DD254001A5 - PROCESS FOR THE PREPARATION OF HETEROCYCLIC OXOPHTALAZINYL ACIDES - Google Patents

Abstract

A heterocyclic oxo-phthalazinyl acetic acid having aldose reductase inhibitory activity of the formula wherein X is oxygen or sulfur, Z is a covalent bond, O, S, NH or CH 2, R 1 is hydroxy or a prodrug group, R 2 is a heterocyclic group R3 and R4 are hydrogen or the same or a different substituent and R5 is hydrogen or methyl. Further, the pharmaceutically acceptable acid addition salts of the above compounds in which R1 is di (C1-C4) alkylamino or (C1-C4) alkoxy substituted by N-morpholino or di (C1-C4) alkylamino can be prepared and the pharmaceutically active base addition salts of the above compounds in which R 1 is hydroxy; These addition salts also have aldose reductase inhibitory activity. Formula I

Description

Process for the preparation of heterocyclic O Field of application of the invention

This invention relates to the preparation of new heterocyclic Oxophthalazinyl-acetic acid, which functions in the treatment of certain chronic complications arising from diabetes mellitus f are as diabetic cataracts, retinopathy and neuropathy, suitable; it further relates to pharmaceutical ^ compositions containing these compounds, and a method of using these compounds. -

Characteristic of known technical solutions In the past, various attempts have been made to obtain more effective oral antidiabetic agents. In general, these efforts have involved the synthesis of novel organic compounds, particularly sulfonylureas, and the determination of their ability to significantly lower blood glucose levels when administered orally. However, little is known about the effect of organic compounds in preventing or ameliorating chronic complications of diabetes, such as diabetic cataract, neuropathy and retinopathy. US Pat. No. 3,821,383 describes aldose reductase inhibitors such as 1,3-dioxo-1H-benz / d, e / -isoquinoline-2- (3H) -acetic acid and derivatives thereof which are said to be useful in the treatment of these disorders. U.S. Patent 4,226,875 teaches the use of spiro-oxazolidinediones in the treatment of diabetes complications as aldose reductase inhibitors. These aldose reductase inhibitors act by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses such as glucose and galactose to the corresponding polyols such as sorbitol and galactitol in humans and animals. In this way, unwanted accumulations of galactitol in the lens of galactosemic patients and sorbitol in the

Lens, the peripheral nerves and kidneys of different gm

Diabetes patients are prevented or reduced. Thus, these compounds are useful as aldose reductase inhibitors for controlling certain chronic diabetic complications, including those in the eye, of therapeutic value since, as is known, the presence of polyols in the lens of the eye

-5.11.36- 38507,

Cataract formation with concomitant loss of lens clarity leads.

U.S. Patent 4,251,528 discloses aromatic carbocyclic oxophthalazinyl acetic acids having aldose reductase inhibiting properties. The patent mentions that 2- (2-pyrid-2-yl-ethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid does not inhibit aldose reductase. Heterocyclic oxophthalazinyl acetic acids and their ethyl esters having an effect on the blood coagulation system are described in Chemical Abstracts 73, 77173y (1970).

The aim of the invention According to the inventive method are compounds having the formula

CH ₂ COR ₁

wherein X is oxygen or sulfur;

Z is a covalent bond, O, S, NH or CH_; R, is hydroxy or a prodrug group; R "is a heterocyclic 5-membered ring having one nitrogen, oxygen or sulfur atom, two nitrogen atoms, one of which may be replaced by oxygen or sulfur, or three nitrogen atoms, one of which may be replaced by oxygen or sulfur, where Ring may be condensed by one or two Fluoi?, Chloro, (C '-C.) - Alkyl or phenyl groups, or r.iit-benzo, or may be substituted by a pyridyl, furyl or thienyl group, wherein the phenyl or benzo group may optionally be substituted by an iodo or trifluoromethylthio group, or by one or two fluoro, chloro, bromo, (C, -C) alkyl,

, (C ₁ -C ₄ ) -alkylthio, (C ₁ -C ₄ ) -alkylsulfinyl-,

(C, -C.) - Alkyl sulfonyl or trifluoromethyl groups may be substituted, wherein pyridyl, furyl or thienyl in the 3-position optionally substituted by fluorine, chlorine, bromine, (C, -C.) -Alkyl or (C, - C) -alkoxy may be substituted; a heterocyclic 6-membered ring containing one to three nitrogen atoms or one or two nitrogen atoms and one oxygen or sulfur atom and the ring may be substituted by one or two (C.-C ₄₎ alkyl or phenyl or condensed with benzo, or by a pyridyl, furyl or thienyl group may be substituted, wherein phenyl or benzo optionally substituted by an iodo or Trifluormethylthiogruppe or by one or two fluoro, chloro, bromo, (C, -C) alkyl, (C , -C) alkoxy, (C ₁ -C ₄ ) alkylthio, (C ₁ -C ₄ ) alkylsulfinyl, (C ₁ -C ₄ ) alkylsulfonyl or trifluoromethyl groups, and wherein pyridyl , Furyl or thienyl optionally substituted in the 3-position by fluorine, chlorine, (C, -C) alkyl or (C, -C) alkoxy; Oxazole or

Thiazole condensed with a 6-membered aromatic group containing one or 2 nitrogen atoms, or with thiophene or furan, each of which may optionally be substituted by a fluoro, chloro, bromo, trifluoromethyl, methylthio or methylsulfinyl group;

imidazolopyridine; Naphthothiazole or naphthoxazole; R ^ and R are identical or different and denote hydrogen, fluorine, chlorine, bromine, trifluoromethyl, (C, -C) alkyl, (C ₁ -C ₄ J -alkoxy, (C ₁ -C ₄₎ alkylthio, ( C ₁ -C ₄ ) -alkylsulfinyl, (C ₁ -C ₄ ) -alkylsulfonyl or nitro, or R- and R ₄ , taken together, are (C ₁ -C ₄ ) -alkanedioxy and R is hydrogen or methyl;

According to the invention, there are further prepared a pharmaceutically acceptable base addition salt of a compound of formula I, wherein 'R is hydroxy, or an acid addition salt of a compound of formula I, wherein the prodrug R-group. Di (C ₁ -C ₄ ) alkylamino or (C ₁ -C ₄ ) alkoxy substituted by N-morpholino or di (C ₁ -C ₄ ) alkylamino.

Specific compounds prepared according to the invention are those in which X is oxygen and those in which R is optionally substituted benzothiazolyl, benzoxazolyl, isoquinolyl, benzothiophenyl, benzofuran-yl or benzimidazolyl or substituted oxadiazolyl or indolyl.

Preferred compounds prepared according to the invention are those in which X is oxygen, Z is a covalent bond or CH, R is hydroxy, R is optionally substituted benzothiazol-2-yl, benzothiazol-5-yl, benzoisothiazol-3-yl, benzoxazole-2 -yl, 2-quinolyl, 2-quinoxalyl, oxazolo / 4, 5-by- ^7- pyridin-2-yl, benzothiophene-2-yl, benzofuran-2-yl or thiazolo / 4, 5b / -pyridine-2-yl 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-yl, and R-, R. uhd Rj. Mean hydrogen.

Further preferred compounds are those in which the methylene bridge connecting the oxophthalazinyl group with R 1 is in the position to a nitrogen atom in R 1, e.g. wherein R "is the above-mentioned benzoxazol-2-yl or 1,2,4-oxadiazol-3-yl.

Further specific compounds prepared according to the invention are those in which R 2-benzothiazolyl wherein the benzo group is substituted by a trifluoromethylthio group or one or two chloro, bromo, methyl, methoxy, trifluoromethyl or 6,7-benzo groups, or those in which R is hydrogen, 5-fluoro, 5-chloro, 5-bromo or 5-methyl and R is hydrogen, 6- or 7-substituted chlorine, bromine, methyl, isopropyl, methoxy, nitro or trifluoromethyl, 4,5-difluoro or 5,7-dichloro, and those in which R is optionally substituted benzothiazol-2-yl or quinoxalyl and R. and R. are each chloro. Specific, preferably prepared compounds of formula I are

Sf \

3- (5-Bromo-2-benzothiazolylmethyl) - 1-oxo-BH-phthalazin-1-ylacetic acid, 3- (5-fluoro-2-benzothiazolylmethyl) -4-oxo-3H-phthalazin-1-yl-acetic acid , 3- (5-trifluoromethyl-2-benzothiazolylmethyl) -4-oxo-SH-phthalazin-1-yl-acetic acid, 3- (5-chloro-2-benzothiazolylmethyl) -4-oxo-3H-phthaiazin-1-yl -acetic acid, 3- (4,5-difluoro-2-benzothiazolylmethyl) -4-oxo-3H-phthalazin-1-yl-acetic acid, 3- (5,7-dichloro-2-benzothiazolylmethyl) -4-oxo-3H-phthalazine -l-yl-acetic acid and 3- (4,7-dichloro-2-benzothiazolylmethyl) -4-oxo-phthalazin-1-yl-acetic acid.

The present invention further relates to the preparation of a composition for inhibiting aldose reductase activity comprising a compound of formula I in an amount effective to inhibit aldose reductase activity in admixture with a pharmaceutically acceptable carrier. Specific and preferred compositions contain the above-described specific and preferred compounds of formula I.

The present invention further relates to a method of treating a diabetic patient, whether human or animal, for diabetes-associated complications, by administering to the subject an effective amount of a compound of Formula I, especially those specific and described above be prepared prepared compounds of formula I.

Explanation of the essence of the invention

The process according to the invention for preparing a compound of the formula I defined above is characterized in that a compound of the formula

with a compound of the formula

R - Z-CHOSO-R,

wherein R, (C, -C.) - Alkoxy, X, Z, R ₂ , R ₃ , R and R are each as defined in claim 1 and R (C, -C.) - Alkyl, trifluoromethyl or Phenyl, optionally substituted by methyl, chlorine, bromine or nitro means.

The numbering sys / * the Compounds of Formula I is like follows: 8th W Xi *> * »^ \ ~ * Xv« I I A ^3N ^ y ^ch 2 ^r 2 5 X

The term "(C ₁ -C 8) -alkyl" as used in the definitions of R ₁ to R ₁ denotes saturated monovalent straight or branched chain aliphatic hydrocarbon radicals having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, t-butyl etc.

The term "prodrug" means a group that is converted in vivo to the active compound of formula I wherein R is hydroxy. Such groups are well known in the art and include ester forming groups to form an ester drug precursor, such as benzyloxy, di- (C, -C.) Alkylaminoethyloxy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl, 5-methyl-2-oxo-1 , 3-dioxol-4-ylmethyl and (C, -C.) -Alkoxy, optionally substituted by N-morpholino, and amide-forming groups, such as di- (C, -C.) -Alkylamino.

The heterocyclic 5-membered ring having 1 to 3 heteroatoms, one of which may be replaced by oxygen or sulfur, includes imidazolyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl.

The heterocyclic 6-membered ring having 1 to 3 nitrogen atoms or 1 or 2 nitrogen atoms and one oxygen or sulfur atom includes triazinyl, pyrimidyl, pyridazinyl, oxazinyl and triazinyl.

The heterocyclic ring may be condensed with benzo to bond to 2 adjacent carbon atoms to form a phenyl group. Such a benzo-heterocyclic ring may be bonded to Z either through the heterocyclic group or through the benzo group of the benzo-heterocyclic ring. The preparation of the compounds in which Z is attached to the benzo group is illustrated in Reaction Scheme B below. Specific examples in which the heterocyclic ring is condensed with a benzo group include benzoxazolyl, · quinazolin-2-yl, 2-benzimidazolyl, quinazolin-4-yl, and benzothiazolyl. The oxazole or thiazole groups condensed with a 6-membered aromatic group containing 1 or 2 nitrogen atoms include spherical isomers, such as oxazolo / 4,5-b / pyridin-2-yl, thiazolo / 4,5 -b / -pyridin-2-yl, oxazolo / 4,5-c / pyridin-2-yl, thiazolo / 4,5-c / pyridin-2-yl, oxazolo / 5, 4-b / pyridine 2-yl, thiazolo / 5,4-b / -pyridin-2-yl, oxazolo / 5, 4-c / -pyridin-2-yl and thiazolo / 5,4-c / -pyridin-2-yl.

According to the invention, the compounds are prepared as shown in Reaction Scheme A.

Phthalic anhydride and its derivatives of formula II are either commercially available or can be prepared by standard methods. The compounds of formula III, wherein R ^{1 is} ethyl or methyl, can be prepared by reacting the compounds II with (carbethoxymethylene) -triphenylphosphorane or (carbomethoxymethyl) -triphenylphosphorane in the Wittig reaction, which in the prior art, for example, in US Pat. No. 4,251,528 and Tetrahedron Letters, 1965, 2357.

Λ It ;? " Ϊ

The compounds of formula IV in which R 'is methyl or ethyl can be formed by reacting the compounds III with hydrazine as described in US Pat. No. 4,251,528. The reaction is preferably carried out in an aqueous solvent, for example aqueous ethanol, dioxane or dimethylformamide, and at 40 to 12O ⁰ C, preferably at reflux temperature. .

The compounds of formula V are formed by reaction of compounds IV in which R 'is hydrogen, methyl or ethyl, with L-CH-ZR ₀ , where L is a separating one

^R 5 group is that can form the compound LH after reaction with the two reagents. L is, for example, chlorine, bromine or OSO _n R ^, wherein R _{r is} (C, -C) alkyl, trifluoromethyl, phenyl or

ZO D i 4

Phenyl, substituted by methyl, chlorine, bromine or nitro, is

REACTION SCHEME A

II

III

IV

α ι, -

In the reaction of compounds IV, in which R 'is methyl or ethyl, the process is generally carried out in a polar solvent, for example an alkanol having 1 to 4 carbon atoms, such as methanol or ethanol, dioxane, dimethylformamide or dimethyl sulfoxide, in the presence of a Base. Suitable bases are alkali metal hydrides or alkoxides having from 1 to 4 carbon atoms, such as sodium or potassium hydride, methoxide or ethoxide. "When using a hydride, a non-aqueous solvent such as dimethylformamide is required. in which R 'is hydrogen (obtained by hydrolysis of compounds IV in which R ^{1 is} methyl or ethyl), at least molar equivalents of the base must be present since the first molar equivalent reacts with the carboxylic acid residue of such a compound Compounds are further preferred to use a hydroxylic solvent to minimize the formation of a corresponding ester.

The reaction to form the compounds V, in which R is alkyl, is preferably carried out with compounds of the formula

L-CH-Z-R_nwhere L is OSO₀R ,. where R 1 is as defined aboveSecond Zo b

^R 5 is ned. This reaction is generally carried out in an inert atmosphere, such as nitrogen, in an aprotic polar solvent, such as dimethylformamide, at temperatures of from 20 to 50 ^° C.

The reaction to form compound V may be at room temperature or, to speed up the process, at higher temperatures.

The compounds of formula I in which R ^{1 is} methyl or ethyl may be hydrolyzed to form the compounds of formula I wherein R is hydrogen. The hydrolysis is carried out at ordinary temperatures and in the presence of e'iner

9 K η η ι

Acid or base, e.g. 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 the presence of water and a solvent, e.g. an alkanol having 1 to 4 carbon atoms, such as methanol, or dioxane.

The compounds of formula I in which R is hydroxyl can be prepared by conventional methods, eg reaction of the corresponding acid chloride, bromide or anhydride with R ₁ H to give the compounds I in which R, an ester-prodrug group is to be esterified. Alternatively, the compounds of formula I in which R, an ester prodrug group, can be prepared by alkylating a solution of the sodium salt of a compound I in which R _{1 is} hydroxy. The alkylating agent may be a chloride. For example, when R _{1 is} benzyloxy, acetoxymethyl or pivaloyloxymethyl, then the alkylating agent is benzyl chloride, chloromethyl acetate and chloromethyl pivalate, respectively. The above sodium salt is generally prepared in situ by reacting a compound I in which R _{1 is} hydroxy with a sodium salt-forming compound such as sodium bicarbonate, sodium hydride or sodium t-butylammonium sulfate in a non-aqueous solvent such as dimethylformamide or methylpyrrolidone.

When R 1 in compounds of formula I is an amide prodrug group, eg, di- (C ₁ -C 4) alkylamino, then a compound I in which R, (C ₁ -C.) - Alkoxy is converted to the corresponding amide by reaction with an amine, eg di- (C ₁ -C) -alkylamine.

The compounds of formula I in which X is sulfur are prepared by reacting the corresponding compounds I in which X is oxygen by known methods, e.g. by reaction with phosphorus pentasulfide, thiaziert.

The compounds of the formula L-CH-Z-R- ,, wherein L is chlorine,

Z is a covalent bond, R is hydrogen and R oxazole or thiazole condensed with Y, where Y is a 6-membered aromatic group containing 1 or 2 nitrogen atoms, or with thiophene or furan, each optionally substituted by a fluoro, Chloro, bromo, trifluoromethyl, methylthio or methylsulfinyl group, or 1,2,4-oxadiazol-3-yl or 1,2,4-thiadiazol-3-yl, optionally substituted by R_, wherein R ₇ Iodine or trifluoromethylthio or one or two fluorine, chlorine, bromine, (C ₁ -C ₄ -alkyl) -, (C ₁ -C ₄ -alkyl-, (C ₁ -C ₄ ) -alkylthio-, ( C, -C) alkylsulfinyl, (C, -C) alkylsulfonyl or trifluoromethyl groups, can be prepared by reacting compounds of the formula

or

VI VII

wherein X is O or S and Y and R are as defined above, with tri - ((C, C) alkoxy) CH_C1. The reaction is generally carried out in a reaction inert solvent, e.g. a (C, -C) -alcohol, such as ethanol, halocarbons, such as chloroform or methylene chloride, or ethereal solvents, such as diglyme. The reaction temperature is in the range of about room temperature to the reflux temperature of the solvent used. The reaction time may be from about 15 minutes to about 2 hours or more.

The starting materials VI and VII are either commercially available or can be prepared by standard methods as described e.g. in J. Am. Chem. 53, 309 (1935) and J. Org. Chem. 29, 2652 (1964).

The tri - ((C 1 -C 4) alkoxy) CH Cl compounds are either known or can be prepared by reacting 1,1,1-trialkoxyethane with N-chlorosuccinimide or with chlorine in pyridine and a chlorohydrocarbon solvent. The first chlorination reaction is generally carried out in a solvent, suitably a non-polar solvent, for example carbon tetrachloride or tetrachlorethylene. The reaction is conveniently carried out at temperatures of about 40 ⁰ C to about the reflux temperature of the solvent. The reaction with chlorine in pyridine must be carried out in the presence of a chlorohydrocarbon solvent having one or more chlorine atoms and one to six carbon atoms, for example methylene chloride, chloroform or trichloroethane.

Scheme B illustrates the preparation of 3- (benzothiazol-5-ylmethyl) -4-oxo-phthalazin-1-yl-acetic acid, which is a compound in which R_ is a benzo-heterocyclic ring wherein the benzo group is in the final Compound is attached to the methylene bridge. Other such compounds in which R "is a benzo-heterocyclic ring wherein the benzo group is attached to the Z in the final compound can be prepared by a similar method. In Scheme B, 5-methylbenzothiazole is reacted with a brominating agent such as N-bromosuccinimide to give 5-bromomethylbenzothiazole, which is then reacted with 4-oxo-3H-phthalazin-1-yl acetate to give ethyl 3- (5- methylbenzothiazolyl) -4-oxo-3H-phthalazin-1-yl acetate is reacted under conditions as described above with reference to Reaction Scheme A for the conversion of compounds IV into compounds V.

REACTION SCHEME B

The pharmaceutically acceptable base addition salts of compounds I in which R 1 is hydroxy can be formed by conventional methods with pharmaceutically acceptable cations. Thus, these salts can be readily prepared by treating the compound of formula I with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a lower alkyl alcohol solution of the compound of formula I may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness. Suitable pharmaceutically acceptable cations for this purpose are e.g. et al Alkali metal cations, such as potassium and sodium, ammonium or water-soluble amine * addition salts, e.g. N-methylglucamine (meglumine), the low A1kano1ammonium- and other base salts with organic amines, which are pharmaceutically acceptable, and

14 alkaline earth metal cations, such as calcium and magnesium.

The pharmaceutically acceptable acid addition salts of the compounds of formula I are prepared in a conventional manner by treating a solution or suspension of free base I with about one chemical equivalent of a pharmaceutically acceptable acid. In isolating the salts, conventional concentration and recrystallization techniques are used. Suitable acids are e.g. Acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic and sulfonic acids, such as methanol sulfonic and benzenesulfonic acids, and related acids. The acid is preferably phosphoric acid.

The novel compounds of formula I and their pharmaceutically acceptable salts are useful as inhibitors of the enzyme aldose reductase in the treatment of chronic complications of diabetes, such as diabetic cataract, retinopathy and neuropathy, which treatment is intended to include both the prevention and amelioration of such diseases. The compound may be administered to a patient in need of such treatment in a variety of conventional routes of administration, i. oral, parenteral and topical. In general, the compounds are administered orally or parenterally at doses between about 0.5 and 25 mg / kg body weight of the subject to be treated per day, preferably from about 1.0 to 10 mg / kg. However, some change in dosage is necessarily made depending on the condition of the patient to be treated. The person responsible for the administration was in each case determine the appropriate dose for the individual patient.

The novel compounds prepared according to the invention can be administered alone or in combination with pharmaceutically acceptable carriers in single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the novel compounds of Formula I and the pharmaceutically acceptable carriers are then readily administered in various dosage forms, such as tablets, powders, lozenges, syrups, injectable solutions, etc. These pharmaceutical compositions may optionally contain additional ingredients such as flavoring agents, excipients, diluents, etc. For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate together with various disintegrants such as starch, alginic acid and certain complex silicates, as well as binders such as polyvinyl pyrrolidone, sucrose, gelatin and acacia gum may be used. Furthermore, for tableting purposes, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often suitable. Solid compositions of similar type can also be used as fillers in soft, hard-filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the critical active ingredient therein may be various sweetening or flavoring agents, coloring matter or dyes and optionally emulsifying or suspending agents together with diluting agents such as water, ethanol, propylene glycol, glycerol and combinations thereof , be combined.

For parenteral administration, solutions of the novel compounds of formula I in sesame or peanut oil, aqueous glycine or in sterile aqueous solution may be used. Such aqueous solutions should, if necessary, be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous or intraperitoneal administration. In this regard, the sterile aqueous media used are all readily available by standard techniques known to those skilled in the art.

The compounds of the formula I can be used not only with advantage for the preparation of the above-described aqueous pharmaceutical compositions for parenteral administration but in particular also for the preparation of pharmaceutical compositions which are suitable as ophthalmic solutions. These ophthalmic solutions are of considerable interest in the treatment of diabetic cataract by topical administration, and the treatment of such diseases in this manner is a preferred embodiment of the present invention. For the treatment of diabetic cataract, therefore, the compounds according to the invention are administered to the eye as an ophthalmic preparation, prepared according to customary pharmaceutical practice; see. e.g. "Remington's Pharmaceutical Sciences", 15th Ed., Pages 1488 to 1501 (Mack Publishing Co. "Easton, Pa.). The ophthalmic preparation contains a compound of formula I 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 acceptable solution, suspension or ointment. These different concentrations appear to be necessary depending on the particular compound used, the condition of the patient being treated, and so on, and the person responsible for the treatment determines the most appropriate concentration for the particular patient.

  , 17

The ophthalmic preparation is preferably in the form of a sterile aqueous solution optionally containing additional ingredients such as preservatives, buffers, toning agents, antioxidants and stabilizers, non-ionic wetting or clarifying agents, viscosity-increasing agents, and the like. Suitable preservatives include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal, etc. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borate, sodium and potassium carbonate, sodium acetate, sodium biphosphate, etc., in amounts sufficient to maintain the pH between about 6 to 8, preferably between about 7 and 7.5 to keep. Suitable toning agents are dextran 40, dextran 70, dextrose, glycerol, potassium chloride, propylene glycol, sodium chloride, etc., so that the sodium chloride equivalent of the ophthalmic solution is in the range of 0.9 + or -0.2. % lies. Suitable anti-oxidants and stabilizers include sodium bisulfite, sodium meta-bisulfite, sodium thiosulfite, thiourea, etc. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol Suitable viscosifying agents include dextran 40, dextran 70 , Gelatin, glycerol, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, etc. The ophthalmic preparation is a patient who requires such treatment by conventional methods, for example in the form of drops or by bathing the Eye in the ophthalmic solution, topically administered to the eye.

The activity of the compounds of the invention as agents for controlling chronic diabetic complications can be determined by various standard biological or pharmacological tests. Suitable assays include (1) measuring their ability to inhibit the enzyme activity of isolated aldose reductase; (2) measuring their ability to sorbital accumulation in the sciatic nerve and the

J 34 ί) Π |

Lens of acute streptozotozinierten, i. diabetic, to reduce or inhibit rats; (3) measuring their ability to reverse already elevated sorbitol levels in the sciatic nerve and lens of chronic streptozotocin-induced diabetic rats; (4) measuring their ability to prevent or inhibit galactitol formation in the lens of acute galactosemic rats; (5) measuring their ability to delay cataract formation and reduce the severity of lens opacities in chronic galactosemic rats; (6) measuring their ability to prevent sorbitol accumulation and cataract formation in the isolated rat lens incubated with glucose; and (7) measuring their ability to reduce already elevated sorbitol levels in the isolated rat lens incubated with glucose.

embodiments

The present invention is illustrated by the following examples, but of course it is not limited to the specific details of these examples. Proton nuclear magnetic resonance ( ¹ HNMR) spectra were measured for solutions in deuterochloroform (CDCl-,), and the peak positions are expressed in parts per milliliter (ppm) down from tetramethylsilane (TMS). The peak shapes are denoted as follows: s = singlet, d = düblet, t = triplet; q = Quartet; m = multiplet; br = wide.

EXAMPLE 1

3- (5-bromobenzothiazol-2-ylmethyl) ^ -oxo ^ H-phthalazin-1-yl-acetic acid (I; R = OH; R = R = H; R = 5-bromobenzothiazol-2-yl;

A ^ _2_j_ 5-dibromothioacetanilide

A mixture of 2,5-dibromoacetanilide (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 off and then extracted with 10% potassium hydroxide solution (2 × 75 ml). The basic aqueous extract was washed with ether (2 × 50 ml) and by addition

acidified by dilute hydrochloric acid to pH 4.0, and the precipitated 2,5-Dibromthioacetanilid was collected and then air-dried (yield 14.4 g; F. 119-124 ⁰ C).

B ^ __ 2-methyl-5-bromobenzothiazole

This compound was prepared by appropriate adaptation of the method described in Synthesis, 1976, 731. To a solution of 2,5-dibromo thioacetanilide (9.27 g) in N-methylpyrrolidinone was added gently sodium hydride (1.93 g as a 50% w / w dispersion in mineral oil). After completion of the addition, the mixture was heated to 150 ⁰ C for 1.5 h. The dark reaction mixture was poured onto ice-water (300 ml) and the brown resinous precipitate extracted with ethyl acetate (2 × 100 ml). The organic extract was washed with water (2 × 100 ml), dried over anhydrous magnesium sulfate and then evaporated. The crude solid obtained was chromatographed over silica gel and afforded the title compound (4.7 g; F. 84-85 ⁰ C).

C ^ _2-bromomethyl-5-bromobenzothiazole

A mixture of 2-methyl-5-bromobenzothiazole (32.0 g), N-bromosuccinimide (25.1 g), carbon tetrachloride (700 ml) and a catalytic amount of benzoyl peroxide (0.2 g) was irradiated under UV irradiation. Lamp heated for 14 h at reflux. The reaction mixture was cooled to room temperature, filtered to remove the precipitated succinimide, and the filtrate was evaporated to dryness. The resulting solid was chromatographed over silica gel to afford the product (7.8 g, mp 107 ⁰ C).

D ^ _EthYl-3-J_5 bromobenzothiazole-2-YlmethYl2; 4-oxo-3H-p_hthalazin-l-yl acetate

To a mixture of ethyl 4-oxo-3H-phthalazin-1-yl acetate (11.6 g) and sodium hydride (288 g, 50% w / w dispersion in mineral oil) in dimethylformamide (150 ml) became 5 Bromo-2-bromomethylbenzothiazole (16.8 g) was added and the resulting mixture was stirred for 1 h at room temperature. This reaction mixture was poured over ice-water (500 ml); it was enough

q -; A

Add 10% HCl to adjust the pH to about 4.0, and collect the precipitated crude solid. The ser was chromatographed over silica gel and the product (yield 15.6 g; .F 160-161 ⁰ C.).

A mixture of ethyl 3- (5-bromobenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl acetate (15.0 g) and dioxane (150 ml) was dissolved by heating on a steam bath, and to this solution was added a solution of 10% potassium hydroxide (20 ml) in ethanol (50 ml). The resulting dark purple solution was stirred for 2 h at room temperature and concentrated to remove excess dioxane and ethanol. The concentrate was diluted with water (100 ml) and the resulting solution was washed with ether (2 × 100 ml). The aqueous layer was collected and added by addition of conc. HCl acidified to pH 2.0. The precipitated solid was crystallized from methylene chloride / ethanol (400 ml / 40 ml) to afford the product (yield 7.65 g, mp 214 ° C).

EXAMPLE 2

3- (2-pyridyl-l, 2,4-oxadiazol-5-ylmethyl) ^ -oxo-SH-phthalazin-1-yl-acetic acid (I; R = OH; R ₃ = R ₄ = H; R ₂ = 2-pyridyl-1,2,4-oxadiazol-5-yl; X = O)

A .__ PYridamidoxim

A mixture of 2-cyanopyridine (15 g), hydroxylamine hydrochloride (10 g), sodium carbonate (15.3 g) and ethanol (100 ml) was refluxed for 24 hours. The reaction mixture was cooled, filtered and the filtrate evaporated to a solid which was extracted with ethyl acetate. The organic extract was dried, evaporated and the residue crystallized from benzene (3.0 g; F. 113-114 ⁰ C). · ·

A mixture of pyridamidoxime (4.5 g), chloroacetic anhydride (8.4 g) and toluene (350 ml) was refluxed for 12 hours. The hot solution was cooled, washed with water (2 × 100 ml), saturated bicarbonate solution (2 × 50 ml) and again with water (2 × 100 ml), and the organic layer was evaporated to a crude solid. This solid was crystallized from hexane to afford the product (3.4 g, mp 89-94 ° C).

To a solution of ethyl 4-oxo-3H-phthalazin-1-yl acetate (1.6 g) and sodium hydride (0.5 g, 50% w / w dispersion in mineral oil) in dimethylformamide (15 ml). For example, 3- (2-pyridyl) -5-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 onto water (50 ml) and extracted with ether. The ether layer was evaporated and the residue chromatographed over silica gel to afford the product (1.0 g, mp 118-128 ° C).

_ _{= =} YY J _-1 ^ ₁₁ 3H ₁

idi ι γ 11 § § § is § §y £ §

To a solution of ethyl 3- (2-pyridyl-l, 2,4-oxadiazol-5-ylmethyl) -4-oxo-3H-phthalazin-1-yl acetate (1.0 g) in methanol (10 ml ) was added 20% aqueous KOH (0.5 ml) and the mixture heated at reflux for 30 minutes. Evaporation of the excess methanol gave an orange residue. The residue was dissolved in water, acidified with acetic acid (1 ml) and the precipitated solid was collected and recrystallized from isopropanol the product (0.53 g; F. 196-100 ⁰ C) crystallized.

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 = R = H ;

1 j 4

' j U' I

?, Zi H

22 R ₂ = 3- (2-trifluoromethylphenyl) -1,2,4-oxadiazol-2-yl)

2-trifluoromethylbenziinidioxime, prepared similar to that in Ber. 1899 32-described methods (1975) (2.9 g; F. 115-116 ⁰ C), and starting from 2-trifluoromethylbenzaldehyde (70 ml) in anhydrous acetone, and then solid potassium carbonate (2.0 g) added. To the resulting slurry, cooled to 15-18 ° C in an ice-water bath, was added a solution of chloroacetyl chloride (1.1 ml) dissolved in acetone (10 ml). After the addition, the ice bath was removed and the reaction mixture was brought to room temperature and stirred for 1.5 h. Evaporation of the acetone, a white residue which after trituration with water O-chloroacetyl-2-trifluormethylbenzimidoxim gave (; 108 F. ⁰ HO-C 3.0 g). This product was mixed with toluene (50 mL) and heated at reflux for 1.5 h. The toluene solution was cooled, washed with saturated aqueous sodium bicarbonate (10 ml) and water, and the organic portion was dried and evaporated. The resulting brown oil was chromatographed over silica gel to afford the title compound as a yellow oil. ¹ HNMR (CDCl ₃ , 60 MHz): 4.0 (s, 2H), 4.4 (s, 2H), 7.3 (s, 5H)

ζ! 2 / "3 ₌ | 2 ₌ tr if luormethyl phenyl 2-1 ^ 2 ^ 4 ₌ oxadia zol ₌ 2 ₌ γ1 ₌

To a mixture of 4-oxo-3H-phthalazin-1-yl-acetate (1.4 g) and sodium hydride (0.43 g, 50% w / w dispersion in mineral oil) in dimethylformamide (10 ml) became 3 - (2-trifluoromethylphenyl) -5-chloromethyl-l, 2,4-oxadiazole (1.7 g) was added and stirred at room temperature for 30 minutes. The reaction mixture was poured onto water (20 ml), acidified to pH 2.0 with 10% HCl and the precipitated solid collected. The solid was triturated with isopropanol to afford the product as a white crystalline solid (1.65 g, mp 111-115 ° C).

C ^ _3_3 / 3 j_2-Trif

A mixture of ethyl 3- (2-trifluoromethylphenyl) -1,2,4-oxadiazol-2-yl-rriethyl-4-oxo-phthalazin-1-ylacetate (1.6 g) and methanol (50 ml) with a Content of 20% w / w aqueous KOH (0.5 ml) was heated for 1 h on a steam bath. Water (20 ml) was added to the residue obtained after evaporation of the methanol, and the pH of the solution was brought to 2 by addition of 10% HCl. The precipitated solid was crystallized from benzene (0.7 g; F. 132-134 ⁰ C).

EXAMPLE 4

3- (N -methylbenzimidazol-2-ylmethyl) ^ -oxo-SH-phthalazin-1-ylacetic acid (I; R = OH; R-R = H; X = O; R = 3- (N-methylbenzimidazole-2-); yl)

A mixture of ethyl 4-oxo-3H-phthalazin-1-yl acetate (2.34 g) and sodium hydride (0.58 g, 50% w / w dispersion in mineral oil) in dimethylformamide (20 ml) Stirred for 15 min at room temperature. To this was added N-methyl-2-chloromethylbenzimidazole (2.4 g, prepared according to JACS, 1943 , 65, (1854)) and stirred for an additional 1 hour. It was then poured onto water (150 ml) and extracted with ethyl acetate (2 × 100 ml). The organic extract was dried, evaporated and the residue chromatographed over silica gel to give the product (2.04 g, mp 118 ° C).

To a solution of 3- (N-methylbenzimidazol-2-yl) -4-oxo-3H-phthalazin-1-yl acetate (2.0 g) in warm methanol (100 ml) was added 10% KOH (10 ml), stirred at room temperature for 2.5 h and then evaporated to a solid. This solid was dissolved in water (50 ml), extracted with ether (50 ml), and the aqueous layer was adjusted to pH 6.0 by the addition of acetic acid. The obtained

White solid was collected, dried and crystallized from a mixture of methanol / methylene chloride to give the title compound (0.68 g, F. 23O ⁰ C and dec.).

EXAMPLE 5

3- (oxazolo / 4,5-b / pyridin-2-ylmethyl) ^ -oxo ^ H-phthalazin-1-yl-acetic acid (I; X = O; R ₁ = OH; R = R = H; R = 0xazolo / 4,5-b / pyridin-2-yl)

A solution obtained by adding ethyl 4-oxo-3H-phthalazin-1-yl acetate (1.25 g) to a suspension of sodium hydride (285 mg, 50% w / w dispersion in mineral oil) in dimethylformamide (10 ml) was added dropwise to a solution of 2-chloromethyl-oxazolo / 4,5-b / pyridine (1.0 g) in dimethylformamide (5 ml). After 2 h, the reaction mixture was poured onto cold water (20 mL) and extracted with ether. The ether extract was washed with water (2 × 50 ml), dried and evaporated. The crude material obtained was chromatographed over silica gel and gave 3- (oxazolo / 4,5-b / pyridin-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl acetate (F. 105-107 ⁰ C) which was used directly in the next stage. The product was dissolved in methanol (5 ml) containing 20% aqueous potassium hydroxide (0.5 ml) and heated on a steam bath for 15 min. The solution was evaporated to dryness, the residue dissolved in water and acidified with acetic acid (2 ml). The yellow precipitate was collected, triturated with hot methanol and filtered to give the title compound as a white solid (0.32 g; F. 228-230 ⁰ C);

EXAMPLE 6

A solution of methyl 3- (2-benzothiazolyl) -4-oxo-3H-phthalazin-1-yl acetate (1.92 g) in methanol (50 ml) containing 10% aqueous potassium hydroxide (5 ml) was stirred for 4 h at room temperature. The solution was concentrated to remove the methanol and the concentrate was diluted with water (75 ml) and then extracted with ethyl acetate. The aqueous portion was separated and concentrated with conc. Hydrochloric acid to pH 2.0

acidified. The precipitated solid was collected and recrystallized from isopropyl alcohol to 3- (2-benzothiazolyl) -4-oxo-3H-phthalazin-1-yl-acetic acid (876 mg; F. 205 ⁰ C with decomposition). Crystallized.

EXAMPLE 7

According to Example 6, the following compounds were prepared:

Table IA substituent

A-Cl 5-Cl 6-Cl 5-Br 6-Br 7-Br 5-SCH ₃ 5-SOCH ₃ 5-SO ₂ CH ₃ 4-Cl, 5-Cl 5-Cl, 6-Cl 4-Cl 6-Cl 4-Cl _f 7-Cl 5-Cl, 7-Cl '5 -CH ₃ 6 -CH ₃ 6 -OCH ₃

5'-F 5'-CH ₃

6,7-benzo, 5'-F 6 _r 7-benzo, 5'-CH.

F;

205 u, Zers. 217 and c.

210-212207 u.Zers.

214

214

173-175 187-188 184 u.Zers.

210-211 and c.

222

192-195188-190223-224213

205 u.Zers.

202 and c.

189 and c.

204-205201-203218-222215-219

.1 A

substituent

6'-Cl 7'-Cl

6'-Cl, 7'-Cl6-Br, 6'-Cl, 7'Cl

6'-Br 6'-CF ₃ 6'-NO ₂ 6'-OCH ₃

7'-Br 7'-CH ₃ 7'-OCH ₃ 7'-CF ₃ 7'-NO ₂ 6,7-benzo, 7'-Cl

5-CF ₃

6'-isopropyl 7'-isopropyl

4-F 4-F, 5-F

5-F 6-isopropyl

F.

198-199

199

189-192

206 and c.

211

210-211

199-201

177-179

192

187-190

198-202

124-126

155-158

209-210

197-198

184-185

99-101

217-218

178-181

222 u.Zers.

160-161

Table IB

CH ₉ CO ₀ H

covalent.Bind, covalent.Bind, covalent.Bind. Heavy sulfur

CH.

CH.

CH.

substituent F .; "C. - '159-160 u.Zers 5-F ₃ 182-183 5-Cl 205 - 150- * 160 5-Cl 100-104

EXAMPLE 8

A mixture 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) became at room temperature Stirred for 2 h under nitrogen. To the resulting solution, 2-bromomethylbenzothiazole (1.14 g) dissolved in dimethylformamide (5 ml) was added, the reaction mixture was stirred for an additional 1 hour and then poured into ice-water (50 ml). The pH of the mixture was brought to 4.0 by addition of 10% hydrochloric acid (5 ml) and extracted with ethyl acetate (100 ml). The extract was washed with water (50 ml), dried (MgSO 4) and evaporated. The crude product (1.92 g), namely methyl (2-benzothiazolyl) -4-oxo-3H-phthalazinyl-1-yl acetate, was characterized by the NMR spectrum (see Table 2). The other compounds of Table 2 were prepared in a similar manner using the corresponding 4-oxo-3H-phthalazin-1-yl-acetate and the 2-bromomethylbenzothiazoles. The melting points are given in ⁰ C.

Substituent R

product

CH.

'HNMR (CDCl 4, 6 OMHz) 3.6 (s, 3H) 4.0 (ε, 2H), 5.7 (ε, 2H), 7.2 (m, 2H), 7.6 (m , 5H), 8.4 (m, lH)

4-F C ₂ H ₅ F. 119-120 5-F C ₂ H ₅ F. 118-120 4-Cl C ₂ H ₅ F. 113-116

Table 2A Peat setting

Substi tuents R ¹ product

5-Cl C ^ H _C F ,. 152-155

5-3r CH ₃ . F. 160-161

7-Er CH ¹ KKMR (CDCl-, 60 Kez): 1.2

(t / J = SHz, 3H), 4.1 (s, 2H), 4.2 (ς, J = SRz, 2K), 5.8 (ε, 2Ε), 7.3 (m, 2H), 7.8 (s, 4H), 8.4 (m, lK)

5-CH ₃ C ₂ H ₅ F. 134-136 4-F, 5-FC ₂ H ₅ F. 118-122 4-Cl, 5-Cl C ₂ H ₅ F..121-122

5-Cl, 6-Cl CH ¹ KNKR (CDCl, 90KHz): 3.70

^J (s, 3H), 4.0o (s, 2H), 5.75 (s, 2H), 7.6-8.0 (m, 5H), 8.3-8.6 (m, IH)

5-Cl, 7-Cl C ₂ H ₅ F. 144-145

4-Cl, 6-Cl CH- 'HNMR (CDCl ,, 90KHz): l _t 20 (t, J =

8Hz, 3H), 4.00 (s, 2H), 4.15 (q, J = 8Hz, 2H), 5.80 (s, 2H) 7.40 (d, J = IHz, IH), 7, 60 (d, J = IHz ₇ IH). , 7.6-7.9 (m, 3H), 8.4-8.6 (m, IH)

4-Cl, 7-Cl C ₂ H ₅ F. 173

6-OCH ₇ CH, ¹ HNMR (CDCl ,, 90MHz): 3.70

^J (s, 3H), 3.80 (5.3H), 4.05 (s, 2H), 5.75 (s, 2H), 7.00 (dd, J = 3.9Hz, 1H) I ₁ 20 (d, J = 3Hz, IH), 7.6-7.9 (m, 4H) _f 8.4-8.6 (m, IH)

5-CH ₃ ^C 2 ^H 5 ^F · ¹²³ " ¹²⁴

6-CH ₇ CH- 'HNMR (CDCl ,, 90MHz): 2.50

^{ό ό} (ε, 3H), 3.75 (ε, 3H), 4.10 (ε, 2Η), 5.90 (s, 2H), 7.35 (d, J = 8Hz, lH), 7, 65-8.10 (m, 4H), 8.5-8.7 (m, IH)

Table 2A Continued

Substituent R Pr.odukt

6-isopropyl C ₃ H ₅ H'NMR (CDCl, 90MHz): 8.40

(m, 1H), 7.9-7.5 (m, 5H), 7.2 (d, J = 9Hz, 1H), 5.79 (s, 2H), 4, 15 (q, J = 9Hz , 2H), 3.85 (s, 2H), 2.98 (Sep., J = 9Ez, IH), 1.28 (d, J = 9Hz, 6K) *, 1.20 (5, J = SEz , 3H)

5'-F

5'-CH.

6,7-benzo, 5'-F

C ₂ H ₅

C ₂ H ₅

6,7-benzo, 5'-CH ₃ C ₃ H ₁

6'-Cl

¹ HNMR (CDCl ₃ , 9 0KHz): 1, 20 (t, J = 8Kz, 3H), 2.00 (ε, 2K), 4.20 (q, J = SEz, 2H), 5.80 (ε , 2Η), 7,2-8, ~ l (m, 7H)

'HNMR (CDCl ₃ , 9 0MHz): 1, 20 (t, J = 8Hz, 3H), 2.95 (ε, 3Η), 3.95 (s, 2H), 4.20 (q, J = SHz , 2H), 5.75 (s, 2H), 7.2-8 _# l (m, 7H)

'HNMR (CDCl, 9 0MKz): 1, 20 (t, J = 8Hz, 3H), 3.95 (s, 2H), 4.20 (q, J = 8Hz, 2H), 5, 90 (ε, 2H), 7.2 5- "8.00 (m, 8H), 8.80 (dd, J = 3.7Hz, IH)

'H NMR (CDCl ,, 90 MHz): l, 20 (t, J = 8Hz, 3H), 2 95 _t' (s, 3H), 3.95 (s, 2H), 4.15 (q, J = SHA , 2H), 5.90 (s, 2H), 7.4-7.95 (m, 8H), 8.80 (πι, IH)

CH 'HNMR (CDCl ,, 90MEz): 1.20 (t, J = 8Hz, 3H), 3.05 (S, 2H), 4.25 (q, J = 8Hz, 2H), 5.85 (ε , 2Η), 7.2-8.1 (m, 6H), 8.50 (d, J = 2Hz, IH)

7'-Cl

C ₂ H ₅ 'HNMR (CDCl ₁ , 9OMHz): 1.25 (t, J = 8Hz, 3H),? _f 00 (s, 2H), 4.20 (q, J = 8Hz, 2H), 5.80 (s, 2H), '7, 25-7, 6 (m, 2H), 7.65-7.90 ( m, 3H), 8.00 (dd, J = 2.9Hz, IH), 8.45 (d, J = 9Hz, lH)

I D 'UU <

substituent

Table 2A Continued R Product

6'-Cl, 7'Cl C_H

₂ H ₅

6'-Br

6'-Isopropyl

6'-OCH

6'-CF

7'Br

7'-CH

C ₂ H ₅

C ₂ H ₅

^C 2 ^H 5

C ₂ H ₅ ¹ EKMR (CDCl-, 90KHz): 1, 20 (t, J = SHz, 3H) J ₁ OO (S, 2K), 4.20 (q, J = SHz, 2H), 5.80 (S, 2H), 7.2-7.6 (m, 2H), 7.7-8.1 (m, 3H), 8.55 (s, IH)

¹ HNMR (CDCl -, 90KHz): Γ, 20 (t, J = SHz, 3H), 3.90 (s, 2H), 4.15 (q, J = SHz, 2E), 5.80 (s, 2H), 7.2-8.1 (m, 6H), 8.60 (d, J = 2Hz, IH)

¹ HKMR (CDCl ,, 90MHz): l, 20 (t, J = 8Hz, 3H) , t, 05 (s, 2H), 4.20 (q, J = 8Hz, 2H), 5.80 (s, 2H), 7.2-7.6 (πι, 2H), 7.7-8, Km, 3H), 8.60 (dd, J = 2.9HZ, 1H), 9.30 (d, J = 3 Hz, lH)

'HNMR (CDCl, 90MHz): 8.25 (s, IH), 7.9 (m, IH), 7.7 (m, 3H), 7.3 (m, 2H), 5.8 (s, 2H), 4.20 (q, J = 9Ez, 2H), 3.95 (s, 2H), 3.1 (sep, J = 9Hz, IH), 1.35 (d, J = 9Hz, 6H ), l, 20 (s, J = 9Hz, 3H)

¹ HNMR (CDCl, 90MHz): 1, 20 (t, J = 8Hz, 3H), 3.95 (brs, 6H), 4.15 (q, J = SHz, 2H), 5.80 (e, 2H ), 7,20-8,10 (m, 7H)

'HNMR (9OMHz, CDCl3): 8.7 (s, 1H), 8.15-7.7 (m, 4H), 7.40 (m, 2H), 5.8 (s, 2H), 4 , 21 (q, J = 9Hz, 2H), 4.0 (s, 2H), l, 22 (5, J = 9Hz, 3H)

¹ HKMR (CDCl ,, 90MHz): 1, 20 (t, J = 8Hz, 3H), j, 90 (s, 2H), 4.15 (q, J = 8Hz, 2H), 5.85 (s, 2H), 7.15-7.50 (m, 2H), 7.6-8.1 (m, 4H), 8.30 (d, J = 9Hz)

'HKMR (CDCl-, 90MHz): 1, 20 (t, J = 8Hz, 3H), 2.60 (s, 3H), 4.15 (s, 2H), 4.20 (q, J = 8Hz, 2H), 5.80 (s, 2H), 7.3-8.2 (m, 6H), 8.30 (d, J = 9Hz, lH)

Table 2A Continued Substituent R Product

7'i: sopropyl

7'OCH

6,7-benzo, 7'-Cl

5

• HNKR (300MHz, CDCl3): 8.24 (d, J = SHz, IH), 7.64Td, J = SRz, IH), 7.62 (d, J = SRz, IH), 7.49 (i.e. , J = SHz, IH), 7.36 (s, lH), 7.2 6 ("t", J = GKz, IH), 7.16 ("t", J = 6Ez, lH), 5, 64 (ε, 2Η), 4.06 (q, J = 9Hz, lH), l _f 30 (d, J = 9Hz, 6H), 1.17 (t, J = SHA, 3H)

¹ HNMR (CDCl ₃ , SOMKz): 1, 20 (t, J = 8Hz, 3H), 3.85 (s, 3H), 3.90

(s, 2H), 4.20 (q, J = 8Hz, 2H), 5.80 (s, 2H), 7.00 (d, J = 2Hz, lH) 7.2-7.5 (m, 3H), 7.75 (dd, J = 2.8Hz, IH), 8.00 (dd, J = 2.7Hz, lH), 8.50

(D, J = 9Hz, lH)

'' HNMR (90MHz, CDCl3): 8.90 (d, J = 9Hz, IH), 8.15-7770 (m, 4H), 7.45-7.2 (m, 2H), 5.8 (ε, 2Η), 4.20 (q, J = 9Hz, 2H), 4.05 (s, 2H), 1.18 (t, J = 9Hz, 3H)

'H ₁ . 'HNMR (CDCl ,, 90MHz): 1.20 (t, J = 8Hz, 3H), 5.05 (s, 2H), 4.20 (q, J = 8Hz, 3H) _r 5.80 (s, 2H), 7 * 2-7, 6 <m, 3H), 7.6-8, Km, 2H), 8.4-8.7 (m, 2H)

: ₉ H _R ¹ HNMR (CDCl ,, 90MKz): l, 20 (t,

J = 8Hz, 3H), 3.00 (s, 2H), 4.20 (q, J = 8Hz, 2H), 5.90 (s, 2H), 7.5-8.0 (m, 7H) , 8.45 (d, J = 9Hz, lH), 8.75-8.90 (n \, lH)

Z ^ E _r F. 134-136 ° C

2 B

Table 2B

CH.

kovalent.Bind.

covalent.Bind, covalent.Bind. S

CH CK CH

substituent

5-CF 5-Cl

product

F. 105-106 ⁰ C F. 86-88 ⁰ C

¹ HNMR (CDC1,, 6OMH ζ): l, 2 (t, J = 9Hz, 3H), 3.85 (s, 2H), 4.2 (9, J = 9Hz, 2H), 6.0 (s , 2H), 7.1-8.0 (m, 7H), 8.2-8.4

EXAMPLE 9

To a mixture of ethyl 4-oxo-3H-phthalazin-l-yl-acetate (23.4 g) in dimethylformamide (175 ml), which was maintained at 10 ⁰ C was within 5 (min batchwise potassium t-butoxide 11.2 g) was added. The resulting orange solution was brought to room temperature and dimethylformamide (25 ml) was added gradually over 15 minutes. After stirring for a further 30 minutes, the mixture was poured onto ice-water (1500 ml). The precipitated solid was total. and washed with a mixture of isopropyl ether / n-hexane (250 ml / 500 ml). The resulting pale yellow solid, namely ethyl 3- (5-trifluoromethyl-2-benzothiazolylmethyl) -4-oxo-phthalazin-1-yl acetate, was air dried (44.3 g, mp 134-136 ° C). ,

EXAMPLE 10

Following the procedure of Example ID, the following compounds were prepared:

2 B ^:! O

7 6

Benzothiazolyl gubstituent

5-Cl

5-Br

5-Cl, 7-Cl

Product not isolated not isolated not isolated

5,6-benzo

Mass spectrum, m / e base tip 431.06 (partially isolated)

F. 167-170 ⁰ C

Following the procedure of Example 6, the following compounds were prepared from the above compounds without their isolation.

6

Benzothiazolyl · subsitu t t

5-Cl 5-Br

5-Cl, 7-Cl 5,6-benzo

F .; ⁰ C 179-183 205-207 190-192 199-201 167-170

23 ^Λ Ο -γ, -

EXAMPLE 11

According to Example 3Β, the following compounds were prepared.

CH ₂ CO ₂ C ₂ H ₅ R

2-F, 6-Cl-phenyl

2-pyridyl 2-Br-phenyl

B-enzyl

2-F-phenyl 3-C, 4-Cl-phenyl

product

¹ HNMR (CDCl ,, 6 CMR ζ): 1, 3 (t, J = 8Hz, 3H), 4.0 (s, 2H), 4.2 (q, J = 8Ez, 2H) 5.8 (s , 2H), 7.3 (m, 3H), 7.8 (m, 3H), 8.4 (m, lH)

F. 118-123 ° C

¹ HKMR (CDCl-, 60MHz): l, 3 (t, J = 8Hz, 3E), 4.0 (s, 2H), 4.2 (q, J = 8Hz, 2H), 5.7 (s, 2H), 7.2 (m, 2H), 7.8 (m, 4H), 8.4

F. 76-80 ° C

F. 100-105 ° C F. 138-140 ° C

EXAMPLE 12

According to Example 3C, the following compounds were prepared.

"-j! -

R F .; ⁰ C 2-Cl-phenyl 164-167 phenyl 202-205 4-Br-phenyl 193-195 2-Methyl-phenyl 182-184 '2-OCH -, - phenyl 174-175 2-F, 6-Cl-phenyl 178-182 3-Cl, 4-Cl-phenyl 220-221 2-pyridyl 196-200 2-Br-phenyl 171-173 benzyl 56-60 2-F-phenyl 210-211 EXAMPLE 13

3- (Quinolin-2-ylmethyl) -4-oxo-3H-6,7-dichloro-phthalazin-1-yl-ureic acid (I; X = O; R = OH; R = quinolin-2-yl; R = R = C1)

A ^ _4 _i 5-dichloroghthalic acid anhydride

A mixture of commercially available 4,5-dichlorophthalic acid (50.4 g) and acetic anhydride (150 ml) was refluxed for 2 hours. After cooling, the precipitated product was collected and dried under vacuum (37.0 g; F. 180-181 ⁰ C).

B _I __32EthoxYcarbonYlrnethYliden _5-i 6-dichlorphthalid A solution of 4,5-dichlorophthalic anhydride (10.0 g) and (carbethoxymethylene) triphenylphosphorane (16.0 g) in chloroform (450 ml) was heated under reflux for 16 h. After evaporation of the chloroform and chromatography of the residue over silica gel, the product was obtained (9.34 g).

C ^ __ _i 7 ethyl-6-dichloro-4-oxo-3H-phthalazin2l ΐγΐ-acetate A mixture of 3-ethoxycarbonylmethylidene-5,6-dichlorphthalid (9.37 g), ethanol (300 ml) and hydrazine (1.1 ml) was heated under reflux for 3 h. After cooling, the precipitated solid was collected (6.85 g, mass spectrum, m / e 300 and 227).

D. The title compound was prepared from ethyl 6,7-dichloro-4-oxo-3H-phthalazin-1-yl acetate and 2-chloromethylquinoline according to the method of Example 6; F. 202-203 ⁰ C.

EXAMPLE 14

3- (Quinolin-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl-acetic acid (I; X = O; R ₁ = OH; R ₃ = R ₄ = H; R ₂ = quinoline-2; yl) '

To a solution of ethyl 4-oxo-3H-phthalazin-1-yl acetate (1.0 g) and sodium hydride (60% w / w dispersion in mineral oil) in dimethylformamide (30 ml) was added 2-bromomethylquinoline ( 1.05 g) was added. The resulting solution was stirred at room temperature for 30 minutes, poured into water (100 ml) containing IN HCl (5 ml) and extracted with ethyl acetate. The organic extract was washed with water (3 × 50 ml), dried and evaporated to give ethyl 3- (quinolin-2-ylmethyl) -4-oxo-phthalazin-1-yl acetate (1.54 g). This substance was dissolved in a water / dioxane mixture (70 ml / 70 ml). To the solution was added 5N potassium hydroxide (5 ml). The solution was stirred at room temperature for 15 minutes, concentrated to remove excess dioxane, diluted with water (150 ml) and extracted with ethyl acetate (3 × 70 ml). The aqueous layer was washed with conc. HCl adjusted to pH 2. The precipitated solid was triturated with hot ethyl acetate and filtered to afford the title compound (0.54 g, mp 193-194 ° C).

EXAMPLE 15

According to Example 6, the following compounds were prepared.

37 Table 3

F .; ⁰ C

Benzisothiazol-3-yl. 168

5- (2-chlorophenyl) -1,4,4-oxadiazol-3-yl 163-165

3-phenylisothiazol-5-yl 169-170

3-phenylisothiazol-4-yl 218

2-phenyl-1,3,4-oxadiazol-5-yl 260

4,5-diphenyloxazol-2-yl 197-200

Quinolin-2-yl 193-194

Quinoxaline-2-yl 215-217

N-methylbenzimidazol-2-yl 230 u.Zers.

Oxazolo / 4,5-b / -pyridin-2-yl 228-230

Thiazolo / 5,4-b / -pyridin-2-yl 216

5,7-dichloroquinolin-2-yl 200-201

6-bromoquinolin-2-yl 205-206

6,8-dichloroquinolin-2-yl 193-195 3-methyl-l, 2,5-thiadiazol-4-yl. 160-162

5-phenyloxazol-2-yl 159-162

4-phenyloxazol-2-yl 181-184

2-phenylthiazol-5-yl 164-165

2-0-fluorophenyl-thiazol-5-yl 184-185

4-phenylthiazol-2-yl 181-184

5-chlorobenzothiophene-2-yl. 205-206

EXAMPLE 16

According to Example 8, the following compounds were prepared.

38 Table 4

product

Benzisothiazol-3-yl CH ₃ 3-phenylisothiazol-5-yl C ₂ H ₅ 3-phenylisothiazol-4-yl C ₂ H ₅

2H? Henyl-l, 3,4-oxadiazol-5-yl

C ₂ H ₅

5- (2-Chloro-phenyl) -CH ₅ 1,2,4-oxadiazol-3-yl

N-Methylbenzimidazol-

2-yi.

¹ HNKR (CDC1, 6OMHζ): 3.7 (s, 3H), 5.0 (S, 2H), 5.8 (s, 2H), 7.6 (m, 7H), 8.3 (m , lH)

F. 9S-104 ° C

¹ HNKR (CDCl, 60KHz): 1, 2 (t, J = 8Hz, 3H), 3.9 (s, 2H), 4.2 (q, J = SHz, 2H), 5.4 (ε, 2Η) 7.6 (m, 7H), 8.4 (m, lH), 8.8 (ε, ΙΗ)

, 6 OMHz): "1, 2 (t, J = 8Hz, 3H), 4.0 (s, 2H), 4.2 (q, J = 8Hz, 2H), 5.7 (e, 2H), 7.4 (m, 3H), 7.8 (ro, 5H), 8.4

¹ HNMR (CDCl, .60MHz): 1, 3 (t, J = 8Hz, 3H), 4.0 (s, 2H), 4.2 (q, J = BHz, 2H), 5.6 (S, 2H), 7.4 (m, 3H), 7.8 (m, 4H), 8.4 (πι, ΙΗ)

F. 118 ° C

^R 2 - ^R l F. product ⁰ C Oxazolo [4,5-b] pyridine-2-yl C ₂ H ₅ ^F - 105-107 ⁰ C Thiazolo [5,4-b] pyridin-2-yl C ₂ H ₅ R. 111-113 ⁰ C 5-Phenylexazo1-2-yl C ₂ H ₅ F. 115-117 ⁰ C 4-phenyloxazol-2-yl C ₂ H ₅ F. 130-131 ⁰ C 2-Phenyl-thiazol-5-yl C ₂ H ₅ F. 104-106 ⁰ C 2-o-fluoro-phenyl-thiazol-5-yl C ₂ H ₅ F. 104-107 ⁰ C 4-Phenyl-thiazol-2-yl ^C 2 ^H 5 - F. 120-124 ⁰ C 5-chlorobenzothiophene-2-yl 139-142

EXAMPLE 17

N-morpholino) ethyl-3- (5,6-dichlorobenzothiazole-2-yl-methyl) -4-oxo-3H-phthalazin-l-yl acetate; hydrochloride

To the sodium salt of N-2-hydroxyethylmorpholine, prepared by careful addition of sodium hydride (0.45 g, 50% w / w dispersion in mineral oil) to a solution of N-2-hydroxyethylmorpholine (1.43 ml) in toluene ( 50 ml), a solution of ethyl 3- (benzothiazol-2-yl-methyl) -4-oxo-5,6-dichloro-phthalazin-1-yl-acetate (1.23 g) in toluene (30 ml ) added. After the reaction mixture was stirred for 24 h at room temperature and 6 h at 60 ° C, it was exposed to gaseous HCl and the precipitated solid was added to saturated aqueous bicarbonate (100 mL) and extracted with ethyl acetate (3 x 100 mL) , The organic layer was dried and evaporated, and the resulting solid was dissolved in acetone (30 ml). This solution was exposed to gaseous HCl to give the title compound (0.12 g) which was characterized by elemental analysis (C = 49.83%, H = 3.83%, N = 9.36%).

EXAMPLE 18

Sodium 3- (5-trifluoromethylbenzothiazole-2-ylmethyl) -4-oxo-3H-phthalazin-l-yl acetate

Sodium methoxide (54 mg) was added to 3 - "(5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-phthalazin-1-yl-acetic acid (0.4 g) in methanol (10 ml) at room temperature A clear solution, which was stirred for 15 min at room temperature, was added to the solution, and the excess methanol was evaporated The residue was triturated with ether (20 ml) and filtered to afford the product (0.43 g, mp> 300 ° C.). ,

EXAMPLE 19

3- (5-Trifluormethy benzothiaζöl-2-ylmethyl!) -4-oxo-3H-phthalazin-1-yl acetate; dicyclohexylamine

To a mixture of 3- (5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-phthalazin-1-yl-acetic acid (0.42 g) in methanol (10 ml) was added dicyclohexylamine (0.2 g) in methanol ( 5 ml) was added. The resulting clear solution was stirred for 15 minutes at room temperature and then evaporated to dryness. Trituration of the residue with ether (30 ml) gave a white solid (0.38 g, mp 207 ^° C.).

EXAMPLE 20

3- (5-Trifluormethy1benzothiazo1-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl-acetic acid; meglumine

A solution of 3- (5-trifluoromethylbenzothiazol-2-ylmethyl) -4-oxo-phthalazin-1-yl-acetic acid (419 mg) and meglumine (196 mg) 'in methanol (50 ml) was stirred at room temperature for 1 h then evaporated to dryness. The residue was triturated with ether (25ml), filtered and the collected solid air-dried (610mg, mp 157 ° C).

K ·

EXAMPLE 21

3- (5-bromobenzothiazole-2-ylmethyl) -4-oxo-phthalazin-l-ylacetic acid; meglumine

A solution of 3- (5-bromobenzothiazol-2-ylmethyl) -4-oxophthalazin-1-yl-acetic acid (430 mg) and meglumine (196 mg) in methanol (50 ml) was stirred at room temperature for 1 h and evaporated to dryness , The residue (25 mL) triturated with ether and the solid collected by filtration (620 mg; F. 138-140 ⁰ C.)

EXAMPLE 22

Ethyl 3- (5-sulfinylmethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-l-yl acetate

To an ice-cold solution of ethyl (5-thiomethylbenzothiazol-2-ylmethyl) -4-oxo-phthalazin-1-yl acetate (1.06 g) in chloroform (10 ml) was added m-chloroperoxybenzoic acid (0.50 g). added. The resulting solution was stirred at 0 to 5 ⁰ C for 1 h. The chloroform solution was washed with 10% sodium bicarbonate solution (3 × 20 ml) and the separated organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel to afford the title compound / 0.81g; ¹ HNMR (CDCl ₃ , 60 MHz): 1.2 (t, J = 8Hz, 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

Ethyl 3- (5-sulfonylmethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthaiazin-1-yl-acetate

A solution of ethyl (5-thiomethylbenzothiazol-2-ylmethyl) -4-oxo-3H-phthalazin-1-yl acetate (1.06 g) and m-chloroperoxybenzoic acid (1.3 g) in chloroform (50 ml). was stirred for 1 h at room temperature. This solution was mixed with 10% sodium

bicarbonate solution (3 × 20 ml) and the organic extract was dried and evaporated to give a light yellow solid (0.85 g, ¹ HNMR (CDCl ₃ , 60 MHz): 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

Ethyl 3- (5-trifluoromethyl-2-rt-methylbenzothiazolyl) -4-oxo-3H-phthalazin-1-yl acetate (I; R ₁ = OC-H; R ₃ = R = H; R = CH; R = 5-trifluoromethyl-2-benzothiazolyl; X = O)

To a solution of 1- (2-benzothiazolyl) ethanol (2.5 g) prepared according to J. Indian Chem. Soc. , 566 (1974) in methylene chloride (50 ml) was added thionyl chloride (3.32 g) and the resulting solution was stirred at room temperature for 1 h. The solution was poured onto ice-water (100 ml) and the organic extract was separated. This extract was washed with aqueous bicarbonate (10 ml of a 5% solution) and then with water. The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated to a light yellow oil (2.08 g).

if trifluoromethyl-2-benzothiazolyl] _ ₌ ethanol2_MesYlat To an ice cold solution of 1- (5-trifluoromethyl-2-benzothiazolyl) ethanol (m.p. 93-94 ⁰ C; 4.94 g) in dry pyridine was added methanesulfonyl chloride (4, 58 g) was added and the resulting solution was stirred at ⁰ ° C. for 1 h. It was poured onto water, extracted with ether and the ether layer washed with -10% hydrochloric acid (2 × 20 ml). The organic extract was dried, evaporated and the residue triturated with hexane to give the desired compound as a solid (5.89 g, mp 89 ° C).

A mixture of 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) at room temperature

stirred for 30 min under nitrogen. To the resulting solution was added 1- (5-trifluoromethyl-2-benzothiazolyl) ethanol mesylate (3.2 g) dissolved in dimethylformamide (5 ml), the reaction mixture was stirred for an additional 1 hour and poured onto ice-water (50 ml). The pH of the mixture was brought to 4.0 by addition of 10% hydrochloric acid (5 ml) and extracted with ethyl acetate (100 ml). The extract was washed with water (50 ml), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with ethyl acetate / chloroform (5/95% mixture). The title compound (2.0 g) was obtained by evaporating the eluents; F. 105-106 ⁰ C.

EXAMPLE 25

S-benzothiazol-S-ylmethylbenzothiazolyl) -4-oxophthaiaζin-1-yl-acetic acid

A. 5-Bromomethylbenzothiazole was prepared according to Example IC to give 5-methylbenzothiazole prepared according to Grazz. Chim.-Ital. , 95, 499 (1965). The products showed the following NMR resonances - TMS (60 MHz, CDCl-J: 4.6 (s, 2H), 7.4 (dd, IH, J = 10 Hz), 7.85 (d, IH, = IOHz), 8.15 (d, J = 2Hz), 9.0 (s, IH).

B. Ethyl 3- (5-methylbenzothiazolyl) -4-oxo-SH-phthalazin-1-yl acetate prepared according to Example ID, had the following NMR resonances - TMS (60 MHz, CDCl '): 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, IH).

C. The title compound was prepared according to Example IE; F. 203-204 ⁰ C.

EXAMPLE 26

Ethyl 3- (5-fluorobenzothiazolyl-2-ylmethyl) -4-oxophthalazin-yl acetate

a on >

To a mixture of ethyl 4-oxo-3H-phthalazin-1-yl-acetate '(2.34 g) in dimethylformamide (15 ml) was added sodium methoxide (0.51 g). To the clear, yellow solution, which after stirring for 5 minutes, was obtained, a solution of 5-fluoro-2-chloromethylbenzothiazole prepared according to Example IC in dimethylformamide (5 ml) was added. After stirring the resulting solution for 1 h, it was poured onto ice-water (50 ml) and extracted with methylene chloride. Evaporation of the organic extract gave a light orange solid which was crystallized from ethanol and the title compound (3.84 g; F. 118-120 ⁰ C).

EXAMPLE A

In Table 5, the first two intermediates were prepared by the method of U.S. Patent 4,251,528 and the remainder by the method of Example 13C

Table 5

product

6-Cl, 7-Cl

6-NO ₂

7-CH ₃

7-OCK ₃

7-NO_

U.S. 4. 251 5 4-225 28 U.S. 4 251 5 8-230 28 F. 18 9-190 1-232 ⁰ C F. 250 ⁰ C 172-174 F. 22 ⁰ C F. 22 ⁰ C F. 23 ⁰ C F. ⁰ C

Table 5 Continued Substituent product

6-.lsopropyl

7-isopropyl 6-CF.

7-CF.

TMS (30GKHz, CDCl-,): 8.28 (e, IH), 7.63 (d, J = 3Hz, 2H), 4.12 (q, J = 9Hz, 2H), 3.92 (s, 2H), 3.04 (sep., J = 9Hz, 1H), 1.25 (d, J = 9Hz, 6H), 1, 16 (t, J = 6Ez, 3H)

TMS (30OMHz, CDCl3): 8.32 (d, J = 9Hz, lH), 7.65 (ad, J = IEz, 9Hz _f IH), 7.55 (s, IH), 4.15 (q , J = 9Hz, 2H), 3.96 (s, 2H), 3.0 6 (sep, J = 9Hz, lH), 1.27 (d _f J = 9Hz, 6H), l, 18 (t , J = 6Hz, 3H)

TMS (90MHz, DMSO-d6): 13.0-12.6 (br, 1H), 8.4 (s, 1H), 8.2-79 {m, 2H), 4.00 (q, J = 9Hz, 2H), 3.98 (s, 2H), 1.0 (t, J = 9Hz, 3H)

TMS (90MHz, DMSO-d6): _13f 0-12.6 (br, IH), 8.5 (d, J = 9Hz, IH) _f 8.22 (m, IH), 8, Ks, IH) , 4.10 (1, J = 9Hz, 2H), 4.10 (s, 2H), _T l 15 (t, J = 9Hz, 3H)

EXAMPLE B

The following intermediates were prepared according to Example IC unless otherwise specified. All melting points are given in ° C.

Table 6

C *, / · - V ν: 46

Substituent R _r ZX product

6-Cl H _ Br ¹ KNMR (CDCl-, 60MHz): 4 _f 75 (s, 2H),

7.35 (dd, J = 2.8Hz, lH), 7.75 (d, J = 2.8Hz, IH), 7 _f 85 (d, J = SHA, IH)

5-Br H - Br F. 107

6-Br H-Br F. 108

7-Br E - Br 'KNMR (CDCl ₇ , 60 MHz): 4.7 (s, 2H),

7.2-8.0 (m, 3H)

5-Cl, 6-Cl H-Br'KNMR (CDCl ₇ , 90MHz): 4.80 (s, 2H),

8.00 (S, IH) 78 _t 15 (s, lH)

4-Cl, 6-Cl H · - Br F. 131-134 ° C

¹ KNMR (CDCl-, 90MHz): 4.80 (s, 2H), 7.45 (d, J = IHz), 7.65 (d, J = IHz, IH)

6-OCH ₇ H-Br 'HNMR (CDCl ₇ , 90MHz): 3.85 (s, 3H), 4.75 (s, 2H) 77.05 (dd, J = 2.9Hz,

IH), 7.25 (d, J = 2Hz, lH), 7.85 (d, J = 9Hz, (IH)

Br ¹ HNMR (CDCl ,, 90MHz): 2.45 (s, 3H) .4.90 (s, 2H) 77.25 (d, J = 7Hz, 1H), 7.60 (s, 1H), 7 , 85 (d, J = 8Hz, lH)

Cl · F. 78-80 Cl F. 114-115

Cl ¹ HNMR (6OMHz, CDCl-): 4.9 (s, 2H), 7.0-79 (m, 3H)

Cl F. 68-70 Cl. 74-76

6-CE ₃ H 5-Cl H 4-Cl * H 4-F * H 4-F, 5-F * H 5-Cl, 7-Cl * H

Substituent 4-Cl, 5-Cl

A-Cl ₁ I-Cl 5-CH ₃

6-isopropyl

5-CF ₃

5-Cl

5-Cl

H H

CH.

CH.

CH.

product

¹ KlWR (6 GMHz, CDCl-I: 4, 7 (s, 2H), 6.6 (d2H, J = IOKz), 7.2 (d, 2H, J = 10Kz)

F

 F.

134-135 114-116

Cl 'EiJKR (9 OKKz, CDCl): 7.85 (cl, J = 9Hz, lK), 7.65 (afj = 3Hz, IH), 7.40 (dd, J = 3Hz, 9Hz, IH), 4 , 9 {s, 2H), 3.00 (sep., J = 6Hz, IH) 1, 35 (d, J = 6Hz, 6H)

Cl 'H NMR (60MHz, CDCl _3): 2.0 (d, 3H, J = 8Hz), 5.4 (q, IH, J = 8Hz), 7.0-8.0 (m, 4H)

- OSO ₂ CH ₃

- OSO ₂ CH ₃

F

 F.

84 92-94

Cl'HNMR (60MHz, CDCl3): 5.25 (s, 2H), 7.0-8.0 (m, 4HT

Cl ¹ HNMR (GOMRZjCDCI.): 5.25 (s, 2H) _r 7 _f 0-8.0 (m, 3HT

prepared according to Can. J. Chem., 43, 2610 (1965)

EXAMPLE C

The following intermediates were prepared by known methods or by the method of Example IB

Table 7

48 substituent product

5-Bromo Chemical Abstracts; 1957

52.6319

6-bromine j. Chem. Soc. 1936, 1225

7-bromo. Liquid; m / e 228

5-Cl, 6-Cl F. 134-135 ° C

6-CK ₃ prepared similar to Ver

driving in J.Chem.Soc .; 1922, 1493, and J. Org. Chem .; 19 76, 41, 776

4C1,6-C1 Synthesis; 1976.730

6-Cl Synthesis; 1976, 730

EXAMPLE D

5- (2-chlorophenyl) -2-chloromethyl-l, 2,4-oxadiazole

_Α ζ __0 ^ 2 ^ ChI orbenzoyl-chloroacetamidoxime chloroacetamidoxime (5 g) (20 mL) dissolved in warm benzene, and 2-chlorobenzoyl chloride (6.4 ml) was carefully added thereto. The obtained mixture was heated for 30 min at 4O ⁰ C and the excess benzene was removed. After cooling to room temperature, the solidified mass was triturated with cold benzene and to obtain the compound (1.6 g; F. 126-130 ⁰ C) filtered.

B. O-2-Chlorobenzoyl-chloroacetamidoxime (1.4 g) was added to diglyme (10 ml) under reflux, and refluxing was continued for 10 minutes. After cooling, the reaction mixture was poured into water (20 ml) containing ether (50 ml). The ether layer was washed with water (2 × 50 ml), saturated aqueous sodium bicarbonate (2 × 10 ml), and the organic layer was dried and evaporated. The residue was chromatographed over silica gel to give the product, namely 0.8 g of a dyed

loose oils; 'HNMr' (CDCl, 60 MHz): 4.7 (s, 2H), 7.45 (m, 3H), 8.1 (m, IH).

EXAMPLE E

Commercially available 2-amino-3-hydroxypyridine (5.0 g) and diglyme (30 ml) were heated to form a solution at 125 ⁰ C. To this solution was added 2-chloro-l, 1,1-triethoxyethane (9.9 g) was added and the resultant mixture for 1 hour at 125 ⁰ C. The solution was cooled to room temperature and then decanted to remove a black by-product residue. The filtrate was diluted with water (50 ml) and the resulting yellow precipitated 2-chloromethyl-oxazblo / 4,5-b / pyridine was collected (1.5 g). A small sample was crystallized from isopropanol; F. 115-118 ⁰ C.

2-Chloromethyl-thiazolo / 5,4-b / pyridine was prepared in a similar manner by mixing a mixture of 3-amino-2-mercaptopyridine (3.6 g), 2-chloro-l, 1,1- triethoxyethane (6.5 g) and ethanol (60 ml) for 4 h at 60 ⁰ C heated the crude solid obtained after evaporation of ethanol was chromatographed over silica gel and yielded 2.94 g of product;. F. 71-73 ° C.

Similarly, 2-chloromethyl-5-trifluoromethylbenzothiazole, mp 52 ⁰ C, was formed from 2-amino-4-trifluoromethylthiophenol hydrochloride and 2-chloro-1,1,1-triethoxyethane in ethanol.

EXAMPLE F.

The intermediates of the formula Hal-CH_R_ were prepared by the methods listed below or by the method of Example E.

Table 8

structure

3-Bromo-methylbenzisothiazole product

R.A. Gillharr ,, Jr., Ph.D. Work, California Institute of Technology, 1969

S-phenyl-S-chloro-methylisothiazole

2-chloro-methy1-5-phenyl

¹ HNMR (CDCl ,, 60KRz): 4.8 (ε, 2H) _f 7.4 (m, 3H), 7.9 (In, 2H)

P, 64-66 ° C

2-chloro-4 ^ methyl-phenyloxazole

'F. 50-52 ^c C

5-chloro-2-phenyl-thiazol ^ methyl

U.K. Patent 1 137

5-Chloro> -inethyl-2-0-fluorphenylthiazol

3-phenyl-4-chloro-methylisothiazole

2-Phenyl-5-chloro-tmethyl-1,3,4-oxadiazole

2-chloro-methyl-5-chloro-benzocthophene

3-chloro-methyl-5- (2-ahlorphenyl) -1,2,4-oxadiazole

N-methyl-2-chloro-methylbenzimidazole

U.K. Patent .1 137

'HNMR (CDCl ,, 60MHz): 4.5 (s, 2H), 7.4 (Hi, 3H), 7.7 (m, 2H)

Chem. Ber. 96, 1049 (1963)

J. Chem. Soc. (C), (1967)

prepared similar to the method in J. Heterocycl. Chem. 16, 1469 (1979). ¹ HNMR (CDCl. *, 60MHz): 4.7 (s, 2H), 7.45 (m, 3H), 8.1 (m, IH)

JACS, 65, 1854 (1943) F. 95 ° C

3-methyl-4-bromo-methyl-1,2,5-thiadiazole J. Heterocycl. Chem., 21, 1157 (1984), b.p. 30-35 ° C / 7 mm

EXAMPLE G

The benzoate of 4-phenylthiazole-2-methanol (7.4 g), prepared according to J. Am. Chem. Soc. , 5_3, 1470 (1931) was dissolved in anhydrous tetrahydrofuran (50 ml). To this solution was added lithium aluminum hydride (525.mg) and the mixture was stirred at room temperature for 1 h. After careful quenching of the excess lithium aluminum hydride with ethyl acetate, the mixture was poured onto ice-cold water (50 ml) and acidified to pH 3 using 10% HCl. The mixture was filtered and the filtrate extracted with ether (3 x 50 ml). The organic extract was dried, evaporated and the crude product purified by chromatography to 4-phenylthiazole-2-methanol (1.8 g). This compound was converted to 4-phenylthiazole-2-methanol methanesulfonate by 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 Helv. Chim. Acta 49, 412 (1966) with the exception of the last two intermediates prepared by the method of J. Med. Chem. 4, 351 (1961).

Table 9 Cl 4 / N

O N

ο ~ ao η

R is phenyl

2-Cl-phenyl

4-Br-phenyl 2-methylphenyl

2-OCH ₃ -phenyl 2-F, 6-Cl-phenyl

2-F-phenyl 3-Cl, 4-Cl-phenyl 2-pyridyl 2-bromo-phenyl 2-CF ₃ -phenyl

B.enzyl

Product b

Helvetica Chimica Acta 49, 412 (1966)

¹ HNMR (CDCl ₃ , 60MBz): 4.8 (s, 2H), 7.4 (m, 3H), 7.9 (m _f IH)

-F.

155-160 ⁰ C

¹ HNMR (CDCl-, 60MHz): 2.6 (s, 3H), 4.7 (s, 2H), 7.3 {m, 3H), 8.0 (m, 1H)

F.

59-62 ° C

¹ HNMR (CDCl-, 60 MHz): 4.8 (s, 2H), 7.3 (m, 3H)

-F. 32-34 ⁰ C F. 38-41 ⁰ C F. 89-94 ⁰ C F. 45-46 ⁰ C

¹ HNMR (CDCl ,, 6OMHz):. 4.8 (s, 2H), 7. 8 (m, 4H)

¹ HNMR (CDCl- ,, 60MRz): 4.0 (s, 2H) J, 4 (s, 2H), 7.3 (s, 5H)

EXAMPLE J

A mixture of 5-chloro-2-hydroxyaniline (10 g), chloroacetamic acid ethyl ester hydrochloride (8.5 g) in chloroform (100 ml) was heated at reflux for 5 hours. The dark brown solution was filtered, washed first with 10% aqueous potassium hydroxide solution (10 ml) and then with water (20 ml). The organic layer was dried (magnesium sulfate) and then evaporated to dryness. The residue was purified by column chromatography (mp 53-56 ° C, yield 8.6 g),

The following intermediates were prepared by the above procedure.

substituent 7 CTI 5 product 63-65 ⁰ C Cl V 5-Bromo 0 <^ ~~ 4 F. 52-53 ⁰ C 5-Cl, 7-Cl F. 105 ⁰ C with decomposition 5,6-dibenzo F.

EXAMPLE K

A. A mixture of 1,1,1-triethoxyethane (97.3 g) and N-chlorosuccinimide (88.1 g) in carbon tetrachloride (600 ml) was heated a'uf 40 ⁰ C and then irradiated with a UV lamp , The reaction exothermed and allowed to continue after the reaction. The precipitated succinimide by-product was filtered off and the filtrate concentrated to remove carbon tetrachloride. The residual liquid was distilled to give pure 2-chloro-1,1,1-triethoxyethane (91.0 g, b.p. 91 ° C / 25 mm).

B. A solution of 2-chloro-l, 1,1-triethoxyethane (5.9 g) and 2-aminothiophenol (2.5 g) was stirred for 15 min at 80 ⁰ C heated. After cooling to room temperature, it was dissolved in methylene chloride (30 ml) and the resulting solution was washed with 3N HCl (10 ml) and then with water (20 ml). The organic portion was evaporated and the residue chromatographed over silica gel to give 2-chloromethylbenzothiazole (3.35 g, 90% yield, mp 34 ⁰ C).

EXAMPLE L 2-Chloromethyl-5-bromobenzothiazole

j -

A mixture of crude I-aminob ^ -bromothiophenol-tin-hydrochloride complex (71.6 g) prepared according to JACS 53, 209 (1931), 2-chloro-1,1,1-triethoxyethane (58.7 g). and ethanol (400 ml) was heated under mild reflux for 30 minutes to give a solution. To the warm solution was added 3N HCl (10 ml) and the precipitated solid was collected, washed with water and then dried to the title compound (35.5 g, mp 107 ⁰ C).

EXAMPLE M

The commercially available 4-chloro-3-nitrobenzotrifluoride (100 g) was dissolved in ethanol (400 ml). To this was added batchwise a solution made by first adding sodium sulfide hydrate (80 g) to hot ethanol (200 ml) and then sulfur (9.6 g). When the initially exothermic reaction subsided, the reaction mixture was refluxed for a further 30 minutes and then cooled to room temperature. The precipitated yellow solid was collected, washed with cold ethanol and then dried to 4,4'-ditrifluoromethyl-2,2'-dinitrodiphenyl disulfide (63.0 g, mp 152-154 ° C). A mixture of this compound (62 g), metallic tin (20 mesh, 132.0 g), ethanol (500 ml) and conc. HCl (200 ml) was heated at 8O ⁰ C under gentle reflux until almost a solution was obtained. Then, the reaction was held at 70 ^° C. for 30 minutes. The warm solution was filtered and the filtrate concentrated under low pressure to a viscous liquid. For this purpose, 6N HCl was added, and the precipitated white solid was the title compound (49.0 g; F. 208-209 ⁰ C) filtered.

To a solution of 2-amino-4-trifluoromethylthiophenol hydrochloride (30.0 g) in ethanol (125 ml) was added 2-chloro

1,1,1-triethoxyethane (31.0 g) was added. The mixture was 1 h at 6O ⁰ C heated. The solution was concentrated to remove excess ethanol and the resulting material extracted with ether (500 ml). The organic extract was washed successively with 10% HCl (20 ml), water (100 ml), 10% sodium bicarbonate solution and water (100 ml) and then evaporated to an amber oil which crystallized upon standing at room temperature (28 , 9 g, mp 52 ⁰ C).

EXAMPLE N

2-chloromethyl-5,6-dichlorobenzoxazole

To a solution of 2,4-dichloro-6-nitrophenol (10.0 g) in water (450 ml) containing sodium bicarbonate (4.8 g) was added sodium dithionate in sufficient quantity to colorlessly add the originally dark solution do. The hot reaction mixture was filtered and the filtrate was cooled to room temperature and the crystallized product, 2-amino-4,6-dichlorophenol (1.6 g), was collected. The 2-amino-4,6-dichlorophenol (1.6 g) was dissolved in ethanol (5 ml) and 2-chloro-1,1,1-triethoxyethane (1.9 g) added. The resulting solution was heated on a steam bath for 1.5 hours. After cooling to room temperature, cold water (5 ml) was added. The precipitated solid was collected and then air-dried to the title compound (1.12 g, mp 52-53 ° C).

EXAMPLE O 2-Chloromethyl-5-bromobenzoxazole

2-Amino-4-bromophenol (1.6 g), prepared according to US Pat. No. 4,157,444, was dissolved in ethanol (5 ml) and became 2-chloro-1,1,1-triethoxyethane (1.9 g) added. The resulting solution was heated on a steam bath for 1.5 h. After cooling the reaction mixture to room temperature, cold water (5 ml) was added. The precipitated solid

(F. 63-65 ⁰ C 1.12 g) was collected air dried and the product.

EXAMPLE P

By a similar procedure to Example KB, 2,2-chloromethyl-5-chlorobenzoxazole (mp 53-56 ° C) was prepared from commercially available 2-amino-4-chlorophenol using ethanol or chloroform as the solvent instead of methylene chloride , Similarly, 2-chloromethyl-5-methylthiobenzothiazole (mp 65-66 ⁰ C) and 2-chloromethyl-5-fluorobenzothiazole (mp 73 ⁰ C) from 2-amino-4-methylthiophenol hydrochloride or 2- Amino-4-fluorothiophenol hydrochloride prepared in ethanol as a solvent.

EXAMPLE Q

5-chloromethyl-2-phenyl-l, 3,4-oxadiazole

A mixture of 2-chloro-l, 1,1-triethoxyethane (4.8g), benzoylhydrazine (3.0g) and ethanol (30ml) was refluxed for 2 hours and the solution was allowed to cool to room temperature , To the precipitated white crystalline solid was added water (10 ml) containing a few drops of 10% HCl. The mixture was stirred for 10 minutes and then filtered and the solid collected. The mother liquor was evaporated to dryness, the residue triturated with water and filtered to afford a second crop of white solid. The combined yield of both amounts was 3.8 g (89%; HNMR identical to the product described in Chem. Ber. 96, 1046 (1969)).

Claims (6)

claims in which X is oxygen or sulfur; 2 is a covalent bond, 0, S _{1 is} NH or CH ₂ ; R _{1 is} hydroxy or a prodrug group; Rp is a heterocyclic S-membered ring having a nitrogen, oxygen or sulfur atom, 2 nitrogen atoms, one of which may be replaced by oxygen or sulfur, or 3 nitrogen atoms, one of which may be replaced by oxygen or sulfur, said ring being substituted by 1 or 2 fluoro, chloro, (C.-C.) - Alkyl or phenyl groups may be substituted or condensed with benzo or substituted by a pyridyl, furyl or Thieny! Group, wherein phenyl or benzo optionally substituted by, an iodine or Trifluoromethylthio group or by 1 or 2 fluoro, chloro, bromo, (C -C) alkyl, , (C ₁ -C ₄ ) -alkylthio, (C ₁ -C ₄ ) -alkylsulfinyl, (C ₁ -C) -alkylsulfonyl or trifluoromethyl groups and where pyridyl, furyl or thienyl are optionally substituted in the Position by fluorine, chlorine, bromine, or (C ₄ -C ₄ ) alkoxy may be substituted; 254 OO? a heterocyclic oleic ring having 1 to 3 nitrogen atoms or 1 or 2 nitrogen atoms and 1 oxygen or sulfur atom, said ring being substituted by 1 or 2 (C ₁ -C ₄ ) -alkyl or phenolic groups or condensed with benzo or by a Pyridyl, furyl or thienyl group may be substituted, wherein phenyl or benzo optionally substituted by an oily or trifluoromethylthio group or 1 or 2 fluoro, chloro, bromo, -, (C ₁ -C ₄ J-AIkOXy-, (C ^ C ^ alkylthio, -, (C ₁ -C ₄ J-AIkYlSuIfOnYl- or Trifuuormethylgruppen may be substituted and wherein pyridyl, furyl or thienyl optionally in the 3-position by fluorine, chlorine, (C ₁ -C ₄ J-AIkYl or (C ₁ -C ₄ ) alkoxy may be substituted; Oxazole or thiazole condensed with a 6-membered aromatic group containing 1 or 2 nitrogen atoms, with thiophene or with furan, each of which may optionally be substituted by a fluoro, chloro, bromo, trifluoromethyl, methylthio or methylsulfinyl group; Imidazolopyridine, naphthothiazole or maphthoxazole; R and R _{4 are the} same or different and are hydrogen, fluorine, chlorine, bromine, trifluoromethyl, (C ₁ -C ₄₎ -alkoxy, (C ₁ -C ₄ -alkylthio, (C ₁ -C ₄₎ (C ₁ -C J-alkylsulfonyl or nitro, or R ₃ and R ₄ taken together, is (C ₁ -C 6 -alkanedioxy; and R ₁ is -saturhyl of f or methyl; or a 3S pharmaceutically acceptable base addition salt of a compound of formula I, in which R _{1 is} hydroxy, or an acid addition salt of a compound of formula I in which R _{1 is} di (C ₁ -C) -alkylamino or (C ₁ -C ₄ ) -alkoxy substituted by N-morpholino or di -tC ^ CJ-alkylamino, characterized in that a compound of the formula in which R ₃ and R are as defined above and R 'is hydrogen, methyl or ethyl, with a compound of the formula L-CH-ZR ₀
I ^{2 R} 5 in which L is a separating group, and, when R 'is methyl or ethyl, hydrolyzing to form corresponding compounds in which R' is hydrogen and, optionally, by reaction with a pharmaceutically acceptable cation in a pharmaceutically acceptable base Converts addition salt and, optionally, R ₁ by Alkyl'ieren the sodium salt of the compound (I) in which R ,. Hydroxy is converted to a prodrug group. 2. The method according to claim 1, characterized in that X is oxygen. 3. The method of claim 1 or 2, characterized in that Z is a covalent bond, R _{1 is} hydroxy and R_, R and R are each hydrogen. 4. The method according to claim 1, 2 or 3, characterized in that Rp 5-bromo-2-benzothiazolyl, 5-fluoro-2-benzothiazolyl, 5-trifluoromethyl-2-benzothiazolyl, 5-chloro-2-benzothiazolyl, 4,5-difluoro-2-benzothiazolyl, 4,7-dichloro-2-benzothiazolyl or 5,7-dichloro-2-benzothiazolyl. 5. The method according to claim 1 or 2, characterized in that R _{3 is} hydrogen, 5-fluoro, 5-chloro, 5-bromo or 5-methyl and R _{4 is} hydrogen, a 6- or 7-substituted chlorine, bromine , Methyl, isopropyl, methoxy, nitro or trifluoromethyl group, 4,5-difluoro, or 5,7-dichloro. 6. The method according to claim 1, characterized in that R is methyl and L is OSO-R, wherein R, (C ₁ -C ₄ ) alkyl, trifluoromethyl or phenyl is optionally substituted by methyl, chloro, bromo or nitro.