CZ387092A3 - Pyridazinoacetic acids, their derivatives, process of their preparation and use - Google Patents

Abstract

Compounds having aldose reductase inhibitory activity of formula (I) wherein X CH2, CH2CH2, -CHCH3, (a); Y=O or S; R<1> 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; R<2> and R<3> are independently selected from hydrogen, fluorine, chlorine, bromine, (C1-C4) alkyl, methyl (C1-C4) alkylthio, (C1-C4) alkoxy and trifluoromethyl or R<2> and R<3> 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 U<1> and U<2> are independently CH2, O or S with the proviso that both U<1> and U<2> are not O or S; R<4> is hydrogen or a prodrug group; or a pharmaceutically acceptable salt thereof.

Description

Technical field

The present invention relates to novel pyridazinone acetic acids and derivatives thereof which are aldosoreductase inhibitors and are useful in the treatment of certain chronic complications associated with diabetes mellitus, such as diabetic cataract (cataract), retinopathy, nephropathy and neuropathy. The compounds may also be used as hypouricemic agents which are useful in lowering blood uric acid levels. The present invention also includes a preparation process

-t. . The compounds of the invention, the intermediates used in the process, the pharmaceutical compositions containing the compounds and the use of the compounds.

BACKGROUND OF THE INVENTION

Many attempts have been made in the prior art to provide effective oral antidiabetic agents. U.S. Patent 3,821,383 discloses aldosoreductase inhibitors such as 1,3-dioxo-1H-benzo [d, e] isoquinoline-2- (3H) acetic acid and derivatives derived therefrom, which are useful in the treatment of chronic complications associated with diabetes. U.S. Pat. No. 4,226,875 describes the use of spiro-oxazolidinediones for the treatment of diabetes-related complications, which are aldosoreductase inhibitors. These aldosoreductase inhibitors function to inhibit the effect of the enzyme aldosoreductase, which mainly acts as a regulator of the reduction of aldoses, such as glucose and galactose, on the corresponding polyols. such as sorbitol and galactitol, both in humans and animals.

In this way, unwanted accumulations of galactitol in the lenses of subjects suffering from galactosemia and sorbitol in the lenses, peripheral nerves and kidneys of subjects suffering from diabetes are prevented or slowed down. It is apparent from the above that such compounds are therapeutically valuable in that they are aldosoreductase inhibitors and thus allow control of certain chronic complications occurring in diabetes, including those of an ophthalmic nature, as it is well known in the art that the presence of of polyols in the eye lens leads to cataract formation and the associated loss of lens brightness.

In French patent application no.

No. 2647676 discloses pyridazinone derivatives having substituted benzyl side chains and benzothiazole side chains, said compounds being aldosoreductase inhibitors. ’

U.S. Pat. No. 4,251,528 discloses aromatic carbocyclic oxophthalazinylacetic acids having aldosoreductase inhibitor properties.

This patent also discloses that 2- (2-pyrid-2-ylethyl) 3,4-dihydro-4-oxophthalazin-1-ylacetic acid is not an aldosoreductase inhibitor. In Chemical Abstracts, 1970, 73,

77173y discloses heterocyclic oxophthalazinylacetic acids and their ethyl esters, which disclose that these compounds have an effect on the blood coagulation system. .......

U.S. Patent No. 4,939,140 discloses heterocyclic oxophthalazinylacetic acids.

U.S. Pat. No. 4,868,301 discloses a process for preparing oxophthalazinylacetic acids having a benzothiazole or other heterocyclic side chain and intermediates thereof.

U.S. Patent No. 4,996,204 protects pyridopyridazinone acetic acids.

In European Patent Application Publication No. WO 97/18516, the disclosure of which is incorporated herein by reference.

No. 397,350, the process for the preparation of oxophthalazinyl acids and analogues thereof, as well as the intermediates of this process.

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

SUMMARY OF THE INVENTION

The invention relates to compounds of formula I:

in which it means:

X is CH ₂ , CH ₂ CH ₂ , -CH (CH ₃ ) or -CH ₂ -C-NH,

Y

Y is oxygen or sulfur.

represents 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 , 2,4-, oxadiazol-5-yl and 5-phenyl-1,2,4-oxadiazol-3-yl, wherein said substituted groups are substituted with one or two substituents independently selected from the group consisting of:

... including fluorine, chlorine, bromine. methyl, methylthio, methoxy, hydroxy and trifluoromethyl,

R and R are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo,

(C 1 -C 4) -alkyl;

1-4 carbon atoms, alkoxy groups containing from 1 to 4 carbon atoms and trifluoromethyl, or

R and R together with the carbon atoms to which they are attached form a V group representing

1 '2 in which p is 1 or 2 and U and U are independently CH ₂ , oxygen or sulfur, provided that both 2 ...

and U is not oxygen or sulfur, represents a hydrogen atom or a prodrug group, and pharmaceutically acceptable salts thereof.

The invention also includes pharmaceutically acceptable salts of the compounds of Formula I. These pharmaceutically acceptable salts include sodium salt, potassium salt, calcium salt and ammonium salt, and salts derived from lower alkyl amines (such as ethylamine salt), lower alkanolamines (such as such as triethanolamine salt) and meglumine.

A specific example of a preferred compound of the present invention is the following

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-12-benzothiazolyl) methyl] -1-pyridazineacetic 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-cyclohexane-3 - ((5,7-difluoro-2-benzothiazolyl) methyl) -1-pyridazineacetic acid,

3,4-dihydro-4-oxo-5,6-cyclohexane-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-pyridazineacetic acid,

3,4-dihydro-4-oxo-5,6-cyclohexane-3 - [(2-fluoro-4-bromo) benzyl] -1-pyridazineacetic acid,

3> 4-dihydro-4-oxo-3- _(; ( "5,7-difluoro-2-benz'othiažolyl) methyl] -1-pyridazineacetic 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-benzo-thiazolyl] methyl] -1-pyridazineacetic acid,

3,4-dihydro-4-oxo-5,6-cyclopentane-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-pyridazineacetic acid,

O

3,4-dihydro-4-oxo-5,6-dimethyl-3 - [(5-bromo-2-benzoxazolyl) methyl] -1-pyridazineacetic acid,

3,4-dihydro-4-oxo-5,6-dimethyl-3 - [[3- (2,3-difluorophenyl) -1,2,4-oxadiazol-5-yl) methyl] -1-pyridazineacetic acid,

3,4-dihydro-4-oxo-5,6-cyclohexane-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. '

Also included within the scope of the present invention are compounds which are useful as intermediates for the preparation of compounds of the present invention of formula (I), which intermediates have the formula (IV):

CH ₂ CO ₂ R ⁴ (IV).

N

R

O

X is C 1, CH ₂ CH _2, -CH _{2 (} CH ₂ ), -C 1, -C-NH, or -CH ₂ -C-NH, and

II

II

R is CN, C, or optionally nh ₂ substituted 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, said substituted groups being substituted with one or two substituents which are independently selected from fluoro, chloro, bromo, methyl, and trifluoromethyl;

R and R are independently selected from hydrogen, C 1 -C 4 alkyl, fluoro, chloro, bromo and trifluoromethyl;

R and R together with the carbon atoms to which they are attached form a V group representing

* 1 2 “• ', in which; ep.- _{with the} letters * l-jor _i '; 2 ·· a _? U7 imagine .a ^ i- _t independently Cl · ^, oxygen or sulfur, with the proviso that both U ¹ *

and U are not oxygen or sulfur, and

R ⁴ represents an alkyl group having 1 to 4 carbon atoms.

The invention also relates to a pharmaceutical composition for inhibiting the effect of aldosoreductase comprising a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to inhibit the effect of aldosoreductase in admixture with a pharmaceutically acceptable carrier. A particular example of a pharmaceutical composition of the present invention and an example of a preferred pharmaceutical composition of the present invention are pharmaceutical compositions comprising the aforementioned specific compound of formula (I) and a preferred compound.

The invention also relates to a method of treating subjects suffering from diabetes, such as animals or humans, and complications associated with diabetes, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. A specific and preferred example of such a process is to administer to a subject a particular compound of formula (I) of the present invention and a preferred compound of the invention.

The present invention further relates to a pharmaceutical composition for use in reducing blood uric acid levels in a mammal, such as a human, comprising a compound of Formula I or a pharmaceutically acceptable salt thereof derived in an amount effective to reduce blood uric acid. blood uric acid levels in admixture with a pharmaceutically acceptable carrier.

The invention also relates to a method of lowering blood uric acid levels in a mammal, comprising administering to said mammal in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. A specific and preferred example of such a process is one comprising administering to a subject a particular compound of formula (I) of the present invention and a preferred compound of the invention.

Unless expressly stated otherwise herein, the term alkyl as used herein refers to straight chain, branched, or cyclic groups as well as groups having both a straight chain moiety and a straight chain moiety. or a cyclic moiety or groups having a branched moiety and a cyclic moiety.

By the term prodrug group used to define the substituent R ⁴ is meant a group that is converted in vivo by replacement with hydrogen. These groups are well known in the art and include, for example, ester-forming groups such as benzyloxy, C1-C4 dialkylaminoethyloxy, acetoxymethyl, pivaloylmethyl, phthalidoyl, ethoxycarbonyloxyethyl ,

5. - m e t hy 1 - 2 - o x o? 13-Dioxol-4-yl-methylsulfonyl and C 1 -C 4 alkoxy optionally substituted with N-morpholino and amide-forming groups, such as a 1-dialkylamino group up to 4 carbon atoms.

The compounds of the present invention can be prepared according to the following reaction scheme.

o o

O

R ³

R ³ (Ph) ₃ P = CHCO ₂ R ⁴

R ²

(4)

O (Ph) ₃ P = CHCO ₂ R ⁴

R ²

(s) O Zn / BrCH ₇ CO, R ⁴

(5)

O (o)

nh ₃ nh ₂

o (3)

WHAT _? R ⁴

--- v- ιΛ

N

AND

NH

NaH / LXR ¹

▼ (11)

- I # '' *

R ³ .

R ²

O

Oj) aqueous KOH

R ³ R ² co ₂ r ⁴

N [

^N x / X

R ¹

H, SO _4, or TFA.

I t

CO 4 H

N!

N.

.R ¹

O (12)

X

The starting anhydrides of formulas 1, 4 and S are either commercially available or can be prepared by standard procedures known in the art. Compounds of formula 2 wherein R 3 is ethyl or t-butyl may be prepared by reaction of compounds of formula 1

s. (t-butoxycarbonylmethylene) triphenylphosphorane or (carboethoxymethylene) triphenylphosphorane, following the Vittig reaction described in Tetrahedron Letters, 1965, 2537.

The compounds of formula 5 can also be prepared in the same manner.

Compounds of formula 9 are prepared by the Reformat reaction method under standard conditions, in the presence of zinc or a mixture of zinc and copper, or by various well known modifications of the Reformat reaction (see, for example, Tetrahedron Letters, 1984, 2569). Suitable solvents for this conversion of compounds of Formula 8 to compounds of Formula 9 are aromatic hydrocarbons (such as benzene) and dialkyl ethers and cyclic ethers (such as tetrahydrofuran). The temperature of the reaction mixture is preferably maintained in the range of about 35 ° C to about 100 ° C, more preferably the reflux temperature.

Compound (6) can be prepared by standard allyl bromination using N-bromosuccinate in carbon tetrachloride at reflux.

A compound of formula 3 is prepared by reacting a compound of formula 2, 6 or 9 with anhydrous hydrazine or an aqueous solution of hydrazine in an alcoholic solvent (such as ethanol) at a temperature in the range of about 20 ° C to about 80 ° C, preferably at about 60 C. ^e in practice the temperature used may be room temperature or the boiling point of the solvent to reflux.

A compound of formula 13 can be prepared by reacting a compound of formula 3 with a compound of formula:

L-X-R ¹ wherein L is chlorine or bromine.

This process is usually carried out in a polar solvent such as one to four carbon atoms ^: carbon (such as methanol or ethanol), dimethylformamide or dimethyl sulfoxide, in the presence of a base. Suitable bases are alkali metal hydrides or alkali metal alkoxides containing one to four carbon atoms, such as sodium hydride or potassium hydride, sodium or potassium methoxide, or sodium or potassium ethoxide. If applicable

’. Hydrotreatment must be carried out using a non-aqueous solvent such as dimethylformamide. This reaction is carried out at ambient temperature or higher (such as at about 100 ° C) to accelerate the process.

Compound of Formula 11 wherein R 1 is phenyl with hydroxy groups, prepared by demethylation of the corresponding methoxy groups. The demethylation is carried out by refluxing in the presence of hydrobromic acid or boron tribromide in methylene chloride at a temperature in the range of about -70 ° C to about 0 ° C. Preferably, the temperature is from -20 ° C to about 0 ° C.

A compound of formula 11 wherein X is CH ₂ , CH ₂ CH ₂ or -CH (CH 2) and the substituent is optionally substituted benzothiazole is also prepared from the corresponding compound of formula

A compound of formula 13 wherein X is CH ₂ , CH ₂ CH _2, or -CH ₂ CH ₂ and R ¹ is CN is prepared by reacting a compound of formula 3 with a compound of formula:

wherein L 1 is chloro or bromo, in the presence of a base. Suitable bases for this reaction are alkali metal hydrides or alkali metal alkoxides containing one to four carbon atoms.

Suitable solvents for this reaction include nonaqueous solvents such as dimethylformamide and dimethyl sulfoxide. A compound of formula 13 in which R is a substituent group CN are reacted with acid addition salts of 2-aminobenzenethiol ⁱⁿ or ámiriópyridinth'ioP * * * · s'kyselinou (e.g., hydrochloride) in the presence of an alkanol containing 1-4 carbon atoms and at a temperature ranging from about 80 ° C to the reflux temperature of the solvent to give a compound of formula 11 wherein R ¹ is optionally substituted benzothiazole. This process can also be applied to a process for the preparation of compounds wherein R 1 is a substituent

1O thiazolpyridine.

Compounds of formula (11) in which the substituent is a monosubstituted benzothiazole group at the 5 or 7 position or a 5,7-disubstituted benzothiazole group, said substituents being selected from the group consisting of fluorine, chlorine, bromine and trifluoromethyl, may also be prepared by compounds of general formula of formula 13 wherein p 'is R or CN

NH,

Compound of Formula 13 (wherein X is CH 2, CH 2 CH 2 or -CH 2 CH 3) and R 6 is CN or CN

S c ^{X, X is} NH _2, is then reacted with compound 14, .., x in which A is fluorine, chlorine, bromine or iodine in the presence of hydrogen sulfide. Usually, this reaction is carried out < in a polar solvent. Suitable solvents include sulfolane, pyridine and N-methylpyrrolidone. Preferably dimethylformamide is used as the solvent. The reaction temperature usually ranges -v ~ r OZM of September aš'i from ⁱ '' ⁱ T 10 C to "about * ·! The boiling point of the solvent used is refluxing. A compound of formula 13 wherein the substituent is CN is reacted with a compound of formula 14 in the presence of a tertiary amine. Suitable tertiary amines include trialkylamines having 2 to 6 carbon atoms, such as triethylamine. These processes can also be applied to a process for the preparation of compounds wherein the substituent is thiazolopyridine. A compound of formula 13 wherein X is CH 2, CH 2 CH 2 or

nn ₂ can be prepared by reacting a compound of formula 13, wherein X is Cl 2, CH 2 CH 2 or -CH 2 CH 2, and

. . tertiary amine, such as. is _, for example, a C 2 -C 6 trialkylamine, such as triethylamine, and in the presence of a solvent such as pyridine or dimethylformamide. Preferably, the reaction is carried out in the presence of dimethylformamide. Typically, the reaction is carried out at temperatures ranging from about ambient temperature (i.e. generally about 100 ° C) to about 100 ° C. Preferably, the temperature for this reaction is in the range of about 40 ° C to about 60 ° C.

The compound of formula-11, wherein X is S is -G-NH-, is prepared by reaction of a compound of formula 11;

in the presence of an aromatic hydrocarbon solvent such as benzene, toluene or xylenes. The reaction is carried out at a temperature in the range of room temperature to 100 ° C, with a temperature in the range of 40 to 60 ° C being preferred.

The compound of formula (11) may be hydrolyzed;

to produce a compound of formula 12. Taxo hydrolysis is carried out in the presence of concentrated sulfuric acid or trifluoroacetic acid, and when R ^{4 is} t-butyl, the reaction is carried out at a temperature in the range of about 0 ° C to rooms.

Where R ^{4 is} methyl or ethyl, the hydrolysis is carried out at the usual temperatures used in these processes, _f 'Ϊ Ί and, in addition, the hydrolysis is carried out in the presence of an acid or a base, a mineral acid such as hydrochloric acid or an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

Unless expressly stated otherwise, it is generally understood that pressure is not critical to the above processes. Typically, reaction pressure values are in the range of from about 0.05 to about 0.2 MPa, with ambient pressure (i.e. about 0.1 MPa) being preferred.

Pharmaceutically acceptable salts of the compounds of formula (I) above may be prepared by reaction with pharmaceutically acceptable cations by conventional methods known in the art. For example, it is possible to readily handle these salts. Preferably, the compounds of formula I are treated with an aqueous solution containing the desired pharmaceutically acceptable cation, followed by evaporation of the solution to dryness, preferably under reduced pressure. Alternatively, the compound of formula I in a lower alcohol solution may be mixed with an alkoxide of the desired metal and the solution thus obtained evaporated to dryness. Suitable pharmaceutically acceptable cations for this purpose are alkali metal cations such as potassium and sodium, ammonium cation or water-soluble amine addition salts such as N-methylglucamine (meglumine), lower alkanolammonium salts and other basic organic salts amines which are pharmaceutically acceptable and alkaline earth metal cations such as calcium and magnesium, but are not limited thereto.

Compounds of formula (I) and pharmaceutically acceptable salts thereof (sometimes referred to herein as "active ingredients") may be useful as inhibitors of the enzyme aldosoreductase in the treatment of chronic complications associated with diabetes, such as diabetic cataract, retinopathy, nephropathy and neuropathy. The active substances according to the invention are ...

can also be used to lower blood uric acid levels in mammals, such as humans. Uric acid deposits (also known as trophi) resulting from non-physiologically elevated plasma levels of uric acid exhibit a tendency to occur in various tissues in the body, resulting in a disease known as gout or gouty arthritis. Uric acid-containing deposits in this disease can occur 'in' cartilage / broom, - bursa ', tendons, connective tissues overlapping bone protrusions, as well as in subcutaneous sites and in the kidney region. Elevated blood uric acid levels may also occur in other numerous diseases, including myeloid leukemia, myeloid dysplasia, pernicious anemia, psoriasis, diabetes mellitus, and renal diseases. In the claims and the description of the present invention, the term treatment refers to both the prevention and alleviation of said conditions. The above active agents may be administered to a subject by conventional administration methods, including oral administration, parenteral administration and topical administration. Typically, the compounds are administered orally or parenterally at dosages ranging from about 2 milligrams / kilogram to 100 milligrams / kilogram of body weight of the subject being treated per day, preferably at a dosage of from 5 milligrams / kilogram. kilogram to 50 milligrams / kilogram per day. However, it will be appreciated that, where necessary, the dosage may be adjusted depending on the condition of the subject being treated. For each individual case, however, the person responsible for treatment must in any case decide on the appropriate dosage.

The active compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers, and may be administered either in single or multiple doses. Suitable pharmaceutically acceptable carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions obtained by combining the active ingredient with a pharmaceutically acceptable carrier can then be formulated and administered in various dosage forms, such as tablets, powders, lozenges, syrup solutions for injection and the like. These pharmaceutical compositions may, if desired, contain, in addition to the aforementioned ingredients, flavoring agents, binders, excipients and the like. For example, for oral administration, tablets containing a variety of excipients such as sodium citrate, calcium carbonate and calcium phosphate can be used together with various disintegrants such as starch, alginic acid and certain complex silicates, and binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, various glidants, such as magnesium stearate, sodium lauryl sulfate and talc, are often used in the preparation of tablets. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules. Lactose or milk sugar and high molecular weight polyethylene glycols are preferred for the manufacture of these capsules.

Where aqueous suspensions or elixirs are required for oral administration, the basic active ingredient may be combined with various sweetening or flavoring agents, coloring or coloring agents, and further if necessary with emulsifying or suspending agents. which are used concomitantly with diluents, such as water, ethanol, propylene glycol, glycerol, and various combinations thereof may also be prepared. '

In the case of parenteral administration, solutions of the active ingredient in sesame oil or peanut oil, in aqueous propylene glycol solution or in sterile aqueous solution may be employed. These aqueous solutions preferably contain buffers, if necessary, and the aqueous diluent is first rendered isotonic with sufficient saline or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.

In this connection, sterile aqueous media are all readily available on the market and can also be prepared by standard methods well known in the art.

The active compounds according to the invention can be used not only advantageously for the preparation of aqueous pharmaceutical compositions for parenteral use as mentioned above, but also for the preparation of pharmaceutical compositions suitable for use as ophthalmic solutions. These ophthalmic solutions are of major importance in the treatment of cataract (diabetic cataract), wherein the ophthalmic solutions are administered topically and the treatment of the disease is one of the preferred embodiments of the present invention. Thus, in the treatment of diabetic cataracts, the active compounds of the invention are applied to the eye in the form of an ophthalmic composition prepared in a conventional manner known in the art of conventional pharmaceutical practice.

1488-1501 (Mack Publishing Co., Easton, Pa.). These ophthalmic compositions contain the active compound in a concentration ranging from about 0.01% to about 1% by weight, preferably from 0.05% to about 0.5% by weight in a pharmaceutically acceptable solution, suspension or ointment. However, with respect to the above-mentioned concentrations, it is of course also possible to use concentrations lying outside,. this range, which depends on the particular compound used, the condition of the subject being treated, and the like, with the responsibility of the attending physician determined for each individual case. These ophthalmic solutions are preferably in the form of sterile aqueous solutions containing, if necessary, other ingredients such as preservatives, buffering agents, tonicity agents, anxioxidants and stabilizing agents, non-ionic wetting or cleaning agents, viscosity and the like. Suitable preservatives include benzalkonium chloride, benzothonium chloride, chlorobutanol, thimerosal and the like. Suitable buffering agents include orthoboric acid, sodium or potassium bicarbonate, sodium or potassium borate, sodium or potassium carbonate, sodium acetate, sodium hydrogen phosphate, and the like, and are used in an amount sufficient to maintain. values. pH in the range from. from about 6 to about 8, preferably from about 7 to about 7.5.

Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, and are used in an amount such that sodium chloride equivalent is ... in this ophthalmic. solution was in the range of _____ about 0.9 plus or minus 0.2%. Suitable anxioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea, and the like. Suitable wetting and cleaning agents include polysorbate 80, polysorbate 20, poloxamer 282, and tyloxapol. Suitable viscosity enhancers include, for example, dextran 40, dextran 70, gelatin, glycerol, hydroxyethylcellulose, hydromethylpropylcellulose, lanolin, ethylcellulose ^; Ultramethylpoly-methyl-glycol glycol polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethylcellulose and the like. The ophthalmic compositions are applied topically to the eye of the subject to be treated by conventional methods such as eye drops or ophthalmic wash solutions.

- 23 used to wash the eye.

The effectiveness of the compounds of this invention as agents for controlling complications associated with diabetes can be determined using a variety of standard biological and pharmacological tests. Suitable tests include:

(1) measuring the ability of the compounds of the invention to inhibit the effect of isolated aldosoreductase;

(2) measuring the ability of these compounds of the invention to reduce or inhibit sorbitol accumulation in sciatic nerves and lenses of acutely streptozotocinated rats, i.e. diabetic rats (in rats with streptozotocin-induced acute diabetes);

(3) measuring the ability of these compounds to alter already elevated levels of sorbitol in sciatic nerves and lenses in rats with chronic streptozotocin-induced diabetes;

(4) measuring the ability of these compounds to prevent or inhibit the formation of galactitol in lenses in rats with acute galactosemia;

(5) measuring the ability of these compounds to slow cataract formation and reduce lens opacity in rats with acute galactosemia;

(6) measuring the ability of these compounds to prevent sorbitol accumulation and cataract formation

- (cataract) · ^4, in isolovanýčh7čóekách ¹ s • kryš.řink.ub.ovaň.ých. -Η- * · r 'glucose; and (7) measuring the ability of these compounds of the invention to reduce already elevated levels of sorbitol in isolated lenses of rats incubated with glucose.

DETAILED DESCRIPTION OF THE INVENTION

The pyridazinone acetic acids and derivatives thereof according to the invention, the preparation process and the intermediates used in this process will be illustrated by the following examples. These examples are illustrative only and are not intended to limit the scope of the invention with respect to the details set forth herein. The melting point values in these examples are uncorrected.

Example 1

3,4-Dihydro-4-oxo-5,6-methyl-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-pyridazin-1-ylacetic acid t-butyl ester.

A. Preparation of 3-oxo-4,5-dimethylfuran t -butyl ester According to this embodiment, there was a solution containing 2,3-dimethylmaleic anhydride (6.3 g, 50 mmol) and (t-butoxycarbonylmethylene) -. triphenylphosphorane: (20.7 g, 55 mmol) in methylene chloride (200 mL) was heated at reflux for 16 hours. The solution was evaporated to dryness and the residue obtained

- 't »y] _ ~ BC * _e QÍštěn momentary řchromátograf by the built - procedure i .. -.

Silica gel, using a 9: 1 mixture of methylene chloride and ethyl acetate, to give 3-oxo-4,5-dimethylfuran-1-ylideneacetic acid t-butyl ester.

Yield: 6.5 g (60%).

z J

B. Preparation of 5,6-Dimethyl-4-oxopyridazin-1-yl-acetic acid t-butyl ester.

In this embodiment, the mixture containing the compound prepared according to embodiment A above (1.3 g, 4 mmol), ethanol (5 ml) and hydrazine hydrate (3.9 ml, 8 mmol) stirred at room temperature for 1 hour. The reaction mixture was diluted with water (2 mL) and acidified with acetic acid (4 mL). In this way, a solid precipitated which was collected, washed with water and then air dried to give the title compound. Yield: 1.3 g (92%).

C. Preparation of 3,4-Dihydro-4-oxo-5,6-dimethyl-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-pyridazin-1-ylacetic acid t-butyl ester.

Potassium t-butoxide (236 mg, 2.1 mg) was added to a solution containing the compound prepared according to the above embodiment B (476 mg, 2 mmol) in dimethylformamide (4 ml). The mixture was stirred for 30 minutes at room temperature. To this reaction mixture was added 2-chloromethyl-5-trifluoromethylbenzothiazole (554 mg). (2.2 mmol) and the mixture was further stirred for an additional 3 hours. The reaction mixture was then quenched with water (20 mL), acidified to a suitable pH by addition of sufficient dilute hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was separated, evaporated to dryness and the residue was chromatographed on silica gel. A methylene chloride mixture was used as eluent

and ethyl ester acetic acid v ratio 9: 1, wherein po elution was required compound referred to in header. Yield: 490 milligrams (54%). ¹ H NMR (CDCl 3, _(- 250 MHz) δ: - . . 1.45 (s, 9H); 2.1 (s. 3H), 2.2 (s, 3H), 3.6 (s, 2H). 5.7 (s, 2H). 7,5 (d. J = 8Hz, 1H) 7.9. (m +, 1H). ...... 8,25 (d_, J = 8Hz , 1H) .. ....... Example 2

3,4-Dihydro-4-oxo-5,6-dimethyl-3 - [(4-bromo-2-fluoro) benzyl] -1-pyridazinyl-acetic acid t-butyl ester.

The title compound of this Example was prepared in the same manner as in Example IC. Yield: 87% ¹ H NMR (CDCl ₃ , 250 MHz) δ:

1.45 (s, 9H), 2.08 (s, 3H), 2.15 (s, 3H),

3.54 (s, 2H); 5.3 (s, 2H); 7.2 (m, 3H);

Example 3

Procedure for the preparation of 4 ' 4 < 5 &lt; 76 &gt; 76 methyl (3 &apos; - [(5 &apos;-( trifluoromethyl) -2-benzothiazolyl] methyl) -1-pyridazinacetic acid acid.

Example 1 (450 mg, 1 mmol) was added to concentrated sulfuric acid (2 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then cooled with ice water (20 mL) to give a solid which was collected. The solid was crystallized from benzene to give the title compound.

Yield: 270 mg (68%).

Melting point: ¹⁷⁴ ° C

Example 4

A process for the preparation of 3,4-dihydro-4-oxo-5,6-dimethyl-3 - [(4-bromo-2-fluoro) benzyl] -1-pyridazin-1-ylacetic acid,

The compound of Example 2 (740 mg, 1.74 mmol) was added to trifluoroacetic acid (2 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was treated with ice water (15 mL) to precipitate a solid which was collected, air dried and crystallized from benzene to give the title compound. Yield: 115 mg (33%).

Melting point: 162 ‘C.

Example·. 5

A process for preparing 3-oxo-4,5-dihydrofuran-1-acetic acid t-butyl ester.

Prepared in the same manner as in Example 1A starting from succinic anhydride (1.98 g, 20 mmol), which was used in place of 2,3-dimethylmaleic anhydride.

¹ H NMR (COCl ₃ , 300 MHz) 5: 1.5 (s, 9H); 2.72 (s, 2H); 3.35 (m, 2H); 5.62 (m, IH). Example 6 Preparation process 5-Bromo-3-oxo-4,5- t -butyl ester dihydrofuran-1- yloctové.

The mixture containing the compound of Example 5, N-bromosuccinimide (-1-, 96 grams, 1-1 mmol) and carbon tetrachloride (25 mL) was heated to reflux. for 4 hours using UV irradiation. The reaction mixture was cooled, the excess carbon tetrachloride was evaporated and the residue was treated with a silica gel chromatography. The title compound was obtained by eluting with methylene chloride and methanol. -hexane in a 1: 1 ratio.

Yield: 2.1 g (76%).

¹ H NMR (CDCl ₃ , 300 MHz) δ:

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-pyridazin-1-ylideneacetic acid t-butyl ester.

To a solution containing Example 6 (2.77 g, 10 mmol) in ethanol (10 mL) was added hydrazine hydrate (1 mL, 20 mmol), and then the solution was stirred at room temperature for 16 hours. Excess ethanol was then evaporated and the concentrate was extracted with ethyl acetate (15 ml). The organic extract was washed with water, separated and evaporated to dryness. The residue was chromatographed on silica gel. The title compound was obtained by eluting with a 1: 1 mixture of methylene chloride and ethyl acetate.

Yield: 1.03 g (49%).

Melting point ; 135 ’C.

Example 8

Preparation of t-butyl-1,3-dihydro-1-hydroxy-3-oxo-5-methyl-1-isofuraneate.

To a solution containing citraconic anhydride (11.2 g, 0.1 mol) in tetrahydrofuran (50 ml) was added a zinc-copper mixture (15.0 g, 0.15 mol) ).

To this mixture was slowly added t-butyl bromoacetate (23.4 g, 0.12 mol) and the mixture was heated at reflux for 3 hours. The reaction mixture thus obtained was cooled; the filtered-filtrate was concentrated under vacuum. The residue was partitioned between 6 N hydrochloric acid (20 mL) and ethyl acetate (250 mL). The organic extract was separated and evaporated to dryness. The residue was chromatographed on silica gel. The title compound was obtained by eluting with a 1: 1 mixture of methylene chloride and ethyl acetate. Yield: 6.2 g (27%).

¹ H NMR (CDCl 3, 300 MHz) δ:

1.45 (s, 9H), 2.05 (s, 3H),

5.85 (s, 1 H).

Example 9

5-Methyl-4-oxopyridazin-1-ylacetic acid t-butyl ester. .....

The compound of Example 8 was dissolved in ethanol (20 mL) and hydrazine hydrate (0.6 g, 12 mmol) was added. The reaction mixture was stirred for 4 hours at room temperature, the solution was concentrated by removing excess ethanol and triturated. 1 N hydrochloric acid solution (10 ml). The solid was collected, air dried and crystallized from ethanol to give the title compound.

Yield: 0.58 g (24%).

Melting point: 114-116 ° C /

Example 10

Preparation of (E) and (Z) isomers of t-butyl ester

3-oxo'-4 \ "5 * cyklbhexárifuran L-yrid'ehc> ^T ~ čt'óv'éT

The title compound was prepared in 46% yield (11.1 grams) as shown in place of 3,4,5,6-tetrahydrophthalic anhydride 2 (15.2 grams = 0, 1 mol). The mixture thus obtained was followed by the same Example 1a except that 3-dimethylmaleine was used

The E-isomer and the Z-isomer were chromatographed on silica gel, eluting with methylene chloride: ethyl acetate 9: 1. The less polar E-isomer was eluted first. More polar ^: The Z-isomer was obtained from the last fractions.

Example, 11

3,4-Dihydro-4-oxo-5,6-cyclohexanopyridazin-1-yl-acetic acid t-butyl ester.

A mixture of (E) and (Z) -isomers of 3-oxo-4,5-cyclohexanofuran-1-ylideneacetic acid t-butyl ester (i.e. the compound of Example 10) was dissolved in ethanol (20 mL), wherein hydrazine hydrate was added to the solution. (2.5 g, 50 mmol). The mixture was heated at reflux for 4 hours and then evaporated to give a gummy residue. The residue was triturated with 1 N hydrochloric acid (10 mL) to give the title compound as a white solid.

Yield: 2.18 g (44%).

Melting point: 179-131 ° C.

Example 1 and d 12

A process for the preparation of 3,4-dihydro, 4-oxo-5,6-dimethyl-3-cyanomethyl-1-phthalazineacetic acid t-butyl ester.

To a solution containing the compound prepared according to Example 1B (7.05 g, 29.6 mmol). in DMF (65 mL) was added potassium tert-butoxide (3.65 g, 32.5 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added bromoacetonitrile (4.26 g, 35.5 mmol) and the mixture was further stirred for an additional 1.5 hours. The reaction mixture was quenched with water (200 mL), acidified to pH 2 by addition of sufficient dilute hydrochloric acid to give a solid which was collected. The solid was air dried and crystallized from cyclohexane / methylene chloride 3: 1.

Yield: 6.26 g (76%).

Melting point: 120 - 123 ° C · ‘Example 13

Process for the preparation of 3,4-dihydro-4-oxo-5,6-cyclohexane-3-cyano-methyl-1-phthalazineacetic acid ethyl ester;

The title compound (in liquid form) was prepared as described in Example 12 except that starting from ethyl ester of the acid.

5,6-cyclohexane-1-phthalazineacetate .. ..... .......

Yield: 58%.

² Η NMR (CDCl ₃ , 300 MHz) δ:

1.25 (t, J = Hz, 3H); 1.8 (m, 4H); 2.4 (m, 2H);

2.6 (m, 2H); 4.1 (q, J = 8Hz, 2H);

5.0 (s, 2H).

The compounds of the following Tables 1-3 are also prepared according to the present invention, and the melting point and NMR spectra for these compounds are also shown.

Table n. 1

R ² R ³ R ⁴ Product ch ₃ ch ₃ τ-butyl Melting point ; 73-74 'C (ch ₂ ) 3 Et Melting point : 64 - 65 •C (ch ₂ ) 4 t-butyl E-Isomer ² H NMR (CDCl ₃ , 250 MHz) δ: 1.48 (s, 9H), 1.73 (m ♦ 4H>, 2.3 (m, 2H), 5.8 (s, 1H). 2.75 (m , 2H), - f ' »'». *--J ^f it. t Z-isomer ¹ H NMR (CDCl ₃ , 1.53 (s, 9H), 250 MHz) 1,75 ( δ: m, 4H), 2.35 (m, 4H); 5,, 25 (2, 1H).

Table 2

R ^Ž ___ .... ......... ... ..... — ............. R ³ , · R ⁴ Product H H t-Bu viz. Example 7 H ch ₃ t-Bu viz. Example 9 ... —----- .. .. --μ- - - · ......- ----- --------- -------------- ^CH 3 ch ₃ x-Bu viz. Example 1B (CH ₂ ) 3 Et NMR (CDCl ₃ , 250 MHz) δ: 1.2 (t, J = 8 MHz, 3 H), 2.1 (m, 2H), 2.9 (m, 4H), 3.6 (s, 2H), 4.2 (q J = 8 MHz, 2H) (ch ₂ ) 4 ' 'T-Bu see 'Example 11 • j, if ¹ r ¹ Et ’ Melting point: 240-242 ° C

- jj Table ΰ. 3

R '

The product t-Bu

5,7-difluorobenzo-thiazol-2-yl

Melting point: 119 ° C

H t-Bu 5-trifluoro- methylbenzo- thiazol-2-yl Melting point 134 * C

^CH 3 t-Bu 5-trifluoromethylbenzothiazol-2-yl

NMR (CDCl ₃ , 250 MHz) δ: 1.45 (s, 9H),

2.1.7 (s, 3H). /. ·; 3.55 (s, 2H),

5.7 (s, 2H).

6.72 (m, IH).

7.5 (m, 1 H),

7.92 (m, IH);

8.25 (m, IH).

Table 3 (continued)

R '

R ^J

Product

CHCHt-Bu 5-trifluoromethylbenzoxhiazol-2-yl Example 1C

CH-

5,7-difluoro- NMR benzothiazole- (CDClj, 250 MHz) δ: ² -yi -..... 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 ; 1H)

CH ₃ CH ₃ t -Bu 4-bromo-2-fluorophenyl see. Example 2 (CH ₂ ) ₃ Et

5 xrífluor- ^X H NMR

methylbenzo- (CDCl-j , 200 MHz) δ: Rhiazol-2-yl 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, 2H).

7.5 (d, J = 9 Hz, IH)

7.9 (d, J = 9 Hz, 1H); 8.2 (s, 1H) .37

Table 3 (continued) R ² R ³ R ⁴ R ¹ Product

_{(CH2) 4}

5-Trifluoro- Melting point:

methylbenzo- 201 ^e C thiazol-2-yl (ch ₂ ) ₄ t-Bu 5-trifluoromethylbenzothiazol-2-yl

Melting point ; 136 "C _{(CH2) 4} t-Bu 5,7-difluorbenzothiazol2-yl- _{(CH2) 4} t-Bu 4-broni72fluorfenyl ^X H NMR

(CDC l ₃ , 250MHz) 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, 1H) 7.6 (m, 1H). * h n: MR (CDC l ₃ , 250MHz) 1.45 (S. 9H), 1.72 (m, 4H) 2.4 (m, lH) 2.58 (m, 2H) 3.51 (s, 2H) 5.27 (s, 2H) 7.2 (m, 3H)

- 3H Table 3 (continued)

R ² R ³ R ⁴ R ¹ Product H H H 5,7-difluoro- Melting point : benzotriazole- 169 ’C H H H 5-trifluoro- Melting point. : methylbenzo- 172-173 ° C. .....  - ...... - - thiazol-2-yl H ch ₃ H 5-trifluoro- Melting point ; mexhylbenzo- 172 “C in thiazol-2-yl CH. CH. H 5-trifluoro- Melting point : __ · ... -. . · ..........- ^- - · t ··· —----- —- ' _ · —-----— · - ----- '---- - - w.— methylbenzo- 174 ° C thiazol-2-yl ch ₃ ch ₃ H 5,7-difluoro- Melting point : benzothiazole- 183 ⁴ C 2-yi - ch ₃ ch ₃ H 5 -bromobenzoxa- Melting point : * zol-2-style ´ r- 206 '- 207' C * ch ₃ ch ₃ H [3- (2,3-difluoro- Melting point : phenyl) -1,2,4- 185-186 ^g C oxadiazol-5-yl] ch ₃ k> ch ₃ H 4-bromo-2-fluoro- Melting point : phenyl 162 ’C

Table 3 (continued)

R ² R ³ R ⁴ R ¹ Product

(CH ₂ ) 3 H 5-trifluoro- methylben20- thiazol-2-yl Temperature 184 ° C thaw _{(CH2) 4} H 5-Trifluoro- methylbenzothiazol-2-yl Temperature 201 ^e C thaw _{(CH2) 4} H 5,7-difluoro- benzothiazole- 2-yl Temperature 157 ° C thaw _{(CH2) 4} H 4-bromo-2-fluorophenyl Temperature 164 ”* C thaw

4-Bromo-2-fluorophenyl-benzothiazol-2-yl

Melting point 202-204 ° C

Melting point 207-208 ° C

H r

5-Trifluoromethylbenzothiazol-2-yl

Melting point: 224-225 ^e C

Table 3 (continued)

_r 2 R ³ R ⁴ R ¹ Product ch ₃ ch ₃ t-Bu 5,7-dichloro- Melting point : - • benzothiazole- 2-yi Mp 113-116 ° C (CH ₂ ) 4 Et 5,7-dichloro- Melting point : .. - ..... .............. ... benzothiazole .-— 2-yl ..... 136 ..- 139 ° C - - - ch ₃ ch ₃ H 5,7-dichloro- benzothiazole- 2-yl Melting point : 200 - 201 ° C ............... -------- —-----------— r ------ ...... ------- (CH ₂ ) 4 H 5,7-dichloro- benzothiazole- 2-yl Melting point : Mp 193-195 ° C -f-JWk ^Λ IW ** · ^J w. iUrX ii · ». J .. · Mk. · 4 »

PATENT CLAIMS

Claims (24)

PATENT CLAIMS 1. A compound of formula I wherein: X is CH ₂ , CH ₂ CH ₂ , -CH (CH ₃ ) or -CH ₂ -C-NH, Y is oxygen or sulfur, R1 represents 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, said substituted groups being substituted with one or two substituents independently selected from fluoro, chloro, bromo, -methyl, and trifluoromethyl, R and R ^J are independently selected from the group consisting of hydrogen, alkyl radicals containing 1 to 4 carbon atoms, fluorine, chlorine, bromine, and trifluoromethyl, or Λ A R ^{z and} R ^j together with the carbon atoms to which they are attached form a V group representing Ί 9 in which p is 1 or 2 and U and U 'are independently CH 2, oxygen or sulfur, provided that both U ¹ and U are not oxygen or sulfur, R ⁴ represents a hydrogen atom or a prodrug group. and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein the substituent is optionally substituted benzothiazol-2-yl, --------- benzoxazol-4-yl or .3-pheny1,2,2,4-oxadiazol-5-yl. The compound of claim 1 wherein X is CH 2, R 1 is optionally substituted benzothiazol-2-yl, R ⁴ is hydrogen and R and R are each hydrogen or methyl or R is hydrogen and R is methyl or R and R together form a cyclohexyl ring or a cyclopentyl ring. The compound of claim 1, wherein X is CH 2, R ¹ is optionally substituted phenyl, R ⁴ is hydrogen, and R and R are each methyl or R and R together form a cyclohexyl ring. The compound of claim 1 wherein X is CH 2, the substituent is optionally substituted benzoxazol-2-yl or 3-phenyl-1,2,4-oxadiazol-5-yl, R and R are each methyl and R ⁴ represents a hydrogen atom. The compound of claim 1 which is: 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-dimethyl-3 - [(2-fluoro-4-bromo) benzyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-cyclohexane-3 - ((5,7-difluoro-2-benzothiazolyl) methyl) -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-cyclohexane-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-cyclohexane-3 - [(2-fluoro-4-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, 3,4-dihydro-4-oxo-6-methyl-3 - [[5-trifluoromethyl] 2-benzothiazolyl] methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-cyclopentane-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-dimethyl-3 - [(5-bromo-2-benzoxazolyl) methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-dimethyl-3 - [[3- (2,3-difluorophenyl) -1,2,4-oxadiazol-5-yl) methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5, 6-cyclohexane-3 - [(5,7-dichloro-2-benzothiazolyl) methyl] -1-pyridazineacetic acid, or 3,4-dihydro-4-oxo-5,6-dimethyl-3 - [(5,7-dichloro-2-benzothiazolyl) methyl] -1-pyridazineacetic acid. 7. Compound of formula IV: in which it means: a hydrogen atom or a group XR ¹ in which X is C1-4, -CH2CH3, -C1-C4-NH S | Or -CH 2 -C-NH, and R is CN, C, or optionally NH ₂ . A 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 substituents independently selected fluoro, chloro, bromo, methyl, and trifluoromethyl, R and R are independently selected from hydrogen, C 1 -C 4 alkyl, fluoro, chloro, bromo, and trifluoromethyl; R and R together with the carbon atoms to which they are attached form a group V representing _: wherein p is 1 or 2 and U ¹ and are independently oxygen or sulfur, provided that both U ^{1 *} and U are not oxygen or sulfur, and R ⁴ represents an alkyl group having 1 to 4 carbon atoms. '. * 2 3 The compound of claim 7, wherein R and R are each methyl, R ⁴ is -C (CH ₃ ) _3, and the substituent is hydrogen. 9. A compound according to claim 7, in which R and R ^J taken together form a cyclohexyl ring, R ⁴ represents an ethyl group, and the substituent is hydrogen. y represents a group λκ, in which Kiere λ means s> A.up ± 4iLi R ³ '' represents an optionally substituted benzothiazol-2-yl or phenyl group and the substituent represents ethyl Group .................. ......... ........ .............. A pharmaceutical composition for inhibiting the effect of an aldosoreductase comprising the compound of formula I according to claim 1 in an amount effective to inhibit the effect of the aldosoreductase in admixture with a pharmaceutically acceptable carrier. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting the effect of aldosoreductase. A pharmaceutical composition for lowering blood uric acid levels; characterized in that it comprises a compound of formula (I) according to claim 1 in an amount effective to reduce the blood uric acid level in admixture with a pharmaceutically acceptable carrier. The compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for lowering blood uric acid levels in a mammal. A process for the preparation of a compound of formula I wherein: Y II ' X is CH ₂ , CH ₂ CH ₂ , -CH (CH ₃ ) or -CH ₂ -C-NH, Y represents oxygen or sulfur: R ^X 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-1,2,4-oxadiazol-3-yl, wherein said substituted groups are substituted with one or two substituents independently selected from fluoro, chlorine, bromine, methyl, and trifluoromethyl, R and R are independently selected from hydrogen, C 1 -C 4 alkyl, fluoro, chloro, bromo, and trifluoromethyl, or R and R together with the carbon atoms to which they are attached form a group V representing (CH ₂ ) or in which p is 1 or 2 and and U "are independently CH 2, oxygen or sulfur, provided both 9 and U are not oxygen or sulfur represents a hydrogen atom or a prodrug group, characterized in that (a) the compound of formula (II) is alkylated: wherein R @ 1 and R @ 2 are the same substituents as mentioned above, and 'represents an alkyl group containing from 1 to 4 carbon atoms, an alkylating agent of the general formula: LXR ¹ wherein:,,. . _ * __ _ .... ........ _ The leaving group is, for example, chlorine or bromine, and X 'and R1 have the same meaning as above, in the presence of a base to give a compound of formula III: in which it means: r! CN or optionally substituted benzothiazole, R and R · ³ have the same meaning as above, R ⁴ represents an alkyl group having 1 to 4 carbon atoms, and X is CH ₂ , CH ₂ CH ₂ or -CH (CH-j), and (b) the compound of formula III is hydrolyzed with a strong acid or aqueous solution of a base to give a compound of formula I wherein R ⁴ is hydrogen and optionally converting the compound of formula (I) so obtained into a pharmaceutically acceptable salt or prodrug thereof, or (c) cyclo-condensing said compound Wherein R is CN, R and R have the same meaning as previously described and R &lt; 2 &gt; X is CH ₂ , CH ₂ CH ₂ or -CH (CH 2), with substituted 2-aminobenzenethiol and acid addition salts in the presence of a polar solvent, and (d) the compound thus obtained in step (a). c) hydrolyzing in the same manner as in step (b) above to give a compound of formula I wherein R ⁴ is hydrogen, followed by optionally converting the compound of formula I so obtained into a pharmaceutically acceptable salt or prodrug thereof or (e) cyclo-condensing the above compound of formula (III) wherein R R is CN or CN R ^z and R · ⁵ have the same meaning as above, R ⁴ represents an alkyl group having 1 to 4 carbon atoms and X is CH _2, CH ₂ CH ₂ or -CHfCH ^) with a compound of the formula: wherein A is a fluorine, chlorine, bromine or iodine atom in a polar solvent in the presence of hydrogen sulfide, and (f) the compound so obtained is hydrolyzed in the same manner as in step (b) above to give a compound of formula I wherein R ⁴ represents a hydrogen atom, and then optionally converted. A compound of formula (I) to a pharmaceutically acceptable salt of formula II; . .d salt or prodrug thereof; 17. The process of claim 16 wherein in the starting compounds, R is optionally substituted benzothiazol-2-yl, benzoxazol-2-yl, or benzothiazol-2-yl; 3-Phenyl-1,2,4-oxadiazol-5-yl. J 1 18. The method according to claim 16, characterized in that in the starting compounds, X represents a group Cl · ^, R ^ is optionally substituted benzothiazol-2-yl, R ⁴ is hydrogen and R ² and R ² are each hydrogen or a methyl group or R ¹⁶ represents a hydrogen atom and R is a methyl group or R and R together form a cyclohexyl ring or a cyclopentyl ring. 19. The method of claim 16 wherein X is CH2 in the starting compounds, R &lt; 1 &gt; is optionally substituted phenyl, R &lt; ⁴ &gt; is hydrogen and R &lt; ² &gt; and R &lt; ² &^gt; together form a cyclohexyl ring. 20. The method according to claim 16, characterized in that in the starting compounds, X represents CH 2, the substituent R is optionally substituted benzoxazol-2-yl or 3-phenyl-l, 2,4-oxadiazol-5-yl, R ² and R @ ² are each methyl, and R ⁴ is hydrogen. A method according to any one of the preceding claims, characterized in that said compounds are compounds from the group consisting of: - 3'-Dihydro-4'-oxo-6'-dimethyl-G - [(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-dimethyl-3 - [(2-fluoro-4-bromo) benzyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-cyclohexane-3 - [(5,7-difluoro-2-benzothiazolyl) methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-cyclohexane-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-cyclohexane-3 - [(2-fluoro-4-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-benzo, thiazolyl] 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-cyclopentane-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-pyridazineacetic acid. . . 3,4-dihydro-4-oxo-5,6-dimethyl-3 - [(5-bromo-2-benzoxazolyl) methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-dimethyl-3 - [[3- (2,3-difluorophenyl) -1,2,4-oxadiazol-5-yl) methyl] -1-pyridazineacetic acid, 3,4-dihydro-4-oxo-5,6-cyclohexane-3 - [(5,7-dichloro-2 ... benzothiazolyl) methyl] -1-pyridazineacetic acid, a 3,4-dihydro-4-oxo-5,6-dimethyl-3 - [(5,7-dichloro-2-benzothiazolyl) methyl] -1-pyridazineacetic acid. 22. A process for preparing a compound of formula IV: O in which means: R ³ is hydrogen or the group XR ^ in which X is C1-4, CH2CH9, -CH2CH3, -CH3-C-NH3 II or -CH 2 -C-NH, a R 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 substituents which are independently selected from the group consisting of _R fluoro, chloro, bromo, methyl, and trifluoromethyl, R and R are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, fluoro, chloro, bromo and trifluoromethyl, or "-" R a R together with the carbon atoms to which they are attached form a group V representing (CH ₂ ) _p or 19 "in which p is 1 or 2 and U and U" are independently Cl · ^, oxygen or sulfur, provided that both ΐΛ and U are not oxygen or sulfur, and R ⁴ represents an alkyl group having 1 to 4 carbon atoms, characterized in that a compound of formula III is reacted: R ³ ch ₂ co ₂ r < (III) wherein X is -C-NH, with phosphorus sulfide in the presence of an aromatic hydrocarbon solvent. A process according to claim 22, wherein in the starting compound R and R are both methyl, R ⁴ is -C (CH ₃ ) _3, and R 6 is hydrogen. 24. The method of claim 22, wherein said method is substantially as follows R @ 9 and R @ 9 together form a cyclohexyl ring, R ^{@ 4} is ethyl and is hydrogen. 25. A process according to claim 22, wherein in the starting compound R and R each represents a methyl group, r3. is a group XR ^, wherein X ^ is CH, R ¹ is an optionally substituted benzothiazol.-2-yl or phenyl and R ⁴ is -C (CH _{3) third} 26. The process of claim 22 wherein R &lt; ³ &gt; and R &^lt; ³ &gt; together form a cyclohexyl ring, R &lt; ³ & gt ^; is XR &lt; ⁴ &gt; yl or phenyl and R ⁴ is ethyl.