JPH041747B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel heterocyclic oxophthalazinyl acetic acids useful in the treatment of chronic complications resulting from diabetes such as diabetic cataracts, membranous retinopathy and neuropathies, pharmaceutical compositions containing this compound, and pharmaceutical compositions containing these compounds. Regarding usage. Various attempts have been made to synthesize more effective oral antidiabetic drugs. Generally, these efforts have involved the synthesis of new organic compounds (particularly sulfonylureas) and the determination of their ability to substantially lower blood glucose levels when administered orally. However, little is known about the effects of organic compounds on preventing or alleviating chronic complications of diabetes such as diabetic cataracts, retinopathy, and neuropathy. U.S. Pat. No. 3,821,383 describes aldose reductase inhibitors such as 1,3-dioxo-1H-benz[d,e]-isoquinoline-2-(3H)-acetic acid and its derivatives useful in treating these conditions. is disclosed. US Pat. No. 4,226,875 teaches the use of spiro-oxazolidinediones as aldose reductase inhibitors in the treatment of diabetic complications. This aldose reductase inhibitor inhibits the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses such as glucose and galactose to responsible polyols such as sorbitol and galactitol in humans and other animals. It works by doing. This method prevents or reduces the undesired accumulation of galactitol in the lens of patients with galactosemia and the undesired accumulation of sorbitol in the lens, peripheral nerve axis, and kidneys of various diabetic patients. Since the presence of polyols in the lens of the eye is known to lead to cataract formation without loss of lens transparency, such compounds may be useful for controlling chronic diabetic complications, including visual ones. It has therapeutic value as an aldose reductase inhibitor. US Pat. No. 4,251,528 discloses aromatic carbocyclic oxophthalazinyl acetic acid with aaldose reductase inhibiting properties. In that patent, 2-(2
-pyrid-2-ylethyl)-3,4-dihydro-4-oxophthalazin-1-yl acetic acid does not inhibit aldo-threductase.
Chemical Abstracts
73, 77173y (1970) discloses that heterocyclic oxophthalazinyl acetic acid and its ethyl ester have effects on the blood coagulation system. In the present invention, the formula [wherein Z is a covalent bond or S; R ₁ is hydroxy or (C ₁ -C ₄ )alkoxy; R ₂ contains one nitrogen and one oxygen or sulfur, or contains two a five-membered heterocyclic ring containing nitrogen and one oxygen or sulfur, the ring being substituted with one ( _C1 - _C4 ) alkyl, pyridyl or phenyl, or fused with benzo; The phenyl or benzo optionally contains one or two fluoro, chloro or bromo, or one (C1-C4)alkyl, ( _C1 - _C4 )alkoxy, (C1-C4) alkyl, ( _C1 - _C4 )alkoxy, (C1 _-C4)
-C ₄ ) alkylthio, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl or trifluoromethyl substituted; chlorobenzothiophene; quinoline; quinazoline; oxazole condensed with pyridine , thiazole or 7-chloro-imidazole; R ₃ and R ₄ are the same or different, hydrogen, fluoro, chloro, bromo, trifluoromethyl,
(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy or nitro; R ₅ is hydrogen or methyl] or a compound of the formula where R ₁ is hydroxy. Addition salt, or R ₁ is di(C ₁ −C ₄ )
Alkylamino or N-morpholino or di(C ₁ -C ₄ )alkylamino substituted (C ₁ -C ₄ )
Acid addition salts of compounds of formula which are alkoxy Particular compounds of the invention are those in which R ₂ is an optionally substituted benzothiazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl or benzimidazolyl or substituted oxadiazolyl or indolyl. . Preferred compounds of the invention are those in which Z is a covalent bond;
R ₁ is hydroxy; R ₂ is optionally substituted benzothiazol-2-yl, benzothiazol-5-
yl, benzisothiazol-3-yl, henzoxazol-2-yl, 2-quinolyl, oxazolo[4,5-b]pyridin-2-yl, benzothiophene-2-yl, benzofuran-2-yl or thiazolo[4] ,5-b]pyridin-2-yl or substituted 1,2,4-oxadiazol-3-yl,
1,2,4-oxadiazol-S-yl, isothiazol-5-yl, isothiazol-4-yl,
1,3,4-oxadiazol-5-yl,1,
2,5-thiadiazol-3-yl,oxazole-
2-yl, thiazol-2-yl or thiazol-
4-yl, and R ₃ , R ₄ and R ₅ are hydrogen. Other suitable compounds include oxophthalazinyl groups.
The methylene bridge connecting R ₂ is, for example, the above-mentioned benzoxazol-2-yl or 1,2,4-
It is located at the alpha position of the nitrogen atom in _R2 , such as oxadiazol-3-yl. Other particular compounds of the invention include R ₂ substituted in the benzo position by one trifluoromethylthio or one or two chloro, bromo, methyl, methoxy, trifluoromethyl or 6,7-benzo. - benzothiazolyl,
and R ₃ is hydrogen, 5-fluoro, 5-chloro,
5-bromo or 5-methyl and R ₄ is hydrogen; 6- or 7-substituted chloro, bromo, methyl, isopropyl, methoxy, nitro or trifluoromethyl; 4,5-difluoro or 4,
7-dichloro, and _R2 is optionally substituted benzothiazol-2-yl and _R3 and _R4 are each chloro. Certain preferred compounds of the formula are 3-(5-bromo-2-benzothiazolylmethyl)-4-oxo-
3H-phthalazin-1-yl-acetic acid, 3-(5-fluoro-2-benzothiazolylmethyl)-4-oxo-3H-phthalazin-1-ylacetic acid, 3-(5
-trifluoromethyl-2-benzothiazolylmethyl)-4-oxo-3H-phthalazin-1-ylacetic acid, 3-(5-chloro-2-benzothiazolylmethyl)-4-oxo-3H-phthalazine -1-ylacetic acid, 3-(4,5-difluoro-2-benzothiazolylmethyl)-4-oxo-3H-phthalazin-1-ylacetic acid, 3-(5,7-dichloro-2
-Benzothiazolylmethyl)-4-oxo-3H-
Phthalazin-1-yl acetic acid and 3-(4,7-
dichloro-2-benzothiazolylmethyl)-4-
It is oxo-3H-phthalazin-1-yl acetic acid. The present invention also relates to compositions for inhibiting aldose reductase activity, comprising an inhibitory effective amount of a compound of formula formula, mixed with a pharmaceutically suitable carrier. Certain suitable compositions include compounds of certain suitable formulas as described above. The present invention includes a method of treating an animal or human diabetic patient with diabetes-related complications by administering an effective amount of a compound of formula. Certain preferred methods consist of administering compounds of the certain preferred formulas described above. In the present invention, in an inert gas, the formula The compound with the formula [wherein R ₁ is (C ₁ -C ₄ ) alkoxy, X, Z, R ₂ , R ₄ and R ₅ are as defined in claim 1, and R ₆ is ( _C1 − _C4 )
phenyl optionally substituted with alkyl, trifluoromethyl or methyl, chloro, bromo or nitro]. The position numbers for compounds of formula are as follows: The term “(C ₁ -C ₄ )alkyl” used in the definition of R ₁ to _R 4 refers to a saturated monovalent linear or Represents a branched aliphatic hydrocarbon group. The term "prodrug" refers to a group that converts in vivo to an active compound of the formula where R ₁ is hydroxy. Such groups are generally known and include benzyloxy, di(C ₁ -C ₄ )alkylaminoethyloxy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl, 5-methyl-2-oxo -1,3-
dioxol-4-ylmethyl, and ester-forming groups and di(C ₁ -C ₄ )alkylamino to form ester drags such as (C ₁ -C ₄ )alkoxy optionally substituted with N-morpholino. amide-forming groups such as Examples of the 5-membered heterocyclic ring include imidazolyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl, and thiadiazolyl. A heterocycle can be fused with benzo and joined at adjacent carbon atoms to form a phenyl group. The benzoheterocycle may be bonded to Z through the heterocyclic group or through the benzo group of the benzoheterocycle. The synthesis of a compound in which Z is attached to a benzo group is demonstrated in reaction scheme B below. Specific examples in which the heterocycle is fused with benzo include benzoxazolyl, quinazolin-2-yl, 2-benzimidazolyl, quinazoline-4-
and benzothiazolyl. Compounds of the invention are synthesized as outlined in Reaction Scheme A. Phthalic acid of the formula and its derivatives can be purchased commercially or synthesized according to standard procedures. Compounds of the formula where R' is ethyl or methyl are described in U.S. Pat. No. 4,251,528 and Tetrahedron Letters.
Letters), 1965, 2357, by reaction with (carbethoxymethylene)triphenylphosphorane or (carbomethoxymethylene)triphenylphosphorane, respectively. . Compounds of formula where R' is methyl or ethyl may be synthesized by reacting compound () with hydrazine as described in US Pat. No. 4,251,528. The reaction is carried out in an aqueous solution such as aqueous ethanol, dioxane or dimethylformamide at a temperature between 40° and 120°C.
Preferably it is carried out at 0.degree. C. (reflux temperature being preferred). The compound of the formula is a compound () in which R' is hydrogen, methyl or ethyl, and L is a leaving group that can form the compound LH by reaction of the two reagents. Synthesize by reacting with L is for example chlor, bromo or phenyl in which R ₆ is substituted with (C ₁ -C ₄ )alkyl, trifluoromethyl, phenyl or methyl, chlor, bromo or nitro
_{OSO2R6 .} Compounds where R′ is methyl or ethyl ()
When reacting, the process is generally carried out in a polar solvent such as a C1-C4 alkanol such as methanol or ethanol, dioxane, dimethylformamide or dimethyl sulfoxide in the presence of a base. Suitable bases are alkali metal hydrides such as sodium or potassium hydride, methoxide or ethoxide or alkali metal hydrides having 1 to 1 carbon atoms.
4 alkoxide. If a hydride is used, a non-aqueous solvent such as dimethylformamide is required. When reacting a compound () in which R′ is hydrogen obtained by hydrolysis of a compound () in which R′ is methyl or ethyl, at least It is necessary that 2 molar equivalents of base be present. Furthermore, when reacting such compounds, it is preferred to use a hydroxyl solvent to minimize the formation of the corresponding ester. The reaction to synthesize compounds () in which R ₅ is alkyl is the formula in which L is OSO ₂ R ₆ , where R ₆ is as defined above. It is successfully synthesized from the compound. This reaction is generally carried out under an inert gas such as nitrogen and in an aprotic polar solvent such as dimethylformamide.
It is carried out at a temperature of 50°C. The reaction for synthesizing compound () is carried out at room temperature or, to accelerate the process, at a higher temperature. Compounds of the formula in which R' is methyl or ethyl are hydrolyzed to obtain compounds of the formula in which R ₁ is hydrogen. Hydrolysis is carried out at room temperature in the presence of a mineral acid such as hydrochloric acid or an alkali metal hydroxide or carbonate such as sodium or potassium hydroxide or carbonate. The reaction is carried out in a solvent such as water and a C1-C4 alkanol such as methanol or dioxane. Esterification of compounds of the formula in which R ₁ is a hydroxyl group by conventional methods such as reaction of R ₁ H with the corresponding acid chloride, bromide or anhydride results in R ₁
is a (C ₁ -C ₄ ) alkoxy group ()
is obtained. Furthermore, compounds of the formula in which R ₁ is a (C ₁ -C ₄ )alkoxy group can be synthesized by alkylating a solution of the sodium salt of the compound () in which R ₁ is hydroxy. The alkylating agent is a chloride. The above sodium salts are generally prepared by preparing compounds in which R ₁ is hydroxy in a sodium salt-forming compound such as sodium bicarbonate, sodium hydride or sodium t-butylammonium sulfate and a non-aqueous solvent such as dimethylformamide or methylpyrrolidone. Synthesize by reacting with formula

[Formula] [In the formula, L is chloro, Z is a covalent bond, R ₅ is hydrogen, and R ₂ is each optionally substituted with fluoro, chloro, bromo, trifluoromethyl, methylthio or methylsulfinyl. thiophene or furan; or R ₇ [wherein R ₇ is one iodo or trifluoromethylthio,
or 1 or 2 fluoro, chloro, bromo, (C ₁ -C ₄ )alkyl, (C ₂ -C ₄ )alkoxy,
1,2,4-oxadiazole optionally substituted with ( _C1 - _C4 )alkylthio, ( _{C1 - C4} )alkylsulfinyl, (C1- _C4 )alkylsulfonyl or trifluoromethyl) -3-yl or 1,2,4-thiadiazol-3-yl]

_[ Formula] is defined above ₎
Synthesized by reacting with (alkoxy) CH ₂ Cl. The reaction generally proceeds in a reaction inert solvent such as a ( _C1 - _C4 ) alcohol such as ethanol, a halocarbon such as chloroform or methylene chloride, or an ethereal solution such as diglyme. The reaction temperature ranges from room temperature to the reflux temperature of the solvent used. Reaction times range from about 15 minutes to about 2 hours or more. The starting materials () can be purchased commercially or from the Journal of the American Chemical Society (J.Am.Chem.Soc.) 53, 309 (1935) and the Journal of Organic Chemistry (J.Org.Chem.). 29, 2652 (1964). Tri(C ₁ -C ₄ )alkoxy)CH ₂ Cl compounds are known or prepared by preparing 1,1,1-trialkoxyethane in pyridine and a hydrocarbon solvent with N-
It can be synthesized by reacting with chlorsuccinimide or chlorin. The initial chlorination reaction is generally carried out in a solvent, preferably a non-polar solvent such as carbon tetrachloride or tetrachlorethylene. The reaction is conveniently carried out in the range of about 40°C to the reflux temperature of the solvent. The reaction with chlorine in pyridine must be carried out in the presence of one or more chlorine atoms and a chlorohydrocarbon solvent containing from 1 to 6 carbon atoms, such as methylene chloride, chloroform or trichloroethane. Reaction mechanism B is a compound in which R ₂ is a benzo-heterocyclic ring with benzo attached to a methylene bridge, 3-(benzothiazole-5
-ylmethyl)-4-oxo-phthalazine-1-
The synthesis of yl acetic acid is illustrated. Other compounds in which R ₂ is a benzo-heterocyclic ring with benzo attached to Z in the final compound may be synthesized in a similar manner. In scheme B, 5-methylbenzothiazole is reacted with a brominating agent such as N-bromsuccinimide to give 5-bromomethylbenzothiazole, which is then reacted with 4-oxo-3H-phthalazin-1-yl acetate. When reacted under conditions as outlined above for the conversion of compound () to compound () in Scheme A, 3-(5-methylbenzothiazolyl)-4-oxo-3H-phthalazin-1-yl acetate is obtained. Pharmaceutically suitable base addition salts of compounds () in which R ₁ is hydroxy may be formed from pharmaceutically suitable cations by conventional methods. These salts can be easily synthesized by treating the compound of the formula with a cation suitable for the desired pharmaceutical, and drying the resulting solution by distillation (preferably under reduced pressure). Alternatively, a lower alkyl alcohol solution of the compound of the formula is mixed with the alkoxide of the desired metal,
The solution is then distilled off to dryness. Pharmaceutically suitable cations suitable for this purpose include (but are not limited to) alkali metal cations such as potassium and sodium, ammonium and N-methylglucamine (meglumine).
water-soluble amine addition salts such as lower alkanol ammonium and other base salts with pharmaceutically suitable organic amines, and alkaline earth metal cations such as calcium and magnesium. Pharmaceutically suitable acid addition salts of compounds of formula are synthesized in the conventional manner by reacting a solution or suspension of the free base (2) with about one chemical equivalent of the pharmaceutically suitable acid. Conventional concentration and recrystallization techniques are used to isolate the salt. Examples of suitable acids include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid,
Sulfonic acids and related acids such as cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, methanesulfonic acid, benzenesulfonic acid, and the like. Preferred is phosphoric acid. The novel compounds of formula and pharmaceutically suitable salts thereof are useful as inhibitors of the enzyme aldose reductase in the treatment of chronic complications of diabetes such as diabetic cataracts, retinopathy and neuropathies. In the claims and specification, treatment is meant to include both prevention and alleviation of such symptoms. The compounds can be administered to patients in need of treatment by a variety of conventional routes of administration, including oral, parenteral and topical. Generally, the compound is administered orally or parenterally at approximately 0.5 and 25 mg/Kg.
(body weight of the patient being treated)/day (preferably about 1.0-10 mg/Kg). However, variations in dosage may necessarily occur depending on the condition of the patient being treated. The person responsible for administration determines the appropriate dose for the individual patient. The novel compounds of this invention may be administered alone or in admixture with a pharmaceutically suitable carrier, either in single or divided doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Pharmaceutical compositions formed by admixing the novel compound of formula and a pharmaceutically suitable carrier are readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, and injection solutions. If desired, the pharmaceutical composition may further contain ingredients such as flavoring agents, binders, excipients, etc. For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be combined with various disintegrants such as starch, alginic acid and certain silicic acid complexes, polyvinylpyrrolidone, sucrose. , gelatin and gum arabic. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions in a similar form can also be employed as fillers in hard-filled gelatin capsules. Materials suitable for this mode include lactose (or milk sugar) and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredients may be combined with various sweetening and flavoring agents, coloring agents and dyes, and emulsifying or suspending agents, if desired, in water, ethanol, propylene glycol, or the like. Can be mixed with diluents such as glycerin and mixtures thereof. For parenteral administration, solutions of the novel compounds of the formula in sesame or peanut oil, aqueous propylene glycol or sterile aqueous solution may be employed. The aqueous solution must be suitably buffered, if necessary, and the liquid diluent must first be made isotonic with sufficient saline or dextrose. This aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. By the way,
The sterile water used is readily available by standard methods known to those skilled in the art. The compounds of the formula are not only advantageously used for the preparation of aqueous pharmaceutical compositions for parenteral administration as described above, but are also particularly advantageous for the preparation of pharmaceutical compositions suitable for use as eye drops. be. This eye drop is primarily relevant for the treatment of diabetic cataracts by topical administration, and the treatment of cataracts by this method is a preferred embodiment of the present invention. For the treatment of diabetic cataracts, the compounds of the invention may be used, e.g.
15th edition, pages 1488-1501 [Mack Publishing,
It is administered to the eye as eye drops prepared according to conventional formulation methods such as those described in Easton, Pa. The eye drops contain a compound of the formula or a pharmaceutically acceptable salt thereof in a concentration of about 0.01 to about 1% by weight (preferably about 0.05 to about 0.5% in a pharmaceutically suitable solution, suspension, or ointment). There is.
Concentrations will inevitably vary depending on the compound used and the patient being treated, and the person responsible for treatment will determine the most appropriate concentration for each individual patient. The eye drops are preferably in the form of a sterile aqueous solution, and if necessary, further ingredients such as preservatives, buffering agents, elasticity agents, antioxidants, stabilizers, nonionic humectants, detergents, viscosity increasing agents, etc. are added. Suitable preservatives include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal, and the like. Suitable buffers include boric acid, sodium bicarbonate, potassium bicarbonate, sodium borate, potassium borate, sodium carbonate, potassium carbonate, sodium acetate,
Examples include sodium biphosphate, which lowers the pH from about 6 to
8 (preferably between about 7 and 7.5). Suitable elasticity agents include dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, etc., and the sodium chloride equivalent of the eye drop solution is within the range of +0.9 or -0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea, and the like. Suitable wetting agents and cleaning agents include polysorbate 80, polysorbate 20, poloxamers.
282 and tyloxabol. Suitable viscosity increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petrolatane, polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, and the like. Eye drops are administered topically to the eye of a patient in need of treatment in a conventional manner, such as by drops or by soaking the eye in an eye drop solution. The activity of the compounds of the invention as agents for controlling the chronic complications of diabetes is determined by a number of conventional biological or pharmaceutical tests. A suitable reagent is
(1) Measurement of the ability of isolated aldose reductase to inhibit the enzymatic activity; (2) Measurement of the ability to reduce or inhibit sorbitol accumulation in the sciatic nerve and lens of diabetic rats treated with acute streptozotocin; (3) Chronic streptozotocin induction Measurement of the ability to reduce the already elevated sorbitol concentration in the sciatic nerve and lens of diabetic rats; (4) Measurement of the ability to prevent or inhibit galactitol formation in the sciatic nerve and lens of diabetic rats treated with acute streptozotocin; 5) Measurement of the ability to delay cataract formation or reduce lens opacity in chronic galactosemic rats; (6) Measurement of the ability to prevent sorbitol accumulation and cataract formation when isolated rat lenses are incubated with glucose; and (7) determining the ability of isolated rat lenses to reduce already elevated sorbitol concentrations by incubating them with glucose. The inhibitory effect of the compounds of the present invention on lens aaldose reductase was tested as follows. Test method The Journal of Biological Chemistry
The method of Hyman and Kinoshita, "Isolation and Characterization of Lens Aldose Reductase", Vol. 1.240P877-882 (1965) was used. Enzyme preparation Aldose reductase (hereinafter abbreviated as AR)
was partially purified from human placenta as a modification of the Hsyman and Kinoshita method reported for the rat lens. Specifically, a freshly obtained placenta was homogenized in 3 volumes of 0.1M potassium phosphate buffer (PH7.0, containing 5mM2-mercaptoethanol) and incubated at 33,000G at 4°C.
Centrifuged for 20 minutes. The supernatant from the previous step was fractionated with 30-75% ammonium sulfate. The resulting pellet was then resuspended in a minimum volume of buffer and dialyzed overnight. dialysate
Chromatography was performed on DEAE cellulose and AR was eluted with a linear gradient of 0-1 M NaCl. The peak fractions with AR activity were collected and one portion of each was frozen and stored.
This method yielded an enzyme preparation with more than 30-fold enrichment in AR activity. Assay method: Aldose reductase was measured using nicotinamide dihydropyridine (NADPH) using an Abbot VP bi-chromatic clinical analyzer.
The decrease in oxidation rate was assayed by measuring at 340 nm for 10 minutes at 24°C. A unit of aldose reductase was defined as 1 micromole of NADPH oxidized at 25° C. per minute with dl-glyceraldehyde as substrate. Test compounds were evaluated at various concentrations. Results were expressed as % inhibition of control rate of NADPH. Assay conditions Aldose reductase was measured in 0.25ml of 50mM potassium phosphate buffer (PH7.1, containing 400mM ammonium sulfate, 0.067mMNADPH and 0.5mM dl-glyceraldehyde). Enough aldo-threductase was added to produce NADPH oxidation equal to 4 milliunits in 10 minutes. Results The results shown in the table below were obtained.

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[Table] Ropyridine
Toxicity All compounds of the present invention have an LD ₅₀ value of more than 200 mg/Kg (body weight) when administered orally to mice. Furthermore, since the therapeutically effective amount of the compound of the present invention is 10 mg/Kg, the therapeutic index exceeds 20. Therefore, it was concluded that the compounds of the present invention are non-toxic. The invention is illustrated in the following examples. However, it is to be understood that the invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance spectra ( ¹ HNMR) were measured in solutions in deuterated chloroform (CDCl ₃ ), and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (TMS). Peak shapes are expressed as follows: S, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, wide. Example 1 3-(5-Brombenzothiazol-2-ylmethyl)4-oxo-3H-phthalazin-1-yl acetic acid (I; _R1 = OH; _R3 = _R4 = H, _R2 = 5- Bromobenzothiazol-2-yl A 2,5-dibromothioacetanilide A mixture of 2,5-dibromoacetonilide (45.0 g), phosphorus pentasulfide (24.4 g) and benzene (500 ml) was refluxed for 18 hours. .After cooling the reaction mixture,
The benzene layer was decanted and extracted with 10% potassium hydroxide solution (2 x 75ml). The basic extract was washed with ether (2 x 50 ml), acidified to pH 4.0 by addition of dilute hydrochloric acid, and the precipitated 2,5-dibromothioacetanilide was collected and air-dried (yield 14.4
g; mp119-124°C). B 2-Methyl-5-bromobenzothiazole This compound was published in Synthesis, 1976,
It was synthesized by applying the method described in 731. 2,
N of 5-dibromothioacetanilide (9.27g)
- Sodium hydrogen (1.93 g as a 50% w/w dispersion in mineral oil) was carefully added to the methyl-pyrrolidinone solution. After the addition is complete, the mixture is
Heated to 150°C for 1.5 hours. The black reaction mixture was poured into ice water (300ml) and the brown gum that separated was extracted with ethyl acetate (2x100ml). The organic extract was washed with water (2 x 100ml), dried over anhydrous magnesium sulfate and evaporated. The resulting crude solid was purified by silica gel chromatography to give the title compound (4.7 g; mp 84-85°C). C 2-bromomethyl-5-bromobenzothiazole 2-methyl-5-bromobenzothiazole (32.0 g), N-bromo succinimide (25.1 g),
A mixture of carbon tetrachloride (700ml) and a catalytic amount of benzoyl peroxide (0.2g) was refluxed under UV lamp irradiation for 14 hours. The reaction mixture was cooled to room temperature and the precipitated succinimide was filtered off.
The liquid was evaporated to dryness. The resulting solid was purified by silica gel chromatography to yield the product (7.8 g; mp 107°C). D 3-(5-bromobenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazine-1
Ethyl 4-oxo-3H-phthalazin-1-ylacetate (11.6 g) and sodium hydride (288
5-bromo-2-bromomethylbenzothiazole (16.8 g) was added to a solution of 50% w/w dispersion in mineral oil) in dimethylformamide (150 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (500 ml), the pH was adjusted to 4.0 by the addition of 10% HCl, and the precipitated crude solid was collected.
This was purified by silica gel chromatography to obtain a product (yield: 15.6 g; mp 160-161°C). E 3-(5-bromobenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazine-1-
Ethyl acetate 3-(5-bromobenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-lylacetate (15.0 g) and dioxane (150 ml)
Warm the mixture on a steam bath to a solution and add 10% potassium hydroxide (20 ml) to ethanol (50 ml) to this solution.
ml) solution was added. The resulting dark purple solution was stirred at room temperature for 2 hours and concentrated to remove excess dioxane and ethanol. The concentrate was diluted with water (100ml) and the resulting solution was washed with ether (2x100ml). The aqueous layers were combined and acidified to pH 2.0 by adding concentrated hydrochloric acid. The precipitated solid was crystallized from methylene chloride/ethanol (400ml/40ml) to give the product (yield 7.65g; mp 214°C). Example 2 3-(2-pyridyl-1,2,4-oxadiazol-5-ylmethyl)-4-oxo-3H-phthalazin-1-yl-acetic acid (I; R ₁ =OH; R ₃ =
R ₄ = H; R ₂ = 2-pyridyl-1,2,4-oxadiazol-5-yl A pyridamide oxime 2-cyanopyridine (15 g), hydroxyamine hydrochloride (10 g), sodium carbonate (15.3 g) and A mixture of ethanol (100ml) was refluxed for 24 hours. The reaction mixture was cooled and filtered, and the liquid was evaporated to give a solid, which was extracted with ethyl acetate. The organic extract was dried and evaporated, and the residue was crystallized from benzene (3.0 g; mp113~
114℃). B 3-(2-pyridyl)-5-chloromethyl-
1,2,4-oxazole A mixture of pyridamide oxime (4.5 g), chloroacetic anhydride (8.4 g) and toluene (350 ml) was added to
Refluxed for an hour. Cool the hot solution with water (2x
100 ml), saturated aqueous sodium bicarbonate solution (2 x 50
ml) and again with water (2 x 100 ml) and evaporation of the organic layer to give a crude solid. Crystallization of this solid from hexane yields the product (3.4 g; m.
p.89-94℃) was obtained. C 3-(2-pyridyl-1,2,4-oxadiazol-5-ylmethyl)-4-oxo-3H-
Ethyl phthalazin-1-ylacetate Ethyl 4-oxo-3H-phthalazin-1-ylacetate (1.6 g) and sodium hydride (0.5
g; 50% w/w dispersion in mineral oil) in dimethylformamide (15 ml).
Chloromethyl-1,2,4-oxadiazole (1.5 g) was added dropwise over 40 minutes. After stirring for a further 10 minutes, the reaction mixture was poured into water (50ml) and extracted with ether. The ether layer was distilled off and the residue was purified by silica gel chromatography to obtain the product (1.0 g; mp 118-128°C). D 3-(2-pyridyl-1,2,4-oxadiazol-5-ylmethyl)-4-oxo-3H-
Phthalazin-1-yl acetate To a solution of ethyl 3-(2-pyridyl-1,2,4-oxadiazol-5-ylmethyl)-4-oxo-3H-phthalazin-1-yl acetate (1.0 g) in methanol (10 ml) A 20% aqueous KOH solution (0.5ml) was added and the mixture was refluxed for 30 minutes. Excess methanol was distilled off to give an orange residue. The residue was dissolved in water and acidified with acetic acid (1 ml), and the precipitated solid was collected and crystallized from isopropanol to yield the product (0.53 g; mp196-200
°C) was obtained. Example 3 3-[3-(2-trifluoromethylphenyl)
-1,2,4-oxadiazol-2-ylmethyl]-4-oxo-3H-phthalazin-1-yl acetic acid (I; R ₁ = OH; R ₃ = R ₄ H; R ₂ = 3-(2-tri fluoromethylphenyl)-1,2,4-oxadisol-2-yl) A 3-[2-trifluoromethylphenyl]-5
-Chloromethyl-2,3,4-oxadiazole 2-trifluoromethylbenzimidioxime (2-trifluoromethylbenzimidioxime) synthesized from 2-trifluoromethylbenzaldehyde in a manner similar to that described in Ber, 1899, 32 (1975). 2.9g; mp115-116℃)
was dissolved in anhydrous acetone (70ml) and then solid potassium carbonate (2.0g) was added. The resulting slurry was cooled to 15-18°C in an ice-water bath and diluted with acetone (10
chloracetyl chlorite (1.1 ml) dissolved in
A solution of was added. After the addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. Distilling off the acetone gave a white residue which, when rubbed with water, gave O-chloroacetyl-2-trifluoromethylbenzimidoxime (3.0 g; mp108-
110℃) was obtained. This product was converted into toluene (50
ml) and refluxed for 1.5 hours. Cool the toluene solution and add a saturated aqueous solution of sodium bicarbonate (10
ml) and water, and the organic layer was dried and evaporated. The resulting brown oil was purified by silica gel chromatography to yield the title compound as a yellow oil. ¹ HNMR (CDCl ₃ , 6 MHz): 4.0 (S, 2H), 4.4
(S, 2H), 7.3 (S, 5H). B 3-[3-(2-trifluoromethylphenyl)-1,2,4-oxadiazol-2-ylmethyl]-4-oxo-3H-phthalazine-1-
Ethyl ylacetate Ethyl 4-oxo-3H-phthalazin-1-ylacetate (1.4 g) and sodium hydride (0.43
3-(2-trifluoromethylphenyl)-5-chloromethyl-1,2,4 in dimethylformamide (10 ml) (50% w/w dispersion in mineral oil)
- Add oxadiazole (1.7 g) and at room temperature
Stir for 30 minutes. The reaction mixture was poured into water (20ml), acidified to PH2.0 with 10% HCl and the precipitated solid was collected. The solid was triturated with isopropanol to give the product as a white crystalline solid (1.65 g;
mp111−115°C) was obtained. C 3-[3-(2-trifluoromethylphenyl)-1,2,4-oxazol-2-ylmethyl]-4-oxo-3H-phthalazin-1-ylacetic acid 3-(2-trifluoromethylphenyl) enyl)-1,
2,4-oxadiazol-2-ylmethyl-4-
Ethyl oxo-3H-phthalazin-1-ylacetate (1.6g) and 20% w/w KOH aqueous solution (0.5ml)
A mixture of methanol (50ml) was heated on a steam bath for 1 hour. Water (20 ml) was added to the residue obtained by distilling off the methanol, and the solution was adjusted to pH 2 by adding 10% HCl. The precipitated solid was crystallized from benzene (0.7 g; mp132−134
℃). Example 4 3-(N-methylbenzimidazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetic acid [I; _R1 = OH; _R3 = _R4 = _HR2 = 3-( N
-methylbenzimidazol-2-yl)] A 3-(N-methylbenzimidazol-2-
ylmethyl)-4-oxo-3H-phthalazine-
Ethyl 1-ylacetate A solution of ethyl 4-oxo-3H-phthalazin-1-ylacetate (2,3,4 g) and sodium hydride (0.58 g; 50% w/w dispersion in mineral oil) in dimethylformamide (20 ml) was stirred at room temperature for 15 hours. Add N-methyl-2-chloromethylbenzimidazole [2.4 g; JACS, 65, 1854] to this solution.
(1943)] and stirred for an additional hour. It was poured into water (150ml) and extracted with ethyl acetate (2x100ml). The organic extract was dried and evaporated, and the residue was purified by silica gel chromatography to yield the product (2.04 g; mp118
°C) was obtained. B 3-(N-methylbenzimidazol-2-ylmethyl)-4-oxo-3H-phthalazine-1
-ylacetic acid 3-(N-methylbenzimidazol-2-yl)
-4-oxo-3H-phthalazin-1-yl ethyl acetate (2.0 g) in warm methanol (100 ml)
10% KOH (10ml) was added, stirred at room temperature for 2.5 hours and evaporated to give a solid. This solid was dissolved in water (50 ml), washed with ether (50 ml), and acetic acid was added to the aqueous layer to adjust the pH to 6.0.
The resulting white solid was collected, dried, and diluted with methanol/
Crystallization from a mixture of methylene chloride gave the title compound (0.68 g; mp 230°C decomposition). Example 5 3-(oxazolo[4,5-b]pyridine-2
-ylmethyl)-4-oxo-3H-phthalazine-
1-yl acetic acid (I: R ₁ = OH; R ₃ = R ₄ = H; R ₂
=oxazolo[4,5-b]pyridin-2-yl) ethyl 4-oxo-3H-phthalazin-1-yl acetate (1.25 g) was dissolved in sodium hydride (285 mg;
The resulting solution was added to a suspension of 50% w/w dispersion in mineral oil in dimethylformamide (10ml).
It was added dropwise to a solution of chloromethyl-oxazolo[4,5-b]pyridine (1.0 g) in dimethylformamide (5 ml). After 2 hours the reaction mixture was poured into cold water (20ml) and extracted with ether. The ether extract was washed with water (2 x 50ml), dried and evaporated. The resulting crude product was purified by silica gel column chromatography to yield 3-(oxazolo(4,
5-b] Ethyl pyridin-2-ylmethyl)-4-oxo-3H-phthalazin-1-yl acetate (m.
p.105-107°C) was obtained and used directly in the next step. The product was dissolved in methanol (5 ml) containing 20% potassium hydroxide aqueous solution (0.5 ml),
Heat on steam bath for 15 minutes. The solution was evaporated to dryness and the residue was dissolved in water and acidified with acetic acid (2ml). The resulting yellow precipitate was collected, triturated with hot methanol, and filtered to give the title compound (0.32 g; mp 228-230°C) as a white solid. Example 6 3-(2-benzothiazolyl)-4-oxo-
Methyl 3H-phthalazin-1-yl acetate (1.92g)
A solution of 10% aqueous potassium hydroxide (5 ml) in methanol (50 ml) was stirred at room temperature for 4 hours.
The solution was concentrated to remove methanol, and the concentrate was diluted with water (75ml) and washed with ethyl acetate. The aqueous layer was separated and acidified to pH 2.0 with concentrated hydrochloric acid.
The precipitated solid was collected and crystallized from isopropyl alcohol to give 3-(2-benzothiazolyl)-4.
-oxo-3H-phthalazin-1-yl acetic acid (876
mg; mp decomposed at 205°C) was obtained. Example 7 The following compounds were synthesized according to Example 6:

【table】

【table】

【table】

Table Example 8 A solution of methyl 4-oxo-3H-phthalazin-1-yl acetate (1.09 g) and sodium hydride (0.269 g; 50% w/w dispersion in mineral oil) in dimethylformamide (25 ml) was heated with nitrogen. 2 at room temperature under air flow
Stir for hours. A solution of 2-bromomethylbenzothiazole (1.14 g) in dimethylformamide (5 ml) was added to the resulting solution and the reaction mixture was stirred for a further 1 hour and poured into ice water (50 ml). The pH of the mixture was brought to 4.0 by adding 10% chlorine (5 ml).
Extracted with ethyl acetate (100ml). The extract was washed with water (50 ml), dried over HgSO ₄ and evaporated.
Crude product (1.92g), (2-benzothiazolyl)-
Methyl 4-oxo-3H-phthalazin-1-yl acetate, was confirmed by NMR spectrum (see Table 2). Other compounds in Table 2 were synthesized in a similar manner using the appropriate 4-oxo-3H-phthalazin-1-yl acetate and 2-bromomethylbenzothiazole. Melting point is °C.

【table】

【table】

[Table] Example 9 Ethyl 4-oxo-3H-phthalazin-1-yl acetate (23.4 g) in dimethylformamide (175
ml) The solution was kept at 10°C and t-butoxypotassium (11.2g) was added in portions over 5 minutes. The resulting orange solution was brought to room temperature and 5-trifluoromethyl-
A solution of 2-chloromethylbenzothiazole in dimethylformamide (25ml) was added slowly over 15 minutes. After stirring for a further 30 minutes, the mixture was poured into ice water (1500ml). The precipitated solid was collected and diluted with isopropyl ether/n-hexane (250ml/500ml).
ml) mixture. The resulting pale yellow solid,
Ethyl 3-(5-trifluoromethyl-2-benzothiazolylmethyl)-4-oxo-phthalazinyl acetate was air dried (44.3 g; mp 134-136°C). Example 10 The following compounds were synthesized according to the method of Example 1D:

Table: The following compounds were synthesized according to the method of Example 6 using the above compounds without isolation.

【table】 Example 11 The following compounds were synthesized according to Example 3B.

【table】 Example 12 The following compounds were synthesized according to Example 3C.

[Table] Example 13 3-(quinolin-2-ylmethyl)-4-oxo-3H-6,7-dichlorophthalazin-1-yl acetic acid (I; R ₁ =OH; R ₂ =quinoline-2- il;
R ₃ = R ₄ = Cl) A 4,5-dichlorophthalic anhydride A mixture of commercially available 4,5-chlorophthalic acid (50.4 g) and acetic anhydride (150 ml) was refluxed for 2 hours. The product that precipitated on cooling was collected and dried under vacuum (37.0 g; mp 180-181°C). B 3-ethoxycarbonylmethylidene-5,6
-Dichlorophthalide 4,5-dichlorophthalic anhydride (10.0 g) and (carboethoxymethylene)triphenylphosphofuran (16.0 g) in chloroform (450 ml)
The solution was refluxed for 16 hours. Distill the chloroform,
The residue was purified by silica gel chromatography to give the product (9.34 g). C 6,7-dichloro-4-oxo-3H-phthalazin-1-yl ethyl acetate 3-ethoxycarbonylmethylidene-5,6-
Dichlorphthalide (9.37g), ethanol (300g)
ml) and hydrazine (1.1 ml) was refluxed for 3 hours. After cooling, the precipitated solid was collected (6.85 g; mass spectrum, m/e 300 and 227). D The title compound (mp 202-203°C) was synthesized according to Example 6 from ethyl 6,7-dichloro-4-oxo-3H-phthalazin-1-ylacetate and 2-chloromethylquinoline. Example 14 3-(quinolin-2-ylmethyl)-4-oxo-3H-phthalazin-1-yl acetic acid (IR ₁ =OH;
R ₃ = R ₄ = H; R ₂ = quinolin-2-yl) of ethyl 4-oxo-3H-phthalazin-1-yl acetate (1.0 g) and sodium hydride (60% w/w dispersion in mineral oil). 2-bromomethylquinoline (1.05 ml) in dimethylformamide (30 ml)
g) was added. The resulting solution was stirred at room temperature for 30 min, poured into water (100 ml) containing 1NHCl (5 ml),
Extracted with ethyl acetate. Wash the organic layer with water (3x
50ml), dried and distilled off to give 3-(quinoline-
Ethyl 2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate (1.54 g) was obtained. This material was dissolved in a water/dioxane mixture (70ml/70ml). Add 5N potassium hydroxide (5ml) to the solution.
was added, stirred for 15 minutes at room temperature, concentrated to remove excess dioxane, diluted with water (150ml) and washed with ethyl acetate (3 x 70ml). Concentrate the water layer.
The PH was adjusted to 2 with HCl and the precipitated solid was rubbed in hot ethyl acetate and filtered to give the title compound (0.54
g; mp193-194°C) was obtained. Example 15 According to Example 6, the following compound was synthesized.

[Table] le
Example 16 According to Example 8, the following compound was synthesized.

【table】

[Table] Ile
Example 17 (N-morpholino)ethyl-3-(5,6-dichlorobenzothiazol-2-ylmethyl)-4-
Oxo-3H-phthalazin-1-yl acetate hydrochloride N-2-hydroxyethylmorpholine (1.43
3-(benzothiazole-
Ethyl 2-ylmethyl)-4-oxo-5,6-dichlorophthalazin-1-ylacetate (1.23g)
toluene (30ml) solution was added. The reaction mixture was stirred at room temperature for 24 hours and then at 60°C for 6 hours, then HCl gas was bubbled through, the precipitated solid was added with saturated aqueous sodium bicarbonate solution (100 ml) and extracted with ethyl acetate (3 x 100 ml). did. The organic layer was dried and evaporated and the resulting solid was dissolved in acetone (30ml). Passing gaseous HCl through this solution gave the title compound (0.12 g), which was analyzed by elemental analysis (C, 49.83
%; H, 3.83%; N, 9.36%). Example 18 Sodium 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-yl acetate.
(5-trifluoromethylbenzothiazole-2-
ylmethyl)-4-oxo-phthalazin-1-yl acetic acid (0.4 g) in methanol (10 ml). After complete addition, a clear solution was obtained after stirring for 15 minutes at room temperature. Excess methanol was distilled off and the residue was triturated with ether (20 ml).
The product (0.43 g; mp>300°C) was obtained after filtration. Example 19 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-yl acetate dihydrochloride 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-yl acetate dihydrochloride
2-ylmethyl)-4-oxo-phthalazine-1
A solution of dichlorohexylamine (0.2 g) in methanol (5 ml) was added to a solution of -yl acetic acid (0.42 g) in methanol (10 ml). The resulting clear solution was stirred at room temperature for 15 minutes and then evaporated to dryness. The residue was triturated with ether (30ml) to give a white solid (0.38g; mp 207°C). Example 20 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetic acid meglumine salt 3-(5-trifluoromethylbenzothiazol-2-ylmethyl) -4-Oxophthalazine-
1-yl acetic acid (419 mg) and meglumine (196
mg) in methanol (50 ml) was stirred at room temperature for 1 hour and evaporated to dryness. The residue was dissolved in ether (25
ml), the solid was collected by filtration and air-dried (610 mg; mp 157°C). Example 21 3-(5-bromobenzothiazol-2-ylmethyl)-4-oxo-phthalazin-1-yl acetic acid meglumine salt 3-(5-bromobenzothiazol-2-ylmethyl)-4-oxo-phthalazine A solution of -1-yl acetic acid (430 mg) and meglumine (196 mg) in methanol (50 ml) was stirred at room temperature for 1 hour and evaporated to dryness, the residue was triturated in ether (25 ml) and the solid was filtered. Collected (620 mg; m.
p.138−140℃). Example 22 Ethyl 3-(5-sulfynylmethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate (5-thiomethylbenzothiazol-2-ylmethyl)-4- An ice-cooled solution of ethyl oxophthalazin-1-yl acetate (1.06 g) in chloroform (110 ml) was added with meta-chloroperbenzoic acid (0.50 g). The resulting solution was stirred for 1 h between 0-5°C, the chloroform solution was washed with 10% aqueous sodium bicarbonate (3 x 20 ml), the organic layer was separated, dried over magnesium sulfate and evaporated. and dried. The residue was purified by silica gel chromatography to give the title compound [0.81
g; ¹ HNMR (CDCl ₃ , 60MHz): 1.2 (t, J = 8
Hz, 3H), 2.65 (s, 3H), 3.95 (s, 2H), 4.1
(q, J=8Hz+2H), 5.75 (s, 2H), 7.4−8.3
(m, 7H)]. Example 23 3-(5-sulfonylmethylbenzothiazole-
Ethyl 2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate (5-thiomethylbenzothiazol-2-ylmethyl-4-oxo-3H-phthalazin-1-ylacetate (1.06 g) and meta- A solution of chloroperbenzoic acid (1.3 g) in chloroform (50 ml) was stirred at room temperature for 1 hour. The solution was washed with 10% aqueous sodium bicarbonate and the organic extract was dried and evaporated to give a pale yellow solid. Obtained (0.85g;
¹ HNMR (CDCl ₃ , 60MHz): 1.2 (t, J=Hz,
3H), 3.1 (s, 3H), 4.0 (s, 2H), 4.15 (q, J
=8Hz, 2H), 5.85 (s, 2H), 7.4-8.3 (m,
7H). Example 24 3-(5-trifluoromethyl-2-α-methylbenzothiazolyl)-4-oxo-3H-phthalazin- _1yl acetic acid (I; _R1 = _OC2H5 ; _R3 = _R4 =
H; R ₅ = CH ₃ ; R ₂ = 5-trifluoromethyl-
2-benzothiazolyl) A 1-(2-benzothiazolyl) ethyl chloride Chlorification of 1-(2-benzothiazolyl) ethanol synthesized according to J. Indian Chem. Soc., 566 (1974) Thionyl chloride (3.32g) was added to a solution in methylene (50ml) and the resulting solution was stirred at room temperature for 1 hour. The solution was poured into ice water (100ml) and the organic layer was separated. The extract was washed with 5% aqueous sodium bicarbonate (10ml) and then water (50ml). The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated to give a pale yellow oil (2.08 g). B 1-(5-trifluoromethyl-2-benzothiazolyl)ethanol mesylate 1-(5-trifluoromethyl-2-benzothiazolyl)ethanol (mp93-97℃, 4.94g)
Anhydrous pyridine solution was cooled on ice, methanesulfonyl chloride (4.58 g) was added, and the resulting solution was heated to 0°C.
The mixture was stirred for 1 hour. It was poured into water, extracted with ether and the ether layer was washed with 10% hydrochloric acid (2 x 20ml). The organic extract was dried and evaporated, and the residue was triturated in hexane to give the desired compound as a solid (5.89 g; mp 89°C). Ethyl 4-oxo-3H-phthalazin-1-yl acetate (2.34 g) and sodium hydride (0.53
g; 50% w/w dispersion in mineral oil) in dimethylformamide (25 ml) was stirred at room temperature under a stream of air for 30 minutes. To the resulting solution was added 1-(5-trifluoromethyl-2-benzothiazolyl) ethanol mesylate (3.2 g) in dimethylformamide (5 ml).
The solution was added and the reaction mixture was stirred for a further 1 hour and poured onto ice water (50ml). 10% hydrochloric acid was added to the mixture to adjust the pH to 4.0, and ethyl acetate (100%
ml). Wash the extract with water (50ml),
It was dried over anhydrous magnesium sulfate and evaporated. The combined product was purified by silica gel chromatography eluting with ethyl acetate-chloroform (5/95% mixture) and the eluate was evaporated to give the title compound (2.0
g; mp105-106°C) was obtained. Example 25 3-(Benzothiazol-5-ylmethylbenzolyl)-4-oxo-phthalazin-1-ylacetic acid A Gazz.Chim.
Example 1C, starting from 5-methylbenzothiazole prepared according to Ital., 95499 (1965).
5-bromomethylbenzothiazole was synthesized in the same manner as above. The product showed the following NMR spectrum (60MHz, CDCl ₃ ): 4.6(s,
2H), 7.4 (dd, 1H, J=10HzJ=2Hz), 7.85
(d, 1H, J=10Hz), 8.15 (d, J=2Hz),
9.0 (s, 1H). B Ethyl 3-(5-methylbenzothiazolyl)-4-oxo-3H-phthalazin-1-ylacetate synthesized according to Example 1D had the following NMR spectrum (60MHz, _CDCl3 ): 1.2 (t,
J=8Hz, 3H), 3.95(s, 2H), 4.2(q, J=
8Hz, 2H), 5.6 (s, 2H), 7.2-8.2 (m, 7H),
9.0 (s, 1H). C The title compound (mp203-
204℃) was synthesized. Example 26 Ethyl 3-(5-fluorobenzothiazolyl-2-ylmethyl)-4-oxo-phthalazin-1-ylacetate Ethyl 4-oxo-3H-phthalazin-1-ylacetate (2.34 g) in dimethylformamide (15
ml) solution was added sodium methoxide (0.51 g). The mixture was stirred for 5 minutes and the resulting clear yellow solution contained 5-
A solution of fluoro-2-chloromethylbenzothiazole in dimethylformamide (5ml) was added.
The resulting solution was stirred for 1 hour, then poured into ice water (50ml) and extracted with methylene chloride. Evaporation of the organic extract gave a pale orange solid, which crystallized from ethanol to give the title compound (3.84 g, mp118-120
°C) was obtained. Example A In Table 5, the first two intermediates were synthesized according to the method of US Pat. No. 4,251,528 and the remaining intermediates were synthesized according to the method of Example 13C.

【table】

TABLE Example B The following intermediates were synthesized according to Example 1C unless otherwise indicated. All melting points are in °C.

【table】

Table: Example C The following intermediates were synthesized by the methods described in the prior art or by the method of Example 1B.

【table】

[Table] Example D 5-(2-chlorophenyl)-2-chloromethyl-1,2,4-oxidiazole A O-2-chlorobenzoyl-chloracetomidoxime Chloracetamidoxime (5g) was dissolved in warm benzene (20ml). Dissolve and carefully add 2-chlorobenzoyl chloride (6.4ml). The resulting mixture was heated at 40° C. for 30 minutes to remove excess benzene. After cooling to room temperature, the solidified mass was rubbed in cold benzene and filtered to give the compound (1.6 g;
mp126−130°C) was obtained. B O-2-chlorobenzoyl-chloroacetamide oxime (1.4 g) was refluxed diglyme (10 ml)
was added and reflux was continued for 10 minutes. After cooling, the reaction mixture was dissolved in water (20 ml) containing ether (50 ml).
poured into. The ether layer was combined with water (2 x 50 ml) and saturated aqueous sodium bicarbonate solution (2 x 10 ml).
The organic layer was dried and distilled off. The residue was purified by silica gel chromatography to produce a colorless oil (0.8 g).
was gotten. ¹ HNMR (CDCl ₃ , 60MHz): 4.7 (s, 2H),
7.45 (m, 3H), 8.1 (m, 1H). Example E Commercially available 2-amino-3-hydroxypyridine (5.0 g) and diglyme (30 ml) were heated to 125°C to give a solution. Add 2-chloro- to this solution.
1,1,1-triethoxyethane (9.9g) was added and the resulting mixture was heated to 125°C for 1 hour.
The solution was cooled to room temperature and decanted to remove the black by-product residue. The solution was diluted with water (50 ml) and the resulting yellow precipitate of 2-chloromethyl-oxazolo[4,5-b]pyridine (1.5 g) was collected.
A small sample was crystallized from isopropanol (mp115-18°C). 3-amino-2-mercaptopyridine (3.6
g) 2-chloromethyl-thiazolo[5,4-b]pyridine by heating a mixture of 2-chloro-1,1,1-triethoxyethane (6.5g) and ethanol (60ml) to 60°C for 4 hours. was synthesized in the same manner. Similarly, 2-amino-4-trifluoromethylthiophenol hydrochloride and 2-chloro-1,
2-chloromethyl-5-trifluoromethylbenzothiazole (mp52°C) was synthesized from an ethanol solution of 1,1-triethoxyethane. Example F An intermediate of formula Hal-CH ₂ R ₂ was synthesized by the method below or by the method of Example E.

【table】

[Table] Example G Benzoate of 4-phenylthiazole-2-methanol (7.4 g) synthesized according to J. Am. Chem. Soc., 53, 1470 (1931) was dissolved in anhydrous tetrahydrofuran (50 ml). . Lithium aluminum hydride (525 mg) was added to this solution and stirred at room temperature for 1 hour. Carefully decompose the excess lithium aluminum hydride with ethyl acetate, pour the mixture onto ice water (50 ml) and dilute with 10% HCl.
Adjusted to PH3. The mixture was filtered and the liquid extracted with ether (3 x 50ml). The organic extract was dried and evaporated, and the crude product was purified by chromatography to obtain 4-phenylthiazole-2-methanol (1.8 g). This compound was converted to 4-phenyltisol-2-methanol, methanesulfonate according to the method described in Example 24B. The melting point of the product was 80°C. Example H The following intermediates were prepared according to the method of Helvitica Chimica Acta, 49412 (1966), except that the last two intermediates were prepared according to the method of Journal of the Medicinal Chemistry (J.Med.Chem.), 49412 (1966).
351 (1961).

[Table] Example J A solution of 5-chloro-2-hydroxyniline (10 g) and chloroacetamidic acid ester hydrochloride (8.5 g) in chloroform (100 ml) was refluxed for 5 hours. The dark brown solution was filtered and washed first with 10% aqueous potassium hydroxide (10ml) and then with water (20ml). The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography (yield 8.6 g; mp53-
56℃). The following intermediates were also synthesized as described above.

[Table] Example K A 1,1,1-triethoxyethane (97.3g)
and N-chlorosuccinimide (88.1 g) in carbon tetrachloride (600 ml) was warmed to 40°C and then
Irradiated with a UV lamp. The reaction becomes exothermic,
When the reaction was completed, the condition subsided. The precipitated succinimide byproduct was filtered off and the liquid was concentrated to remove carbon tetrachloride. Distillation of the remaining liquid yielded pure 2-chloro-1,1,1-tricyethane (91.0 g; bp 91°C/25 mm). B A solution of 2-chloro-1,1,1-trixiethane (5.9 g) and 2-aminothiophenol (2.5 g) was heated to 80<0>C for 15 minutes. After cooling to room temperature, it was dissolved in methylene chloride (30 ml) and the resulting solution was dissolved in 3NHCl (10 ml) and water (20 ml).
ml). The organic layer was distilled off, and the residue was purified by silica gel chromatography to obtain 2-chloromethylbenzothiazole (3.35
g, yield 90%; mp34°C) was obtained. Example L 2-chloromethyl-5-bromobenzothiazole Crude 2 synthesized according to JACS, 53209 (1931)
A mixture of -amino-4-bromthiophenol tin hydrochloride complex (71.6 g), 2-chloro-1,1,1-triethoxyethane (58.7 g) and ethanol (400 ml) was gently refluxed for 30 minutes. . 3NHCl (10 ml) was added to the hot solution and the precipitated solid was collected, washed with water and dried to yield the title compound (35.5
g; mp107°C) was obtained. Example M A 2-amino-4-trifluoromethylthiophenol hydrochloride Commercially available 4-chloro-3-nitrobenzotrifluoride (100 g) was dissolved in ethanol (400 ml). To this solution was added dropwise a solution prepared by first adding sodium sulfide hydrate (80 g) and then sulfur (9.6 g) to hot ethanol (200 ml). After the initial exothermic reaction subsides, the reaction mixture is
It was refluxed for 30 minutes and cooled to room temperature. The precipitated yellow solid was collected, washed with cold ethanol, and then dried to yield 4,4'-ditrifluoromethyl-2,2'-dinitrophenyl disulfide (63.0 g; mp152
-154℃) was obtained. This compound (62g), metal tin (20 mesh, 132.0g), ethanol (500g),
ml) and concentrated HCl (200 ml) was gently refluxed at 80°C to form a solution. The reaction was then held at 70°C for 30 minutes, the warm solution was filtered, and the liquid was concentrated under reduced pressure to obtain a viscous liquid. To this was added 6NHCl and the precipitated white solid was filtered to give the title compound (49.0 g; mp 208-209°C). B 2-chloromethyl-5-trifluoromethylpenzothiazole 2-amino-4-trifluoromethyltriphenol hydrochloride (30.0 g) in ethanol (125 ml)
2-chloro-1,1,1-triethoxyethane (31.0 g) was added to the solution. the mixture for 1 hour
The solution was heated to 60°C, concentrated to remove excess ethanol, and the residue was extracted with ether (500ml).
The organic extract was mixed with 10% HCl (20ml), water (100ml),
10% aqueous sodium bicarbonate solution and water (100ml)
After washing and evaporation, a yellowish brown oil was obtained, which crystallized upon standing at room temperature (28.9 g; mp 52°C). Example N 2-Chloromethyl-5,7-dichlorobenzoxazole A first black solution of 2,4-dichloro-6-nitrophenol (10.0 g) in water (450 ml) containing sodium bicarbonate (4.8 g) Sufficient sodium dithionate was added to render the solution colorless. The hot reaction mixture was filtered and the liquid cooled to room temperature to yield the crystalline product, 2-amino-
4,6-dichlorophenol (1.6g) was obtained. Dissolve the 2-amino-4,6-dichlorophenol (1.6 g) in ethanol (5 ml),
-Chloro-1,1,1-triethoxyethane (1.9g) was added. The resulting solution was placed on a steam bath.
After warming for 1.5 hours and cooling to room temperature, add cold water (5 ml)
was added. The precipitated solid was collected and air dried to give the title compound (1.12g; mp52-53°C). Example O 2-chloromethyl-5-bromobenzoxazole 2-amino-4-bromophenol (1.6 g) synthesized according to U.S. Pat. No. 4,157,444 was dissolved in ethanol (5 ml) and 2-chloro-1,1 ,1
-Triethoxyethane (1.9g) was added. The resulting solution was warmed on a steam bath for 1.5 hours and after cooling to room temperature cold water (5 ml) was added. The precipitated solid was collected and air-dried to yield the product (1.12 g; mp63−
65℃) was obtained. Example P Commercially available 2-
2-chloromethyl-5-chlorobenzoxazole (mp53-56°C) was synthesized from amino-4-chlorophenol using ethanol or chloroform instead of methylene chloride as a solution.
Similarly, 2-amino-4-methylthiophenol hydrochloride and 2-amino-4-
2- respectively from fluorothiophenol hydrochloride
Chloromethyl-5-methylbenzothiazole (mp65-66℃) and 2-chloromethyl-5-
Fluorobenzothiazole (mp73℃) was synthesized. Example Q 5-chloromethyl-2-phenyl-1,3,4
-Oxadiazole A mixture of 2-chloro-1,1,1-triethoxyethane (4.8g), benzoylhydrazine (3.0g) and ethanol (30ml) was refluxed for 2 hours and the solution was cooled to room temperature. A few drops of 10% HCl in water (10 ml) were added to the precipitated white crystalline solid. The mixture was stirred for 10 minutes and then filtered to collect the solids. The mother liquor was evaporated to dryness and the residue was triturated in water and filtered to give a second crop of white solid. The combined yield of the two products was 3.8 g (89%; ¹ HMR Chem.Ber.96,
1049 (1969)).

Claims (1)

[Claims] 1 formula [wherein Z is a covalent bond or S; R ₁ is a hydroxy or (C ₁ -C ₄ ) alkoxy group; R ₂ contains one nitrogen and one oxygen or sulfur, or contains two a five-membered heterocyclic ring containing nitrogen and one oxygen or sulfur, the ring being substituted with one (C ₁ -C ₄ ) alkyl, pyridyl or phenyl, or fused with benzo. ,
The phenyl or benzo optionally contains one or two fluoro, chloro or bromo, or one ( _C1 - _C4 )alkyl, ( _C1 - _C4 )alkoxy,
Substituted with (C ₁ -C ₄ )alkylthio, (C ₁ -C ₄ )alkylsulfinyl, (C ₁ -C ₄ )alkylsulfonyl or trifluoromethyl; chlorobenzothiophene; quinoline; quinazoline; pyridine and Condensed oxazole, thiazole or 7
-chloro-imidazole; R ₃ and R ₄ are the same or different, hydrogen, fluoro, chloro, bromo, trifluoromethyl,
(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy or nitro; R ₅ is hydrogen or methyl] or a compound of the formula wherein R ₁ is hydroxy. addition salt, or R ₁ is di(C ₁ −
Acid addition salts of compounds of formula wherein _C4 )alkylamino or N-morpholino or di( _C1 - _C4 )alkylamino is substituted ( _C1 - _C4 )alkoxy. 2. The compound according to claim 1, wherein R ₂ is optionally substituted benzothiazolyl, benzoxazolyl, benzothiophenyl or benzofuranyl, substituted oxadiazolyl or indolyl. 3 Z is a covalent bond, R ₁ is hydroxy, R ₂ is optionally substituted benzothiazol-2-yl, benzothiazol-5-yl, benzothiazol-
3-yl, benzoxazol-2-yl, 2-
Quinolyl, oxazolo[4,5-b]pyridine-
2-yl, benzothiophen-2-yl, benzofuran-2-yl or thiazolo[4,5-b]
pyridin-2-yl, or substituted 1,
2,4-oxadiazol-3-yl,1,2,4
-oxadiazol-5-yl, isothiazol-5-yl, isothiazol-4-yl, 1,
3,4-oxadiazol-5-yl,1,2,
5-thiadiazol-3-yl, oxazol-2-
yl, thiazol-2-yl or thiazol-4-
The compound according to claim 1, wherein R ₃ , R ₄ and R ₅ are hydrogen. 4 Claims in which R ₂ is 2-benzothiazolyl substituted at the benzo site by one trifluoromethylthio or one or two chloro, bromo, methyl, methoxy, trifluoromethyl or 6,7-benzo A compound according to item 1 or 2. 5 R ₃ is hydrogen, 5-fluoro, 5-chloro, 5
-bromo or 5-methyl, R ₄ is hydrogen; 6-
or chloro, bromo, methyl, isopropyl, methoxy, nitro or trifluoromethyl at the 7-position; R ₃ and R ₄ are 4,5-difluoro or 5,7-dichloro, according to claim 1 or 2 compound. 6 R ₂ is optionally substituted benzothiazole-2
3. The compound according to claim 1 or 2, wherein R ₃ and R ₄ are each chloro. 7. The compound according to claim 1, which is in the form of a sodium salt or an N-methylglucamine salt. 8 formula [wherein Z is a covalent bond or S; R ₁ is hydroxy or (C ₁ -C ₄ )alkoxy; R ₂ contains one nitrogen and one oxygen or sulfur, or contains two a five-membered heterocyclic ring containing nitrogen and one oxygen or sulfur, the ring being substituted with one ( _C1 - _C4 ) alkyl, pyridyl or phenyl, or fused with benzo;
The phenyl or benzo optionally contains one or two fluoro, chloro or bromo, or one ( _C1 - _C4 )alkyl, ( _C1 - _C4 )alkoxy,
Substituted with (C ₁ -C ₄ )alkylthio, (C ₁ -C ₄ )alkylsulfinyl, (C ₁ -C ₄ )alkylsulfonyl or trifluoromethyl; chlorobenzothiophene; quinoline; quinazoline; pyridine and Condensed oxazole, thiazole or 7
-chloro-imidazole; R ₃ and R ₄ are the same or different, hydrogen, fluoro, chloro, bromo, trifluoromethyl,
(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy or nitro; R ₅ is hydrogen or methyl] or a compound of the formula where R ₁ is hydroxy. Addition salt, or R ₁ is di(C ₁ −C ₄ )
Alkylamino or N-morpholino or di(C ₁ -C ₄ )alkylamino substituted (C ₁ -C ₄ )
A composition for inhibiting aldose reductase activity comprising an acid addition salt of an alkoxy compound of the formula and a pharmaceutically suitable carrier.