SDIs and antihypertensive agents. Particularly preferred SSRIs for use in this invention are fluoxetine, sertraline and sibutramine or a pharmaceutically acceptable salt of said fluoxetine, sertraline or sibutramine. It is particularly preferred that said SSRI is sertraline hydrochloride. It is also preferred that said antihypertensive agents are ACE inhibitors. Particularly preferred ACE inhibitors for use in this invention are enalapril and captopril.
This invention is also directed to a method of treating diabetic complications in mammals comprising administering to said mammal zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat triethanolamine. Diabetic complications which are treated by zopoirestat ethanolamine, zopolrestat diethanolamine or zopolrestat triethanolamine, pharmaceutical compositions comprising zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat triethanolamine and the combinations of this invention include, but are not limited to, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, microangiopathy, macroangiopathy, cataracts and myocardial infarction.
This invention is also directed to a method of treating diabetic complications in mammals comprising administering to said mammal a pharmaceutical composition comprising a combination of zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat triethanolamine and a second pharmaceutical agent or a pharmaceutically acceptable salt of said second pharmaceutical agent where said second pharmaceutical agent is an NHE-1 inhibitor, a SSRI, a GPI, a SDI or an antihypertensive agent.
This invention is also directed to a kit comprising:
a) a first unit dosage form comprising zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat triethanolamine and a pharmaceutically acceptable carrier, vehicle or diluent;
b) a second unit dosage form comprising a second pharmaceutical agent, a prodrug thereof or a pharmaceutically acceptable salt of said second pharmaceutical agent or said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent; and
c) a container.
25. This invention is particularly directed to such a kit wherein said second pharmaceutical agent is a sodium/hydrogen ion exchange (NHE-1) inhibitor, a selective serotonin retuptake inhibitor (SSRI), a glycogen phosphorylase inhibitor (GPI), a sorbitol dehydrogenase inhibitor (SDI) or an antihypertensive agent.
The term “treating”, “treat” or “treatment” as used herein includes curative, preventative (e.g., prophylactic) and palliative treatment.
DETAILED DESCRIPTION OF THE INVENTION
The salts of this invention, i.e., zopolrestat ethanolamine, also known as [4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine salt; zopolrestat diethanolamine, also known as [4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid diethanolamine salt; and zopolrestat triethanolamine, also known as [4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine salt, are readily prepared as set forth below.
4-Oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid, also known as zopolrestat, is dissolved in an appropriate reaction inert solvent. As used herein, the expression “reaction inert solvent” refers to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. Preferred solvents include methanol, ethanol, n-propanol, isopropanol, acetone, ethyl methyl ketone, diethyl ketone and methyl isobutyl ketone. A particularly preferred solvent for this reaction is acetone. To this solution is added ethanolamine, diethanolamine or triethanolamine. The reaction mixture is stirred at about ambient temperature to about the refluxing temperature of the solvent being used for about two hours to about six hours, preferably at ambient temperature for about two hours. The salt of this invention is isolated from the reaction mixture by methods well known to those skilled in the art. It is preferred that the reaction mixture is directly evaporated. The residue from the evaporation is preferably crystallized from an appropriate solvent or mixture of solvents.
Zopolrestat is prepared as disclosed in U.S. Pat. No. 4,939,140, which is incorporated herein by reference. Methods for measuring the aldose reductase inhibitory activity of the compounds and compositions of this invention are disclosed therein.
Measurement of the water solubility of the salts of this invention is accomplished by using methods well known to those skilled in the art. Specifically, to a weighed amount of zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat triethanolamine, distilled water is added in small portions until a clear solution is obta
Benson Gregg C.
Pfizer Inc
Raymond Richard L.
Richardson Peter C.
Ronau Robert T.
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