MXPA97009450A - Piridiniminil-1,2-benzoisoxazoles and -benzoisotiazoles as agents antipsicoti - Google Patents

Abstract

Novel pyridiniminyl-1,2-benzoisoxazoles and -benzoisothiazoles, intermediates and process for the preparation thereof and methods for relieving memory dysfunction and treating depression are described using the 1,2-benzoisoxazoles and -benzoisothiazoles and intermediates or compositions of the same ones

Description

PIRIDINIMINIL-1,2-BENZOISOXAZOLES AND -BENZOISOTIAZOLES AS ANTIPSYCHOTIC AGENTS The present invention relates to 1,2-benzoisoxazoles and -benzoisothiazoles. More particularly, the present invention relates to pyridiniminyl-1,2-benzoisoxazoles and benzoisothiazoles of Formula 1 wherein Ri is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, lower alkyl of -C (= O) O-lower alkyl, 2,3-dioxolane, phenyl, cinnamyl, phenyl substituted by lower alkyl, lower alkoxy , halogen, hydroxyl, nitro or trifluoromethyl; Z is hydrogen, halogen, lower alkyl or nitro; x is oxygen or sulfur, Z is hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, nitro or trifluoromethyl; n is from 1 to 12; the geometric isomers, optical isomers or pharmaceutically acceptable salts thereof, useful for relieving memory dysfunction and is therefore indicated in the treatment of Alzheimer's disease as well as in the treatment of depression.

Subgenépco for the compounds of formula 1 are those wherein X is oxygen and R, is hydrogen or lower alkyl, and those wherein x is oxygen and Ri is phenyl or phenyl substituted by lower alkyl, lower alkoxy, halogen, hydroxyl, nitro or trifluoromethyl The present invention also relates to ap? r? d? n? lam? no-1,2-benzoisoxazoles and benzisothiazoles of the formula 2 wherein Q is hydrogen, halogen, lower alkyl or nitro, X is oxygen or sulfur, Z is hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, nitro, or trifluoromethyl, the optical isomers, or pharmaceutically acceptable salts thereof, useful as intermediates for the preparation of p? r? d? m? n? l-1, 2-benzoisoxazoles and benzoisothiazoles of Formula 1 and also for the relief of memory dysfunction and depression treatment Unless note otherwise, the following terms have the given definitions. As used throughout the specification and appended claims, the term "alkyl" refers to a straight or bred chain hydrocarbon radical that does not contain saturation and that has 1 to 8 carbon atoms Examples of alkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-hexyl, 3-hexyl, 4-heptyl, 2- octyl and the like The term "alkoxy" refers to a monovalent substituent consisting of an alkyl group attached through an oxygen ether having its valence ligature free from ether oxygen Examples of alkoxy groups are methoxy, ethoxy, propoxy, 1-butox ?, 1-pentox ?, 3-hexox ?, 4-heptox , 2-octoxy and the like The term "alkenyl" refers to a straight or bred chain hydrocarbon radical containing more than one carbon to two carbons binding and having from 3 to 7 carbon atoms such as such as propenyl, 2-butenyl, 3-ethyl-2-pentene and the like, the term "alkynyl" refers to a straight or bred chain hydrocarbon radical containing unsaturation in the form of a ligation of a only carbon to triple carbon and having 3 to 7 carbon atoms such as 2-propylene, 2-butyl, 1-methyl-2-butyl, 4-methyl β-2-pentene, 4,4-d ?methyl-2-butynyl and the like, the term "cycloalkyl" refers to a saturated hydrocarbon group having at least one carbocyclic ring, the ring containing from 3 to 10 át carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-octyl, 1-adamantyl and the like The term 'alkanol' refers to a compound formed by a combination of an alkyl group and hydroxy radical Examples of alkanols are methanol, ethanol , 1 and 2-propanol, 2,2-d? Methanol, hexanol, octanol and the like The terms "halogen", Hal "or" halo "refers to a member of the fluorine, chlorine, bromine or iodine family . The term "lower" as applied to any of the groups mentioned above, refers to a group having a carbon skeleton that contains up to and includes 6 carbon atoms. The compounds of the present invention that lack an element of symmetry exist as optical antipodes and as the racemic forms thereof. The optical antipodes can be prepared from the corresponding racemic forms by normal optical resolution techniques, involving, for example, the separation of diastereomeric salts from those present compounds characterized by the presence of a basic amino group and an optically active acid or by synthesis of optically active precursors. The present invention encompasses all optical isomers and racemic forms thereof of the compounds described and claimed herein and the formulas of the compounds shown herein are intended to encompass all possible optical isomers of the compounds thus described. R .V. Effland, et al., Discloses in EP 0 594 000 A 1, published on April 27, 1994, several substituted pyridinylamino-benzoisozazoles and benzoisothiazoles which are useful as antidepressants. The novel pyridinim-1, 2-benzoisoxazoles can be prepared by following steps A, A 'and B as set forth in the Reaction Scheme. The benzoisothiazoles of the present invention can be prepared by following steps A and B as set forth in the Reaction Scheme. As described in the Reaction Scheme, steps A and B, to prepare a pyridinimyl-1,2-benzoisoxazole of the formula 1_, wherein X is oxygen, for example, a pyridiniminyl-1,2-benzoisoxazole 1, a aminobenzoisozaxol 3 is condensed with a halopyridine of the formula 5 wherein Hal is chloro or bromo and Q is as before to produce a pyridinylamino-1,2-benzoxyisoxazole 2 wherein X, Q, and Z are as before, which, in turn, is alkylated with an alkyl halide of the formula 6 Hal- (CH2) nR1 6 where Hal is chlorine or bromine and Rt and n are as before to give a final pyridiniminyl-1,2-benzoisoxazole 1 wherein Ri, Q, X, Z and n are as before. The condensation of amine 3 with halopyridine 5 is generally ied out in a polar aprotic solvent, for example, N-methylpyrrolidinone, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, or dimethyl sulfoxide. While the condensation temperature is not narrowly critical, temperatures elevated on the scale from about 100 ° to about 150 ° can be used to facilitate the reaction, depending on the reaction solvents. A condensation temperature of about 130 ° C is preferred. The alkylation is conveniently ied out in an inert solvent such as acetonitrile at the reflux temperature of the reaction medium. The alkylation can be ied out at reduced temperatures, for example, within the range of about room temperature to approach approximately the reflux temperature of the medium. Alternatively, the alkylation can be achieved in an inert solvent such as an aprotic dipolar solvent (dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoramide, and the like) in the presence of a base such as, for example, an alkali metal hydride, viz. lithium, sodium or potassium, with sodium hydride being preferred. The alkylation temperature can vary from about room temperature to about 80 ° C. An alkylation temperature of about 60 ° C is preferred. The starting 3-amino-1,2-benzoisoxazole 3, for example, an aminobenzoisoxazole 3, wherein X is oxygen and Z is as before, is commercially available or can be prepared by the process described in G.M. Shutske and K.J. Kapples, Journal of Heterocvclic Chemistrv. 26. 1293 (1989). In addition, the starting 3-amino-1,2-benzisothiazoles are readily prepared by one of ordinary skill in the art, for example, following the procedures discussed by Rahman and Scrowston, J. Chem. Soc. Perkin Trans. I. 2973 (1983) and 385 (1984).

As described in the Reaction Scheme, steps A 'and B, the 3-pyridinylamino-1,2-benzoisoxazole intermediate 2, for example, a pyridinylamino benzoisoxazole 2 wherein X is oxygen and Q and Z are as before, in the alternative, they can be prepared by treating a 2-fluoro or 2-nitro-N-4-pyridinylbenzoamide 7 with thionyl chloride followed by the treatment of the imidoyl chloride, thus obtained, generally without purification, with O-trimethylsilylhydroxylamine, for give an amidoxime, and treat amidoxime, also without purification, with a base to give a pyridinyl-1,2-benzoisoxazole 2. Specifically, 2,5-difluoro-N-pyridinylbenzoamide 7, wherein Q is hydrogen and Z is 5 -fluoro is treated with thionyl chloride in the presence or absence of a solvent (1,1-dichloroethane) at reflux temperature of the reaction medium to provide 2,5-difluorophenyl-N- (1 H) -pyridinimidoyl chloride which , in turn, is treated with O-trimethylsilylhydroxylamine in an ether solvent such as tetr ahidorfuran at room temperature to give 2,5-difluoro-4- (pyridinylamino) methanone oxime and the latter with an alkali metal alkoxide such as potassium butoxide in an etheric or dipolar aprotic solvent such as tetrahydrofuran or dimethylformamide, respectively, at a elevated temperature to give 5-fluoro-3- [4- (pyridinyl) amino] -1,2-benzoisoxazole. One of ordinary skill in the art would readily recognize that the corresponding 1,2-benzisothiazoles of the present invention are prepared in a manner analogous to the procedure described in the Reaction Scheme, steps A and B as set forth above to prepare the reactions. , 2-benzoisoxazoles 2 and 3. Pyridiniminyl-1, 2-benzoisoxazols and -benzoisothiazoles and related compounds of the present invention are useful as agents for alleviating memory dysfunction, particularly dysfunctions associated with decreased cholinergic activity such as that found in Alzheimer's disease. The relief of memory dysfunction activity was demonstrated in the in vitro inhibition of acetylcholinesterase analysis, an analysis for the determination of a drug's ability to inhibit the inactivation of acetylcholine, a neurotransmitter involved in the etiology of dysfunction of the memory and dementia of Alzheimer's. In this analysis, a modification of a test described by GL Ellman, et al., Biochemical Pharmacology, 7, 88 (1961), the following reagents were prepared and used: 1. 0.05M Phosphate pH Regulatory Solution (pH 7.2) A monobasic sodium phosphate monohydrate solution (6.85 g) in distilled water (100 ml) was added to a solution of dibasic sodium phosphate heptahydrate (13.4 g) and distilled water (100 ml) until a pH of 7.2 was obtained. The solution was diluted from 1 to 10 with distilled water. 2. Substrate in pH Regulatory Solution. The Phosphate pH 0.05M buffer solution (pH 7.2) was added to acetylcholine (198 mg) at a total volume of 100 ml, ie, a sufficient amount (g) up to 100 ml. ,5-dithiobisnitrobenzoic acid in buffer solution of PH Phosphate pH 0.05M buffer solution (pH 7.2) was added to 5,5-dithiobisnitrobenzoic acid to a total volume of 100 ml, that is, a sufficient amount (g) up to 100 ml. 4. Drug Target Solution A 2 millimolar stock solution of the test drug was prepared in a sufficient quantity of acetic acid or dimethyl sulfoxide to volume with 5,5-dithiobisnitrobenzene Acid in pH Regulating Solution. The drug's mother solution is serially diluted (1:10) so that the final concentration of the cuvette is 10"4 molar Wistar male rats were decapitated, the brains were quickly removed, the striated bodies were dissected, weighed and homogenized in 19 volumes (approximately 7 mg protein / ml) of 0.05 M phosphate pH Regulatory solution (pH 7.2) using a Potter-Elvehjem homogenizer An aliquot of 25 μl of this suspension was added to 1 ml of the vehicle or various concentrations of the test drug and preincubated for 10 minutes at 37 ° C. Enzyme activity was measured with a Beckman DU-50 spectrophotometer with the following software and instrument attachments: 1. Kinetics Soft-Pac ™ Module # 598273; 2. Program # 5 Kindata; 3. Source-Vis; 4. Wavelength - 412 nm; . Close - none; 6. Cuvettes - 2 ml cuvettes using autosampler 6; 7. Blank space - 1 for each substrate concentration; 8. Time interval - 15 seconds (15 or 30 seconds for kinetics); 9. Total time - 5 minutes (from 5 to 10 minutes for kinetics); 10. Graph - yes; 11. Expansion - autoscale; 12. Inclination - increasing; 13. Results - yes (gives the inclination); and 14. Factor - 1. The reagents are added to the blank and sample trays in the following manner: 1. Blank space: 0.8 ml of 5,5-dithiobisnitrobenzoic acid, 0.8 ml of Substrate in Solution PH regulator 2. Control: 0.8 ml of 5,5-dithiobisnitrobenzoic Acid / Enzyme 0.8 ml of Substrate in pH Regulatory Solution. 3. Drug: 0.8 ml of 5,5-dithiobisnitrobenzoic Acid / Drug / Enzyme 0.8 ml of Substrate in pH Regulatory Solution The values in the blanks were determined for each operation in order to control the non-enzymatic hydrolysis of substrate and these values were automatically subtracted by the Kindata program available in the kinetics package module.

This program also calculates the rate of absorbance change for each cuvette. For Determinations of C or The substrate concentration is 10 millimolar diluted to 1: 2 in analysis producing final concentration of 5 millimolar. The concentration of 5,5-dithiobisnitrobenzoic acid is 0.5 millimolar producing final concentration of 0.25 millimolar. % inhibition = Control Slope - Drug Slope x 100 Slope Control Clso values are calculated from the log-probit analysis TABLE I Inhibition of Compound Acetyl Cholinesterase Activity Cl50 (5M) 3- [1-phenylmethyl-N-4 (1H) -pyridinimyl] -1,2- 0.28 benzoisoxazol 3- [1-phenylpropyl-N-4 (1 H) -pi-ridiniminyl] -0.61,2-benzoisoxazole 6- methoxy-3- [1-phenylmethyl-N-4 (1H) -0.09 pyridiniminyl] -1,2-benzoisoxazole 3- [1 - (4-f luorofenyl) methyl-N-4 (1 H) - 0.44 pyridinim in il] -1,2-benzoisoxazole Tacrine 0.32 Relief of memory dysfunction is achieved when the present pyridiniminyl-1,2-benzoisoxasols and -benzoisothiazoles and related compounds are administered to a subject requiring such treatment as an oral dose, parenteral or intravenous effective 0.10 to 50 mg / kg of body weight per day. A particularly effective amount is about 10 mg / kg of body weight per day. However, it should be understood that for any particular subject, the specific dose regimens should be adjusted according to the individual need and professional judgment of the person administering or supervising the administration of the above-mentioned compound. It should further be understood that the doses set forth herein are illustrative only and that, to no degree, limit the scope or practice of the invention. The pyridiniminyl-1,2-benzoisoxazoles and -benzoisothiazoles of the present invention are also useful as agents for treating depression. The treatment of depression is demonstrated in the inhibition in vitro of the analysis of monoamine oxidase, an analysis for the determination of the ability of a drug to inhibit the enzyme monoamine oxidase. In this analysis, a modification of an analysis described by M. V. Kindt, et al., Europ. J. Pharmacol. 146: 313: 318 1988. The following reagents were prepared: 1. pH Regulating Solution (0.5 M), pH 7.4; 134.4 g of dibasic sodium phosphate heptahydrate is. for 1 liter in distilled water (A). 17. 3 g of monobasic sodium phosphate, q.s. for 250 ml in distilled water (B). Adjust pH from A to 7.4 by slowly adding B (required volumes) Dilute to 1:10 in distilled water (0.05 M phosphate pH buffer, pH 7.4) 2. 0.25 M sucrose (pH regulated phosphate): 21.4 g of sucrose , cs for 250 ml with 0.05 M phosphate pH buffer 3. Substrate for monoamine oxidase-A: a. Serotonin creatinine sulfate (5-hydroxytryptamine) was obtained from Sigma Chemical Company. A 5 mM stock solution was made in 0.01 N hydrochloride. The solution is used to dilute the specific activity of [3H] -hydroxytryptamine. b. [3H] -5-Hydroxytryptamine binoxalate (20-30 Ci (mmoles) from New England Nuclear was obtained C. 12 μl of [3 H] -5-hydroxytryptamine was added to 2 ml of the 5 mN hydroxytryptamine solution: ( the final amine concentration in the analysis is 200 μM: see below). 4. Substrate for monoamine oxidase - B. a. -phenethylamine is obtained from Sigma Chemical Company. A stock solution of 5 mM is formed in 0.01 N hydrochloride. The solution is used to dilute the specific activity of [14 C] -phenethylamine. b. [Ethyl-1 -14C] -phenethylamine hydrochloride (40-50 mCi / mmoles) is obtained from New England Nuclear. c. Add 12 μl of [1 C] -fetenylamine to 2 ml of the 5 mM phenethylamine solution. (The final amine concentration in the analysis is 200 μM: see below). 5. Equal amounts of the monoamine oxidase A (5-hydroxytryptamine) and monoamine oxidase-B (- phenethylamine) substrates are combined to simultaneously test both types of monoamine oxidase, ie, the mixed stock solution of 5-hydroxytryptamine 2.5 mN and - 2.5 mM phenethylamine, 40 μl of this mixed solution gives a final concentration of 200 μM of each amine in the analysis. When testing only one type of monoamine oxidase, the stock solutions of 5 mM should be diluted 1: 1 with distilled water before adding 40 μl to the incubation mixture; that is, same final amine concentration 200 μM. 6. The stock solutions of the test drugs are prepared in appropriate vehicles and diluted in series to give final concentrations ranging from 10"7 to 10" 3 molar in the analysis. Lower concentrations can be formed for more potent drugs. Tissue Preparation Male Wistar rats of 150-250 grams were sacrificed and the brains were removed rapidly. The entire brain minus the cerebellum was homogenized in 30 volumes of 0.25 M sucrose with pH regulated with phosphate solution, cooled on ice, using a Potter-Elvehjem homogenizer. The homogenate was centrifuged at 1000 g for 10 minutes and the supernatant (S 1) was decanted and recentrifuged at 18,000 g for 20 minutes. The resulting pellet (P2) was resuspended in fresh 0.25 M sucrose and serves as the tissue source for mitochondrial monoamine oxidase. C. Analysis 10 μl of 0.5 M phosphate buffer, pH 7.4 50 μl of water or appropriate drug concentration 400 μl of your tissue pensions The tubes were pre-incubated for 15 minutes at 37 ° C and the analysis was started by adding 40 μl of the combined substrate ([3 H] -hydroxytryptamine and [1 C] -phenethylamine) at intervals of 15 seconds. The tubes were incubated for 30 minutes at 37 ° C and the reaction was stopped by the addition of 0.3 ml of 2N hydrochloric acid. The blank values of the tissue were determined by adding the acid before the radioactive substrate. The oxidative products of the reaction were extracted with ethyl acetate / toluene (1: 1). Add 5 ml of this mixture to the tubes, stir for 15 seconds the extract of the deaminated metabolites in the organic phase and let separate from the aqueous phase. Place the tubes in acetone / dry ice bath to freeze the aqueous layer. When this layer is frozen, pour the top organic layer into a scintillation vial. Add 10 m of Liquiscint and count the samples using established window points for 1 C in the channel and 3H in the second channel. The IC5o values were determined by a log-probit analysis.

Results TABLE II Compound Monoamine IC50 (μM) Monoamine Oxidase A Oxidase B 6-chloro-3- [1-propyl-N- 1.65 27.82 4 (1 H) pyriniminyl-1,2-benzosoxazole 3- [1-phenylmethyl-N- 9.0 33.7 4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole 3- [1- (2-phenylethyl) -N-3.0 15.9 4 (1H) -pyridiniminyl] -1,2-benzoisoxazole 6-methoxy-3 [1- 3.0 25.2 phenylmethyl-N-4 (1H) -pyridiniminyl] -1, 2-benzoisoxazole Bromaromine 0.18 23.4 Treatment for depression is achieved when pyridiniminyl-1,2-benzoisoxazoles or -benzoisothiazoles and related compounds are administered to a subject requiring such treatment as an effective oral, intravenous or intravenous dose of 0.10 to 50 mg / kg body weight per day. A particularly effective amount is about 10 mg / kg of body weight per day. However, it should be understood that for any particular subject, the specific dose regimens should be adjusted according to the individual need and professional judgment of the person administering or supervising the administration of the above mentioned compound. It should be further understood that the doses set forth herein are illustrative only and that to no degree, limit the scope or practice of the invention. Acetylcholinesterase inhibitors and monoamine oxidase inhibitors are known in the art to be useful for relieving memory dysfunction and antidepressants, respectively. (See V. Kumar in Alzheimer's Disease: Therapeutic Strategies, E. Giacobini and R. Becker Eds, Birkhauser, Boston 1994 for utility of memory dysfunction and KF Tipton in Biochemical and Pharmacological Aspects of Depression, KF Tipton and UBH Youdin, Eds , Taylor and Francis, London 1989 for antidepressant utility It is understood by some of ordinary skill in the art that humans, mice, rats and the like are included within the scope of the term "mammal." The effective amounts of the compounds of The invention can be administered to a subject by one of several methods, for example, orally or as in capsules or tablets, parenterally in the form of sterile solutions or suspensions and in some cases intravenously in the form of sterile solutions. free, while by themselves they are effective, can be formulated and administered in the form of their pharmaceutically acceptable addition salts s for purposes of stability, convenience of crystallization, increased solubility and the like. Pharmaceutically preferred addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid and the like, salts of monobasic carboxylic acids such as, for example, example, acetic acid, propionic acid and the like, salts of dibasic carboxylic acids such as, for example, maleic acid, fumaric acid, oxalic acid and the like and salts of tribasic carboxylic acids such as, for example, carboxy succinic acid, citric acid and the like The active compounds of the present invention can be administered orally, for example, with an inert diluent or with an edible carrier. They can be enclosed in gelatin capsules or tablets in tablets. For the purpose of oral therapeutic administration, the mentioned compounds can be incorporated with excipients and used in fo of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like These preparations must contain at least 05% of active compounds, but may vary depending on the particular form and can conveniently be between 4% and about 75% by weight of the unit. The amount of the compound present in said composition is such that an adequate dose will be obtained. Preferred compositions and preparations according to the present invention are prepared so that the oral unit dose form contains between 0-300 mg of active compound Tablets, pills, capsules, troches and the like, may also contain the following ingredients, a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotes; a slider such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl, salicylate or orange flavor can be added. When the unit dose is a capsule, it may contain in addition to the materials of the above type, a liquid vehicle such as fatty oil. Other unit dose forms may contain other different materials that modify the physical form of the unit dose, for example, as coatings. These tablets or pills may be coated with sugar, shellac or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, colorants and colors and flavors. The materials used to prepare these different compositions must be pharmaceutically pure and non-toxic in the amounts used. For purposes of parenteral therapeutic administration, the active compounds of the invention can be incorporated into a solution or suspension. These preparations must contain at least 0.1% of the compound mentioned above, but may vary between 05 and about 50% of the weight thereof. The amount of active compound in said compositions is such that an adequate dose will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral unit dose contains between 0.5 to 100 mg of the active compound. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite, agents; chelators such as ethylenediaminetetraacetic acid; pH regulating solutions such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. Parenteral preparations can be packed in ampoules, disposable syringes or multiple ampoules made of glass or plastic. The compounds of the invention include: a. 6-methyl-3- [1-propyl-N-4 (1H) pyridiniminyl] -1,2-benzoisoxazole: b. 5-hydroxy-3- [1-methyl-N-4 (1H) pyridiniminyl] -1,2-benzoisoxazole; c. 3- [1-ethyl-N-4 (1H) pyridiniminyl] -5-trif luoromethyl-1,2-benzoisoxazole; d. 3- [1- (2-propenyl) -N-4 (1H) pyridiniminyl] -1,2-benzoisoxazole; and. 3- [1- (2-propenyl) -N-4 (1 H) p i ridi n i m in i I] -1,2-benzoisoxazole; F. 3- [1-cyclohexyl-N-4 (1 H) p i rid i n imi I] -1,2-benzoisoxazole; g. 3- [1- (4-hydroxyphenylmethyl-N-4 (1H) pyridiniminyl] -1,2-benzoisothiazole; h.3- [1-propyl-N-4 (1H) pyridiniminyl] -1,2-benzoisothiazole; 3- [1-propyl-N- [2-chloro-4- (1H) pyridiniminyl] -1,2-benzoisoxazole; j. 3- [1-propyl-N- [2-methyl-4- (1H) pyridiniminyl] -1,2-benzoisoxazole; k. 3- [1-propyl- N- [2-nitro-4 (1H) pyridiniminyl] -1,2-benzoisoxazole; I. 3- [1-decyl-N-4 (1 H) pyrimidiniminyl] -1,2-benzoisoxazole; m 5-m ethyl-3- (4-pyridinylamine) -1,2-benzoisoxazole; n.6-hydroxy-3- (4-pyridinylamino) -1, 2 -benzoisoxazole, or 7-nitro-3- (4-pyridinylamino) -1,2-benzoisoxazole; p.3- (4-pyridinylamino-3-trifluoromethyl) -1,2-benzoisoxazole; chloro-4-pyridinylamino) -1,2-benzoisixazole; r. 3- (2-chloro-4-pyridinylamino) -1,2-benzoisoxazole; s.3- (2-nitro-4-pyridinylamino) -1, 2 -benzoisoxazole and t-3- (4-pyridinylamino) -1,2-benzisothiazole The following examples present normal syntheses as described in the Reaction Scheme Reagents and starting materials are commercially available. They will be prepared easily by someone with ordinary experience in the field. It is understood that these examples are illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "kg" refers to kilograms; "g" refers to grams; "mg" refers to milligrams; "μg" refers to micrograms; ppm refers to parts per million; "mmoles" refers to millimoles; "mL" refers to milliliters; "cm" refers to centimeters; "L" refers to liters; "° C" refers to degrees Celsius; "mmHg" refers to millimeters of mercury; "rpm" refers to revolutions per minute; "Rf" refers to retention factor; "pe" refers to boiling point; "pf" refers to melting point; "desc" refers to decomposition; "[a] D20" refers to specific rotation of the sodium D line at 2O0 C obtained in a cell of 1 decimeter; "c" refers to concentration in g / ml; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "DMG" refers to dimethylformamide; "M" refers to molar; "mM" refers to millimolar; "μM" refers to micromolar; "nM" refers to nanomolar; "μL" refers to microliters; "CLAR" refers to liquid chromatography of high performance, "eq" refers to equivalents; "nr" refers to hours; "N" refers to normal; and "μCi" refers to microcupes. EXAMPLE ONE CI or 6-chloro-3- [1-propyl-N- (1H) pyridiniminyl-11,2-benzoisoxazole hydrochloride To a suspension of sodium hydride washed with pentane (380 mg) in dimethylformamide (5 ml) was added 1- bromopropane (0.862 ml) followed by 6-chloro-3- (4-pyridyl) amino-1,2-benzoisoxazole (2.33 g) in dimethylformamide (10 ml) dropwise. After stirring for 1.5 hr, 0.3 ml of 1-bromopropane was added and the reaction mixture was heated at 60 ° C for half an hour. The reaction mixture was cooled and partitioned between diethyl ether and water. The precipitate was collected and washed with water and diethyl ether to give 1.21 g of the free base product. The free base was taken up in methanol / ethereal hydrogen chloride, and the solution was concentrated. The residue was triturated with diethyl ether and then recrystallized from methanol / diethyl ether to give 992 mg (32%) of product from two crops, mp 278 ° C (d), after drying under high vacuum, phosphorus pentoxide, and heat the xylene to reflux. Analysis: Calculated for C? SH14N3OCI-HCI: 55.57% C 4.66% H 12.96% N Found: 55.39% C 4.55% H 12.97% N EXAMPLE TWO 3-M- (4,4-dimethyl) pentyl-N-4 (1 H) -pyridiniminyl-1-2.2-benzoisoxazole borohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.2 g) and 1-Bromo-4-dimethyl-pentane (3.1 g) in acetonitrile (25 ml) was heated under reflux for 24 hr. The reaction mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum, to give 0.60 g, (27%) of product. Two recrystallizations of isopropanol produced the analytically pure sample, mp 236-237 ° C. Analysis: Calculated for C? 9H24BrN3O: 58.46% C 6.21% H 10.77% N Found: 58.18% C 5.91% H 10.0% N EXAMPLE THREE 3-M-phenyl methyl-N-4 (1 H) -pyridiniminiH-1,2-benzoisoxasol Brohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-bezoisoxazole (0.84 g) and benzyl bromide ( 0.68 g) in acetonitrile (20 ml) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.4 g (92%) of product, mp 285-287 ° C. Analysis: Calculated for C19H16BrN3O: 59.70% C 4.22% H 10.99% N Found: 59.65% C 4.34% H 11.15% N EXAMPLE FOUR 3-p- (2-Phenylethyl) -N-4 (1 H) -pi Ridiniminyl-1,2-benzoisoxazole Bromohydrate A mixture of 3 - [(4-pyridinyl) amino-1,2-benzoisoxazole (1.0 g) and bromide of phenethyl (0.87 g) in acetonitrile (19 ml) was heated under reflux for 10 hr. The reaction mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.0 g (54%) of product, mp 259-261 ° C. Analysis: Calculated for C20H18BrN3O: 60.62% C 4.58% H 10.60% N Found: 60.41% C 4.61% H 10.61% N EXAMPLE FIVE 3-M- (3-phenylpropin-N-4 (1 H) -pyridinium mini 11-1.2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.07 g) and 3-Phenylpropyl bromide (1.51 g) in acetonitrile (25 mL) was heated under reflux for 24 hr.The mixture was allowed to cool to room temperature, and the precipitate was collected.The precipitate was washed with diethyl ether and dried under vacuum to give 1.27 g (61%) of product, mp 226-227 ° C. Analysis: Calculated for C2? H20BrN3O: 61.47% C 4.91% H 10.24% N Found: 61.37% C 5.11% H 10.15% N EXAMPLE SIX 3-M- (4-phenylbutyl) -N-4 (1 H? -pyridiniminyl-1, 2-benzoisoxazole Bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) Y 1-Bromo-4-phenylbutane (1.0 g) in acetonitrile (25 mL) was heated under reflux for 24 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.30 g (65%) of product, mp 207-208 ° C. Analysis: Calculated for C22H22BrN3O: 62.27% C 5.23% H 9.90% N Found: 62.26% C 5.18% H 9.90% N EXAMPLE SEVEN 3f 1- (5-phenylpentyl-N-4 (1 H) -pyridiniminyl-1,2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] 1,2-benzoisoxazole (1.0 g) and 1-bromo- 5-phenylpentane (1.13 g) in acetonitrile (25 ml) was heated under reflux for 24 hr.The mixture was allowed to cool to room temperature and the precipitate was collected.The precipitate was washed with diethyl ether and dried in vacuo to give 0.85. g (41%) of product, mp 213-214 ° C. Analysis: Calculated for C23H24BrN3O: 63.02% C 5.52% H 9.59% N Found: 63.02% C 5.47% H 9.62% N EXAMPLE EIGHT 3-M- (2-Methylphenmethyl-N-4 (1 H) -pyridiniminyl-1-2-benzoisoxazole Bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) and alpha-bromo-2-xylene (0.63 ml) in acetonitrile (25 ml) was heated under reflux for 24 hr.The mixture was allowed to cool to room temperature and the precipitate was collected.The precipitate was washed with diethyl ether and dried vacuum to give 1.47 g (78%) of the product, mp 261-262 ° C. Analysis: Calculated for: C20H18BrN3O: 60.62% C 4.58% H 10.60% N Found: 60.35% C 4.45% H 10.63% N EXAMPLE NINE 3-M Bromohydrate - (4-methyl IfeniDmeti IN-4 (1 H) -pi-ridiniminyl-1,2-benzoisoxazole A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) and alpha-bromo-4-xylene (0.63 ml) in acetonitrile (25 ml) was heated under reflux for 24 hr.The mixture was allowed to cool to room temperature and the precipitate was collected.The precipitate was washed with diethyl ether and dried vacuum to give 1.43 g (76%) of the product, mp 240-242 ° C. Analysis: Calculated for: C20H? 8BrN3O: 60.62% C 4.58% H 10.60% N Found: 60.46% C 4.38% H 10.60% N EXAMPLE TEN 3-f 1 - (3-methyl-n-nyl) -methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1, 2 -benzoisoxazole (1.0 g) and alpha-bromo-3-xylene (0.64 ml) in acetonitrile (25 ml) was heated under reflux for 24 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.43 g (76%) of the product, m.p. 232-233 ° C. Analysis: Calculated for: C20H? 8BrN3O: 60.62% C 4.58% H 10.60% N Found: 60.70% C 4.63% H 10.41% N EXAMPLE ELEVEN 3-f1- (3-methoxyphenyl) methyl-N-4 (1 H) -pyridiniminoH-1,2-benzoisoxazole hydrochloride A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) ) and 3-methoxybenzyl chloride (0.68 ml) in acetonitrile (25 ml) was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried in vacuo to give 0.99 g (52%) of the product, m.p. 244-245 ° C. Analysis: Calculated for: C20H18CIN3O2: 65.31% C 4.93% H 11.42% N Found: 65.12% C 4.61% H 11.36% N EXAMPLE TWELVE 3-M- (3-fluoropheninmethyl-N-4 (1 H) -pyridiniminiH-1,2-benzoisoxazole Bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) and bromide 3-Fluorobenzyl (0.58 ml) in acetonitrile (25 ml) was heated under reflux for 1 h The mixture was allowed to cool to room temperature and the precipitate was collected.The precipitate was washed with diethyl ether and dried in vacuo to give 1.40. g (73%) of the product, mp 248-249 ° C. Analysis: Calculated for: C19H15BrFN3O: 57.02% C 3.78% H 10.50% N Found: 56.85% C 3.48% H 10.42% N EXAMPLE THIRTEEN 3-f 1 - (2-f luorofenyl) methyl-N -4 (1 H) -pyridiniminyl-1, 2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) and 2-fluorobenzyl bromide (0.56 ml) in acetonitrile (25 ml) was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.43 g (74%) of the product, m.p. 260-261 ° C. Analysis: Calculated for: C? 9H? SBrFN3O: 57.02% C 3.78% H 10.50% N Found: 56.77% C 3.87% H 10.53% N EXAMPLE FOURTEEN 3-f1- (4-fluorophenyl) methyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) and 4-fluorobenzyl bromide (0.59 ml) in acetonitrile (25 ml) was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.38 g (73%) of the product, m.p. 259-260 ° C. Analysis: Calculated for: C19H15BrFN3O: 57.02% C 3.78% H 10.50% N Found: 57.79% C 3.85% H 10.54% N EXAMPLE FIFTEEN 3-f 1- (3-nitrophenyl) methyl-N-4 (1 Hl-pyridiniminyl) -2-benzoisoxazole hydrochloride A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) and 3-Nitrobenzyl chloride (0.81 ml) in acetonitrile (25 ml) was heated under reflux for 24 h The mixture was allowed to cool to room temperature and the precipitate was collected The precipitate was washed with diethyl ether and dried under vacuum give 0.63 g (35%) of the product, mp 292-293 ° C. Analysis: Calculated for: C? 9H? 5CIN4O3: 59.62% C 3.95% H 14.64% N Found: 59.45% C 3.91% H 14.77% N EXAMPLE DIECISEIS 3-f 1 - (2-nitrofenyl I) methyl-N -4 (1 H) -pyridinimin M-1, 2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1, 2-Benzoisoxazole (1.0 g) and 2-nitrobenzyl bromide (1.02 g) in acetonitrile (25 ml) was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.51 g (75%) of the product, m.p. 221-222 ° C.

Analysis. Calculated for: C? 9H15BrFN4O3: 53.41% C 3.54% H 13.11% N Found: 53.34% C 3.29% H 13.09% N EXAMPLE SEVENTEEN 3-f1- (4-trifluoromethylphenyl) methyl-N-4 (1 H) -pyridiniminyl-1, 2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) ) and 4-trifluoromethylbenzyl bromide (1.13 ml) in acetonitrile (25 ml) was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.67 g (78%) of the product, m.p. 245-246 ° C. Analysis: Calculated for: C? 9H15BrFN3O: 53.35% C 3.36% H 9.33% N Found: 53.17% C 3.39% H 9.24% N EXAMPLE EIGHTEEN 3-f1- (3-trifluoromethylphenyl) methyl-N-4 (1 H) -pyridiniminip-1,2-benzoisoxazole hydrochloride A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g) ) and 3-trifluoromethylbenzyl chloride (0.73 ml) in acetonitrile (25 ml) was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 0.52 g (27%) of the product, m.p. 254-255 ° C. Analysis: Calculated for: C? 9H15CIF3N3O: 59.20% C 3.73% H 10.35% N Found: 59.02% C 3.64% H 10.35% N EXAMPLE NINETEEN -Fluoro-3-f1-phenylmethyl-N-4 (1 H) -pyridiniminyl-1, 2-benzoisoxazole bromohydrate A mixture of 5-fluoro-3- [1-phenylmethyl-N-4 (1 H) -p iridimethyl] -1,2-benzoisoxazole (0.70 g) and benzyl bromide (0.52 ml) in acetonitrile (15 ml) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.16 g (95%) of the product, m.p. 276-277 ° C. Analysis: Calculated for: C19H15BrFN3O: 57.02% C 3.78% H 10.50% N Found: 54.04% C 3.74% H 10.42% N EXAMPLE TWENTY 6-Methoxy-3-f1-phenylmethyl-N-4 (1H) -pi Ri dini minill-l, 2-benzoisoxazole bromohydrate A mixture of 6-methoxy-3 - [(4-pyridinyl) amino] -1, 2 Benzoisoxazole (0.85 g) and benzyl bromide (0.60 ml) in acetonitrile (18 ml) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.26 g (87%) of the product, m.p. 264-265 ° C. Analysis: Calculated for: C? 9H15BrN3O2: 58.26% C 4.40% H 10.19% N Found: 57.89% C 4.44% H 10.11% N EXAMPLE TWENTY-ONE 6-Nitro-3-f1-phenylmethyl-N-4 (1 H) -pyridiniminyl-1, 2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (0.80 g) and benzyl bromide (0.53 ml) in acetonitrile (15 ml) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.23 g (92%) of the product, m.p. 270-272 ° C. Analysis: Calculated for: C? 9H15BrN4O3: 53.41% C 3.54% H 13.11% N Found: 53.31% C 3.32% H 13.12% N EXAMPLE TWENTY-TWO -Fluoro-3-f4- (pyridinyl) amino-1,2-benzoisoxazole A mixture of 2,5-difluoro-N-4-pyridinylbenzamide (10 g) and thionyl chloride (45 ml) was refluxed for 3 hours. hr. The reaction mixture was evaporated in vacuo and the residual imidoyl chloride was used without purification. O-Trimethylsilylhydroxylamine (10.3 g) was added rapidly to a suspension of imidoyl chloride in tetrahydrofuran (215 ml) and the mixture was stirred at room temperature for 18 hr. The reaction mixture was filtered, the solids were treated with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The filtrate was treated dropwise with tetra-n-butylammonium fluoride solution (1 M in tetrahydrofuran, 42.7 ml). The solution was stirred at room temperature for 10 min, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried over magnesium sulfate anhydride, filtered and the filtrate was concentrated. The residue was washed with methanol. The filtrate was combined with the aqueous phase and basified with saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. The residue was washed with ethyl acetate to give amidoxime; the total amount of amidoxime was 6.2 g (58%) used immediately without further purification. Potassium t-butoxide (1.97 g) was added to a portion of the amidoxime (4.0 g) suspended in tetrahydrofuran (80 ml) and the mixture was heated under reflux for 12 hr. The reaction mixture was allowed to cool to room temperature and was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solutionwere dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. Recrystallization of the acetonitrile residue provided 2.55 g (69%) of product, mp 248-249 ° C. Analysis: Calculated for: C12H8FN3O: 62.88% C 3.52% H 18.33% N Found: 62.7% C 3.51% H 18.35% N EXAMPLE TWENTY-THREE H? 2CCH = CHC? 2H 6-Chloro-3- (4-pyridyl) amino1-1,2-benzoisoxazole maleate To a solution of 3-amino-6-chloro-1,2-benzoisoxazole (5.0 g) in N-methylpyrrolidone 60 ml) added 4-chloropyridine hydrochloride (9.1 g). The mixture was stirred vigorously at 130 ° C for 1.5 hr. The reaction mixture was cooled, saturated sodium bicarbonate solution and water were added. The precipitate was collected, washed with water, dried with air and flash chromatographed on silica (7x15 cm column), eluting first with ethyl acetate and then with 10% methanol / ethyl acetate. The appropriate fractions were collected and concentrated. The maleate was formed by treatment of the residue with maleic acid in methanol. Recrystallization from ethanol gave 1.17 g (10.9%) of the product, mp 203 (dec), after drying under high vacuum and the xylene was heated to reflux. Analysis: Calculated for C16H12CIN3Os: 53.13% C 3.34% H 11.62% N Found: 53.02% C 3.14% H 11.44% N EXAMPLE TWENTY-FOUR 1/2 H? 2CC = CHC? 2H: H2O Hemifumarate 6-methoxy-3,4- (pyridinyl) amino-1, 2-benzoisoxaxol monohydrate A mixture of 2-fluoro-4-methoxy-N-pyridinylbenzoamide (11.0 g) and thionyl chloride (16 g) in dichloroethane ( 10 mL) was heated under reflux for 1 hr and the reaction mixture was allowed to cool to room temperature. Diethyl ether was added and the imidoyl chloride was collected by filtration. O-Trimethylsilylhydroxylamine (10.6 g) was added rapidly to a suspension of the imidioyl chloride in tetrahydrofuran (220 ml) and the resulting mixture was stirred at room temperature for 20 hr. The reaction mixture was diluted with ethyl acetate and basified with saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and the saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. Trituration of the residue with ethyl acetate afforded 9.3 g of amidoxime, was used below without further purification. Potassium t-butoxide (0.54 g) was added to a portion of the amidoxime (1.2 g) in dimethylformamide (23 ml) and the mixture was heated at 60 ° C for 1 hr. The reaction mixture was allowed to cool to room temperature and was diluted with saturated ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. The residue was chromatographed on a RAPTLC (4 mm Chromatotron ™ plate), eluting with methanol / ethyl acetate. The appropriate fractions were collected and concentrated to provide 0.55 g (50%) of product free base. The product free base was dissolved in hot methanol and treated with an equivalent amount of fumaric acid. The precipitate was collected to give 0.51 g of analytically pure product, mp 261-263 ° C. Analysis: Calculated for: C13H13N3O3-0.5C O4H4: 56.78% C 4.77% H 13.24% N Found: 56.65% C 4.74% H 12.98% N EXAMPLE TWENTY-FIVE 6-Fluoro-3-f4- (pyridinyl) aminol-1, 2-benzoisoxazole hydrochloride A mixture of 2,4-difluoro-N-4-pyridinylbenzoamide (10 g) and thionyl chloride (15 g) was heated under reflux for 1 hr and the reaction mixture was allowed to cool to room temperature. Diethyl ether was added and the imidoyl chloride was collected. O-Trimethylsilylhydroxylamine (10.3 g) was added rapidly to a suspension of the imidoyl chloride formed above in tetrahydrofuran (210 ml) and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate and basified with saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solutionwere dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. Trituration of the residue with ethyl acetate gave 5.74 g of amidoxime, used immediately without further purification. Potassium t-butoxide (2.3 g) was added to a portion of the amidoxime (4.7 g) suspended in tetrahydrofuran (100 ml) and the mixture was heated under reflux for 0.75 hr. The reaction mixture was allowed to cool to room temperature and was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. Recrystallization from the ethyl acetate / methanol residue gave 2.47 g (54%) of product free base in two crops. The filtrates were concentrated and the residue was recrystallized. Recrystallization of the residue left after concentration of the mother liquors of acetonitrile gave an additional 1.12 g (26%) of product free base. A portion of the product free base (1 g) was dissolved in hot methanol and treated with methanolic hydrochloric acid. The precipitate was collected by filtration to give 0.67 g of analytically pure product, mp >300 ° C. Analysis: Calculated for C12H9CIFN3O: 54.25% C 3.41% H 15.82% N Found: 54.07% C 3.64% H 15.80% N EXAMPLE TWENTY-SIX 7-Fluoro-3- (4-pyridinylamino) -1,2-benzoioxazole A mixture of 2,3-difluoro-N-4-pyridinylbenzoamide (10 g) in thionyl chloride (45 ml) was heated under reflux for 4 hr , the reaction mixture was allowed to cool to room temperature. Dichloroethane and diethyl ether were added. The precipitated imidoyl chloride (10.0 ml) was collected. O-Trimethylsilylhydroxylamine (10.3 g) was added rapidly to a suspension of the imidoyl chloride formed above in tetrahydrofuran (210 ml) and the mixture was stirred at room temperature for 18 hr. 10% hydrochloric acid (50 ml) was added and the reaction mixture was stirred at room temperature for 1 hr. The solution was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried over magnesium sulfate anhydride, filtered and the filtrate was concentrated. Trituration of the residue with ethyl acetate gave 5.9 g of amidoxime, used immediately without further purification. Potassium t-butoxide (1.1 g) was added to a portion of the amidoxime (2.25 g) suspended in tetrahydrofuran (45 ml) and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature and was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated.

Recrystallization from the ethyl acetate / methanol residue gave 1.25 g (61%) of product, mp 234-236 ° C. Analysis: Calculated for C? 2H9FN3O: 62.88% C 3.52% H 18.33% N Found: 62.63% C 3.35% H 18.47% N EXAMPLE TWENTY-SIX 6-Nitro-3- (4-pyridinylamino) -1,2-benzoisoxazole A mixture of 2,4-dinitro-N-4-pyridinylbenzoamide (14.4 g) and diphosphorus pentachloride (12.5 g) in dichloroethane (100 ml) was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature and the precipitated imidoyl chloride was collected (13.2 g). O-Trimethylsilylhydroxylamine (12.1 g) was added quickly to a suspension of the imidoyl chloride formed above in tetrahydrofuran (200 ml) and the mixture was stirred at room temperature for 18 hr. Subsequent addition of water precipitated a solid (4.06 g) which was collected from filtration. The filtrate was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. Trituration of the residue with ethyl acetate and then with hot methanol gave 1.81 g of product. The combination of the two batches provided 5.86 g (39%) of amidoxime, which was used immediately without further purification. Potassium t-butoxide (2.1 g) was added to a portion of the amidoxime (5.3 g) suspended in tetrahydrofuran (80 ml) and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature and was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. Recrystallization from the ethyl acetate / methanol residue gave 3.22 g (74%) of product, mp 296-300 ° C. Analysis: Calculated for C12H8N4O3: 62.88% C 3.52% H 18.33% N Found: 62.63% C 3.35% H 18.47% N EXAMPLE TWENTY-EIGHT 3-f 1 - (2-ButinM) -N-4 (1 H) -pyridiniminyl-1,2-benzoisoxazole Bromohydrate A mixture of 3- (4-pyridinylamino) -1,2-benzoisoxazole (0.9 g) and 4-bromo -2-butyne (0.86 g) in acetonitrile (25 ml) was heated under reflux for 1 hr. The reaction mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and recrystallized from ethanol to give the product, mp 229-230 ° C. Analysis: Found for C? 6H? 4BrN3O: 55.83% C 4.10% H 12.21% N 55.54% C 3.99% H 12.36% N EXAMPLE TWENTY-NINE 3-f 1- (3-Bromo-2-butynyl) -N-4 (1 H) -pyridiniminoH-1,2-benzoisoxazole bromohydrate A mixture of 3- (4-pyridinylamino) -1,2-benzoisoxazole (1 g) Y 2,4-dibromo-2-butyne (1.51 g) in acetonitrile (25 ml) was heated under reflux for 1 hr. The reaction mixture was allowed to cool to room temperature and the precipitate was collected. The precipitate was washed with diethyl ether and dried under vacuum to give 1.2 g (65%) of the product, mp 217-218 ° C. Analysis: Found for C? 6H? 4BrN3O: 45.20% C 3.56% H 9.88% N 45.36% C 3.74% H 9.94% N EXAMPLE THIRTY 6-trifluoromethyl-3- (4-pyridinylamino) -1,2-benzoisoxazole A mixture of 2-fluoro-4-trifluoromethyl-N-4-pyridinylbenzoamide (29 g, 101.8 mmol) and phosphorus pentachloride (15.9 g, 1.2 eq ) in dichloroethane (70 ml) was heated to reflux for one hour. The reaction mixture was allowed to cool to room temperature and subsequently diethyl ether was added. The precipitated imidoyl chloride (25 g) was collected by filtration. O-Trimethylsilylhydroxylamine (19.0 g, 2.2 eq) was added quickly to a suspension of the imidoyl chloride formed above in tetrahydrofuran (750 ml) and the resulting mixture was stirred at room temperature for 20 hours. Dilute hydrochloric acid was added and the mixture was stirred 10 minutes at room temperature. The reaction was diluted with ethyl acetate and basified carefully with saturated sodium bicarbonate solution. The layers were separated and the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The crude product (14.7 g) was triturated with ethyl acetate to provide the amidoxime (12.7 g). Amidoxime was dissolved in THF and potassium butoxide (5.2 g, 1.1 eq) was added in one portion. The reaction was stirred at room temperature for 2 hours. The reaction was diluted with water and ethyl acetate. The organic layer was collected and washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was triturated with ethyl acetate to give the compound (7.3 g, 63%). The title compound was recrystallized from methanol, mp 249-250 ° C. Analysis: Calculated for: C? 3H8F3N3O: 55.92% C 2.89% H 15.05% N Found: 55.76% C 2.73% H 15.13% N EXAMPLE THIRTY AND ONE -trifluoromethyl-3- (4-pyridinylamino) -1,2-benzoisoxazole. Syn-anti-2-fluoro-5-trifluoromethylphenyl-4-pyridinylaminomethanone oxime (10.7 g, 35.8 mmol) was dissolved in THF (400 ml) and butoxide. of potassium (44 g, 1.1 eq) was added in one portion. The reaction was stirred for 6 hours at room temperature under nitrogen. The reaction was diluted with water and ethyl acetate. The organic layer was collected and washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Taxation with ethyl acetate gave the title compound (7.0 g, 70%). The title compound was recrystallized from methanol, mp > 280 ° C. Analysis: Calculated for C? 3H8F3N3O: 55.92% C 2.89% H 15.05% N Found: 55.88% C 2.69% H 15.01% N EXAMPLE THIRTY TWO 6-methoxy-3-f4- (3-bromopyridinyl) amino-1,2-benzoisoxazole N-bromosuccinimide (1.8 g, 1.1 eq) was added in one portion to a slurry of 6-methoxy-3- [4-pyridinylamino] -1,2-benzoisoxazole (2.2 g, 9.1 mmol) and silica gel 60 (3.0 g) in carbon tetrachloride (50 ml). The mixture was heated to reflux for one hour and subsequently stirred overnight at room temperature. The reaction was filtered and the filtrate was washed with aqueous sodium thiosulfate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a Prep 500 Chromatograph (silica gel, 2% methanol / ethyl acetate) to give the title compound (0.97 g, 33%). The title compound was recrystallized from methanol, mp 152-153 ° C. Analysis: Calculated for C? 3H10BrN3O2: 48.77% C 3.15% H 13.13% N Found: 48.60% C 3.24% H 13.13% N EXAMPLE THIRTY AND THREE -methoxy-3-f4- (3,5-dibromopyridinyl) amino1-1,2-benzoisoxazole In a manner analogous to the procedure described in example thirty-two, the title compound (0.95 g, 26%) was prepared from 6-methoxy-3- [4-pyridinylamino] -1,2-benzoisoxazole (2.2 g, 9.1 mmol). The title compound was recrystallized from methanol, mp 180-181 ° C. EXAMPLE THIRTY FOUR -methoxy-3- (4-pyridinylamino) -1,2-benzoisoxazole In a manner analogous to the procedure described in example twenty-five, the title compound was prepared (1.2 g, 20% after recrystallization with acetonitrile, mp 248-). 251 ° C) from 2-fluoro-5-methoxy-N-4-pyridinylbenzoamide (9.39 g, 38.2 mmol). In the last step, the intermediate was heated in N-methyl pyrrolidinone at about 100 ° C to give the title compound.

EXAMPLE THIRTY FIVE 3- (4-pyridinylamino) -7-trif luoromethyl-1, 2-benzoisoxazole In a manner analogous to the procedure described in example thirty, the title compound was prepared (4.35 g, 76%, after recrystallization with acetonitrile, 248 -249 ° C (dec)) from 2-fluoro-N- (4-pyridinyl) -3-trifluoromethylbenzoamide (10 g, 35.2 mmol). EXAMPLE THIRTY AND SIX 7-methoxy-3- (4-pyridinylamino) -1,2-benzoisoxazole In a manner analogous to the procedure described in example thirty, the title compound was prepared (3.0 g, 65% after recrystallization with acetonitrile, mp 226- 227 ° C) from 2-fluoro-3-methoxy-N-4-pyridinylbenzoamide (25 g, 102 mmol). In the last step, the intermediate was heated in N-methyl-pyrrolidinone at about 100 ° C to give the title compound. EXAMPLE THIRTY AND SEVEN Bromohydrate 3- (4-pyridinylamino) -1,2-benzoisoxazol-7-ol monohydrate A solution of 7-methoxy-3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (3 g, 12.4 mmoles) in 124 ml of a 1: 1 mixture of 48% HBr and acetic acid was heated to reflux for 24 hours. Subsequently, the mixture was allowed to cool to room temperature and the precipitated product was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (3.1 g, 78%), mp 270-273 ° C. Analysis: Calculated for C12H13BrN3O3: 44.19% C 3.71% H 12.88% N Found: 43.79% C 3.79% H 12.84% N EXAMPLE THIRTY-EIGHT 4-fluoro-3- (4-pyridinylamino) -1,2-benzoisoxazole In a manner analogous to the procedure described in example twenty-five, the title compound (2.1 g, 43%) was prepared from 2,6-difluoro -N-4-pyridinylbenzoamide (5 g, 21.4 mmol). The title compound was recrystallized from hot ethyl acetate, mp 160-161 ° C. Analysis Calculated for C12H8FN3O: 62.88% C 3.52% H 18.33% N Found: 62.72% C 3.71% H 18.21% N EXAMPLE THIRTY-NINE 7-Fluoro-3-f1-phenylmethyl-N-4 (1 H) -pyridiniminyl-1,2-benzoisoxazole Bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (0.70 g, 3. 05 mmoles) and benzyl bromide (0.52 g, 3.05 mmol) in acetonitrile (15 ml) was heated under reflux for 1.5 hr. Subsequently, the mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (1.16 g, 95%), mp; 300 ° C. Analysis: Calculated for C? 9H15BrFN3O: 57.02% C 3.78% H 10.50% N Found: 56.78% C 3.67% H 10.73% N EXAMPLE FORTY 3-f1- (2-propenyl) -N-4 (1 H) -pyridiniminH-1,2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (1.0 g, 4.73 mmol ) and allyl bromide (0.45 g, 1 eq) in acetonitrile (25 ml) was heated under reflux for one hour. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (1.15 g, 73%), mp 250-251 ° C. Analysis: Calculated for C? 5H14BrFN3O: 54.23% C 4.25% H 12.65% N Found: 54.05% C 4.21% H 12.58% N EXAMPLE FORTY ONE 3-f1- (phenylmethyl) -N-4 (1H) -pyridiniminip-6-trifluoromethyl-1, 2-benzoisoxazole bromohydrate A mixture of 6-trifluoromethyl-3- (4-pyridinylamino) -1,2-benzoisoxazole (1.0 g, 3.58 mmol) and benzyl bromide (0.51 g, 1.2 eq) in acetonitrile (25 ml) was heated under reflux for one hour. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (1.2 g, 74%), mp 244-245 ° C. Analysis: Calculated for C20H15BrF3N3O: 53.35% C 3.35% H 9.33% N Found: 53.23% C 3.28% H 9.22% N EXAMPLE FORTY-TWO 3-f1- (phenylmethyl) -N-4 (1 H) -pyridiniminyl-1-5-trifluoromethyl-2-benzoisoxazole bromohydrate A mixture of 5-trifluoromethyl-3- (4-pyridinylamino) -1,2-benzoisoxazole ( 1.0 g, 3.58 mmol) and benzyl bromide (0.51 g, 1.2 eq) in acetonitrile (25 mL) was heated under reflux for one hour.

The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (1.3 g, 81%), mp 274-275 ° C. Analysis: Calculated for C20H? SBrF3N3O: 53.35% C 3.36% H 9.33% N Found: 53.16% C 3.34% H 9.38% N EXAMPLE FORTY THREE 6-Methoxy-3-f1-phenylmethyl-N-4 (1 H) -3-bromo-pyridinium mini hydrochloride 11-1, 2-benzoisoxazole A mixture of 6-methoxy-3- [4- (3-bromopyridinyl) amino] -1,2-benzoisoxazole (0.7 g, 2.2 mmol) and benzyl bromide (0.31 g, 1.2 eq) in acetonitrile (25 mL) was heated under reflux for one hour. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (0.48 g, 45%), mp 241-242 ° C. Analysis: Calculated for C20H? 7Br2N3O2: 48.91% C 3.49% H 8.55% N Found: 48.75% C 3.48% H 8.52% N EXAMPLE FORTY-FOUR 6-f luoro-3-f 1-f-enyl methyl-N-4 (1 H) -pyridiniminyl-1, 2-benzoisoxazole hydrochloride A mixture of 6-fluoro-3 [(4-pyridinyl) amino-1, 2 -benzoisoxazole (0.70 g, 3.05 mmol) and benzyl bromide (0.52 g, 3.05 mmol) in acetonitrile (15 mL) was heated to reflux for 1.5 hours. The mixture was allowed to cool to room temperature and the precipitated product was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give a white powder (1.1 g). The white powder was treated with saturated sodium bicarbonate to basify and the aqueous solution was extracted with ethyl acetate. The combined organic extracts were concentrated under vacuum to give the free base of the title compound (0.65 g). The free base was dissolved in hot isopropanol and treated with a solution of HCl (g) in isopropanol. After cooling, the title compound was collected by filtration (0.39 g, 36%), mp 267-269 ° C (dec.). Analysis: Calculated for C19H15CIFN3O: 64.14% C 4.25% H 11.81% N Found: 63.79% C 4.31% H 11.47% N EXAMPLE FORTY-FIVE 3-f1- (Phenylmethyl-N-4 (1H) -pyridinimin-7-trifluoromethyl-1, 2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino) -7-trifluoromethyl-1 , 2-benzoisoxazole (0.80 g, 2.87 mmol) and benzyl bromide (0.49 g, 2.87 mmol) in acetonitrile (15 mL) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (0.99 g, 77%), mp 275-277 ° C (dec). Analysis: Calculated for C20H15BrF3N3O: 53.35% C 3.36% H 9.33% N Found: 53.14% C 3.33% H 9.55% N EXAMPLE FORTY-SIX 3-f1-phenylmethyl-N-4 (1 H) -pyridiniminin-2, 2-benzoisoxazole bromohydrate A mixture of 5-methoxy-3 - [(4-pyridinyl) amino] -1,2-benzoisoxazole (0.70 g, 2.9 mmol) and benzyl bromide (0.5 g, 2.9 mmol) in acetonitrile (15 mL) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (1.09 g, 91%), mp 277-278 ° C. Analysis: Calculated for C20H18BrN3O2: 58.26% C 4.40% H 10.19% N Found: 53.23% C 4.30% H 10.32% N EXAMPLE FORTY-SEVEN F4- (3-benzofd-isoxazolylimino) -1- (4H) -pyridinyl-acetic acid methyl ester bromohydrate A mixture of 3- (4-pyridinylamino) -1,2-benzoisoxazole (0.9 g, 4.3 mmol) and methyl bromoacetate (0.44) g, 1.1 eq) in acetonitrile (25 ml) was heated under reflux for one hour. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried in vacuo to give the title compound (1.1 g, 70%), mp 235-236 ° C. Analysis: Calculated for C15H14BrN303. 49.47% C 3.87% H 11.54% N Found: 49.48% C 3.90% H 11.67% N EXAMPLE FORTY-EIGHT 7-Methoxy-3-f-1- (phenylmethyl) -N-4 (1 H) -pyridinimin-1,2-benzoisoxazole bromohydrate A mixture of 7-methoxy-3 - [(4-pyridinyl) amino) - 1,2-benzoisoxazole (0.70 g, 2.9 mmol) and benzyl bromide (0.5 g, 2.9 mmol) in acetonitrile (15 mL) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (0.99 g, 83%), mp 253-254 ° C (dec). Analysis: Calculated for C20H18BrN3O2: 58.26% C 4.40% H 10.19% N Found: 57.99% C 4.56% H 10.26% N EXAMPLE FORTY-NINE 4-Fluoro-3-M- (phenylmethyl) -N-4 (1 H) -pyridiniminyl-2, 2-benzoisoxazole Bromohydrate Hemihydrate A mixture of 4-fluoro-3 - [(4-pyridinyl) amino) -1 , 2-benzoisoxazole (0.8 g, 3.5 mmol) and benzyl bromide (0.42 g, 1 eq) in acetonitrile (50 ml) was heated under reflux for one hour. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (0.8 g, 57%). The title compound was recrystallized with methanol / isopropanol, mp 200-201 ° C (dec). Analysis: Calculated for C19H15BrFN3O 0.5H2O: 55.75% C 3.95% H 10.27% N Found: 56.11% C 4.03% H 10.51% N EXAMPLE FIFTY 6-Fluoro-3-f1 - (phenyl methyl I) -N-4 (1 H) -pyridini mini 11-1.2- benzoisoxazole hydrochloride A mixture of 6-fluoro-3 - [(4-pyridinyl) amino) -1 , 2-benzoisoxazole (1.43 g, 6.24 mmol) and methyl iodide (0.89 g, 6.24 mmol) in acetonitrile (30 mL) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The slightly yellow solid was washed with diethyl ether and dried under vacuum to give the title compound (1.93 g, 83%), mp 272-275 ° C (dec). Analysis: Calculated for C? 3HnFIN3O: 42.07% C 2.99% H 11.32% N Found: 42.07% C 2.92% H 11.31% N EXAMPLE FIFTY-ONE 6-Methoxy-3-f1- (phenylmethyl) -N-4 (1 H) -pyridiniminyl-1, 2-benzoisoxazole hydrochloride A mixture of 6-methoxy-3 - [(4-pyridinyl) amino) -1, 2 Benzoisoxazole (1.1 g, 4.56 mmol) and methyl iodide (0.65 g, 4.56 mmol) in acetonitrile (20 mL) was heated under reflux for 1.5 hr. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The slightly yellow solid was washed with diethyl ether and dried under vacuum to give the title compound (1.5 g, 86%), mp 262-264 ° C (dec). Analysis: Calculated for C? 4H? 4IN3O: 43.88% C 3.68% H 10.97% N Found: 43.77% C 3.58% H 10.96% N EXAMPLE FIFTY-TWO 3-f1- (Trans-3-phenyl-2-propenyl) -N-4 (1 H) -pyridiniminin-1,2-benzoisoxazole bromohydrate A mixture of 3 - [(4-pyridinyl) amino] -1, 2 Benzoisoxazole (1.0 g, 4.73 mmol) and cinnamyl bromide (0.93 g, 1 eq) in acetonitrile (25 ml) was heated under reflux for one hour. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried under vacuum to give the title compound (1.8 g, 93%), mp 243-244 ° C. Analysis: Calculated for C2? H18BrN3O: 61.78% C 4.44% H 10.29% N Found: 61.67% C 4.27% H 10.34% N EXAMPLE FIFTY THREE 3-f 1-f2- 1, 3-dioxalano Bromohydrate) ethyl 1 -N-4p H) -pyr? Di ni mi or II- 1,2-benzoisoxazole A mixture of 3- (4-pyridinylamino) -1, 2 Benzoisoxazole (1.2 g, 5.7 mmol) and 2- (2-bromoethyl) -1,3-dioxolane (0.73 ml, 1.1 eq) in acetonitrile (25 ml) was heated under reflux for 1 hour. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration. The white solid was washed with diethyl ether and dried in vacuo to give the title compound (0.95 g, 42%), mp 220-221 ° C. Analysis: Calculated for C? 7H? 8BrN3O3: 52.05% C 4.63% H 10.71% N Found: 51.86% C 4.51% H 10.52% N EXAMPLE FIFTY FOUR 7-chloro-3-f4- (pyridinyl) amino] -1,2-benzoisothiazole 4-chloropyridine hydrochloride (2.2 eq) was added to 3-amino-7-chloro-1, 2-benzoisothiazole (1 eq) in N-methylpyrrolidone. The mixture was stirred at 130 ° C for 1.5 hours. The resulting mixture was cooled and then saturated sodium bicarbonate solution and water were added. The title compound was extracted into ethyl acetate, the combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the title compound.

EXAMPLE FIFTY AND FIVE 7-Chloro-3-f-1-f-enyl methyl-N -4 (1 H) -pyridiniminyl-1, 2-benzoisoxazole bromohydrate A mixture of 7-chloro-3 - [(4-pyridinyl) amino] -1, 2-benzoisoxazole (1 eq) and benzyl bromide (1 eq) were combined in acetonitrile and heated to reflux for 1.5 hours. The mixture was allowed to cool to room temperature and the precipitate was collected by filtration and dried under vacuum to give the title compound. REACTION SCHEME

Claims (48)

1. CLAIMS 1. A compound of the formula:
2. Wherein Ri is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, -C (= O) O-lower alkyl, 1,3-dioxolane, phenyl, cinnamyl, phenyl substituted by lower alkyl, lower alkoxy, halogen, hydroxyl, nitro or trifluoromethyl: Q is hydrogen, halogen, lower alkyl or nitro; X is oxygen or sulfur; Z is hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, nitro or trifluoromethyl; n is from 1 to 12; the geometric isomers, the optical isomers or the pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein R-i is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, phenyl substituted by lower alkyl, lower alkoxy, halogen, hydroxyl, nitro or trifluoromethyl.
3. 3. A compound according to claim 2, wherein X is oxygen and Rt is hydrogen or lower alkyl.
4. 4. A compound according to claim 2, wherein X is oxygen and R is phenyl or phenyl substituted by lower alkyl, lower alkoxy, halogen, hydroxyl, nitro or trifluoromethyl.
5. 5. A compound according to claim 2 which is 6-chloro-3- [1-propyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
6. 6. A compound according to claim 2, which is 3- [1- (4,4-dimethylpentyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole
7. 7. A compound according to claim 2, which is 3- [1- (phenylmethyl) -N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole
8. 8. A compound according to claim 2, which is 3- [1- (2 phenylethyl) -N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole
9. 9. A compound according to claim 2, which is 3- [1- (3-phenylpropyl) -N-4 (1H ) -pyridiniminyl] -1,2-benzoisoxazole
10. 10. A compound according to claim 2, which is 3- [1- (4-phenylbutyl) -N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
11. 11. A compound according to claim 2, which is 3- [1- (5-phenylpentyl) -N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole
12. 12. A compound according to claim 2, what is 3- [1- (2-methylphenyl) methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
13. 13. A compound according to claim 2, which is 3- [1- (4-methylphenyl) methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
14. 14. A compound according to claim 2 which is 3- [1- (3-methylphenyl) methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
15. 15. A compound according to claim 2, which is 3-f 1 - (3-methoxy-f-enyl) -methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
16. 16. A compound according to claim 2, which is 3- [1- (3-fluorophenyl) methyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
17. 17. A compound according to claim 2, which is 3- [1- (2-fluorophenyl) methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
18. 18. A compound according to claim 2, which is 3- [1- (4-fluorophenyl) methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
19. 19. A compound according to claim 2, which is 3- [1- (3-nitrophenyl) methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
20. 20. A compound according to claim 2, which is 3- [1- (2-nitrophenyl) methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
21. 21. A compound according to claim 2, which is 3- [1- (4-trifluoromethyl-fyl) methyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
22. 22. A compound according to claim 2, which is 3- [1- (3-trifluoromethylphenyl) methyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
23. 23. A compound according to claim 2, which is 5-fluoro-3- [1-phenylmethyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
24. 24. A compound according to claim 2, which is 6-methoxy-3- [1-phenylmethyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
25. 25. A compound according to claim 2, which is 6-nitro-3- [1-phenylmethyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
26. 26. A compound according to claim 2, which is 3- [1- (2-butynyl) -N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
27. 27. A compound according to claim 2, which is 3 - [(3-bromo-2-butenyl) -N-4 (1 H) -pi-ridi or m-nyl] -1,2-benzoisoxazole.
28. 28. A compound according to claim 2, which is 7-fluoro-3- [1-phenylmethyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
29. 29. A compound according to claim 2, which is3- [1- (2-propenyl) -N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
30. 30. A compound according to claim 2, which is 3- [1- (phenylmethyl) -N-4 (1H) -pyridiniminyl] -6-trif luoromethyl-1,2-benzoisoxazole.
31. 31. A compound according to claim 2, which is 3- [1- (phenylmethyl) -N-4 (1 H) -pyridiniminyl] -5-trifluoromethyl-1,2-benzoisoxazole.
32. 32. A compound according to claim 2 which is 6-methoxy-3- [1-phenylmethyl-N-4 (1H) -3-bromo-pyridiniminyl] -1,2-benzoisoxazole.
33. 33. A compound according to claim 2, which is 6-fluoro-3- [1-phenylmethyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
34. 34. A compound according to claim 2, which is 3- [1-phenylmethyl-N-4 (1H) -pyridiniminyl] -7-trifluoromethyl-1,2-benzoisoxazole.
35. 35. A compound according to claim 2, which is 5-methoxy-3- [1-phenylmethyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
36. 36. A compound according to claim 2, which is 4- (3-benzo [d] isoxazolylimino) -1-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
37. 37. A compound according to claim 2, which is 7-methoxy-3- [1-phenylmethyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
38. 38. A compound according to claim 2, which is 4-f Ioro-3-f 1 -phenylmethyl- N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
39. 39. A compound according to claim 2, which is 6-fluoro-3- [1-phenylmethyl-N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
40. 40. A compound according to claim 2, which is 6-methoxy-3- [1-phenylmethyl-N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
41. 41. A compound according to claim 2, which is 3- [1- (trans-3-phenyl-2-propenyl) -N-4 (1H) -pyridiniminyl] -1,2-benzoisoxazole.
42. 42. A compound according to claim 2 which is 3- [1- [2- (1,3-dioxalane) ethyl] -N-4 (1 H) -pyridiniminyl] -1,2-benzoisoxazole.
43. 43. A method for relieving memory dysfunction in mammals which comprises administering to a mammal that requires relief of memory dysfunction, an amount effective to alleviate memory dysfunction of a compound of claim 1.
44. 44. A method for alleviating dysfunction memory in mammals comprising administering to a mammal that requires relief of memory dysfunction, an amount effective to alleviate memory dysfunction of a compound of the formula: Where Q is hydrogen, halogen, lower alkyl or nitro; X is oxygen or sulfur; Z is hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, nitro or trifluoromethyl; the optical isomers or pharmaceutically acceptable salts thereof.
45. 45. A method for treating depression in mammals comprising administering to a mammal requiring treatment for depression, an effective amount for treating depression of a compound of claim 1.
46. 46. A composition for alleviating memory dysfunction comprising an auxiliary and as the active ingredient, an effective amount for alleviating memory dysfunction of a compound of claim 1.
47. 47. A composition for treating depression comprising an auxiliary and as the active ingredient, an effective amount for treating depression of a compound of the claim 1.
48. 48. A process for preparing a compound of the formula: Wherein Ri is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, -C (= O) O-lower alkyl, 1,3-dioxolane, phenyl, cinnamyl, phenyl substituted by lower alkyl, lower alkoxy, halogen, hydroxyl, nitro or trifluoromethyl; Q is hydrogen, halogen, lower alkyl or nitro; X is oxygen or sulfur; Z is hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, nitro or trifluoromethyl; n is from 1 to 12; the geometric isomers, the optical isomers, or the pharmaceutically acceptable salts thereof, the alkylation comprising a compound of the formula. Where Q, x and Z are defined as before, with a compound of the formula: Hal- (CH2) nR1 Where Hal is Cl or Br, and n and R are defined as before.