CA2107104A1 - Pyridazinone acetic acids as aldose reductase inhibitors - Google Patents

Abstract

Compounds having aldose reductase inhibitory activity of formula (I) wherein X CH2, CH2CH2, -CHCH3, (a); Y=O or S; R1 is an optionally substituted 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 are substituted with one or more and preferably two substituents that are independently selected from fluorine, chlorine, bromine, methyl, and trifluoromethyl; R2 and R3 are independently selected from hydrogen, fluorine, chlorine, bromine, (C1-C4) alkyl, methyl (C1-C4) alkylthio, (C1-C4) alkoxy and trifluoromethyl or R2 and R3 taken together with the carbons to which they are attached form a group W, wherein W is (b) or (c) 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.

Description

:

-`~N092/17446'~l O 7 1 0 ~ PCT/US92tO1603 -Backaround 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 csrtain - lO 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 l,3-dioxo-lH-benz-[d,e]-isoquinoline-2-(3H)-acetic acid and derivatives thereof to be useful for the treatment of ;
c~ronic 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 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 o~ lens clarity.
French Patent Publication No. 2647676 relates to pyridazinone derivatives having substituted benzyl side . :
... ' .
' ,.

c ,~,,"",,j,,.., ,,.",, ,, ,,; ~

210710~
WO92/17~6 PCT/US92/01603 ~~

chains and benzothiazole side chàins which are described as being inhibitors of aldose reductase.
U.S. Patent 4,251,528 disclos~s aromatic car~ocyclic oxophthalazinyl acetic ~-ld~ ~2v~,.g aldose ~eductase inhibiting properties. The patent mentions that 2-(2-pyrid-2-ylethyl)-3,4-dihydro-a-o~ophthal~7ln-l-ylacetic acid does not inhibit aldose reductas2. X2t2.0cyclic oxophthalazinyl acetic acids and thei ethyl est2rs ~aving an sfIect on the blood clotting system are discl~sed in Chemical A~stracts 1970, 73, 77173y.
U.S. Patent No. ~,939,1i~0 is diroctod to heterocyclic oxophthalazinyl ac~tic ~ci~s.
U. S. Patent No. 4,868,301 ls dirocted to processes and intermediates for the preparation of o~ophthalazinyl acetic acids having benzothiazole or oiher heterocyclic side chains.
U. S. Patent No. 4,996,204 is directed to Pyridopyridazinone acetic acids.
European Patent Publication No. 0,397,350 is directed to a process and intermediates for the preparation of oxophthalazinyl acids and analogs thereof.
International Application No. PC~/US89105637 relates to substituted oxophthalazinyl acetic acids and analogs thereof.
25Summarv of the Invention -.
The present invention relates to a compound of the formula CH2C 02R4 . ., ;: ~ 30 N

R /~f X~

~ .

`^`WO92/17446 2 1 0 7 1 0 ~ PCT/US92/01603 wherein Y , .
X is CH~, CH2CH2, -C~(CH3) or -CH2-C-NH; -Y = o or S; -R1 is an optionally substituted group selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl, ~enzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl, oxazolopy idin-2-yl, 3-phenyl l,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 th2_ ar~
independently selected from fluorine, chlorine, bromine, methyl, methylthio, methoxy, hydroxy and trifluoromethyl;
R2 and R3 are independently selected from hyd~ogen, 15 fluorine, chlorine, bromine, (C~-C4)alkyl, (Cl-C4)alkylthio, ;~
(Cl-C4)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 l or 2 and U~ and u2 are independently CH2, 25 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.
~-The present invention also relates to the -pharmaceutically acceptable salts of the compounds of 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]-l-pyridazineacetic acid;

21071~
WO92tl7446 PCT/US92/01603 ~~

3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-trifluoromethyl)-2-benzothiazoly)methyl]-l-py~idazin~2cet1c acid; :~ .
3,4-Dihydro-4-oxo-5,6-di~L~yl-3-~[(2-fluoro-4-bromo)benzyl]-l-pyrida ineac~ti~ acid;
3,4-Dihydro-4-oxo-5,6-cyclohexano-3[t5,7-difluoro-2-benzothiazolyl)methyl]-l-pv-lda~in~ac~Llc acid;
3,4-Dihydro-4-oxo-~,6-cyrlohexano-3-[[5(trilluoro-methyl)-2-benzothiazolyl]methyl]-l-~vridazineacetic acid;~:
3~4-Dihydro-4-o~o-5~ 5-C~y5~ oh~ no-3- [ ( ~-fluoro-4-bromo)benzyl]-l-pyrida in~ac__ic z~
3,4-Dihydro-4-oxo-,-[(5,7-dl.luo.o-2-~nzo~hi -zolyl)methyl]-l-pyridazineacelicaci~;
3,4-Dihydro-4-oxo-[[5-(t-ifluoromethyl)-2-b2nzo-thiazolyl~methyl]-l-pyridazineacetic acid; , 3,4-Dihydro-4-oxo-6-methyl-3-~[5-trifluoromethyl]-2- - .
benzothiazolyl)methyl]-l-pyridazineacetic acid; ;
3,4-Dihydro-4-oxo-5,6-cyclopentano-3-[~5-(tri-fluoromethyl)-2-benzothiazolyl]methyl~-l-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-bromo-2-benzoxa- - .
zolyl)methyl]-l-pyridazineacetic acid; :
3,4-Dihydro-4-oxo-S,6-dimethyl-3-[~3-(2~3-difluoro-phenyl)-1,`2,4-oxadiazol-5-yl~-methyl]-l-pyridazineacetic r~ . , acid; and 3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5~7-dichloro-2 benzothiazolyl)methyl]-l-pyridazineacetic acid;
3,4-D-ihydro-4-oxo-5,6-dimethyl-3-[(5,7-dichloro-2-benzothiazolyl?methyll-l-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:
: i 2tO7~ 0~
` WO 92/17446 PCI'/US92/01603 . . ,:
-5- ;
CH2Co2R4 ::
R3 l ~ :
\ ~ ~N : ::

R 2J~l/ R 5 wherein R5 is hydrogen or XRI wherein : ~
0 S ,. ' X is CH2, CH2CH2, -CHtCH3), -C~2-C-NH or -CH2-C-Nn; and :: .
s Rl is CN, c~ or 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-1,2,4-oxadiazol-3-yl wherein said substituted groups are substituted with one or two substitutents that are .
:; independently selected from fluorine, chlorine, ~romine, methyl, and trifluoromethyl;
R2 and ~3 are indepe~dently selected from hydrogenr (c,-C4) alkyI, 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 / Ul : ~ ~c~2)p ~ or ~ ~ ~

.....
~- 30 wherein p is 1 or 2 and U~ and u2 are independently CH2, ~; - O or S with the proviso that both Ul and U2 are not O or S;
: and R4 is (C,-C4) alkyl.
The present invention also relates to a pharmaceutical .
composition for inhibition of aldose reductase activity .
comprising a compound of formula I or a pharmaceutically .

wog~ ~67lCil PCT/US92/01603 acceptable salt thereof in an amount effective in the inhibition of aldose reducLasP ~c ivity, n admixtur~ with a pharmaceutically acceptable car.ier. Specific and preferred compositions con_ain t:~ spe_l ~ aild preLo~r-d compounds of formula I as described above.
The 3resent invention furth~ a.~ o a method ~I
treating a diabetic host such as an anim~l or a human for diabetes-associated com~lica;ions w;nich comprises administering to the host an eI~'C~i'te ~elln~ of ~ compo-~ind of formula I or a pharmac~u-'- c~ ac_ea.a~ sal~ .~e:^e~L.
Specific and preferraid ~etho~s com3~i~e ~d~inis~2ri~g specific and preferred compounds of ~ ^...ula I as described above.
The present invention further relates to a 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 acceptable carrier.
The present invention also relates to a method of lowering blood uric acid levels in a ma~malian subject which comprises administering to a mammal in need or such treatment an effective amount of a compound of formula I or a pharmaceutically acceptable szlt thereof. Specific and preferred methods comprise administering specific and preferred compounds of formula I as described above.
Detailed Description of the I~vention Unless otherwise indicated, the term "alkyl," as used 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 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 (Cl-C4) al~yl amino ethyloxy, -, . . : .. . ~ , .; .; .: :: .

21Q7~0~
~ 092/17446 PCT/US92/Ot603 . .

-7- ~
acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxy ~ :
carbonyloxyethyl, 5-methyl-2-oxo-1,3-dioxol-4-yl methyl, and (Cl-C4) alkoxy optionally substituted by N-morpholino and amide-forming groups such as di (Cl-C4) alkylamino.
The compounds of the present invention are prepared as :
outlined in the following reaction scheme.
' -~

. , ":.

' ; ' ''.'.' ~:

: ' ' ~ . ~

WO 92/17446 2 1 n 7 1 0 4 PCI~IJS92/01603 '-`

N O

Z~C / ~ '' "' O
~ ': .
2: _ ~ . .
X " Z ...
' o X ~ N
Z--Z ~ Z--= , ~ r-~, Z~u ~, ~
~; ~ Z

m ~ .
~`' ' . , Z o~
o~ N U
.~ o U o /
~ ~~ '~

. , . ~ ~ l ~ l l O U N
1 _ U :.",~
~ ~I =
~ ~ . m ~ ~ . ::.

- ~ \F ~ " ~ \F ~D
J

WO92/17~6 ~107t O4 PCT/US92/01603 _g_ 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-butoxycarbonylmethylene)triphenylphosphorane or (car-bothoxym_thylene)triphenylphosphorane, respectively, in the Wittig reaction described in Tetrahedron Letters 1965, 2537.
The compounds of formula 5 may also be prepared by the lo same procedure.
~he compounds of formula 9 are obtained using stand2r~
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 35C to about 100C, 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 hydrazine in an alcoholic solvent (e.g., ethanol) at a temperature of about 20C to about 80C, preferably about 60C. Thus the temperature may be room temperature or the reflux temperature of the solvent.
The compounds of formula 13 are obtained on reacting compounds of formula 3 with L-X-RI 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 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 - 21071~
W092/17446 PCT/US92tO1603 ~- -such as dimethylformamide is required. The reaction is run at room temperature, or at higher temper7tures (a~out 1~0C) ~-to accelerate the process.
~he compounds of ~ormula 11 wherein Rl is ~h-n~1 Yi hydroxy groups are prepared by demethylating the corresponding methoxy groups. Demethylation is ~f--.~c_2 ~ ~7 refluxing hydrobromic acid or ~orontribromide in methylene chloride at a temperature between about -70C and abcut 0C.
The preferred temperature is betw2en about -~0C and 2~0Ut 10 0C.
The compounds of formula 11 whPr2in X is CY,2, -HlCH,~ o.
-CH(CH3) and R' is optionàlly substituted ~en~otai~ole a _ also prepared via the compounds OI Iormula 13. The compounds of formula 13 wherein X is CH2, CH2CH2, or -CH(CH3) and Rl is CN are prepared by reacting compounds of formula 3 with L~-X-RI (wherein Ll is Cl 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 dimethylformamide and dimethylsulfoxide. The compounds of formula 13 wherein Rl is CN are reacted with acid addition salts of 2-aminobenzenethiols or aminopyridinethiols (e.a., hydrochlorides) in Cl to C4 alkanols at a temperature from about 80C to reflux temperature of the solvent to obtain compounds of the formula 11 wherein Rl is optionally substituted benzothiazole. ~hese procedures are also applicable to the preparation of compounds wherein R~ is thiazolopyridine.
The compounds of formula 11 wherein R~ is 5 or 7 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 R~ is CN or C/ . The compounds of formula 13 (wherein X is CH2, CH2CH2, CH(CH3), Rl is CN or W092/17446 2 1 0 7 1 0 ~ P~T/~S92/01603 c~\~ ) are reacted with a compound of formula 14 where A is F, Cl, 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 pyrrolidone. The preferred solvent is dimethylformamide.
The reaction temperature is yenerally between about 110C
and about 180C, preferably the reflux temperature of the solvent. The compound of formula 13 wherPin R' is CN is reacted with the compound of formula 14 in the presence of lo a tertiary amine. Suitable tertiary amines are tri-(c~
C~j)alkylamines, e.g. triethylamine. These procedures are also applicable to the preparation of compounds wherein Rl is thiazolopyridine. The compound of the formula 13 wherein X
is CH2, CH2CH2, or CH(CH3) and Rl is ~ may be prepared by lS reacting a compound of the formula 13 wherein X is CH2, CH2CH2 or CH(CH3) and Rl 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 in dimethylformamide. Generally, the reaction is conducted at temperatures between about ambient temperature generally, about 25C) and about 100C. Preferably, the reaction temperature is between abo`ut 40 and about 60C.
S ;
Il ' :.
Compounds of formula 11 wherein X is -C-NH- are -prepared by reacting compounds of formula 11 wherein X is -:: ...

I~ . .
-C-NH with phosphorous pentasulfide in aromatic hydrocarbon solvents such as benzene, toluene or xylenes. The reaction is run at between room temperature and 100C, preferably at 35 between 40-60C. ~; -~ l U i l U ~

The compounds of formula ll may be hydrolyzed to obtain compounds of formula 12. ~he hydrolysis is carrl~d ou~
the presence of concentrated su~furic 2cld 3_ trifluoroac~tic acid when R~ is t-~utyl a~ abou oo^ L~
temperature. When R4 is methyl or ethyl, the hydrolysis proceeds at conventional temp2r2Lures and in the p-~s2nse 3-^
acid or base such as mineral acid, for example nydroc`nloric acid, or an alkali metal hydroxide such as sodium o potassium hydroxide.
Unless otherwise indica.ed, th2 ~-_ssu~
foregoing reac.ions are no- c.itical. f-ens_~lly, _h_ reaction pressu-res will be in ,he range o^ a~ou_ o., atmospheres, preferably ambient pressure (abou~ on~
atmosphere).
The pharmaceutically acceptable salts or compounds or the formula I may be formed with pharmaceutically acceptabie ~;~
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 acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a lower alXyl 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 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 amines which are pharmaceut^ically 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 aldose reductase in the treatment of chronic complications ; of diabetes, such as diabetic cataracts, retinopathy nephropathy and neuropathy. The active compounds can also --~092/17~6 2 1 Q 7 ~ ~ 4 PCT/US92/01603 be used for lowering blood uric acid levels in mammals, e.g.
humans. Uric acid containing deposits (also known as trophi) rPsulting from unphysiologically elevated plasma uric acld levels tend to occur in various tissues throughout the body, leading to the disease condition ~nown 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 uric acid l~vels 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 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 between about 2 and lO0 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 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 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 as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, 210710~
W092/17~6 PCT/US92/01603 binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as iodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegran~
such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidonQ, 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 27 SO bQ Qmp7 o~er7 ~S . ~, fillers in soft and hard fillQd gelatin capsules. ?rQrorrQ~
materials for this include lactose or milk sugar and h gh molecular weight polyethylene glycols. When 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 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 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 skilled in the art.
~ he 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 .
compositions suitable for use as ophthalmic solutions. Such ophthalmic solutions are of principal interest for the treatment of diabetic cataracts by topical administration .' ' " .' . . " '. ' ' . ' ' ' 1 ' . , . . ; ' ' ' . ~ . '. ' . :, ' ' `,` ; ' .'` . ' ' ' ' ' ~' ' , .

: : `

-- WO92/17446 2 i 0 71 0 ~ PCT/US92/01603 -lS-and the treatment of such conditions in this manner is a preferred ~mbodiment of the present invention. Thus, for the treatment of diabetic cataracts the active compounds of this in~ention are administ~red to the eye of an ophthalmic preparàtion prepared in accordance with conventional pharmaceutical practic~, see for example "Remington~s Pharmaceutical sciences~ 15th Edition, pa~es 1488 to 1501 (Mack Publishing co., Easton, Pa). The ophthalmic prepara~lon will contain an active compound in a concent.ation from about 3.01 to about 1% ~y weight, preferably Crom 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 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 ingredients, for example preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, viscosity-increàsing agents and the like.
Suitable preservatives include benzalkonium chloride, benzothonium 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 in the range 0.9 plus or minus 0.2%. Suitable antioxidants and stabilizers include sodium bisuIfite, sodium metabisulfite, sodium - thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, 21071~4 W092/17~6 PCT/US92/01603 poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydromethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the li~e. 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 ~y bathing the ey~ in the ophthalmic solution.
The activity of the compounds of the present inv~n~
as agents for the control of chronic diabetic complications may be detérmined ~y a number of standard biological or pharmacological tests. Suitable tests include (l) measuring their ability to inhibit the enzyme activity of isolated 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 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) 2S 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.
30 ~ 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.

:~ :
' ~` WO92/17~6 2 J. 0 7 1 ~ 4 PCT/US92/01603 Example 1 t-~utvl 3 4-dihvdro-4-oxo-5.6-dimethvl-3-~r5-ttri-fluoromethyl)-2-benzothiazolyl]methyl~-1-pyridazine-1-vlacetate A. 3-oxo-4 5-dimethylfuran-1-ylidene acetic acid t-butyl 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 re'^lu~ed -o 16 hours. The solution was evaporated to dryn~ss and the residue was purified by flash chromatography on siiica gel using a 9:1 mixture of methylene chloride and ethyl acetate to obtain 3-oxo-4,4-dimethylfuran-1-ylidene acetic acid t-butyl ester (yield: 6.5 g; 60%).
B. t-butvl 5.6-dimethvl-4-oxo-pyridazine-1-vlacetate A mixture of the tile compound of Example lA (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 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-butyl 3.4-dihydro-4-oxo-5.6-dimethyl-3- r r 5-rtri-fluoromethvl)-2-benzothiazolyl]methyl~-1-pyridazine-1-ylacetate To a solution of the title compound of Example lB (476mg, 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-thiazole (554 mg, 2.2 mmol) was added to the reactionmixture 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 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 2~071~
W092/l7~6 PCT/US92/01603 compound (yield: 490 mg; 54%). tH NMR (CDCl3, 250 MHz) 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, lH), 7.9(m, lH), 8.25(d, J= 8Hz, lH).
Example 2 t-butyl 3.4-dihydro-4-oxo-5,6-dimethyl-3- r L4-bromo-2-fluoro!benzvl-l ~yridazine-1-ylacetate.
The title compound was prepared according to the procedure set forth in Example lC (yield: 87%). lH NMR
(CDCl3 250 ~Hz~ 1.45 (s, 9H), 2.08(s, 3H), 2.15 (s, 3H), 3.5~' ~s, 2H), 5-.3 (s, 2H), 7.2 (~, 3H).
Exam~le 3 3 4-dihvdro-4-oxo-5.6-dimethyl-3-~[5-~trifluoromethv~-2-benzothiazolYllmethyll-1-~yridazine acetic acid The title compound of Example 1 (450 mg, 1 mmol) was 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.
174C.
Exam~le 4 - 3.4-dihydro-4-oxo-5 6-dimethyl-3- r ( 4-bromo-2-fluoro)benzyl)-1-pyridazine acetic acid The title compound of Example 2 (740 mg, 1.74 mmol) was 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. 162C.
ExamPle S
3-oxo-4 5-dihydrofuran-1-ylac~tic acid t-butvl ester The title compound was prepared according to Example lA
starting from succinic anhydride in place of 2,3-dimethylmaleic anhydride (1.98 g, 20 mmol); IH NMR (CDCl3, 35 300 MHz) ~ 1.5 (s, 9H), 2.72 (m, 2H), 3.35 (m, 2H), 5.62 (m, lH). ;~

.' WO92/17446 210 710 ~ PCT/US92/01603 Exam~le 6 5-bromo-3-oxo-4 5-dihvdrofuran-1-~laceticacid t-butvl ester A mixture of the title compound of Example 5 N-bromosuccinimide (1.96 g, 11 mmol) and carbon tetrachloride(25 mL) was refluxed under a W 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 n-hexane gave the title compound (yield, 2.1.g; 76%), IH NMR
(CDCl3, 300 MHz) ~ 1.5 (s,9H), 3.1 (m, lH), 3.4 (m, lH), 5.6 (s, lH), 5.8 (m, lH).
Exam~le 7 4-oxo-3-H-pYridazine-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 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. 135C.
Exam~le 8 t-butvl-1 3-dihvdro-1-hvdroxy-3-oxo-5-methvl-1-isofuran acetate To a solution of citraconic anhydride (11.2 g, 0.1 mol) in tetrahydrofuran (50 mL) was added zinc-copper couple (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 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 . _ .... ., ... . . ~ . .... .

~ ~ u ~ s WO92/17~6 PCT/US92/01603 acetate gave the title compound (yield, 6.2; 27%), 1H NMR
(300 MHz, CDCl3) ~ 1.45 (s,9H), 2.05 (~,3H), 5.85 (s,lH).
Example 9 t-butyl 5-methyl-4-oxo-eyridazine-1-ylacetate 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 lN
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 rz~ 3-oxo-4 5-cvclohexanofuran-1-ylideneacetic acid t-butyl ester The title compound was prepared in 46% yield (11.1 g) according to Example lA, 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
isomers was chromatographed over silica gel and eluted with a 9l 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-dihydro-4-oxo-5.6-cyclohexano~vridazine-1-Ylacetate A mixture of ~E) and (Z) 3-oxo-4,5-cyclohexanofuran-1-ylideneacetic acid t-butyl ester (5.0 g, 20 mmol) (The title compound of Example 10) was dissolved in ethanol (20 mL) and 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 lN hydrochloric acid (10 mL) to obtain the title compound as a white solid (yield, 2.18 g; 44%), m.p. 179-181C.

.: :, , , . ~ : .. . . . , : . . .
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WO92/17446 2 1 0 7 1 0 ~ PCT/US92/01~3 Exam~le 12 t-Butyl 3.4-dihydro-4-oxo-5 6-diméthYl-3-cYanomethYl-l-phthalazineacetate To a solution of the title compound of Example lB t7.05 g, 29.6 mmol) in DMF (65 ml) was added potassium tert-bitoxide (3.65g, 32.5 mmol) and stirred at ambient temperature for 30 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 (200 mL), 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, 120-123C.
ExamDle 13 Ethvl 3 4-dihYdro-4-oxo-5.6-cyclohexano-3-cYnanomethYl-.-phthalazineacetate The title compound (liquid) was prepared according to Example 12, but starting from ethyl 5,6-cyclohexano-1-phthalazineacetate (yield, 58%); ~HNMR (CDCl3, 300 MHz) ~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).
Additional compounds prepared in accordance with the present invention are shown in ~ables 1-3. Tables 1-3 include melting point or NMR spectrum for the compounds ; described. ;

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Claims (30)

-27-

1. A compound of the formula I

wherein X is CH2, CH2CH2, -CH(CH3), or ;
Y=O or S;
R1 is benzothiazol-2-yl optionally 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, (C1-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 or 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.

2. A compound according to claim 1 wherein X is CH2, R1 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.

3. A compound according to claim 1 selected from the group consisting of:
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-dimethyl-3-[(5-trifluoromethyl)-2-benzothiazolyl)methyl]-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-benzo-thiazolyl]methyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-3[(5,7-difluoro-2-benzothiazolyl ) methyl ] -1-pyridaz ineacetic acid;
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(trifluoro-methyl)-2-benzothiazolyl)methyl)-l-pyridazineacetic acid.
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-dichloro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid; and 3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7-dichloro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid .

4. A compound of the formula wherein R5 is hydrogen or XR1 where in X is CH2, CH2CH2, -CH(CH3), -CH2--NH or -CH2--NH; and R1 is benzothiazol-2-yl optionally 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, (C1-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 or 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;
and R4 is (C1-C4)alkyl.

5. A compound according to claim 4 wherein R2 and R3 are each methyl, R4 is -C(CH3)3 and R5 is hydrogen.

6. A compound according to claim 4 wherein R2 and R3 taken together form a cyclohexyl ring, R4 is ethyl and R5 is hydrogen.

7. A compound according to claim 4 wherein R2 and R3 are each methyl, R5 is XR1 wherein X is CH2, and R4 is -C(CH3)3.

8. A compound according to claim 4 wherein R2 and R3 taken together form a cyclohexyl ring, R5 is XR1 wherein X is CH2, and R4 is ethyl.

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

10. A method of inhibiting aldose reductase activity comprising administering to a diabetic host an effective amount of a compound of claim 1.

11. A pharmaceutical composition for lowering blood uric acid levels comprising a compound of claim 1 in an amount effective for lowering blood uric acid levels in admixture with a pharmaceutically acceptable carrier.

12. A method for 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 claim 1.

13. A process for the preparation of a compound of the formula I

wherein X is CH2, CH2CH2, -CH(CH3), or ;
Y=O or S;
R1 is benzothiazol-2-yl optionally 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, (C1-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 or 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;
comprising:

. -31-(a) alkylating a compound of the formula II

wherein R2, and R3 are as defined above and R4 is C1-alkyl with an alkylating agent of the formula L-X-R1 wherein L is a leaving group such as chloro or bromo and X and R1 are as defined above in the presence of a base to obtain a compound of the formula III

wherein R1 is CN or optionally substituted benzothiazole; R2 and R3 are as defined above, R4 is C1-C4 alkyl, X is CH2, CH2CH2 or -CH(CH3); and (b) hydrolyzing the compound of formula III with a strong acid or aqueous base, to form a compound of Formula I wherein R4 is hydrogen, and if desired, converting a compound of Formula I so formed to a pharmaceutically acceptable salt or prodrug thereof; or (c) cyclocondensing a compound of the formula III
above wherein R1 is CN; R2 and R3 are as defined above and R4 is C1-C4 alkyl, X is CH2, CH2CH2 or -CH(CH3) with substituted 2-aminobenzenethiol and acid addition salts in the presence of a polar solvent; and (d) hydrolyzing the resulting compound of (c) in accordance with step (b) above, to form a compound of formula I wherein R4 is hydrogen, and if desired, converting the compound of Formula I so formed to a pharamaceutically acceptable salt or prodrug thereof; or (e) cyclocondensing a compound of the formula III
above wherein R1 is CN, , R2 and R3 are as defined above and R4 is C1-C4 alkyl and X is CH2, CH2CH2,CH(CH3) with a compound of the formula wherein A is F, Cl, Br or I in a polar solvent in the presence of hydrogen sulfide; and f. hydrolyzing the resulting compound in accordance with step (b) above to form a compound of Formula I wherein R4 is hydrogen, and if desired, converting the compound of Formula I so formed to a pharmaceutically acceptable salt or prodrug thereof.

14. A process according to claim 13 wherein X is CH2, 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.

15. A process according to claim 13 wherein said compound is selected from the group consisting of:
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-dimethyl-3-[(5-trifluoromethyl)-2-benzothiazolyl)methyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-difluoro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid;
3 , 4 - D i h y d r o - 4 - o x o -5 , 6 - c y c lo h e x a n o -3 -[[5(trifluoromethy1)-2-benzothiazolyl]methyl]-1-pyridazineacetic acid;

3, 4 -Dihydro-4-oxo-3[(5,7-difluoro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-6-[[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(trifluoro-methyl)-2-benzothiazolyl]methyl]-l-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-cyclohexano-3-[(5,7-dichloro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid; and 3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5,7-dichloro-2-benzothiazolyl)methyl]-1-pyridazineacetic acid .

16. A process for the preparation of a compound of the formula wherein R5 is hydrogen or XR1 wherein X is CH2, CH2CH2, -CH(CH3), -CH2--NH or -CH2--NH; and R1 is benzothiazol-2-yl optionally 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, (C1-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 or 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;
and R4 is (C1-C4)alkyl comprising:
reacting a compound of the formula lll wherein X is -NH with phosphorous pentasulfide in the presence of an aromatic hydrocarbon solvent.

17. A process according to claim 16 wherein R2 and R3 are each methyl, R1 is -C(CH3)3 and R5 is hydrogen.

18. A process according to claim 16 wherein R2 and R3 taken together form a cyclohexyl ring, R4 is ethyl and R5 is hydrogen.

19. A process according to claim 16 wherein R2 and R3 are each methyl, R5 is XR1 wherein X is CH2, and R4 is -C(CH3)3.

20. A process according to claim 16 wherein R2 and R3 taken together form a cyclohexyl ring, R5 is XR1 wherein X is CH2, and R4 is ethyl.

21. A compound of the formula wherein X is CH2, CH2CH2, -CH(CH3), or -CH2--NH;
Y=O or S;
R1 is an optionally substituted group selected from 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 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, (C1-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 or 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.

22. A compound of the formula wherein R5 is hydrogen or XR1 wherein X is CH2, CH,CH2 -CH(CH3), -CH2--NH or -CH2--NH; and R1 is CN, or an optionally substituted group selected from 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 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, (C1-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 or 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;
and R4 is (C1-C4) alkyl.

23. A compound according to Claim 21 wherein R1 is optionally substituted benzoxazol-2-yl or 3-phenyl-1,2,4-oxadiazol-5-yl.

24. A compound according to claim 21 wherein X is CH2, R1 is optionally substituted benzoxazol-2-yl, or 3-phenyl-1,2,4-oxadiazol-5-yl, R2 and R3 are each methyl, and R4 is hydrogen.

25. A compound according to claim 21 selected from the group consisting of:
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-[(2-fluoro-4-bromo)benzyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-bromo-2-benzoxazolyl)methyl]-1-pyridazineacetic acid; and 3,4-Dihydro-4-oxo-5,6-dimethyl-3-[[3-(2,3-difluorophenyl)-1,2,4-oxadiazol-5-yl]-methyl]-1-pyridazineacetic acid.

26. A process for the preparation of a compound of the formula I

wherein X is CH2, CH2CH2, -CH(CH3), or -CH2--NH;
Y=O or S;
R1 is an optionally substituted group selected from 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 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, (C1-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 or 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;
R1 is hydrogen or a prodrug group;
comprising:
(a) alkylating a compound of the formula II

wherein R2, and R3 are as defined above and R4 is C1-C4 alkyl with an alkylating agent of the formula L-X-R1 wherein L is a leaving group such as chloro or bromo and X and R1 are as defined above in the presence of a base to obtain a compound of the formula III

wherein R1 is CN or optionally substituted benzothiazole; R2 and R3 are as defined above, R4 is C1-C4 alkyl, X is CH2, CH2CH2 or -CH(CH3); and (b) hydrolyzing the. compound of formula III with a strong acid or aqueous base, to form a compound of Formula I wherein R4 is hydrogen, and if desired, converting a compound of Formula I so formed to a pharmaceutically acceptable salt or prodrug thereof; or (c) cyclocondensing a compound of the formula III
above wherein R1 is CN; R2 and R3 are as defined above and R4 is C1-C4 alkyl, X is CH2, CH2CH2 or -CH(CH3) with substituted 2-aminobenzenethiol and acid addition salts in the presence of a polar solvent; and (d) hydrolyzing the resulting compound of (c) in accordance with step (b) above, to form a compound of formula I wherein R4 is hydrogen, and if desired, converting the compound of Formula I so formed to a pharamaceutically acceptable salt or prodrug thereof; or (e) cyclocondensing a compound of the formula III
above wherein R1 is CN, , R2 and R3 are as defined above and R4 is C1-C4 alkyl and X is CH2, CH2CH2,CH(CH3) with a compound of the formula wherein A is F, Cl, Br or I in a polar solvent in the presence of hydrogen sulfide; and f. hydrolyzing the resulting compound in accordance with step (b) above to form a compound of Formula I wherein R4 is hydrogen, and if desired, converting the compound of Formula I so formed to a pharmaceutically acceptable salt or prodrug thereof.

27. A process according to Claim 26 wherein R1 is optionally substituted benzoxazol-2-yl or 3-phenyl-1,2,4-oxadiazol-5-yl.

28. A process according to claim 26 wherein X is CH2, R1 is optionaiLy substituted benzoxazol-2-yl, or 3-phenyl-1,2,4-oxadiazol-5-yl, R2 and R3 are each methyl, and R4 is hydrogen.

29. A process according to claim 26 wherein said compound is selected from the group consisting of:
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-[(2-fluoro-4-bromo)benzyl]-1-pyridazineacetic acid;
3,4-Dihydro-4-oxo-5,6-dimethyl-3-[(5-bromo-2-benzoxazolyl)methyl]-1-pyridazineacetic acid; and 3,4-Dihydro-4-oxo-5,6-dimethyl-3-[[3-(2,3-difluorophenyl)-1,2,4-oxadiazol-5-yl]-methyl]-1-pyridazineacetic acid.

30. A process for the preparation of a compound of the formula wherein R5 is hydrogen or XR1 wherein X is CH2, CH2CH2, -CH(CH3), -CH2--NH or -CH2--NH; and R1 is CN, or an optionally substituted group selected from 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 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, (C1-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 or 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;
and R4 is (C1-C4)alkyl comprising:
reacting a compound of the formula III

wherein X is with phosphorous pentasulfide in the presence of an aromatic hydrocarbon solvent.