NZ242152A - 1-pyridazine acetic acid derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £42152 Priority Cctc;"): Compiste Specificai:cn Filed: Class: Vl.h<°t3R:.CPVJO^sJoi C9^^?/c^-. rtWG&JsQ.

//Ccs>7 Pf*i 7/U^.7 ?& W PK1. .. nto 2 6 JUL 1994 Publication Date: ■ • i?#2- P.O. Journsl, No: Clasa Cont: Uf\ NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION f N.Z. PATENT OFFICE 27 HAR ® PYRIDAZINONE ACETIC ACIDS We, PFIZER INC., a corporation organized under the laws of the State of Delaware, United States of America, of 235 East 42nd Street, New York, State of New York, United States of America, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (followed by page 1A) -lA- PYRIDAZINONE ACETIC ACIDS Background of the Invention This invention relates to novel pyridazinone acetic acids and derivatives thereof which are aldose reductase inhibitors and which are useful in the treatment of certain 10 chronic complications arising from diabetes mellitus, such as diabetic cataracts, retinopathy, nephropathy and neuropathy. These compounds can also be used as hypouricemic agents, useful for lowering blood uric acid levels. The invention further relates to novel pharmaceutical compositions containing such compounds and to a method of using these compounds.

In the past, various attempts have been made to obtain more effective oral anti-diabetic agents. U.S. Patent No. 3,821,383 discloses aldose reductase inhibitors like 1,3-20 dioxo-lH-benz-[d,e]-isoquinoline-2-(3H)-acetic acid and derivatives thereof to be useful for the treatment of chronic complications of diabetes. U.S. Patent 4,226,875 teaches the use of spiro-oxazolidinediones for treating complications of diabetes as aldose reductase inhibitors. 25 Such aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. In 3 0 this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nerves and kidneys of various diabetic subjects are prevented or reduced. Accordingly, such compounds are of therapeutic value as aldose reductase inhibitors for 3 5 controlling certain chronic diabetic complications, including those of an ocular nature, since it is known in the art that the presence of polyols in the lens of the eye leads to cataract formation, with a concomitant loss of lens clarity. 40 French Patent Publication No. 2647676 relates to pyridazinone derivatives having substituted benzyl side 1 52 chains and benzothiazole side chains which are described as being inhibitors of aldose reductase.

U.S. Patent 4,251,528 discloses aromatic carbocyclic oxophthalazinyl acetic acids having aldose reductase inhibiting properties. The patent mentions that 2-(2-pyrid-2-ylethyl)-3,4-dihydro-4-oxophthalazin-l-ylacetic acid does not inhibit aldose reductase. Heterocyclic oxophthalazinyl acetic acids and their ethyl esters having an effect on the blood clotting system are disclosed in Chemical Abstracts 1970. 73, 77173y.

U.S. Patent No. 4,939,140 is directed to heterocyclic oxophthalazinyl acetic acids.

U. S. Patent No. 4,868,301 is directed to processes and intermediates for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains.

U. S. Patent No. 4,996,204 is directed, to Pyridopyridazinone acetic acids.

European Patent Publication No. 0,397,3 50 is directed to a process and intermediates for the preparation of oxophthalazinyl acids and analogs thereof.

International Application No. PCT/US89/05637 relates to substituted oxophthalazinyl acetic acids and analogs thereof.

Summary of the Invention The present invention relates to a compound of the formula CH2C02R \ \ ,4 2 1 wherein X is CH 2/ Y II CH2CH2, -CH(CH3) or -CH2-C-NH; Y = O or S; R1 is an optionally substituted group selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopyridin-2-yl, 3-phenyl 1,2,4-oxadiazol-5-yl, and 5-phenyl-l,2,4-oxadiazol-3-yl wherein said substituted groups are substituted with one or two substituents that are independently selected from fluorine, chlorine, bromine, methyl, methylthio, methoxy, hydroxy and trifluoromethyl; R2 and R3 are independently selected from hydrogen, fluorine, chlorine, bromine, (C,-C4) alkyl, (C^-C,,) alkylthio, (Cj-CJ alkoxy and trifluoromethyl or R2 and R3 taken together with the carbons to which they are attached form a group W, wherein W is (CH2)p or wherein p is 1 or 2 and U1 and U2 are independently CH2, 25 O or S with the proviso that both Ul and U2 are not 0 or S; R4 is hydrogen, or a prodrug group; or a pharmaceutically acceptable salt thereof. The present invention also relates to the pharmaceutically acceptable salts of the compounds of 3 0 formula I. Such pharmaceutically acceptable salts include sodium, potassium, calcium and ammonium and those derived from lower alkylamines (e.g. ethylamine), lower alkanolamines (e.g. triethanolamine) and meglumine.

Specific preferred compounds of the invention are: 35 3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7 difluoro-2- benzothiazolyl)methyl]-1-pyridazineacetic acid; 3 , 4-Dihydro-4-oxo-5,6-dimethy1-3-[(5-trifluoromethyl)-2-benzothiazoly)methyl]-1-pyridazineacetic acid; 3 , 4-Dihydro-4-oxo-5,6-dimethy1-3-[[(2-fluoro-4-bromo)benzyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-5,6-cyclohexano-3[(5, 7-difluoro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid; 3 , 4-Dihydro-4-oxo-5,6-cyclohexano-3-[[5(trifluoromethyl) -2-benzothiazolyl]methyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(2-fluoro-4-bromo)benzyl]-1-pyridazineacetic acid; 3 , 4-Dihydro-4-oxo-3-[ (5,7-difluoro-2-benzothia-zolyl)methyl]-1-pyridazineaceticacid; 3,4-Dihydro-4-oxo-[[5-(trifluoromethyl)-2-benzothiazolyl ]methyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-6-methyl-3-[[5-trifluoromethyl]-2-benzothiazolyl]methyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-5,6-cyclopentano-3-[[5-(tri-fluoromethyl)-2-benzothiazolyl]methyl]-1-pyridazineacetic acid; 3 , 4-Dihydro-4-oxo-5 , 6-dimethyl-3-[ (5-bromo-2-benzoxa-zoly1)methyl]-1-pyridazineacetic acid; 3 , 4-Dihydro-4-oxo-5 , 6-dimethy 1-3- [ [ 3 - (2 , 3-dif luoro-phenyl) -1,2, 4-oxadiazol-5-yl] -methyl] -1-pyridazineacetic acid; and 3 , 4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-dichloro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7-dichloro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid.

The present invention also relates to compounds which are useful as intermediates for preparing the compounds of formula I having the general formula: -5— CHgCOgR4 0 wherein R5 is hydrogen or XR1 wherein OS ll X is CH2, CH2CH2/ -CH(CH3), -CH2-C-NH or -CH2-C-NH; and R1 is CN, c/ or an optionally substituted group ^nh2 selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl, 15 benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopyridin-2-yl, 3-phenyl 1,2,4-oxadiazol-5-yl, and 5-phenyl-1,2,4-oxadiazol-3-yl wherein said substituted groups are substituted with one or two substitutents that are independently selected from fluorine, chlorine, bromine, 20 methyl, and trifluoromethyl; R2 and R3 are independently selected from hydrogen, (Cj-C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl or R2 and R3 taken together with the carbons to which they are attached form a group W, wherein W is u1 (CH2)p 3 0 wherein p is 1 or 2 and U1 and U2 are independently CH2, O or S with the proviso that both Ul and U2 are not O or S; and R4 is (Cj-C4) alkyl.

The present invention also relates to a pharmaceutical composition for inhibition of aldose reductase activity 3 5 comprising a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective in the inhibition of aldose reductase activity, in admixture with a pharmaceutically acceptable carrier. Specific and preferred compositions contain the specific and preferred 5 compounds of formula I as described above.

The present invention further relates to a method of treating a diabetic host such as an animal or a human for diabetes-associated complications which comprises administering to the host an effective amount of a compound 10 of formula I or a pharmaceutically acceptable salt thereof. Specific and preferred methods comprise administering specific and preferred compounds of formula I as described above.

The present invention further relates to a 15 pharmaceutical composition which can be used for lowering blood uric acid levels in mammals, e.g., humans comprising a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective for lowering blood uric acid levels in a admixture with a pharmaceutically 20 acceptable carrier.

The present invention also relates to a method of lowering blood uric acid levels in a mammalian subject which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula I or 25 a pharmaceutically acceptable salt thereof. Specific and preferred methods comprise administering specific and preferred compounds of formula I as described above.

Detailed Description of the Invention Unless otherwise indicated, the term "alkyl," as used 3 0 herein, includes linear branched and cyclic groups as well as groups having both linear and cyclic or branched and cyclic portions.

The term "prodrug" as used in the definition of R4 denotes a group that is converted in vivo resulting in 35 replacement by hydrogen. Such groups are generally known in the art and include ester forming groups, to form an ester prodrug, such as benzyloxy, di (Ci~C4) alkyl amino ethyloxy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxy carbonyloxyethyl, 5-methyl-2-oxo-l, 3-dioxol-4-yl methyl, and (Cj-CJ alkoxy optionally substituted by N-morpholino and amide-forming groups such as di(C,-C4) alkylamino.

The compounds of the present invention are prepared as outlined in the following reaction scheme.

COgR4 N I N-X-R1 14 11 \ A 12 ffS3 Anhydrides of formula 1,4 and 8 are either commercially available or may be prepared according to standard procedures. The compounds of formula 2 wherein R3 is ethyl or t-butyl are prepared by reacting the compounds 1 with (t-5 butoxycarbonylmethylene)triphenylphosphorane or (car-bothoxymethylene)triphenylphosphorane, respectively, in the Wittig reaction described in Tetrahedron Letters. 1965, 2537.

The compounds of formula 5 may also be prepared by the 10 same procedure.

The compounds of formula 9 are obtained using standard Reformatsky reaction conditions with zinc or zinc-copper couple or using a variety of well-known modifications of the Reformatsky reaction (see, for example, Tetrahedron Letters. 15 1984, 2569). Suitable solvents for the conversion of 8 to 9 include aromatic hydrocarbons (e.g., benzene) and dialkyl ethers and cyclic ethers (e.g., tetrahydrofuran). The temperature is preferably maintained at about 35°C to about 100°C, more preferably at reflux.

A compound of the formula 6 is prepared by standard allylic bromination using N-bromosuccinic in refluxing carbon tetrachloride.

The compounds of formula 3 are prepared by reacting the compounds of formula 2, 6 or 9 with anhydrous or aqueous 25 hydrazine in an alcoholic solvent (e.g., ethanol) at a temperature of about 20°C to about 80°C, preferably about 60°C. Thus the temperature may be room temperature or the reflux temperature of the solvent.

The compounds of formula 13 are obtained on reacting 3 0 compounds of formula 3 with L-X-R1 wherein L is chloro or bromo. The process is generally carried out in a polar solvent such as an alkanol having one to four carbon atoms (e.g. methanol or ethanol), dimethylformamide or dimethylsulfoxide, in the presence of a base. Suitable 3 5 bases are alkali metal hydrides or alkoxides of one to four carbon atoms, such as sodium or potassium hydride, methoxide or ethoxide. When a hydride is used, a non-aqueous solvent such as dimethylformamide is required. The reaction is run at room temperature, or at higher temperatures (about 100°C) to accelerate the process.

The compounds of formula 11 wherein Rl is phenyl with 5 hydroxy groups are prepared by demethylating the corresponding methoxy groups. Demethylation is effected by refluxing hydrobromic acid or borontribromide in methylene chloride at a temperature between about -70°C and about 0°C. The preferred temperature is between about -20°C and about 10 0°C.

The compounds of formula 11 wherein X is CH2, CH2CH2 or -CH(CHj) and R1 is optionally substituted benzothiazole are also prepared via the compounds of formula 13. The compounds of formula 13 wherein X is CH2, CH2CH2, or -CH(CH3) 15 and R1 is CN are prepared by reacting compounds of formula 3 with L^-X-R1 (wherein L, is CI or Br) in the presence of a base. Suitable bases are alkali metal hydrides or alkoxides of one to four carbon atoms. Suitable solvents for the reaction include non-aqueous solvents such as 20 dimethylformamide and dimethylsulfoxide. The compounds of formula 13 wherein R1 is CN are reacted with acid addition salts of 2-aminobenzenethiols or aminopyridinethiols (e.g., hydrochlorides) in C, to C4 alkanols at a temperature from about 80°C to reflux temperature of the solvent to obtain 2 5 compounds of the formula 11 wherein Rl is optionally substituted benzothiazole. These procedures are also applicable to the preparation of compounds wherein R1 is thiazolopyridine.

The compounds of formula 11 wherein R1 is 5 or 7 30 monosubstituted or 5,7-disubstituted benzothiazole with substituents selected from fluorine, chlorine, bromine and trifluoromethyl are also prepared via compounds of the formula 13 wherein R1 is CN or • The compounds of ^nh2 formula 13 (wherein X is CH2, CH2CH2, CH(CH3), R1 is CN or ) are reacted with a compound of formula 14 where A is NHg F, CI, Br or I in the presence of hydrogen sulfide. Generally, the reaction is conducted in a polar solvent. Suitable solvents include sulfolane, pyridine and N-methyl 5 pyrrolidone. The preferred solvent is dimethylformamide. The reaction temperature is generally between about 110°C and about 180°C, preferably the reflux temperature of the solvent. The compound of formula 13 wherein R1 is CN is reacted with the compound of formula 14 in the presence of 10 a tertiary amine. Suitable tertiary amines are tri-(C2-C6)alkylamines, e.g. triethylamine. These procedures are also applicable to the preparation of compounds wherein R1 is thiazolopyridine. The compound of the formula 13 wherein X is CH2, CH2CH2, or CH(CH3) and R1 is may be prepared by NHj reacting a compound of the formula 13 wherein X is CH2, CH2CH2 or CH(CH3) and R1 is CN with hydrogen sulfide in the presence of tertiary amines such as tri (C2-C6) alkyl amines, e.g. triethylamine, in the presence of a solvent such as pyridine or dimethylformamide. Preferably, the reaction is conducted 20 in dimethylformamide. Generally, the reaction is conducted at temperatures between about ambient temperature (generally, about 25°C) and about 100°C. Preferably, the reaction temperature is between about 40 and about 60°C.

S II Compounds of formula 11 wherein X is -C-NH- are prepared by reacting compounds of formula 11 wherein X is O 11 -C-NH with phosphorous pentasulfide in aromatic hydrocarbon solvents such as benzene, toluene or xylenes. The reaction is run at between room temperature and 100°C, preferably at 35 between 40-60°C.

The compounds of formula 11 may be hydrolyzed to obtain compounds of formula 12. The hydrolysis is carried out in the presence of concentrated sulfuric acid or trifluoroacetic acid when R4 is t-butyl at about 0°C to room 5 temperature. When R4 is methyl or ethyl, the hydrolysis proceeds at conventional temperatures and in the presence of acid or base such as mineral acid, for example hydrochloric acid, or an alkali metal hydroxide such as sodium or potassium hydroxide.

Unless otherwise indicated, the pressures of the foregoing reactions are not critical. Generally, the reaction pressures will be in the range of about 0.5 to 2 atmospheres, preferably ambient pressure (about one atmosphere).

The pharmaceutically acceptable salts of compounds of the formula I may be formed with pharmaceutically acceptable cations by conventional methods. Thus, these salts may be readily prepared by treating the compound of formula I with an aqueous solution of the desired pharmaceutically 20 acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a lower alkyl alcohol solution of the compound of formula I may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness. Suitable 25 pharmaceutically acceptable cations for this purpose include, but are not limited to, alkali metal cations such as potassium and sodium, ammonium or water-soluble amine addition salts such as N-methylglucamine(meglumine), the lower alkanolammonium and other base salts with organic 3 0 amines which are pharmaceutically acceptable, and alkaline earth metal cations such as calcium and magnesium.

The compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter, also referred to as the active compounds) are useful as inhibitors of the enzyme 3 5 aldose reductase in the treatment of chronic complications of diabetes, such as diabetic cataracts, retinopathy nephropathy and neuropathy. The active compounds can also be used for lowering blood uric acid levels in mammals, e.g. humans. Uric acid containing deposits (also known as trophi) resulting from unphysiologically elevated plasma uric acid levels tend to occur in various tissues throughout 5 the body, leading to the disease condition known as gout and gouty arthritis. Uric acid containing deposits in such conditions may occur in cartilage, bone, bursae, tendons, connective tissue overlying bony prominences, as well as, subcutaneously and in the area of kidney. Elevated blood 10 uric acid levels also occur in number of other disease conditions including myeloid leukemia, myeloid dysplasia, pernicious anemia, psoriasis, diabetes mellitus and renal disease. As used in the claims and specification hereof, treatment is meant to include both the prevention and 15 alleviation of such conditions. The active compounds 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, these compounds will be administered orally or parenterally at dosages 20 between about 2 and 100 mg/kg body weight of the subject to be treated per day, preferably from 5 to 50 mg/kg per day. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any 25 event, determine the appropriate does for the individual subject.

The active compounds may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical 3 0 carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. The pharmaceutical compositions formed by combining the active compounds and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms such 3 5 as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical 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 5 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 10 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. When aqueous suspensions or elixirs are desired for oral administration, 15 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. 20 For parenteral administration, solutions of an active compound 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 25 sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those 30 skilled in the art.

The active compounds may not only be advantageously employed for the preparation of aqueous pharmaceutical compositions for parenteral administration, as described above, but also for the preparation of pharmaceutical 35 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 active compounds of this invention are administered to the eye of an ophthalmic 5 preparation prepared in accordance with conventional 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 an active compound in a 10 concentration from about 0.01 to about 1% by weight, preferably from about 0.05 to about 0.5% in a pharmaceutically acceptable solution, suspension or ointment. Some variation in concentration will necessarily occur, depending on the particular compound employed, the 15 condition of the subject to be treated and the like, and the person responsible for treatment will determine the most suitable concentration for the individual subject. The ophthalmic preparation will preferably be in the form of a sterile aqueous solution containing, if desired, additional 20 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, benzothonium chloride, chlorobutanol, thimerosal and the 25 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. 30 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 in the range 0.9 plus or minus 0.2%. Suitable antioxidants and stabilizers 35 include sodium bisulfite, sodium metabisulfite, 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, hydromethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl 5 alcohol, polyvinylpyrrolidone, 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. 10 The activity of the compounds of the present invention as agents for the control of chronic diabetic complications may be determined by a number of standard biological or pharmacological tests. Suitable tests include (1) measuring their ability to inhibit the enzyme activity of isolated 15 aldose reductase; (2) measuring their ability to reduce or inhibit sorbitol accumulation in the sciatic nerve and lens of acutely streptozotocinized, i.e. diabetic, rats; (3) measuring their ability to reverse already-elevated sorbitol levels in the sciatic nerve and lens of chronic 20 streptozotocin-induced diabetic rats; (4) measuring their ability to prevent or inhibit galactitol formation in the lens of acutely galactosemic rats; (5) measuring their ability to delay cataract formation and reduce the severity of lens opacities in chronic galactosemic rats; (6) 25 measuring their ability to prevent sorbitol accumulation and cataract formation in isolated rat lens incubated with glucose; and (7) measuring their ability to reduce already elevated sorbitol levels in isolated rat lens incubated with glucose.

The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples. In the examples, melting points are uncorrected.

Example 1 t-butvl 3 . 4-dihvdro-4-oxo-5 . 6-dimethvl-3- r f 5- ftri- f luoromethyl) -2-benzothiazolyl 1 methvl 1 -l-pvridaz ine-1-vlacetate A. 3-OXO-4.5-dimethvlfuran-l-vlidene acetic acid t- butvl ester A solution of 2,3-dimethylmaleic anhydride (6.3 g, 50 mmol) and (t-butoxycarbonylmethylene) triphenylphosphorane (20.7 g, 55 mmol) in methylene chloride (200 mL) was 10 refluxed for 16 hours. The solution was evaporated to dryness and the residue was purified by flash chromatography on silica gel using a 9:1 mixture of methylene chloride and ethyl acetate to obtain 3-oxo-4,4-dimethylfuran-l-ylidene acetic acid t-butyl ester (yield: 6.5 g; 60%). 15 B. t-butvl 5.6-dimethvl-4-oxo-pyridazine-l-vlacetate A mixture of the tile compound of Example 1A (1.3 g, 4 mmol), ethanol (5 mL) and hydrazine hydrate (3.9 mL, 8 mmol) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (2 mL) and acidified with 20 acetic acid (4 mL). The precipitated solid was collected, washed with water and then air-dried to obtain the title compound (yield: 1.3 g; 92%).

C. t-butvl 3.4-dihvdro-4-oxo-5,6-dimethvl-3-fr5-(tri-f luoromethyl) - 2-benzothiazolyl 1 me thy 11 - l-pvr idaz ine-1-25 vlacetate To a solution of the title compound of Example IB (476 mg, 2 mmol) in dimethylformamide (4 mL) was added potassium t-butoxide (236 mg, 2.1 mmol) and stirred for 30 minutes at room temperature. 2-Chloromethyl-5-trifluoromethylbenzo-30 thiazole (554 mg, 2.2 mmol) was added to the reaction mixture and stirring continued for another 3 hours. The reaction was quenched with water (20 mL), acidified to pH by addition of sufficient dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was 35 collected, evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9:1 mixture of methylene chloride and ethyl acetate gave the title ?4 2 15 compound (yield: 490 mg; 54%). *H NMR (CDC13, 250 MHz) 6 1.45(s, 9H), 2.1(s, 3H), 2.2(s, 3H) , 3.6(s, 2H), 5.7(s, 2H) , 7.5(d, J=8 Hz, 1H), 7.9(m, 1H), 8.25(d, J= 8Hz, 1H).

Example 2 t-butvl 3.4-dihvdro-4-oxo-5.6-dimethvl-3-r(4-bromo-2- fluoro)benzvl-1 pvridazine-l-vlacetate.

The title compound was prepared according to the procedure set forth in Example 1C (yield: 87%) . !H NMR (CDClj 250 MHz)S 1.45 (s, 9H) , 2.08(s, 3H), 2.15 (s, 3H) , 10 3.54 (s, 2H), 5.3 (s, 2H), 7.2 (m, 3H).

Example 3 3.4-dihvdro-4-oxo-5.6-dimethvl-3-fT 5-(trifluoromethyl-2-benzothiazolvllmethvll-1-pvridazine acetic acid The title compound of Example 1 (450 mg, 1 mmol) was 15 added to concentrated sulfuric acid (2 mL) and stirred at room temperature for 30 minutes. The reaction was quenched with ice-water (20 mL) and the resulting solid was collected. The solid was crystallized from benzene to provide the title compound (yield: 270 mg; 68%), m.p. 20 174 °C.

Example 4 3 . 4-dihvdro-4-oxo-5.6-dimethvl-3-r (4 -bromo-2 -fluoro)benzyl)-1-pvridazine acetic acid The title compound of Example 2 (740 mg, 1.74 mmol) was 25 added to trifluoroacetic acid (2 mL) and stirred at room temperature for 30 min. The reaction was quenched with ice-water (15 mL) and the precipitated solid was collected, air-dried and crystallized from benzene to obtain the title compound (yield: 115 mg; 33%) , m.p. 162°C. 30 Example 5 3-OXO-4.5-dihvdrofuran-l-vlacetic acid, t-butvl ester The title compound was prepared according to Example 1A starting from succinic anhydride in place of 2,3-dimethylmaleic anhydride (1.98 g, 20 mmol); *H NMR (CDC13, 35 300 MHz) S 1.5 (s, 9H), 2.72 (m, 2H), 3.35 (m, 2H), 5.62 (m, 1H) .

Example 6 -bromo-3-oxo-4.5-dihvdrofuran-l-vlacetic acid. t-butvl ester A mixture of the title compound of Example 5 N-5 bromosuccinimide (1.96 g, 11 mmol) and carbon tetrachloride (25 mL) was refluxed under a UV lamp for 4 hours. The reaction was cooled, excess carbon tetrachloride was evaporated and the residue was chromatographed on silica gel. Elution with a 1:1 mixture of methylene chloride and 10 n-hexane gave the title compound (yield, 2.1.g; 76%), 'H NMR (CDC13, 300 MHz) 6 1.5 (s,9H), 3.1 (m, 1H), 3.4 (m, 1H), 5.6 (s, 1H) , 5.8 (m, 1H) .

Example 7 4-oxo-3-H-pvridazine-l-vlidene acetic acid t-butvl ester To a solution of the title compound of Example 6 (2.77 g, 10 mmol) in ethanol (10 mL) was added hydrazine hydrate (1 mL, 20 mmol) and then stirred at room temperature for 16 h. Excess ethanol was evaporated and the concentrate was 2 0 extracted with ethyl acetate (15 mL) . The organic extract was washed with water, collected and evaporated to dryness. The residue was chromatographed over silica gel. Elution with a 1:1 mixture of methylene chloride and ethyl acetate gave the title compound (yield, 1.03 g; 49%), m.p. 135°C. 25 Example 8 t-butvl-1.3-dihvdro-l-hvdroxy-3-oxo-5-methvl-l-isofuran acetate To a solution of citraconic anhydride (11.2 g, 0.1 mol) in tetrahydrofuran (50 mL) was added zinc-copper couple 30 (15.0 g, 0.15 mol). Then t-butyl bromoacetate (23.4 g, 0.12 mol) was added slowly and then refluxed for 3 hours. The reaction was cooled, filtered and the filtrate was concentrated under vacuum. The residue was partitioned between 6N hydrochloric acid (20 mL) and ethyl acetate (250 3 5 mL) . The organic extract was collected and evaporated to dryness. The residue was chromatographed over silica gel. Elution with a 1:1 mixture of methylene chloride and ethyl acetate gave the title compound (yield, 6.2; 27%), ^ NMR (300 MHz, CDClj) S 1.45 (s,9H), 2.05 (s,3H), 5.85 (S,1H).

Example 9 t-butvl 5-methvl-4-oxo-pvridazine-l-vlacetate 5 The title compound of Example 8 was dissolved in ethanol (20 mL) and hydrazine hydrate (0.6 g, 12 mmol) was added to the solution. After stirring for 4 h at room temperature, the solution was concentrated by removing excess ethanol and the concentrate was triturated with IN 10 hydrochloric acid (10 mL). The resulting solid was collected, air-dried and crystallized from ethanol to obtain the title compound (yield, 0.58 g; 24%), m.p. 114-116°C.

Example 10 (E) and fZ) 3-oxo-4.5-cvclohexanofuran-l-vlideneacetic 15 acid t-butvl ester The title compound was prepared in 46% yield (11.1 g) according to Example 1A, starting from 3,4,5,6-tetrahydrophthalic anhydride in place of 2,3-dimethylmaleic anhydride (15.2 g, 0.1 mol). This mixture of E and Z 20 isomers was chromatographed over silica gel and eluted with a 9:1 mixture of methylene chloride and ethyl acetate. The less polar E isomer was eluted first. The more polar Z isomer was obtained from later fractions.

Example 11 t-butvl 3,4-dihvdro-4-oxo-5.6-cvclohexanopyridazine-l- vlacetate A mixture of (E) and (Z) 3-oxo-4,5-cyclohexanofuran-l-ylideneacetic acid t-butyl ester (5.0 g, 20 mmol) (The title compound of Example 10) was dissolved in ethanol (20 mL) and 30 to the solution was added hydrazine hydrate (2.5 g, 50 mmol). This was refluxed for 4 h and then evaporated to a gummy residue. This was triturated with IN hydrochloric acid (10 mL) to obtain the title compound as a white solid (yield, 2.18 g; 44%), m.p. 179-181°C. • -21-Example 12 t-Butvl 3.4-dihvdro-4-oxo-5.6-dimethvl-3-cvanomethvl-l-phthalazineacetate To a solution of the title compound of Example IB (7.05 5 g, 29.6 mmol) in DMF (65 ml) was added potassium tert-bitoxide (3.65g, 32.5 mmol) and stirred at ambient temperature for 3 0 min. Bromoacetonitrile (4.26 g, 35.5 mmol) was added to it and stirring was continued for another 1.5 h. The reaction was quenched with water (2 00 mL) , 10 acidified to pH 2 by addition of sufficient dilute hydrochloric acid and the resulting solid was collected. The solid was air-dried and then crystallized from a 3:1 mixture of cyclohexane and methylene chloride (6.26g, 76%); mp, 120-123 °C.

Example 13 Ethvl 3.4-dihvdro-4-oxo-5.6-cvclohexano-3-cvnanomethvl-1-phthalaz ineacetate The title compound (liquid) was prepared according to Example 12, but starting from ethyl 5,6-cyclohexano-l-20 phthalazineacetate (yield, 58%); 'HNMR (CDC13, 300 MHz) S 1.25 (t,J=Hz, 3H), 1.8 (m,4H), 2.4 (m,2H), 2.6 (m, 2H), 4.1 (q, J=8 Hz, 2H) , 5.0 (s, 2H) . 40 45 50 M1 1 Additional compounds prepared in accordance with the present invention are shown in Tables 1-3. Tables 1-3 include melting point or NMR spectrum for the compounds described.

Table 1 co2R4 R2 CH3 (CHJj (CH,)4 R3 CHj R4 t-Bu Et t-Bu Product m.p.73-74C m.p.64-65°C E-isomer, 'H NMR(CDClj, 250 MHz)5 1.48(s, 9H), 1.73(m, 4H), 2.3(m, 2H), 2.75(m, 2H), 5.8(s,lH).

Z-isomer, 'H NMR (CDClj, 250 MHZ)<5 1.53 (s,9H), 1.75 (m, 4H), 2.35(m,4H), 5.25 (2, 1H) Table 2 CCUR4 R2 H H CHj (CHJ, (CHJ)4 R3 H CHj CH, R4 t-Bu t-Bu t-Bu Et t-Bu Product see Example 7 see Example 9 see Example IB 'H NMR (CDClj. 250 MHz)6 1.2 (t, J = 8 MHz, 3H), 2.1 (m, 2H), 2.9 (m, 4H), 3.6 (s, 2H), 4.2 (q, J = 8 MH2, 2H) see Example 11 Q0C Et m.p. 240-242°C 40 45 50 Table 3 _EL EL R4 R1 Product H H t-Bu ,7-difluorobenzothiazol-2-y 1 m.p. 119-C H H t-Bu -trifluoromethylbenzothiazoI-2-yl m.p. 134°C H CHj t-Bu -trifluoromethylbenzothiazol-2-yl 'H NMR (CDClj, 250 MHZ)5 1.45(s,9H), 2.17(s,3H), 3.55(s, 2H), 5.7(s. 2H), 6.72(m, IH), 7.5(m, IH), 7.92(m, IH), 8.25(m. IH) CHJ CH, t-Bu -trifluoromethylbenzothiazol-2-yl Example 1C CHj CH, t-Bu ,7-difluorobenzothiazol-2-yl 'H NMR (CDC1, 250 MHz)5 1.45(s, 9H), 2.13(s,3H), 2.2(s, 3H), 3.6(s, 2H), 5.7(s, 2H), 6.9(m, IH), 7.53(m, IH) CHj CHJ t-Bu 4-bromo-2-fluorophenyl Example 2 (CHJ, Et ,-trifluoromethylbenzothiazol-2yl 'H NMR (CDClj, 200 MHz)5 1.2(t, J = 8Hz,3H),2.1(m,2H), 2.9(m, 4H), 3.6(s, 2H), 4.15 (q, J = 8Hz, 2H), 5.8(s,: 7.5(d, J = 9Hz, IH), 7.9(d, J IH), 8.2 (s, IH) (CHJ, t-Bu -trifluoromethylbenzothiazol-2-yl m.p. 136°C (CHJ, t-Bu ,7-difluorobenzothiazol-2-yl 'H NMR(CDClj, 250 MHz)5 1.45(2,9H), 1.73(m, 4H), 2.4(m, 2H), 2.63(m, 2H), 3.55(s, 2H), 5.3(s, 2H), 6.9(m, IH), 7.6 (m, IH) (CHJ, t-Bu 4-bromo-2-fluorophenyl 'H NMR (CDClj. 250 MHz)5 1.45(s, 9H), 1.72(m, 4H), 2.4(m, IH), 2.58(m,2H), 3.51(s,2H), 5.27(s, 2H), 7.2 (m, 3H)

Claims (17)

\a9 i -24- Table 3 (continued) R2 Ri. R4 R1 Product 5 H H H 5,7-difluorobenzothiazol-2-y 1 m.p. 169°C H H H 5-trifluoromethylbenzothiazol-2-yl m.P.172-173°C 10 H CHj H 5-trifluoromethylbenzothiazol-2-yl m.p. 172°C CHj CHj H 5-trifluoromethylbenzothiazol-2-yl m.p 174°C CHj CHj H 5,7-difluorobenzothiazol-2yl m.p. 183°C 15 CHj CHj H 5-bromobenzoxazol-2-yl m.p. 206-207°C CHj CHj H [3-(2,3-difluorophenyl)-l ,2, 4-oxadiazol-5-yl] m.p. 185-186°C 20 CH, CHj H 4-bromo-2-fluorophenyl m.p. 162°C (CHJ, H 5-trifluoromethylbenzothiazol-2-yl m.p. 184°C 25 (CHJ, H 5-trifluoromethylbenzothiazol-2-yl m.p. 201 °C (CHJ, H 5,7-difluorobenzothiazol-2-yl m.p. 157"C (CHJ, H 4-bromo-2-fluorophenyl m.p. 164°C 30 OOJ H 4-bromo-2-fluorophenyl m.p. 202-204°C ox H bcnzothiazol-2-yl m.p. 207-208°C coc H 5-trifluoromethylbenzothiazol-2-yl m.p. 224-225 °C 35 CH, CHj t-Bu 5,7-dichlorobenzothiazol-2-yl m.p. 113-116°C (CHJ, Et 5,7-dichlorobenzothiazol-2-yl m.p. 136-139°C 40 CHj CH, H 5,7-dichlorobenzothiazol-2-yl m.p. 200-201.5 °C (CHJ, H 5,7-dichlorobenzothiazol-2-y 1 m.p. 193-195°C -25- WHAT'J/WE CL&IM IS: claims

1. A compound of the formula CH2C0eR4 A, 10 15 20 \ \ wherein y ii 25 X is CH2, CH2CH2, -CH(CH3), or -CH2-C-NH; Y=0 or S; R1 is an optionally substituted group selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopyridin-2-yl, 3-phenyl 1,2,4-oxadiazol-5-yl, and 5-phenyl-l,2,4-oxadiazol-3-yl wherein said substituted groups are substituted with one or two substitutents that are independently selected from fluorine, chlorine, bromine, methyl, and trifluoromethyl; R2 and R3 are independently selected from hydrogen, (Ct-C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl or R2 and R3 taken together with the carbons to which they are attached form a group W, wherein W is 30 (CH or 35 wherein p is 1 or 2 and U1 and U2 are independently CH2, O or S with the proviso that both U1 and U2 are not O or S; R4 is hydrogen or a prodrug group; or a pharmaceutically acceptable salt thereof. 4 -26-

2. A compound according to Claim 1 wherein R1 is optionally substituted benzothiazol-2-yl, benzoxazol-2-yl or 3-phenyl-l,2,4-oxadiazol-5-yl.

3. A compound according to claim 1 wherein X is CH2, 5 Rl is optionally substituted benzothiazol-2-yl, R4 is hydrogen and R2 and R3 are each hydrogen or methyl or R2 is hydrogen and R3 is methyl or R2 and R3 taken together form a cyclohexyl ring or a cyclopentyl ring.

4. A compound according to claim 1 wherein X is CH2, 10 R1 is optionally substituted phenyl, R4 is hydrogen and R2 and R3 are each methyl or R2 and R3 taken together form a cyclohexyl ring.

5. A compound according to claim 1 wherein X is CH2, R1 is optionally substituted benzoxazol-2-yl, or 3-phenyl- 15 1,2,4-oxadiazol-5-yl, R2 and R3 are each methyl, and R4 is hydrogen.

6. A compound selected from the group consisting of: 3 , 4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7-difluoro-2- benzothiazolyl)methyl]-1-pyridazineacetic acid; 20 3,4, -Dihydro-4-oxo-5,6-dimethyl-3-[ (5-tr if luoromethyl) - 2 -benzothiazolyl) methyl ] -1-pyridaz ineacetic acid; 3 , 4-Dihydro-4-oxo-5,6-dimethyl-3-[[(2-fluoro-4-bromo)benzyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[ (5,7-difluoro-2-25 benzothiazolyl)methyl]-1-pyridazineacetic acid; 3 , 4-Dihydro-4-oxo-5, 6-cyclohexano-3-[ [5 (trifluoromethyl) - 2- benzothiazolyl]methyl] -1 -pyridazineacetic acid; 3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(2-fluoro-4-30 bromo)benzyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-3[(5,7-difluoro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-[ [ 5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-pyridazineacetic acid; 35 3,4—Dihydro—4-oxo-6-methyl—3-[ [5-trif luoromethyl]-2- benzothiazolyl]methyl]-1-pyridazineacetic acid; -27- 3,4-Dihydro-4-oxo-5,6-cyclopentano-3- [ [ 5 (trifluoromethyl) -2-benzothiazolyl]methyl]-l-pyridazineacetic acid. 3,4-Dihydro-4-oxo-5, 6-dimethyl-3 -[(5-bromo-2-benzoxazoly1)methyl]-1-pyridaz ineacetic acid; 5 3,4-Dihydro-4-oxo-5,6-dimethyl-3-[ [3—(2,3 — difluorophenyl)-l,2,4-oxadiazol-5-yl]-methyl]-1-pyridazineacetic acid; 3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-dichloro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid; 10 3 , 4-Dihydro-4-oxo-5,6-dimethy1-3-[ (5,7-dichloro-2- benzothiazolyl)methyl]-1-pyridazineacetic acid.

7. A compound of the formula CH2C0eR4 R3 JL 15 V 20 wherein R5 is hydrogen or XR1 wherein o S ii II X is CH2/ CH2CH2, -CH(CH3) , -CH2-C-NH or -CH2-C-NH; and 25 R1 is CN, or an optionally substituted group HHg selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopyridin-2-yl, 3-phenyl 1,2,4-oxadiazol-5-yl, and 5-phenyl-1,2,4-oxadiazol-3-yl wherein said substituted groups 30 are substituted with one or two substitutents that are independently selected from fluorine, chlorine, bromine, methyl, and trifluoromethyl; R2 and R3 are independently selected from hydrogen, (Cj-C4) alkyl, fluorine, chlorine, bromine, and trifluoromethyl 4 -28- or R2 and R3 taken together with the carbons to which they are attached form a group W, wherein W is or wherein p is 1 or 2 and U1 and U2 are independently CH2, 0 or S with the proviso that both U1 and U2 are not O or S; 10 and R4 is (Ci~C4)alkyl.

8. A compound according to claim 7 wherein R2 and R3 are each methyl, R4 is -C(CH3)3 and R5 is hydrogen.

9. A compound according to claim 7 wherein R2 and R3 taken together form a cyclohexyl ring, R4 is ethyl and R5 is 15 hydrogen.

10. A compound according to claim 7 wherein R2 and R3 are each methyl, R5 is XR1 wherein X is CH2, R1 is optionally substituted benzothiazol-2-yl or pheynyl and R4 is -C(CH3)3.

11. A compound according to claim 7 wherein R2 and R3 20 taken together form a cyclohexyl ring, R3 is XR1 wherein X is CH2, R1 is optionally substituted benzothiazol-2-yl or phenyl and R4 is ethyl.

12. A pharmaceutical composition for inhibition of aldose reductase activity comprising a compound of claim 1 25 in an amount effective in the inhibition of aldose reductase activity in admixture with a pharmaceutically acceptable carrier.

13. A pharmaceutical composition for lowering blood uric acid levels comprising a compound of claim I in an amount effective for lowering blood uric acid levels in admixture with a pharmaceutically acceptable carrier.

14. A compound of the formula I or a pharmaceutically acceptable salt thereof substantially as herein described with reference to any example thereof.

15. A compound of the formula as defined in claim 7 substantially as herein described with reference to any example thereof.

16. A pharmaceutical composition as defined in claim 12 substantially as herein described with reference to any example thereof.

17. A pharmaceutical composition as defined in claim 13 substantially as herein described with reference to any example thereof. PF17BR tMC. By the authorised agents A J PARK & SON 1 K A ^ 16 MAY 1SS4oj| I i - /