SUBSTITUTED AZOLE DERIVATIVES, PHARMACEUTICAL COMPOSITION CONTAINING THE DERIVATIVES, AND METHOD FOR TREATING PARKINSON'S DISEASE USING THE SAME

Title of Invention: SUBSTITUTED AZOLE DERIVATIVES, PHARMACEUTICAL COMPOSITION CONTAINING THE DERIVATIVES, AND METHOD FOR TREATING PARKINSON S DISEASE USING THE SAME Technical Field

[1] The present disclosure relates to a substituted azole derivative represented by the Formula (I) showing efficacy against Parkinson's disease, a pharmaceutical composition containing an effective amount of the derivative, and a method for treating Parkinson's disease by administering the same to mammals.

[2]

[3] Parkinson's disease is a difficult-to-treat, progressive disorder which is the second most common neurodegenerative disease, and is socially and economically problematic because its incidence rate continues to rise as the population of seniors increases. Currently, about 4 million people worldwide are known to have the disease, and it is understood that the number of new cases per year is growing by about 50 thousand in U.S. alone. The incidence rate of one in 1,000 is more prevalent-in older age groups. The disorder is known to be mostly associated with aging, environmental factors such as neurotoxin accumulation from agricultural chemicals, etc., active oxygen, genetic factors (about 5% to about 10%), etc are known to have effects on the incidence. However, the exact cause of incidence is unknown. As for genetic factors, gene mutations such as a-synuclein, Parkin, PINK-1, UCH-L1, DJ-1, etc. are known to be associated with incidence.

[4]

[5] Anatomical studies show that Parkinson's disease is associated with a broad range of degeneration of dopaminergic substantia nigra neurons located in the basal ganglia of the brain. When about 60% to about 80% of the amount of dopamine produced by substantia nigra neurons is damaged, it can no longer facilitate the movement of the extrapyramidal tract system, thereby resulting in Parkinson's symptoms.

[6]

[7] Because the exact cause of Parkinson's disease has not been determined, treatment methods for ameliorating symptoms are usually used, rather than fundamental cures.

Therapeutic agents currently used or under development are as follows. Drugs which are predominantly developed and used include dopamine precursors such as Levodopa as a dopamine supplement and dopamine receptor agonists such as Fenofibrate. In addition, COMT inhibitors which maintain the dopamine concentration in the brain by inhibiting dopamine metabolism and ΜΑΟ-Β (monoamine oxidase Β) inhibitors are being used. As a neurotransmitter enhancing drug besides dopamine, antimuscarinics and NMDA antagonists are developed and used, and continuous efforts are being made to use or develop neuronal protective agents, antioxidants, inhibitors of neuronal apoptosis, and agonists for brain function as therapeutic agents. Surgical therapies such as deep brain stimulation are applied to terminal stage patients who can no longer benefit from drug therapies.

[8]

[9] Selegiline (Deprenyl) as a ΜΑΟ-Β inhibitor has been used as a drug for treating Parkinson's disease and is considered a gold standard. However, its use has many limitations due to hepatotoxicity and production of metamphetamine as a metabolite.

Azilect (Rasagiline) was first commercially introduced in Europe in 2005 and approved by the US FDA in 2006 as a new ΜΑΟ-Β inhibitor, and emerged as a new therapeutic agent for Parkinson's disease that overcomes the disadvantages of Selegiline. If clinical tests can verify that Azilect has neuronal protective effects that other current therapeutic agents lack, the value of the drug as a new therapeutic agent will be greatly enhanced.

[10]

[11] However, because both Selegiline and Rasagiline are irreversible ΜΑΟ-Β inhibitors, they may inhibit the activity of ΜΑΟ-Β until new ΜΑΟ-Β is produced in vivo, thereby increasing the possibility of unpredictable side effects. As an alternative to make up for these shortcomings, a new drug to show potent enzyme inhibitory activity in a reversible manner is expected to be superior to conventional irreversible inhibitors in terms of safety and efficacy. While a reversible ΜΑΟ-Β inhibitor called Safinamide has been developed and is under clinical testing (Phase III), an exceptional reversible ΜΑΟ-Β inhibitor has not been developed yet.

[12]

[13] Thus, an aspect of the present invention provides compositions having efficacy against Parkinson's disease and pharmaceutically acceptable salts thereof.

[14]

[15] An aspect of the present invention also provides a pharmaceutical composition for treatment of Parkinson's disease.

[16]

[17] Another aspect of the present invention further provides a method for treating Parkinson's disease in a mammal by administering an effective amount of the compound to the mammal.

[18]

[19] According to an aspect of the present invention, there are provided substituted azole derivatives represented by Formula (I) having efficacy against Parkinson's disease and pharmaceutically acceptable salts thereof:

[20]

[21] Formula (I)

[22] According to another aspect of the present invention, there are provided pharmaceutical compositions for treatment of Parkinson's disease, including an effective amount of the substituted azole derivative.

[23]

[24] According to still another aspect of the present invention, there are provided methods for treating Parkinson's disease in a mammal by administering an effective amount of the substituted azole derivative to the mammal.

[25]

[26] According to still another aspect of the present invention provides a use of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for treatment of Parkinson's disease, and a use of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for preparation of a medicament suitable for treating Parkinson's disease.

[27]

[28] The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features will be apparent from the description and drawings, and from the claims.

[29] The compound of Formula (I) may be used as a pharmaceutical composition for treatment of Parkinson's disease by inhibiting the activity of ΜΑΟ-Β.

[30]

[31] Reference will now be made in detail to the embodiments of the present disclosure, examples of which are illustrated in the accompanying drawings.

[33] One embodiment of the present disclosure relates to substituted azole derivatives represented by Formula (I) and pharmaceutically acceptable salts thereof:

[34]_Rl

[35] Formula (I)

[36] wherein, R is selected from the group consisting of substituted or unsubstituted C₄-C₁₅ arylalkyl and C₄-Ci₅ heteroarylalkyl; and substituted or unsubstituted linear, branched or cyclic Ci-Ci₀ alkyl;

[37] Y is selected from the group consisting of O and -N-Ri;

[38] Ri is at least one selected from the group consisting of Η and linear or branched Ci-C₃ alkyl;

[39] R₂ is selected from the group consisting of Η and halogen;

[40] A is selected from the group consisting of Ν, O, and S;

[41] Β is selected from the group consisting of C and Ν;

[42] Ζ is selected from the group consisting of substituted or unsubstituted heterocyclic ring; carbamate; -0C(=0)NR₃R4; NH₂; NR₅R₆; NC(=NH)NH₂; and -NC(=0)NH₂;

[43] each of and R₄ is independently selected from the group consisting of Η; Ci-C₅ alkyl unsubstituted or substituted by at least one selected from the group consisting of NH₂, and NR₇R₈; heterocyclic ring unsubstituted or substituted by Ci-C₃ alkyl; or R₃ and R₄ together may form a 5- or 7-membered heterocyclic ring unsubstituted or substituted by C,-C₃ alkyl;

[44] each of R₅ and R₆ is independently selected from the group consisting of Η; C₂-C₃ alkene; C₂-C₃ alkyne; and linear or branched Ci-C₇ alkyl unsubstituted or substituted by at least one selected from the group consisting of -OH, -C(0)NH₂, Ci-C₃ alkoxy, and carbamate, or R₅ and R₆ together may form a substituted or unsubstituted aliphatic cyclic amine or aromatic cyclic amine;

[45] each of R₇ and R₈ is at least one independently selected from the group consisting of Η and linear or branched Ci-C₃ alkyl;

[46] m is an integer of 0 to 4; and

[47] η is an integer of 0 to 5.

[48]

[49] More specifically, a preferred compound is an azole derivative and a pharmaceutically acceptable salt thereof: wherein,

[50] R is selected from the group consisting of C₄-Ci₅ arylalkyl unsubstituted or substituted by at least one selected from the group consisting of halogen, trifluoromethyl, trifluoroalkoxy, -N0₂, C(=0)OCH₃, linear or branched Ci-C₆ alkyl, Ci-C₆ alkoxy, phenyl, phenyloxy, benzyloxy, -C(=0)H, -OH, and -C=N-OH; C₄-Ci₅heteroarylalkyl unsubstituted or substituted by at least one selected from the group consisting of halogen, C(=0)OCH₃, linear or branched Ci-C₆ alkyl, Ci-C₆ alkoxy, phenyl, phenyloxy, benzyloxy, -C(=0)H; linear, branched, or cyclic C1-C10 alkyl unsubstituted or substituted by at least one selected from the group consisting of unsubstituted or substituted C₄-Ci₅heteroarylalkyl, Ci-C₃alkyloxy, Ci-C₃ alkylthio, carbamate, (-OC(=0)NH₂), tert-butyl-OC(=0)NH-, -NH₃⁺, -NH₂, -OH, -C(=0)0CH₂CH₃, NHC(=0)NH₂, trifluoromethylsufanyl, trifluoromethyl, and -CN; if R is C₄-Ci₅ heteroarylalkyl, wherein the heteroaryl group is selected from the group consisting of imidazole, chlorothiophen, naphthalene, benzothiazole, pyridine, quinoline, benzotriazole, isoxazole, furan, N-oxopyridine, N-methylpyridine and benzo[l,3]dioxole;

and if R is C₄-Ci₅ arylalkyl, wherein the aryl group is selected from the group consisting of phenyl, phenyloxy, benzyloxy and naphthalene.

[51] Ζ is selected from the group consisting of imidazole, piperidine, pyrrolidine, triazole, and tetrazole unsubstituted or substituted by at least one substituent selected from the group consisting of OH, carbamate, linear or branched Ci-C₄ alkyl, halogen, -N0₂, NH₂, -CF₃, -CN, and phenyl; carbamate; -0C(=0)NR₃R4; NH₂; NR₅R₆; NC(=NH)NH₂, and -NC(=0)NH₂;

[52] each of R₃ and R₄ is independently selected from the group consisting of Η; Ci-C₅ alkyl unsubstituted or substituted by at least one selected from the group consisting of NH₂, and NR₇R₈; and piperidine, piperazine, and diazepane unsubstituted or substituted by Ci-C₃ alkyl, or R₃ and R₄ together may form piperidine, piperazine, imidazole, pyrrolidine, triazole, tetrazole, diazepane or morpholine unsubstituted or substituted by Q-Q alkyl;

[53] each of R₅ and R₆ is independently selected from the group consisting of Η; C₂-C₃ alkene; C₂-C₃ alkyne; and linear or branched Ci-C₄ alkyl unsubstituted or substituted by at least one selected from the group consisting of -OH, -C(0)NH₂, Ci-C₃ alkoxy, and carbamate, or R₅ and R₆ together may form piperidine, piperazine, imidazole, tetrazole, triazole, pyrrolidine or morpholine substistuted or unsubstituted by at least one selected from the group consisting of OH, carbamate, Ci-C₃ alkyl, halogen, phenyl, and -N0₂;

[54] each of R₇ and R₈ is at least one independently selected from the group consisting of Η and linear or branched Ci-C₃ alkyl;

[55] Β is C or Ν;

[56] m and η are independently 0 or 1; and

[57] Υ, Ri, A, and R₂ are as defined above.

[59] Compounds well known to those skilled in the art, which may be easily prepared there from azole derivatives, may be used to prepare an azole derivative of Formula (1). Thus, it is to be understood that the following description related to a preparation method of the azole derivative is only illustrative of the present invention and is not meant to limit the scope of the present invention as modifications may be selectively made on the sequence of the unit operation if necessary.

[60]

[63] R is preferably a benzyl group, and R_l5 R₂, Z, Β, m, and η are as mentioned above. A general synthetic method is as follows: An aldehyde (I) as a starting material may be used to obtain an oxime (II). Subsequently, a [3+2] cycloaddition of the obtained oxime compound with alkyne or nitrile may be performed under the NaOCl conditions to obtain an azole compound (III or IV), followed by introduction of a desired functional group to obtain a final compound (V).

[67] R is preferably a benzyl group, and R₂, Z, Β, and mare as mentioned above. A general synthetic method is as follows: An amide (VI) as a starting material may be used to obtain an oxathiazolone (VII). Subsequently, a [3+2] cycloaddition of the obtained oxathiazolone compound with alkyne or nitrile may be performed under the NaOCl conditions to obtain a thiazole compound (VIII), followed by reduction of this compound and introduction of a functional group to obtain a final compound (X).

[68]

[69] Scheme 3

[70]

[71] R, R₂, Ζ, A, m, and Β are as mentioned above. A general synthetic method is as follows: A débenzylation of a compound (XI) as a starting material may be performed to obtain a hydroxyphenyl derivative (XII), followed by introduction of a desired functional group to obtain a final compound (XIII).

[72]

[73] Scheme 4

[74]

[75] R, Ri, R₂, Ζ, A, m, and Β are as mentioned above. A general synthetic method is as follows: A reduction of a nitrophenyl derivative (XIV) as a starting material may be performed to synthesize an aminophenyl derivative (XV), followed by reductive amination with a desired aldehyde to obtain a final compound (XVI).

[76]

[77] In addition, the azole derivative includes a compound represented by Formula (I) as well as pharmaceutically acceptable acids or base addition salts thereof and stereochemically isomeric forms thereof. The salts include anything as long as they maintain the activity of a parent compound in a subject to be administered and do not cause any adverse effect.

[78]

[79] Examples of such salts include, but are not specifically limited to, inorganic and organic salts, and salts of the following acids are preferably selected. More specifically, they include acetic, nitric, aspartic, sulfonic, sulfuric, maleic, glutamic, formic, succinic, phosphoric, phthalic, tannic, tartaric, hydrobromic, propionic, benzenesulfonic, benzoic, stearic, esyl, lactic, bicarbonic, bisulfuric, bitartaric, oxalic, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, toluenesulfonic, edisylic, esylic, fumaric, gluceptic, pamoic, gluconic, glycollylarsanilic, methylnitric, polygalactouronic, hexylresorcinoic, malonic, hydrabamic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactobionic, mandelic, estolic, methylsulfuric, mucic, napsylic, muconic, p-nitromethanesulfonic, hexamic, pantothenic, monohyrogen phosphoric, dihyrogen phosphoric, salicylic, sulfamic, sulfanilic, methanesulfonic, teoclic acids, etc.

[80]

[81] In addition, the base salt forms include, for example, ammonium salts, alkal and alkaline earth salts, e.g. lithium, sodium potassium, magnesium, and calcium salts, salts with organic base, e.g. benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine, etc.

[82]

[83] Conversely, the salt forms may be converted by treatment with an appropriate base or acid into the free base or acid form.

[84]

[85] The term "addition salt" as used herein includes the solvates which the compounds of formula (I) as well as the salts thereof are able to form. Such solvates are, for example, hydrates, alcoholates, etc.

[86]

[87] Furthermore, the term "stereochemically isomeric forms" of the compounds of Formula (I) as used herein defines all the possible different compounds which the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, the mixtures containing all diastereomers and enantiomers of the basic molecular structure.

[88]

[89] In particular, stereogenic centers may have an R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either a cis- or transconfiguration. Compounds including double bonds can have an Ε or Ζ-stereochemistry at the double bond. Stereochemically isomeric forms of the compounds represented by Formula (I) are obviously intended to be embraced within the scope of this invention

[91] As defined in Formula (I), examples of preferred azole derivatives are as follows.

[92]

[93] Examples of the compound, in which Y is O; Ζ is carbamate; and R, Ri-R₈, A, Β, m, and η are as described above, include carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-benzyloxy-phenyl)-[l,2,4]oxadiazol-5-ylmethyl ester, carbamic acid 3-(4-benzyloxy-phenyl)-isothiazol-5-ylmethyl ester, carbamic acid 3-(4-benzyloxy-phenyl)-[l,2,4]thiadiazol-5-ylmethyl ester, carbamic acid 3-(4-benzyloxy-2-chloro-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-benzyloxy-3-chloro-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-benzyloxy-3-bromo-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-benzyloxy-3-fluoro-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-benzyloxy-3,5-dimethyl-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(l-phenyl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-fluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-fluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-fluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,6-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,3-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,4-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-chloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-chloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-chloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,6-dichloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,5-dichloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-chloro-5-fluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3- [4-(3-nitro-benzyloxy)-phenyl] -isoxazol-5-ylmethyl ester,

4- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester, carbamic acid 3-[4-(4-methyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-methyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-methoxy-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, 3-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-isopropyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-tert-butyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(biphenyl-4-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-formyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-formyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid

3 - {4- [4-(hydroxyimino-methyl)-benzyloxy] -phenyl} -isoxazol-5-ylmethyl ester, carbamic acid

3 - {4- [3-(hydroxyimino-methyl)-benzyloxy] -phenyl} -isoxazol-5-ylmethyl ester, carbamic acid 3-(4-methoxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-ethoxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-prop-2-ynyloxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-propoxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-butoxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-pentoxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-hexyloxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-cyclohexylmethoxy-phenyl)-isoxazol-5-ylmethyl ester, [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-acetic acid ethyl ester, carbamic acid 3-(4-methylsulfanylmethoxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3- (4-methoxymethoxy-phenyl)-isoxazol-5-ylmethyl ester, {3-[4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-propyl}-carbamic acid tert-butyl ester, carbamic acid 3-[4-(3-ureido-propoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-propyl ester, 4- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-butyric acid ethyl ester, carbamic acid 3-[4-(3-amino-propoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-hydroxy-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 2- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-ethyl ester, carbamic acid 3- [4-(4-hydroxy-butoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-(4-trifluoromethylsulfanylmethoxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4,4,4-trifluorobutoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-cyano-propoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-imidazol-l-yl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(5-chloro-thiophen-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(naphthalen-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(benzothiazol-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(pyridin-3-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(pyridin-4-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(5-methoxy-4,6-dimethyl-pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-dichloro-pyridin-4-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(quinolin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(benzotriazol-l-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester,

5- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester, carbamic acid l-[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-ethyl ester, carbamic acid 2-[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-ethyl ester, carbamic acid 3-[4-(l-oxy-pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 1- [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-1-methyl-ethyl ester, carbamic acid

1 - {3-[4-(pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-yl}-ethyl ester,

2- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxymethyl]-l-methyl-pyridinium iodide, carbamic acid 3-(4-cyclopentylmethoxy-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,4-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester , carbamic acid 3-[4-(2,5-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester , carbamic acid 3-[4-(2,4-dichloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester , carbamic acid 3-[4-(2-chloro-6-fluorobenzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-methyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(benzo[l,3]dioxol-5-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester, and carbamic acid 3-{4-[3-(t-butylnitronyl)-benzyloxy]-phenyl}-isoxazol-5-ylmethyl ester.

[95] Examples of the compound, in which Y is N-Ri; Ζ is carbamate; and R, Ri-R₈, A, Β, m, and η are as described above, include carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(benzyl-methyl-amino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,6-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,3-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,4-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,4-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,5-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-chloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-chloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-chloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,3-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,4-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,5-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,6-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,4-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,3,5-trichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,3,6-trichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-trifluoromethyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-trifluoromethyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-bis-trifluoromethyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-methyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-methyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-methyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-isopropyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2,4-dimethyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(2-methoxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3-methoxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-methoxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-phenoxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(4-benzyloxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-{4-[(5-phenyl-isoxazol-3-ylmethyl)-amino]-phenyl}-isoxazol-5-ylmethyl ester, carbamic acid 3-{4-[(thiophen-2-ylmethyl)-amino]-phenyl}-isoxazol-5-ylmethyl ester, carbamic acid 3-{4-[(furan-3-ylmethyl)-amino]-phenyl}-isoxazol-5-ylmethyl ester, carbamic acid 3-{4-[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-phenyl}-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-di-tert-butyl-4-hydroxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-dimethyl-4-hydroxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,5-di-tert-butyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(3,4,5-trihydroxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester, carbamic acid 3-[4-(benzyl-ethyl-amino)-phenyl]-isoxazol-5-ylmethyl ester, and carbamic acid 3-[4-(benzyl-propyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.

[96]

[97] Examples of the compound, in which Y is O; Ζ is 0-C(=0)NR₃R4; and R, Ri-R₈, A, Β, m, and η are as described above, include imidazole-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, methyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, dimethyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, diethyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, ethyl-methyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, pyrrolidine-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, piperidine-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, morpholine-4-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, piperazine-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, N',N'-dimethyl-hydrazinecarboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, (3-amino-propyl)-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, (2-amino-ethyl)-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, piperidine- 1-yl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, (4-methyl-piperazin-l-yl)-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, 4-methyl-piperazin-1 -carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, piperidine-4-yl-carbamic acid 3- (4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, and

4- [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethoxycarbonyl] - [ 1,4]diazepan-1 -ium chloride.

[98]

[99] Examples of the compound, in which Y is O; Ζ is -NR₅R₆; and R, Ri-R₈, A, Β, m, and η are as described above, include [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-prop-2-ynyl-amine, l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-piperidin-4-ol, carbamic acid

1 -[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-piperidin-4-yl ester, 3-(4-benzyloxy-phenyl)-5-imidazol-l-ylmethyl-isoxazole, 3-(4-benzyloxy-phenyl)-5-(2-methyl-imidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(4-methyl-imidazol-l-ylmethyl)-isoxazole,

3 - [4- (3 -fluoro-benzyloxy ) -phenyl] - 5 -imidazol-1 -ylmethyl-isoxazole, 3-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-imidazol-l-ylmethyl-isoxazole, l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-lH-[l,2,4]triazole,

1- [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-lH-[l,2,3]triazole,

2- [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-2H-tetrazole,

1- [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-2H-tetrazole,

3- [4-(2,4-difluoro-benzyloxy)-phenyl]-5-imidazol-l-ylmethyl-isoxazole,

5- imidazol-l-ylmethyl-3-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-isoxazole,

3- [4-(4-fluoro-benzyloxy)-phenyl] -5-imidazol-1 -ylmethyl-isoxazole,

3- [4-(4-chloro-benzyloxy)-phenyl] -5-imidazol-1 -ylmethyl-isoxazole,

3 - [4- (4-fluoro-benzyloxy) -phenyl] - 5 - (4-methyl-imidazol-1 -ylmethyl) -isoxazole, 3-[4-(3-fluoro-benzyloxy)-phenyl]-5-(4-methyl-imidazol-l-ylmethyl)-isoxazole, 3-[4-(2,4-difluoro-benzyloxy)-phenyl]-5-(4-methyl-imidazol- l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-pyrrolidin-l-ylmethyl-isoxazole,

1 - [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl] -piperidine, [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-dimethyl-amine, [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-diethyl-amine, [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-urea, Ν[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-guanidine,

2- {[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-acetamide, 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-propionamide, 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-2-methyl-propionamide, carbamic acid 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-propyl ester hydrochloride, 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-ethanol, 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-propan-l-ol,

2- {[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl] -amino} -butan-1 -ol, 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-2-methyl-propan-l-ol, 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-3-methyl-butan-l-ol, 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-propan-l,3-diol, [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-(2-methoxy-ethyl)-amine, allyl[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amine, carbamic acid

2- {[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-ethyl ester, [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-methyl-prop-2-ynyl-amine,

3- (4-benzyloxy-phenyl)-5-(2-isopropyl-imidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(4-bromo-imidazol-l-ylmethyl)-isoxazole,

3 - (4-benzyloxy-phenyl) -5 - (4,5 -dichloro-imidazol-1 -ylmethyl) -isoxazole, 3-(4-benzyloxy-phenyl)-5-(2-methyl-4,5-dichloro-imidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(2-nitro-imidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(4-phenyl-imidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(4-nitro-imidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(2-ethyl-4-methyl-imidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(2-chloroimidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(2-bromoimidazol-l-ylmethyl)-isoxazole, 3-(4-benzyloxy-phenyl)-5-(2-bromo-4,5-dichloroimidazol-l-ylmethyl)-isoxazole, 3- (4-benzyloxy-phenyl)-5- (2,4,5-tribromo-imidazol-1 -ylmethyl)-isoxazole, and 3-(4-benzyloxy-phenyl)-5-(2-ethyl-imidazol-l-ylmethyl)-isoxazole.

[100]

[101] One embodiment of the present invention provides pharmaceutical compositions for treatment of Parkinson's disease containing the substituted azole derivative as an active ingredient and a pharmaceutically acceptable carrier.

[102]

[103] In preparation of the pharmaceutical compositions, a carrier may be selected according to a formulation for preparation and may be mixed with the azole derivative of Formula (I) as an active ingredient in an appropriate ratio for formulation.

[104]

[105] The carrier is typically used in preparation, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[106]

[107] It is found that the MAO enzyme is involved in dopamine degradation, resulting in oxidative damage which contributes to the cause of degenerative brain disease such as Alzheimer's and Parkinson's disease. More specifically, it is known that ΜΑΟ-Α and ΜΑΟ-Β overexpressed in glial cells and astrocytes of the brain of a patient with dementia respectively are responsible for the oxidative damage.

[108]

[109] As confirmed in Table 1 in the following Example205, the azole derivatives of Formula (I) and pharmaceutically useful salts thereof have potent inhibition of ΜΑΟ-Β activity, and thus the compound of Formula (I) may be used alone or in combination with pharmaceutically acceptable carriers, as a therapeutic agent for brain disease, including Parkinson's disease.

[HO]

[111] The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical, transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. When the oral preparation is prepared, conventional pharmaceutical carriers may be used. For oral liquid dosage forms such as suspensions, syrups, elixirs and solutions, acceptable carriers may include, for example, water, glycol, oil, alcohol, etc.

For solid oral dosage forms such as powders, pills, capsules, and tablets, carriers may include starch, sugar, kaolin, lubricants, binders, disintegrating agents, etc. The preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient chosen. For easy administration and uniform dosage, it is preferably prepared in unit dosage form.

[112]

[113] The pharmaceutical compositions to be prepared according to one embodiment of the present invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, granules, pellets, troches, dragees, pills or lozenges, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, elixirs, syrups, etc., or parenterally in the form of solutions for injection. Other pharmaceutical compositions for parenteral administration include dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also considered as being within the scope of the present invention. Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, etc. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.

[115] One embodiment of the present invention provides a method for treating Parkinson's disease in a mammal by administering an effective amount of the substituted azole derivative to the mammal.

[116]

[117] The term "effective amount" means an amount of active ingredient effective to alleviate or reduce symptoms of a disease requiring treatment, or to reduce or retard the onset of clinical markers or symptoms of a disease in need of prevention. The therapeutically effective amount may be empirically determined by experimenting with compounds of interest in known in vivo and in vitro model systems for a disease requiring treatment.

[118]

[119] When the active ingredient of the composition, specifically the azole derivative of Formula (I), is administered for clinical purpose, the active ingredient is typically administered in unit dosage form or divided dosage form, containing an amount of about 0.01 mg to about 100 mg of the active ingredient. The total daily dosage is about 0.01 mg to about 100 mg per kg of body weight and preferably about 0.1 mg to about 10 mg per kg of body weight. However, assessing the conditions of a patient thoroughly and considering the activity of the drug to be administered, a specific dosage which is not included in the range may be administered.

[120]

[121] In addition, when the azole derivative of Formula (I) is administered in combination with Levodopa, the derivative shows efficacy at lower dosage than when it is solely administered. Thus, the azole derivative may be administered along with Levodopa.

Levodopa, a precursor of dopamine, functions to supplement low levels of dopamine in the substantia nigra and thus has been used as a therapeutic agent for Parkinson's disease. Levadopa is preferably administered with a DOPA decarboxylase inhibitor as a supplement to maintain the mobility of Levodopa by preventing Levodopa from being absorbed in the peripheral zone and increase the bioavailability of Levodopa.

The DOPA decarboxylase inhibitor may include, but is not limited to, preferably benserazide, carbidopa, etc.

[122]

[123] When the azole derivative of Formula (I) is administered in combination with Levodopa, preferably the Levodopa is administered with DOPA decarboxylase. Thus, a group which is administered Levodopa with DOPA decarboxylase can be called 'a Levodopa goup' for convenience in the present detailed description. That is 'a Levodopa goup' means administering Levodopa with DOPA decarboxylase

[124]

[125] When the azole derivative of Formula (I) is administered in combination with Levodopa,the azole derivative may be administered in unit dosage form containing an amount of about 0.001 mg to about 100 mg of azole derivative per kg of body weight in combination with about 0.5 mg to about 100 mg of Levodopa per kg of body weight and about 0.1 mg to about 10 mg of DOPA decarboxylase inhibitor per kg of body weight. When administered to a human subject, the ratio of the Levodopa to the DOPA decar-boxylase inhibitor is preferably about 4:1, and the ratio of the azole derivative of Formula (I) to the Levodopa is preferably about 1:50-1:5000, but is not limited to the range.

[126]

[127] In the combinatorial administration, it is preferred that the azole derivative of Formula

(I), benserazide, and DOPA carboxylase inhibitor are orally administered, and the azole derivative may be orally administered and benserazide and DOPA decar-boxylase inhibitor may be intraperitoneally administered. However, the administration route is not limited thereto. It is preferred that the azole derivative, benserazide, and DOPA decarboxylase inhibitor is simultaneously administered. However, the azole derivative may be administered in advance about 30 to about 60 minutes prior to the administration of Levodopa and DOPA decarboxylase inhibitor in order to sufficiently deliver the absorbed compound after the compound is administered. Levodopa may be also administered about 30 to about 60 minutes after DOPA decarboxylase inhibitor is administered in order to block the absorption of Levodopa in the peripheral nervous system and help in the delivery of Levodopa to the central nervous system. The combinatorial administration may decrease the dose of Levodopa to minimize side effects which may be caused by administration in large doses for a prolonged period.

[128]

[129] The daily dosage of the azole derivative is preferably administered once to twice a

day. When the azole derivative is administered with Levodopa group as confirmed in Examples for treatment of Parkinson's disease, it can be confirmed that the administration of the azole derivative of Formula (I) in combination with Levodopa group shows better behavior improvement effects than in a single administration group.

[130]

[131] It is known that prolonged administration of Levodopa, typically used in treatment of

Parkinson's disease, results in reduced efficacy and occurrence of tremors and involuntary hand tremors, and it is also known that when the administration of Levodopa is stopped, an adverse side effect known as "OFF-time" aggravates the symptoms of Parkinson's disease to a more significant level than before the drug was administered

(Putterman, et al., 2007, Evaluation of Levodopa Dose and Magnitude of Dopamine Depletion as Risk Factors for Levodopa-Induced Dyskinesia in a Rat Model of Parkinson’s Disease, J. Phamacol. Exp. Ther. 323(1): 277-284).

[133] The specific dosage for a specific patient must be empirically determined in determining an optimal dosage under a specific circumstance according to the specific compound to be used, body weight of the patient, sex, health condition, diet, time or method of administration, excretion rate, mixing ratio of the medicine, severity of the disease, etc.

[134]

[135] Depending on the situation, the azole derivative of Formula (I) may be used in the form of a prodrug thereof in formulation of an active pharmaceutical composition.

[136]

[137] The azole derivative of Formula (I) may be administered in one or several times, in combination with pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions according to one embodiment of the present invention may be formulated as pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques. For convenience, the formulation may be present in unit dosage form according to methods known to those skilled in the art of pharmaceutics.

[138]

[139] Other ingredients, which do not inhibit the action of an active ingredient or help the action of the active ingredient, may be further added to the composition according to one embodiment of the present invention, and may be formulated in various forms known to those skilled in other arts.

[140]

[141] Furthermore, the present invention provides a use of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for treatment of Parkinson's disease, and a use of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for preparation of a medicament suitable for treating Parkinson's disease.

[142]

[143] In the use, the effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is preferably administered to a mammal in combination with Levodopa and DOPA decarboxylase inhibitor.

[144]

[145] The compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in unit dosage form containing about 0.01 mg to about 10 mg, preferably with the total daily dosage of about 0.1 mg to about 10 mg per kg of body weight.

[146]

[147] The DOPA decarboxylase may be benserazide or carbidopa.

[148]

[149] Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, the Examples are provided only for a better understanding of the present invention and the scope of the present invention should not be construed to be limited thereby in any manner.

[150]

[151] Example 1: Synthesis of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazole-5-ylmethyl ester

[152]

[153] 1.1 Synthesis of 4-benzyloxy-benzaldehyde oxime

[154] 4-benzyloxybenzaldehyde (4.24 g, 20 mmol) was dissolved with stirring in a mixed solution of ethanol and water (3:1, 100 mf) at 0.2 Μ. To this added were NH20H-HC1 (2.78 g, 40 mmol) and sodium acetate (2.46 g, 30 mmol,) and the mixture was stirred at room temperature for about 30 minutes. The completion of the reaction was confirmed by liquid chromatography, and then water and ethanol were distilled under reduced pressure to obtain a pale yellow solid compound. The solid compound was extracted three times with water and ethyl acetate, the organic solvent layer was distilled off under reduced pressure, and then a crude compound was recrystallized from ethyl acetate /hexane (1:10) to obtain a white solid compound. The following reaction was performed on the thus-obtained solid without further purification.

[155]

[156] 1.2 Synthesis of [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol

[157] 4-benzyloxy-benzaldehyde oxime (2.27 g, 10 mmol-a compound of 92% purity) was dissolved in methylene chloride (40 mi, 0.25 Μ), to which solution was added propargyl alcohol (1.77 mi, 30 mmol). To the resulting solution was very slowly dropwise added 10% NaOCl (13.7 mi, 20 mmol) at 0°C, using a dropping funnel. After the addition of NaOCl was completed, the mixture was stirred for about 5 hours while increasing the temperature slowly to room temperature. The completion of the reaction was confirmed by liquid chromatography, and the mixture was distilled under reduced pressure to remove the methylene chloride. Water (200 mi) was added to the residue and the resulting solid was filtered off. The filtered compound was washed with excess of water and finally washed with diethyl ether. The thus-obtained solid compound was recrystallized from ethyl acetate/hexane (1:2) to obtain 2.50 g of [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol as a white sold.

[158] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 4Η), 7.1(d, 2Η), 6.5 (s, 1Η), 5.1 (s, 2Η), 4.8(s, 2Η)

[159]

[160] 1.3 Synthesis of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester 1.04 mi of chlorosulfonyl isocyanate (12 mmol) was slowly added to [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (2.813 g, 10 mmol) in THF (50 mi, 0.2 Μ) in a 250 mf-flask at -78°C. The consumption of all the starting materials was confirmed by liquid chromatography, and then water was added to the reaction mixture. After 1 hour, the THF was distilled off under reduced pressure, and the resulting solid after addition of 100 mi of water to the mixture was filtered off. The filtered solid was each washed with 100 mi of water and a solution of ethyl acetate/ hexane (1/2) and then dried to obtain 3.4 g of a crude product (95.9% pure). The crude compound was recrystallized from an ethyl acetate/hexane/methylene chloride (1/4/1) solution containing 1% Μ℮ΟΗ to obtain 2.743 g of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester of 99% purity.

[162] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 4Η), 7.1(d, 2Η), 6.6 (s, 1Η), 5.2(s, 2Η), 5.1 (s, 2Η), 4.8(brs, 2Η)

[163]

[164] Example 2: Synthesis of carbamic acid

3-(4-benzyloxy-phenyl)-[ 1,2,4]oxadiazol-5-ylmethyl ester

[165]

[166] An experiment was performed in the same manner as in Example 1, using ethyl ethyl cyanoformate instead of propargyl alcohol.

[167] 1H-NMR (CDC13, 200ΜΗζ) δ 8.1(d, 2Η), 7.5(m, 4Η), 7.1(d, 2Η), 6.6 (s, 1Η), 5.2(s, 2Η), 5.0 (s, 2Η)

[168]

[169] Example 3: Synthesis of carbamic acid

3- (4-benzyloxy-phenyl)-isothiazol-5-ylmethyl ester

[170]

[171] 3.1 Synthesis of 5-(4-benzyloxy-phenyl)-[l,3,4]oxathiazol-2-one

[172] 4-benzyloxybenzamide (0.66 g, 2.98 mmol) and 0.26 mi of chlorocarbonyl sulfenyl chloride were dissolved in 10 mi of benzene, refluxed for 3 hours, and stirred at 50°C for 12 hours. The organic solvent was distilled off under reduced pressure, and the resulting solid was washed with n-hexane to obtain 0.78 g of

5- (4-benzyloxy-phenyl)- [ 1,3,4]oxathiazol-2-one.

[173]

[174] 3.2 Synthesis of 3-(4-benzyloxy-phenyl)-isothiazol-5-carboxylic acid methyl ester 5-(4-benzyloxy-phenyl)-[l,3,4]oxathiazol-2-one (0.4 g, 1.4 mmol) and 0.23 mi of methyl propionate were dissolved in 10 mf of chlorobenzene and then refluxed overnight. The solvent was distilled off under reduced pressure and the obtained crude compound was purified by silica gel column chromatography to obtain 3-(4-benzyloxy-phenyl)-isothiazol-5-carboxylic acid methyl ester as a desired compound.

[176]

[177] 3.3 Synthesis of carbamic acid 3-(4-benzyloxy-phenyl)-isothiazol-5-ylmethyl ester The 3-(4-benzyloxy-phenyl)-isothiazol-5-carboxylic acid methyl ester obtained above was reduced to alcohol using NaBH4, and then the same procedure as in Example 1-3 was performed to obtain carbamic acid 3-(4-benzyloxy-phenyl)-isothiazol-5-ylmethyl ester as a desired compound.

[179] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(d, 2Η), 7.3(m, 4Η), 7.0(d, 2Η), 5.3(s, 2Η), 5.1 (s, 2Η), 3.7(s, 1Η), 3.6 (brs, 2Η)

[180]

[181] Example 4: Synthesis of carbamic acid

3-(4-benzyloxy-phenyl)-[ 1,2,4]thiadiazol-5-ylmethyl ester

[182]

[183] An experiment was performed in the same manner as in Example 3, using ethyl cyanoformate instead of methyl propionate.

[184] 1H-NMR (CDC13, 200ΜΗζ) δ 8.2(d, 2Η), 7.4(m, 4Η), 7.0(d, 2Η), 5.5(s, 2Η), 5.1 (s, 2Η)

[185]

[186] Example 5: Synthesis of carbamic acid

3- (4-benzyloxy-2-chloro-phenyl)-isoxazol-5-ylmethyl ester

[187]

[188] 5.1 Synthesis of 4-benzyloxy-2-chloro-benzaldehyde

[189] 3-chloro-4-hydroxybenzaldehyde (1.0 g, 6.3 mmol), potassium carbonate (1.7 g, 12.3 mmol), and t-butylammonium iodide (1.0 g, 2.7 mmol) were dissolved in acetonitrile (40 mi, 0.16 Μ), to which solution was slowly added dropwise benzyl bromide (1.2 mi, 9.4 mmol), and reacted at room temperature overnight. The completion of the reaction was confirmed by liquid chromatography, and then acetonitrile was distilled under reduced pressure. A crude solid compound was extracted with ethyl acetate and the solvent was distilled under reduced pressure to obtain a white solid compound. This was recrystallized from ethyl acetate /hexane (1:9) to obtain 1.4 g of

4- benzyloxy-2-chloro-benzaldehyde as a white solid compound.

[190]

[191] 5.2 Synthesis of carbamic acid 3-(4-benzyloxy-2-chloro-phenyl)-isoxazol-5-ylmethyl ester

[192] Instead of 4-benzyloxybenzaldehyde, the 4-benzyloxy-2-chloro-benzaldehyde obtained above was used in the same manners as in Examples 1-1, 1-2, and 1-3 to obtain carbamic acid 3-(4-benzyloxy-2-chloro-phenyl)-isoxazol-5-ylmethyl ester as a desired compound.

[193] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 1Η), 7.4(m, 5Η), 7.1(d, 1Η), 6.98(dd, 1Η), 6.78 (s, 1Η), 5.24(s, 2Η), 5.11(s, 2Η), 4.84(brs, 2Η)

[194]

[195] Example 6: Synthesis of carbamic acid

3-(4-benzyloxy-3-bromo-phenyl)-isoxazol-5-ylmethyl ester

[196]

[197] An experiment was performed in the same manner as in Example 5, using

3-bromo-4-hydroxybenzaldehyde instead of 4-benzyloxy-2-chloro-benzaldehyde.

[198] 1H-NMR (CDC13, 200ΜΗζ) δ 8.03(s, 1Η), 7.67(d, 1Η), 7.4(m, 5Η), 7.02(d, 1Η),

6.58 (s, 1Η), 5.22(s, 4Η), 4.76(brs, 2Η)

[199]

[200] Example 7 : Synthesis of carbamic acid

3-(4-benzyloxy-3-chloro-phenyl)-isoxazol-5-ylmethyl ester

[201]

[202] An experiment was performed in the same manner as in Example 5, using

2- chloro-4-hydroxybenzaldehyde.

[203] 1H-NMR (CDC13, 200ΜΗζ) δ 7.85(d, 1Η), 7.66(d, 1Η), 7.41(m, 5Η), 7.03(d, 1Η), 6.58 (s, 1Η), 5.22(s, 4Η), 4.79(brs, 2Η)

[204]

[205] Example 8: Synthesis of carbamic acid

3- (4-benzyloxy-3-fluoro-phenyl)-isoxazol-5-ylmethyl ester

[206]

[207] An experiment was performed in the same manner as in Example 5, using

2- fluoro-4-hydroxybenzaldehyde.

[208] 1H-NMR (CDC13, 200ΜΗζ) δ 7.57(d, 1Η), 7.40(m, 6Η), 7.08(t, 1Η), 6.56 (s, 1Η), 5.21(s, 4Η), 4.77(brs, 2Η)

[209]

[210] Example 9: Synthesis of carbamic acid

3- (4-benzyloxy-3,5-dimethyl-phenyl)-isoxazol-5-ylmethyl ester

[211]

[212] An experiment was performed in the same manner as in Example 5, using

3,5-dimethyl-4-hydroxybenzaldehyde.

[213] 1H-NMR (CDC13, 200ΜΗζ) δ 7.42(m, 7Η), 6.60 (s, 1Η), 5.21(s, 4Η), 4.77(brs, 2Η)

[215] Example 10: Synthesis of carbamic acid

3-[4-(l-phenyl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[216]

[217] 10.1 Synthesis of carbamic acid 3-(4-hydroxy-phenyl)-isoxazol-5-ylmethyl ester Carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester was obtained in the same manners as in Examples 1-1, 1-2, and 1-3 in Example 1. The compound was dissolved in Μ℮ΟΗ, and underwent a hydrogenation using 10 wt% Pd/C to synthesize carbamic acid 3-(4-hydroxy-phenyl)-isoxazol-5-ylmethyl ester.

[219]

[220] 10.2 Synthesis of carbamic acid 3-[4-(l-phenyl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[221] Carbamic acid 3-(4-hydroxy-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.64 mmol) and potassium carbonate (180 mg, 1.28 mmol) were dissolved in 10 mi of acetonitrile, to which was added dropwise (l-bromoethyl)benzene (131 μΑ, 0.96 mmol), and reacted at room temperature overnight. The completion of the reaction was confirmed by liquid chromatography, and then acetonitrile was distilled under reduced pressure.

A crude solid compound was extracted with ethyl acetate and the solvent was distilled under reduced pressure to obtain a white solid compound. This was recrystallized from methylene chloride:Μ℮ΟΗ (9:1) to obtain carbamic acid 3-[4-(l-phenyl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester as a white solid compound.

[222] 1H-NMR (CDC13, 200ΜΗζ) δ 7.65(d, 2Η), 7.35(m, 5Η), 6.94(d, 2Η), 6.53(d.2H), 5.38(s, 1Η), 5.19(s, 2Η), 4.84(brs, 2Η), 1.67(s, 3Η)

[223]

[224] Example 11 : Synthesis of carbamic acid 3-[4-(2-fluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[225]

[226] The compound was synthesized using 2-fluorobenzyl bromide in the same manner as in Example 10.

[227] 1H-NMR (CDC13, 200ΜΗζ) δ 7.76(d, 2Η), 7.52(t, 1Η), 7.15(m, 3Η), 7.07 (d, 2Η), 5.23(s, 2Η), 5.20(s, 2Η) 4.82(brs, 2Η)

[228]

[229] Example 12: Synthesis of carbamic acid

3- [4-(3-fluoro-benzyloxy)-phenyl] -isoxazol-5-ylmethyl ester

[230]

[231] The compound was synthesized using 3-fluorobenzyl bromide in the same manner as in Example 10.

[232] 1H-NMR (DMSO, 200ΜΗζ) δ 7.79(d, 2Η), 7.52(m, 4Η), 7.14(d, 2Η), 6.99 (s, 1Η), 5.20(s, 2Η), 5.12(s, 2Η)

[233]

[234] Example 13: Synthesis of carbamic acid 3-[4-(4-fluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[236] The compound was synthesized using 4-fluorobenzyl bromide in the same manner as in Example 10.

[237] 1H-NMR (CDC13, 200ΜΗζ) δ 7.76(d, 2Η), 7.43(t, 2Η), 7.10(m, 4Η), 6.60(s, 1Η), 5.23(s, 2Η), 4.78(brs, 2Η)

[238]

[239] Example 14: Synthesis of carbamic acid 3-[4-(2,6-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[240]

[241] The compound was synthesized using 2,6-di-fluorobenzyl bromide in the same manner as in Example 10.

[242] 1H-NMR (CDC13, 200ΜΗζ) δ 7.75(d, 2Η), 7.30(m, 1Η), 7.07(d, 2Η), 6.94(t, 2Η), 6.57(s, 1Η), 5.20(s, 2Η), 5.16(s, 2Η), 4.91(brs, 2Η)

[243]

[244] Example 15: Synthesis of carbamic acid 3-[4-(2,3-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[245]

[246] The compound was synthesized using 2,3-di-fluorobenzyl bromide in the same manner as in Example 10.

[247] 1H-NMR (CDC13, 200ΜΗζ) δ 7.70(d, 2Η), 6.96(m, 3Η), 6.72(d, 2Η), 6.55(s, 1Η), 5.18(s, 2Η), 5.06(s, 2Η), 4.77(brs, 2Η)

[248]

[249] Example 16: Synthesis of carbamic acid 3-[4-(3,5-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[250]

[251] The compound was synthesized using 2,6-di-fluorobenzyl bromide in the same manner as in Example 10.

[252] 1H-NMR (CDC13, 200ΜΗζ) δ 7.76(d, 2Η), 7.20(m, 3Η), 7.03(d, 2Η), 6.60(s, 1Η), 5.23(s, 2Η), 5.08(s, 2Η), 4.84(brs, 2Η)

[253]

[254] Example 17: Synthesis of carbamic acid 3-[4-(3,4-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[255]

[256] The compound was synthesized using 3,4-di-fluorobenzyl bromide in the same manner as in Example 10.

[257] 1H-NMR (CDC13, 200ΜΗζ) δ 7.77(d, 2Η), 7.01(m, 4Η), 6.79(t, 1Η), 6.60(s, 1Η), 5.23(s, 2Η), 5.1 l(s, 2Η), 4.84(brs, 2Η)

[258]

[259] Example 18: Synthesis of carbamic acid 3-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[260]

[261] The compound was synthesized using 2,4,6-tri-fluorobenzyl bromide in the same manner as in Example 10.

[262] 1H-NMR (CDC13, 200ΜΗζ) δ 7.54(d, 2Η), 6.86(d, 2Η), 6.56(t, 2Η), 6.45(s, 1Η), 4.98(s, 2Η), 4.91(s, 2Η)

[263]

[264] Example 19: Synthesis of carbamic acid 3-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[265]

[266] The compound was synthesized using 3-trifluoromethy 1-benzyl bromide in the same manner as in Example 10.

[267] 1H-NMR (CDC13, 200ΜΗζ) δ 7.74(d, 2Η), 7.58(d, 2Η), 6.58(1, 1Η), 5.20(s, 1Η), 5.15(s, 2Η), 4.70 brs, 2Η)

[268]

[269] Example 20: Synthesis of 3-[4-(3-chloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[270]

[271] The compound was synthesized using 3-chlorobenzyl bromide in the same manner as in Example 10.

[272] 1H-NMR (CDC13, 200ΜΗζ) δ 7.74(d, 2Η), 7.44(s, 1Η), 7.30(m, 3Η), 7.03(d, 2Η), 6.58(s, 1Η), 5.21(s, 2Η), 5.09(s, 2Η), 4.78(brs, 2Η)

[273]

[274] Example 21: Synthesis of carbamic acid 3-[4-(2-chloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[275]

[276] The compound was synthesized using 2-chlorobenzyl bromide in the same manner as in Example 10.

[277] 1H-NMR (CDC13, 200ΜΗζ) δ 7.74(d, 2Η), 7.44(s, 1Η), 7.30(m, 3Η), 7.03(d, 2Η), 6.58(s, 1Η), 5.21(s, 2Η), 5.09(s, 2Η), 4.78(brs, 2Η)

[278]

[279] Example 22: Synthesis of carbamic acid 3-[4-(4-chloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[280]

[281] The compound was synthesized using 4-chlorobenzyl bromide in the same manner as in Example 10.

[282] 1H-NMR (DMSO, 200ΜΗζ) δ 7.80(d, 2Η), 7.48(m, 4Η), 7.13(d, 2Η), 7.78(brs, 2Η), Example 23: Synthesis of carbamic acid 3-[4-(2,6-dichlorobenzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[285]

[286] The compound was synthesized using 2,6-dichlorobenzylbromide in the same manner as in Example 10.

[287] 1H-NMR (CDC13, 200ΜΗζ) δ 7.78(d, 2Η), 7.38(m, 3Η), 7.11(d, 2Η), 6.6l(s, 1Η), 5.34(s, 2Η), 5.24(s, 2Η), 4.79(brs, 2Η)

[288]

[289] Example 24: Synthesis of carbamic acid 3-[4-(2,5-di-chloro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[290]

[291] The compound was synthesized using 2,5-dichlorobenzyl bromide in the same manner as in Example 10.

[292] 1H-NMR (CDC13, 200ΜΗζ) δ 7.79(d, 2Η), 7.60(s, 1Η), 7.32(m, 2Η), 7.08(d, 2Η), 6.61(s, 1Η), 5.24(s, 2Η), 5.19(s, 2Η), 4.79(brs, 2Η)

[293]

[294] Example 25: Synthesis of carbamic acid 3-[4-(2-chloro-5-fluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[295]

[296] The compound was synthesized using 2-chloro-5-fluorobenzyl bromide in the same manner as in Example 10.

[297] 1H-NMR (CDC13, 200ΜΗζ) δ 7.78(d, 2Η), 7.29(m, 3Η), 7.10(d, 2Η), 6.6l(s, 1Η), 5.24(s, 4Η), 4.82(brs, 2Η)

[298]

[299] Example 26: Synthesis of carbamic acid

3- [4-(3-nitro-benzyloxy)-phenyl] -isoxazol-5-ylmethyl ester

[300]

[301] The compound was synthesized using 3-nitrobenzyl bromide in the same manner as in Example 10.

[302] 1H-NMR (CDC13, 200ΜΗζ) δ 8.4(s, 1Η), 8.2(d, 1Η), 7.8(d, 2Η), 7.6(t, 1Η), 7.1(d, 2Η), 6.6(s, 1Η), 5.2(s, 4Η)

[303]

[304] Example 27 : Synthesis of

4- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester

[305]

[306] The compound was synthesized using methyl 4-(bromomethyl)benzoate in the same manner as in Example 10.

[307] 1H-NMR (CDC13, 200ΜΗζ) δ 8.1(d, 2Η), 7.8(d, 2Η), 7.6(d, 2Η), 7.1(d, 2Η), 6.6(s, 1Η), 5.3(s, 2Η), 5.2(s, 2Η), 4.0(s, 3Η)

[308]

[309] Example 28: Synthesis of 3-[4-(4-methyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[310]

[311] The compound was synthesized using 4-methylbezyl bromide in the same manner as in Example 10.

[312] 1H-NMR (CDC13, 200ΜΗζ) δ 7.5(d, 2Η), 7.1(d, 2Η), 7.0(d, 2Η), 6.8 (d, 2Η), 6.5(s, 1Η), 5.0(s, 2Η), 4.9(s, 2Η), 2.2(s, 3Η)

[313]

[314] Example 29: Synthesis of carbamic acid 3-[4-(2-methyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[315]

[316] The compound was synthesized using 2-methylbezyl bromide in the same manner as in Example 10.

[317] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(s, 1Η), 7.1(m, 3Η), 7.0(d, 2Η), 6.5(s, 1Η), 5.1(s, 2Η), 5.0(s, 2Η), 2.2(s, 3Η)

[318]

[319] Example 30: Carbamic acid 3-[4-(3-methoxy-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[320]

[321] The compound was synthesized using 2-methoxybenzyl bromide in the same manner as in Example 10.

[322] 1H-NMR (DMSO, 200ΜΗζ) δ 7.81(d, 2Η), 7.30(t, 1Η), 7.13(d, 2Η), 6.98(m, 6Η), 5.16(s, 2Η), 5.13(s, 2Η), 3.77(s, 3Η)

[323]

[324] Example 31 : Carbamic acid 3-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[325]

[326] The compound was synthesized using 3-trifluoromethylbenzyl bromide in the same manner as in Example 10.

[327] 1H-NMR (CDC13, 200ΜΗζ) δ 7.74(d, 2Η), 7.52(m, 4Η), 7.07(d, 2Η), 6.59(s, 1Η), 5.33(s, 2Η), 5.22(s, 2Η), 4.76(brs, 2Η)

[328]

[329] Example 32: Carbamic acid 3-[4-(4-isopropyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[330]

[331] The compound was synthesized using 4-isopropylbenzyl bromide in the same manner as in Example 10.

[332] 1H-NMR (CDC13, 200ΜΗζ) δ 7.74(d, 2Η), 7.32(dd, 4Η), 7.05(d, 2Η), 6.58(s, 1Η), 5.21(s, 2Η), 5.08(s, 2Η), 4.92(brs, 2Η), 2.98(m, 1Η), 1.25(d, 6Η)

[333]

[334] Example 33: Carbamic acid 3-[4-(4-tert-butyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[335]

[336] The compound was synthesized using 4-tert-butyl-benzyl bromide in the same manner as in Example 10.

[337] 1H-NMR (CDC13, 200ΜΗζ) δ 7.74(d, 2Η), 7.40(m, 4Η), 7.05(d, 2Η), 6.59(s, 1Η), 5.20(s, 2Η), 5.08(s, 2Η), 4.78(brs, 2Η), 1.32(s, 9Η)

[338]

[339] Example 34: Carbamic acid 3-[4-(biphenyl-4-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[340]

[341] The compound was synthesized using 4-(bromomethyl)biphenyl in the same manner as in Example 10.

[342] 1H-NMR (CDC13, 200ΜΗζ) δ 7.70(d, 2Η), 7.48(m, 9Η), 7.01(d, 2Η), 6.57(s, 1Η), 5.14(s, 2Η), 5.11 (s, 2Η)

[343]

[344] Example 35: Synthesis of carbamic acid 3-[4-(3-formyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[345]

[346] The compound was synthesized using 3-(bromomethyl)benzaldehyde in the same manner as in Example 10.

[347] 1H-NMR (CDC13, 200ΜΗζ) δ 10.1(s, 1Η), 8.1(s, 1Η), 7.9(d, 1Η), 7.8(m, 3Η), 7.6(t, 1Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.23(s, 4Η), 5.2(s, 2Η), 4.8(brs, 2Η)

[348]

[349] Example 36: Synthesis of carbamic acid 3-[4-(4-formyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[350]

[351] The compound was synthesized using 4-(bromomethyl)benzaldehyde in the same manner as in Example 10.

[352] 1H-NMR (CDC13, 200ΜΗζ) δ 10.0(s, 1Η), 7.9(d, 2Η), 7.8(d, 2Η), 7.6(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 4Η), 4.8(brs, 2Η)

[354] Example 37: Synthesis of carbamic acid

3 - {4- [4-(hydroxyimino-methyl)-benzyloxy] -phenyl} -isoxazol-5-ylmethyl ester

[356] 4-carbamic acid 3-[4-(4-formyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester was synthesized, and then a formation of oxime was performed in the same manner as in Example 1-1 to obtain carbamic acid 3-{4-[4-(hydroxyimino-methyl)-benzyloxy]-phenyl}-isoxazol-5-ylmethyl ester as a desired compound.

[357] 1H-NMR (CDC13, 200ΜΗζ) δ 8.0(s, 1Η), 7.7(d, 2Η), 7.5(d, 2Η), 7.3(d, 2Η), 6.9(d, 2Η), 6.5(s, 1Η), 5.1(s, 2Η), 5.0(s, 2Η)

[358]

[359] Example 38: Synthesis of carbamic acid

3 - {4- [3-(hydroxyimino-methyl)-benzyloxy] -phenyl} -isoxazol-5-ylmethyl ester

[361] 4-carbamic 3-[4-(3-formyl-benzylxoy)-phenyl]-isoxazol-5-ylmethyl ester was synthesized, and then a synthesis was performed in the same manner as in Example 36.

[362] 1H-NMR (CDC13, 200ΜΗζ) δ 8.1(s, 1Η), 7.7(d, 2Η), 7.5(s, 1Η), 7.4(m, 3Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η)

[363]

[364] Example 39: Synthesis of carbamic acid 3-(4-methoxy-phenyl}-isoxazol-5-ylmethyl ester

[365]

[366] The compound was synthesized using iodomethane in the same manner as in Example 10.

[367] 1H-NMR (CD30D, 200ΜΗζ) δ 7.8(d, 2Η), 7.0(d, 2Η), 6.8(s, 1Η), 5.2(s, 2Η), 3.9(s, 3Η)

[368]

[369] Example 40: Synthesis of carbamic acid 3-(4-ethoxy-phenyl]-isoxazol-5-ylmethyl ester

[370]

[371] The compound was synthesized using iodoethane in the same manner as in Example 10.

[372] 1H-NMR (CD30D, 200ΜΗζ) δ 7.8(d, 2Η), 7.0(d, 2Η), 6.8(s, 1Η), 5.2(s, 2Η), 4.1(q, 2Η), 1.4(t, 3Η)

[373]

[374] Example 41: Synthesis of carbamic acid 3-(4-prop-2-ynyloxy-phenyl)-isoxazol-5-ylmethyl ester

[376] The compound was synthesized using propargyl bromide in the same manner as in Example 10.

[377] 1H-NMR (CD30D, 200ΜΗζ) δ 7.8(d, 2Η), 7.1(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 2.6(t, 1Η)

[378]

[379] Example 42: Synthesis of carbamic acid 3-(4-propoxy-phenyl)-isoxazol-5-ylmethyl ester

[380]

[381] The compound was synthesized using iodopropane in the same manner as in Example 10.

[382] 1H-NMR (CD30D, 200ΜΗζ) δ 7.7(d, 2Η), 7.0(d, 2Η), 6.7(s, 1Η), 5.2(s, 2Η), 4.0(t, 2Η), 1.8(m, 2Η), l.l(t, 3Η)

[383]

[384] Example 43: Synthesis of carbamic acid 3-(4-butoxy-phenyl)-isoxazol-5-ylmethyl ester

[385]

[386] The compound was synthesized using iodobutane in the same manner as in Example 10.

[387] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.3(s, 2Η), 4.8(brs, 2Η), 4.0(t, 2Η), 1.8(m, 2Η), 1.5(m, 2Η), 1.1 (t, 3Η)

[388]

[389] Example 44: Synthesis of carbamic acid 3-(4-pentoxy-phenyl)-isoxazol-5-ylmethyl ester

[390]

[391] The compound was synthesized using iodopentane in the same manner as in Example 10.

[392] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.3(s, 2Η), 4.8(brs, 2Η), 4.0(t, 2Η), 1.8(m, 2Η), 1.4(m, 4Η), 1.1 (t, 3Η)

[393]

[394] Example 45: Synthesis of carbamic acid 3-(4-hexyloxy-phenyl)-isoxazol-5-ylmethyl ester

[395]

[396] The compound was synthesized using iodohexane in the same manner as in Example 10.

[397] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.3(s, 2Η), 4.8(brs, 2Η), 4.0(t, 2Η), 1.8(m, 2Η), 1.4(m, 6Η), 1.1 (t, 3Η)

[398]

[399] Example 46: Synthesis of carbamic acid 3-(4-cyclohexylmethoxy-phenyl)-isoxazol-5-ylmethyl ester

[400]

[401] The compound was synthesized using (bromomethyl)cyclohexane in the same manner as in Example 10.

[402] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 3.8(d, 2Η), 1.8(m, 6Η), 1.2(m, 5Η)

[403]

[404] Example 47: Synthesis of [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-acetic acid ethyl ester

[405]

[406] The compound was synthesized using ethyl bromoacetate in the same manner as in Example 10.

[407] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.7(s, 2Η), 4.3(q, 2Η), 1.3(t, 3Η)

[408]

[409] Example 48: Synthesis of [carbamic acid 3-(4-methylsulfanylmethoxy-phenyl)-isoxazol-5-ylmethyl ethyl ester

[410]

[411] The compound was synthesized using chloromethyl methyl sulfide in the same manner as in Example 10.

[412] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.20(s, 2Η), 4.9(brs, 2Η), 2.3(s, 3Η)

[413]

[414] Example 49: Synthesis of carbamic acid 3-(4-methoxymethoxy-phenyl)-isoxazol-5-ylmethyl ethyl ester

[415]

[416] The compound was synthesized using chloromethyl methyl ether in the same manner as in Example 10.

[417] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(d, 2Η), 7.1(d, 2Η), 6.6(s, 1Η), 5.2(s, 4Η), 4.9(brs, 2Η), 3.5(s, 3Η)

[418]

[419] Example 50: Synthesis of carbamic acid {3-[4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-propyl}-carbamic acid tert-butyl ester

[420]

[421] The compound was synthesized using N-boc-3-bromopropylamine in the same manner as in Example 10.

[424] Example 51 : Synthesis of carbamic acid 3-[4-(3-amino-propoxy)-phenyl]-isoxazol-5-ylmethyl ester hydrochloride

[425]

[426] The compound in Example 50 was stirred in 1Μ HC1 in ethyl acetate solution for 4 hours, and then the obtained solid was filtered to obtain carbamic acid 3-[4-(3-amino-propoxy)-phenyl]-isoxazol-5-ylmethyl ester hydrochloride as a desired compound.

[427] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 8.0(brs, 3Η), 7.8(d, 2Η), 7.1(d, 2Η), 7.0(s, 1Η), 5.1(s, 2Η), 4.1(t, 2Η), 3.0(m, 2Η), 2.0(t, 2Η)

[428]

[429] Example 52: Synthesis of carbamic acid 3-[4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-propyl ester

[430]

[431] 4-(5-hydroxymethyl-isoxazol-3-yl)-phenol and 3-bromo-1-propanol were used to synthesize 3-[4-(5-hydroxymethyl-isoxazol-3-yl)-phenoxy]-propan-l-ol in the same manner as in Example 10, and then a carbamoylation of the compound was performed in the same manner as in Example 1-3 to obtain carbamic acid

3- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-propyl ester as a desired compound.

[432] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 6.9(d, 2Η), 6.5(s, 1Η), 5.1(s, 2Η), 4.2(t, 2Η), 4.0(t, 2Η), 2.0(m, 2Η)

[433]

[434] Example 53: Synthesis of

4- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-butyric acid ethyl ester

[435]

[436] The compound was synthesized using ethyl bromobutyrate in the same manner as in Example 10.

[437] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 6.9 (d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.2(q, 2Η), 4.1(t, 2Η), 2.5(t, 2Η), 2.1(m, 2Η), 1.3(t, 3Η)

[438]

[439] Example 54: Synthesis of carbamic acid

3- [4-(3-ureido-propoxy)-phenyl] -isoxazol-5-ylmethyl ester

[440]

[441] A carbamoylation of the compound carbamic acid 3-[4-(3-amino-propoxy)-phenyl]-isoxazol-5-ylmethyl hydrochloride in Example 51 was performed to obtain carbamic acid 3-[4-(3-ureido-propoxy)-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.

[442] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 7.8(d, 2Η), 7.05(d, 2Η), 7.0(s, 1Η), 6.8(brs, 2Η), 6.0(brs, 1Η), 5.4(s, 2Η), 5.1(s, 2Η), 4.1(t, 2Η), 3.1(m, 2Η), 1.8(t, 2Η)

[443]

[444] Example 55: Synthesis of carbamic acid 3-[4-(2-hydroxy-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[445]

[446] 5 equivalents of NaBH4 was added to 200 mg of the compound [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-acetic acid ethyl ester in Example 47 while stirring in the presence of a 10 mf THF/5 mi water solvent. After stirring for 12 hours, the solvent was distilled off under reduced pressure and 20 mi of 1-N HC1 solution was added to the reactants, followed by extraction three times with 20 mi of ethyl acetate. The obtained organic layer was put under reduced pressure to obtain carbamic acid 3-[4-(2-hydroxy-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.

[447] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 7.8(d, 2Η), 7.1(d, 2Η), 7.0(s, 1Η), 6.8(brs, 2Η), 5.2(s, 2Η), 4.0(t, 2Η), 3.7(t, 2Η)

[448]

[449] Example 56: Synthesis of carbamic acid

2- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-ethyl ester

[450]

[451] A carbamoylation of the compound carbamic acid

3- [4-(2-hydroxy-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester in Example 55 was performed in the same manner as in Example 1-3 to obtain carbamic acid

2- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-ethyl ester as a desired compound.

[452] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 7.8(d, 2Η), 7.1(d, 2Η), 7.0(s, 1Η), 6.7(brs, 2Η), 5.1(s, 2Η), 4.2(t, 2Η), 3.4(m, 2Η)

[453]

[454] Example 57: Synthesis of carbamic acid

3- [4-(4-hydroxy-butoxy)-phenyl] -isoxazol-5-ylmethyl ester

[455]

[456] A reduction of the compound

4- [(4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-butyric acid ethyl ester in Example 53 was performed in the same manner as in Example 55 to obtain 3-[4-(4-hydroxy-butoxy)-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.

[457] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 7.8(d, 2Η), 7.05(d, 2Η), 7.0(s, 1Η), 6.8(brs, 2Η), Example 58: Synthesis of carbamic acid 3-(4-trifluoromethylsulfanylmethoxy-phenyl)-isoxazol-5-ylmethyl ester

[460]

[461] The compound was synthesized using chloromethyl trifluoromethyl sulfide in the same manner as in Example 10.

[462] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.6(s, 2Η), 5.2(s, 2Η), 4.8(brs, 1Η)

[463]

[464] Example 59: Synthesis of carbamic acid 3-[4-(4,4,4-trifluoro-butoxy)-phenyl]-isoxazol-5-ylmethyl ester

[465]

[466] The compound was synthesized using l,l,l-trifluoro-4-bromobutane in the same manner as in Example 10.

[467] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 1Η), 4.0(t, 2Η), 2.3(m, 2Η), 2.0(m, 2Η)

[468]

[469] Example 60: Synthesis of carbamic acid 3-[4-(3-cyano-propoxy)-phenyl]-isoxazol-5-ylmethyl ester

[470]

[471] The compound was synthesized using l-cyano-4-bromobutane in the same manner as in Example 10.

[472] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 1Η), 4.1(t, 2Η), 2.6(t, 2Η), 2.1(m, 2Η)

[473]

[474] Example 61: Synthesis of carbamic acid

3- [4-(2-imidazol-1 -yl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[475]

[476] {3-[4-(2-chloro-ethoxy)-phenyl]-isoxazol-5-yl}-methanol was synthesized using

4- (5-hydroxymethyl-isoxazol-3-yl)-phenol and 2-bromo-l-chloroethane in the same manner as in Example 10, and then 2 equivalents of imidazole and 3 equivalents of potassium carbonate were added to the compound and refluxed with acetonitrile. After 12 hours of the reaction, the solvent was dried under reduced pressure and purified by column chromatography to obtain {3-[4-(2-imidazol-l-yl-ethoxy)-phenyl]-isoxazol-5-yl}-methanol. A carbamoylation of the compound was performed in the same manner as in Example 1-3 to obtain carbamic acid 3-[4-(2-imidazol-l-yl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.

[477] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 7.8(d, 2Η), 7.7(s, 1Η), 7.25(s, 1Η), 7.05(d, 2Η), 7.0(s, 1Η), 6.9(s, 1Η), 6.8(brs, 2Η), 5.1(s, 2Η), 4.3(t, 2Η), 4.4(t, 2Η)

[478]

[479] Example 62: Carbamic acid 3-[4-(5-chloro-thiophen-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[480]

[481] The compound was synthesized using 2-chloro-5-(chloromethyl)thiophene in the same manner as in Example 10.

[482] 1H-NMR (CDC13, 200ΜΗζ) δ 7.70(d, 2Η), 7.0(d, 2Η), 6.83(d, 2Η), 6.56(s, 1Η), 5.17(s, 2Η), 5.13(s, 2Η)

[483]

[484] Example 63: Carbamic acid 3-[4-(naphthalen-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[485]

[486] The compound was synthesized using 2-bromomethylnaphthalene in the same manner as in Example 10.

[487] 1H-NMR (CDC13, 200ΜΗζ) δ 7.91(m, 5Η), 7.53(m, 2Η), 7.15(d, 2Η), 6.59(s, 1Η), 5.30(s, 2Η), 5.22(s, 2Η)

[488]

[489] Example 64: Carbamic acid 3-[4-(benzothiazol-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[490]

[491] The compound was synthesized using 2-bromomethyl-l,3-benzothiazole in the same manner as in Example 10.

[492] 1H-NMR (CDC13, 200ΜΗζ) δ 8.0(d, 1Η), 7.8(d, 1Η), 7.7(d, 2Η), 7.4(m, 2Η), 7.1(d, 2Η), 6.6(s, 2Η), 5.5(s, 2Η)

[493]

[494] Example 65: Carbamic acid 3-[4-(pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[495]

[496] The compound was synthesized using 2-bromomethylpyridine in the same manner as in Example 10.

[497] 1H-NMR (CDC13, 200ΜΗζ) δ 8.6(s, 1Η), 7.7(d, 3Η), 7.5(d, 1Η), 7.2(d, 1Η), 7.1(d, 2Η), 6.6(s, 1Η), 5.3(s, 2Η), 5.2(s, 2Η), 4.8(brs, 2Η)

[498]

[499] Example 66: Carbamic acid 3-[4-(pyridin-3-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[501] The compound was synthesized using 3-bromomethylpyridine in the same manner as in Example 10.

[502] 1H-NMR (CDC13, 200ΜΗζ) δ 8.7(s, 1Η), 8.6(s, 1Η), 8.0(d, 1Η), 7.7(d, 2Η), 7.5(s, 1Η), 7.0(d, 2Η), 5.2(s, 4Η), 4.7(brs, 2Η)

[503]

[504] Example 67: Carbamic acid 3-[4-(pyridin-4-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[505]

[506] The compound was synthesized using 4-bromomethylpyridine in the same manner as in Example 10.

[507] 1H-NMR (CDC13, 200ΜΗζ) δ 8.6(s, 2Η), 8.7(d, 2Η), 7.4(d, 2Η), 6.9(d, 2Η), 5.1(s, 4Η), 4.7(brs, 2Η)

[508]

[509] Example 68: Carbamic acid 3-[4-(5-methoxy-4,6-dimethyl-pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[510]

[511] The compound was synthesized using

2- chloromethyl-4-methyl-3,5-dimethylpyridine hydrochloride in the same manner as in Example 10.

[512] 1H-NMR (DMSO, 200ΜΗζ) δ 8.7(s, 1Η), 7.9(d, 2Η), 7.4(d, 2Η), 7.1(s, 1Η), 6.8(brs, 2Η), 5.6(s, 2Η), 5.2(s, 2Η), 4.1(s, 3Η), 2.5(s, 3Η), 2.4(s, 3Η)

[513]

[514] Example 69: Carbamic acid

3- [4-(3,5-dichloro-pyridin-4-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[515]

[516] The compound was synthesized using 2,6-dichloro-4-chloromethylpyridine in the same manner as in Example 10.

[517] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(s, 2Η), 7.3(s, 2Η), 7.0(d, 2Η), 7.7(d, 2Η), 7.5(s, 1Η), 7.0(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(s, 2Η)

[518]

[519] Example 70: Carbamic acid 3-[4-(quinolin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[520]

[521] The compound was synthesized using 2-chloromethylquinoline monohydrochloride in the same manner as in Example 10.

[522] 1H-NMR (CDC13, 200ΜΗζ) δ 8.3(d, 1Η), 8.2(d, 1Η), 7.7(m, 6Η), 7.1(d, 2Η), 6.5(s, Example 71 : Carbamic acid 3-[4-(benzotriazol-l-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[525]

[526] The compound was synthesized using 1-chloromethyl-lH-benzotriazole in the same manner as in Example 10.

[527] 1H-NMR (CDC13, 200ΜΗζ) δ 8.0(d, 1Η), 7.7(d, 2Η), 7.6(d, 1Η), 7.5(d, 1Η), 7.1(d, 2Η), 6.6(s, 2Η), 6.51(s, 1Η), 5.1(s, 2Η)

[528]

[529] Example 72: Synthesis of carbamic acid 3-[4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[530]

[531] The compound was synthesized using 4-chloromethyl-3,5-dimethylisoxazole in the same manner as in Example 10.

[532] 1H-NMR (CDC13, 200ΜΗζ) 7.7(d, 2Η), 7.0(d, 2Η), 6.6(s, 2Η), 5.1(s, 2Η), 4.8(s, 2Η), 2.4(s, 3Η), 2.25(s, 3Η)

[533]

[534] Example 73: Synthesis of 5-[4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester

[535]

[536] The compound was synthesized using methyl 5-(chloromethyl)-2-furoate in the same manner as in Example 10.

[537] 1H-NMR (CDC13, 200ΜΗζ) 7.7(d, 2Η), 7.1(d, 1Η), 7.0(d, 2Η), 6.5(s, 2Η), 6.5(d, 1Η), 5.1(s, 2Η), 5.0(s, 2Η), 3.8(s, 3Η)

[538]

[539] Example 74: Carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester

[541] 74.1 Synthesis of 4-nitro-benzaldehyde oxime

[542] 4-nitroaldehyde (3 g, 19.9 mmol) was dissolved with stirring in a mixture of ethanol and Η20 (3:1 100 mf). To the solution were added NH20H-HC1 (2.78 g, 40 mmol) and pyridine (1.92 mU, 23.8 mmol) and refluxed for about 2 hours. The completion of the reaction was confirmed by liquid chromatography, and then water and ethanol were distilled under reduced pressure to obtain a pale yellow solid compound. The compound was washed with HC1, and was recrystallized from ethyl acetate/hexane (1:9) to obtain 4-nitro-benzaldehyde oxime which has a white color.

[543]

[544] 74.2 Synthesis of [3-(4-nitro-phenyl)-isoxazol-5-yl]-methanol

[545] 4-nitro-benzaldehyde oxime (2.40 g, 14.4 mmol) was dissolved in methylene chloride (70 me, 0.2 Μ), and then propargyl alcohol (2.51 me, 43.2 mmol) was added to the solution. To the resulting solution was slowly added dropwise 10% NaOCl (17.8 me, 28.8 mmol) using a dropping funnel. After the addition of NaOCl was completed, the mixture was stirred for about 5 hours while increasing the temperature slowly to room temperature. The completion of the reaction was confirmed by liquid chromatography, and then the mixture was distilled under reduced pressure to remove methylene chloride. Water (200 me) was added to the residue and the resulting solid was filtered off. The filtered compound was washed with excess of water and finally washed with diethyl ether. The thus-obtained solid compound was recrystallized from ethyl acetate/hexane (1:2) to obtain [3-(4-nitro-phenyl)-isoxazol-5-yl]-methanol in a white sold phase.

[546]

[547] 74.3 Synthesis of [3-(4-amino-phenyl)-isoxazol-5-yl]-methanol

[548] [3-(4-nitro-phenyl)-isoxazol-5-yl]-methanol (300 mg, 1.58 mmol) was placed in a 250-me Parr reactor flask, to which were added 50 me of ethanol and 10 wt% Pd/C. The mixture was reacted under 40 psi of hydrogen in the Parr reactor for about 1 hour. The completion of the reaction was confirmed by TLC, and then a filtrate by means of a CELITE® (CELITE is a registered trademark of Imerys Minerals California Inc., San Jose, CA, USA) placed was distilled under reduced pressure to obtain a yellow solid compound. This was recrystallized from ethyl acetate/hexane (1:2) to obtain [3-(4-amino-phenyl)-isoxazol-5-yl]-methanol in a yellow solid state.

[549]

[550] 74.4 Synthesis of [3-(4-benzylamino-phenyl)-isoxazol-5-yl]-methanol

[551] [3-(4-amino-phenyl)-isoxazol-5-yl]-methanol (185 mg, 0.97 mmol) and benzaldehyde (118 jik, 1.16 mmol) were dissolved in 20 me of methanol, to which solution was added 2 to 3 drops of acetic acid. The reaction was performed at room temperature for about 1 hour. Sodium cyano borohydride (91 mg, 1.45 mmol) was slowly added to the mixture at 0°C, a reaction was performed for 12 hours while increasing the temperature to room temperature, and then methanol was distilled under reduced pressure to obtain a pale yellow solid compound. The solid compound was extracted three times with water and ethyl acetate, the organic solvent layer was separated and distilled under reduced pressure, and then a crude compound was purified by column chromatography on silica gel using ethyl acetate/ hexane (1:2) to obtain [3-(4-(benzylamino-phenyl)-isoxazol-5-yllmethanol as a white solid.

[552]

[553] 74.5 Synthesis of carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester [3-(4-benzylamino-phenyl)-isoxazol-5-yl]-methanol (178 mg, 0.63 mmol) was REPLACEMENT SHEET

dissolved in THF (20 mf, 0.03 Μ), to which was added CDI (154 mg, 0.95 mmol).

After the mixture was stirred at room temperature for about 1 hour, 1 mi of ammonium hydroxide was added and the resulting mixture was stirred for another 3 hours. The completion of the reaction was confirmed by liquid chromatography, and the THF was distilled under reduced pressure to obtain a pale yellow solid compound. The solid compound was extracted three times with water and ethyl acetate, the organic solvent layer was dried under reduced pressure, and then a crude compound was purified by column chromatography on silica gel using ethyl acetate/ hexane (1:3) to obtain carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester as a white solid.

[555] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(m, 5Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.3(s, 2Η)

[556]

[557] Example 75: Carbamic acid 3-[4-(benzyl-methyl-amino)-phenyl]-isoxazol-5-ylmethyl ester

[558]

[559] An experiment was performed using carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.46 mmol) in Example 74 as a starting material and formaldehyde (20 μΑ, 0.70 mmol) in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(benzyl-methyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.

[560] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.2(m, 5Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 5.1(brs, 2Η), 4.6(s, 2Η), 3.1(s, 3Η)

[561]

[562] Example 76: Carbamic acid 3-[4-(4-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[563]

[564] 76.1 Synthesis of carbamic acid 3-(4-amino-phenyl)-isoxazol-5-ylmethyl ester Carbamic acid 3-(4-amino-phenyl)-isoxazol-5-ylmethyl ester was synthesized in the same manners as in Examples 74.1, 74.2, 74.3, and 74.5 in Example 74.

[566]

[567] 76.2 Synthesis of carbamic acid 3-[4-(l-phenyl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[568] An experiment was performed using the above-obtained carbamic acid 3-(4-amino-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.64 mmol) as a starting material and 4-fluorobenzaldehyde (82 μΑ, 0.77 mmol) in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(4-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester.

[569] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(m, 2Η), 7.1(t, 2Η), 6.7(d, 2Η), 6.5(s, Example 77: Carbamic acid 3-[4-(3-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[572]

[573] The compound was synthesized using 3-fluorobenzaldéhyde in the same manner as in Example 76.

[574] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(m, 2Η), 7.1(m, 2Η), 6.7(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.9(brs, 2Η), 4.4(s, 2Η)

[575] Example 78: Carbamic acid 3-[4-(2-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[576]

[577] The compound was synthesized using 2-fluorobenzaldehyde in the same manner as in Example 76.

[578] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(m, 2Η), 7.1(m, 2Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.9(brs, 2Η), 4.4(s, 2Η)

[579]

[580] Example 79: Carbamic acid 3-[4-(2,6-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[581]

[582] The compound was synthesized using 2,6-difluorobenzaldehyde in the same manner as in Example 76.

[583] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.2(m, 2Η), 6.9(t, 1Η), 6.8(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.5(s, 2Η)

[584]

[585] Example 80: Carbamic acid 3-[4-(2,3-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[586]

[587] The compound was synthesized using 2,3-difluorobenzaldehyde in the same manner as in Example 76.

[588] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.1(m, 3Η), 6.7(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.5(s, 2Η)

[589]

[590] Example 81 : Carbamic acid 3-[4-(2,4-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[591]

[592] The compound was synthesized using 2,4-difluorobenzaldehyde in the same manner as in Example 76.

[595] Example 82: Carbamic acid 3-[4-(3,5-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[596]

[597] The compound was synthesized using 3,5-difluorobenzaldehyde in the same manner as in Example 76.

[598] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 6.9(d, 2Η), 6.7(t, 1Η), 6.6(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.4(s, 2Η)

[599]

[600] Example 83: Carbamic acid 3-[4-(2,5-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[601]

[602] The compound was synthesized using 2,5-difluorobenzaldehyde in the same manner as in Example 76.

[603] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.1(m, 2Η), 7.0(m, 1Η), 6.7(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.5(s, 2Η)

[604] Example 84: Carbamic acid 3-[4-(3,4-difluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[605]

[606] The compound was synthesized using 3,4-difluorobenzaldehyde in the same manner as in Example 76.

[607] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.2(m, 3Η), 6.7(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.4(s, 2Η)

[608]

[609] Example 85: Carbamic acid 3-[4-(4-chloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[610]

[611] The compound was synthesized using 4-chlorobenzaldehyde in the same manner as in Example 76.

[612] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(d, 4Η), 6.6(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.3(s, 2Η)

[613]

[614] Example 86: Carbamic acid 3-[4-(2-chloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[615]

[616] The compound was synthesized using 2-chlorobenzaldehyde in the same manner as in Example 76.

[617] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.4(m, 2Η), 7.2(m, 2Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.5(s, 2Η)

[618]

[619] Example 87 : Carbamic acid 3-[4-(3-chloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[620]

[621] The compound was synthesized using 3-chlorobenzaldéhyde in the same manner as in Example 76.

[622] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.4(s, 1Η), 7.2(m, 3Η), 6.5(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.4(s, 2Η)

[623]

[624] Example 88: Synthesis of carbamic acid 3-[4-(2,3-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[625]

[626] The compound was synthesized using 2,3-dichlorobenzaldehyde in the same manner as in Example 76.

[627] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.4(d, 1Η), 7.3(d, 1Η), 7.2(t, 1Η), 6.6(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.5(s, 2Η)

[628]

[629] Example 89: Synthesis of carbamic acid 3-[4-(2,4-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[630]

[631] The compound was synthesized using 2,4-dichlorobenzaldehyde in the same manner as in Example 76.

[632] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.4(d, 1Η), 7.3(s, 1Η), 7.2(t, 1Η), 6.6(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.5(s, 2Η)

[633]

[634] Example 90: Synthesis of carbamic acid 3-[4-(2,5-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[635]

[636] The compound was synthesized using 2,5-dichlorobenzaldehyde in the same manner as in Example 76.

[637] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.4(s, 1Η), 7.3(d, 1Η), 7.2(d, 1Η), 6.6(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.4(s, 2Η)

[638]

[639] Example 91: Synthesis of carbamic acid 3-[4-(2,6-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[641] The compound was synthesized using 2,6-dichlorobenzaldehyde in the same manner as in Example 76.

[642] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.4(m, 2Η), 7.2(d, 1Η), 6.8(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.6(s, 2Η)

[643]

[644] Example 92: Synthesis of carbamic acid 3-[4-(3,4-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[645]

[646] The compound was synthesized using 3,4-dichlorobenzaldehyde in the same manner as in Example 76.

[647] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.45(s, 1Η), 7.4(d, 1Η), 7.2(d, 1Η), 6.6(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.4(s, 2Η)

[648]

[649] Example 93: Synthesis of carbamic acid 3-[4-(3,5-dichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[650]

[651] The compound was synthesized using 3,5-dichlorobenzaldehyde in the same manner as in Example 76.

[652] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.3(s, 3Η), 6.7(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.4(s, 2Η)

[653]

[654] Example 94: Synthesis of carbamic acid 3-[4-(2,3,5-trichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[655]

[656] The compound was synthesized using 2,3,5-trichlorobenzaldehyde in the same manner as in Example 76.

[657] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.4(s, 1Η), 7.3(s, 1Η), 6.6(d, 2Η), 6.55(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.5(s, 2Η)

[658]

[659] Example 95: Synthesis of carbamic acid 3-[4-(2,3,6-trichloro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[660]

[661] The compound was synthesized using 2,3,6-trichlorobenzaldehyde in the same manner as in Example 76.

[662] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.4(d, 1Η), 7.3(d, 1Η), 6.8(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.7(s, 2Η)

[663]

[664] Example 96: Carbamic acid 3-[4-(3-trifluoromethyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[665]

[666] The compound was synthesized using 2-(trifluoromethyl)benzaldehyde in the same manner as in Example 76.

[667] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.5(m, 4Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.9(brs, 2Η), 4.5(s, 2Η)

[668]

[669] Example 97 : Carbamic acid 3-[4-(4-trifluoromethyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[670]

[671] The compound was synthesized using 4-(trifluoromethyl)benzaldehyde in the same manner as in Example 76.

[672] 1H-NMR (CDC13, 200ΜΗζ) δ 8.0(d, 4Η), 7.8(d, 2Η), 6.9(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.7(brs, 2Η), 4.5(s, 2Η)

[673]

[674] Example 98: Carbamic acid 3-[4-(3,5-bis-trifluoromethyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[675]

[676] The compound was synthesized using 3,5-bis-(trifluoromethyl)benzaldehyde in the same manner as in Example 76.

[677] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(m, 3Η), 7.7(d, 2Η), 6.7(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2H),4.1(s, 2Η)

[678]

[679] Example 99: Carbamic acid 3-[4-(2-methyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[680]

[681] The compound was synthesized using 2-methylbenzaldehyde in the same manner as in Example 76.

[682] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.2(m, 4Η), 6.9(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.3(s, 2Η), 2.4(s, 3Η)

[683]

[684] Example 100: Carbamic acid 3-[4-(4-methyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[685]

[686] The compound was synthesized using 4-methylbenzaldehyde in the same manner as in Example 76.

[687] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.2(m, 4Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, Example 101: Carbamic acid 3-[4-(3-methyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[690]

[691] The compound was synthesized using 3-methylbenzaldehyde in the same manner as in Example 76.

[692] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.2(m, 4Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.9(brs, 2Η), 4.4(s, 2Η), 2.4(s, 3Η)

[693]

[694] Example 102: Carbamic acid 3-[4-(4-isopropyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[695]

[696] The compound was synthesized using 4-isopropylbenzaldehyde in the same manner as in Example 76.

[697] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.2(m, 4Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.7(brs, 2Η), 4.3(s, 2Η), 1.5(brs, 1Η), 1.2(s, 6Η)

[698]

[699] Example 103: Carbamic acid 3-[4-(2,4-dimethyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[700]

[701] The compound was synthesized using 2,4-dimethylbenzaldehyde in the same manner as in Example 76.

[702] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.1(m, 3Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 5.0(brs, 2Η), 4.3(s, 2Η), 2.4(s, 6Η)

[703]

[704] Example 104: Carbamic acid 3-[4-(2-methoxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[705]

[706] The compound was synthesized using 2-methoxybenzaldehyde in the same manner as in Example 76.

[707] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(d, 2Η), 7.6(t, 2Η), 7.0(m, 2Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.7(brs, 2Η), 4.4(s, 2Η), 3.9(s, 3Η)

[708]

[709] Example 105: Carbamic acid 3-[4-(3-methoxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[710]

[711] The compound was synthesized using 3-methoxybenzaldehyde in the same manner as in Example 76.

[712] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.5(d, 1Η), 7.3(m, 2Η), 6.9(d, 1Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.4(s, 2Η), 3.9(s, 3Η)

[713]

[714] Example 106: Carbamic acid 3-[4-(4-methoxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[715]

[716] The compound was synthesized using 4-methoxybenzaldehyde in the same manner as in Example 76.

[717] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(m, 2Η), 6.9(m, 4Η), 6.5(d, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.3(s, 2Η), 4.0(s, 3Η)

[718]

[719] Example 107: Synthesis of carbamic acid 3-[4-(4-phenoxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[720]

[721] The compound was synthesized using 4-phenoxybenzaldehyde in the same manner as in Example 76.

[722] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(dd, 4Η), 7.1(m, 5Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.4(s, 2Η)

[723]

[724] Example 108: Synthesis of carbamic acid 3-[4-(4-benzyloxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[725]

[726] The compound was synthesized using 4-benzyloxybenzaldehyde in the same manner as in Example 76.

[727] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.4~7.2(m, 7Η), 6.9(d, 2Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 4.8(brs, 2Η), 4.3(s, 2Η)

[728]

[729] Example 109: Synthesis of carbamic acid 3-{4-[(5-phenyl-isoxazol-3-ylmethyl)-amino]-phenyl}-isoxazol-5-ylmethyl ester

[731] The compound was synthesized using 5-phenyl-isoxazol-3-carbaldehyde in the same manner as in Example 76.

[732] 1H-NMR (CDC13, 500ΜΗζ) δ 7.8(d, 2Η), 7.7(d, 1Η), 7.5(m, 3Η), 6.8(d, 2Η), 6.75(d, 1Η), 6.55(s, 1Η), 6.5(s, 1Η), 5.2(s, 2Η), 54.8(brs, 2Η), 4.5(s, 2Η)

[733]

[734] Example 110: Synthesis of carbamic acid

3- {4-[(thiophen-2-ylmethyl)-amino]-phenyl}-isoxazol-5-ylmethyl ester

[736] The compound was synthesized using thiophene-3-carbaldehyde in the same manner as in Example 76.

[737] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.25(d, 1Η), 7.05(s, 1Η), 7.0(d, 1Η), 6.7(d, 2Η), 6.55(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.6(s, 2Η)

[738]

[739] Example 111: Synthesis of carbamic acid

3- {4-[(furan-3-ylmethyl)-amino]-phenyl}-isoxazol-5-ylmethyl ester

[740]

[741] The compound was synthesized using 3-furaldehyde in the same manner as in Example 76.

[742] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.4(d, 2Η), 6.7(d, 2Η), 6.5(s, 1Η), 6.4(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.2(s, 2Η)

[743]

[744] Example 112: Synthesis of carbamic acid 3-{4-[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-phenyl]-isoxazol-5-ylmethyl ester

[746] The compound was synthesized using 3,5-dimethyl-isoxazolecarbaldehyde in the same manner as in Example 76.

[747] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.5(s, 2Η), 2.4(s, 3Η), 2.2(s, 3Η)

[748]

[749] Example 113: Synthesis of carbamic acid 3-[4-(3,5-di-tert-butyl-4-hydroxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[751] The compound was synthesized using 3,5-di-t-butyl-4-hydroxybenzaldehyde in the same manner as in Example 76.

[752] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.2(s, 2Η), 6.7(d, 2Η), 6.57(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.2(s, 2Η), 1.45(s, 18Η)

[753]

[754] Example 114: Synthesis of carbamic acid 3-[4-(3,5-dimethyl-4-hydroxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[756] The compound was synthesized using 3,5-di-methyl-4-hydroxybenzaldehyde in the same manner as in Example 76.

[757] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.0(s, 2Η), 6.7(d, 2Η), 6.57(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.2(s, 2Η), 2.2(s, 6Η)

[758]

[759] Example 115: Synthesis of carbamic acid 3-[4-(3,5-di-tert-butyl-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[760]

[761] The compound was synthesized using 3,5-di-t-butyl-benzaldehyde in the same manner as in Example 76.

[762] 1H-NMR (CDC13, 500ΜΗζ) δ 7.6(d, 2Η), 7.4(s, 1Η), 7.2(s, 2Η), 6.7(d, 2Η), 6.57(s, 1Η), 5.2(s, 2Η), 4.8(brs, 2Η), 4.3(s, 2Η), 1.3(s, 18Η)

[763]

[764] Example 116: Synthesis of carbamic acid 3-[4-(3,4,5-trihydroxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester

[765]

[766] [3-(4-amino-phenyl)-isoxazol-5-yl]-methanol was reacted with 3,4,5-trihydroxybenzaldehyde in a Μ℮ΟΗ solvent to form an imine, and then Si-BH3CN was added to the reaction solution and stirred at room temperature for 48 hours. A solution obtained by filtration of the reactant was distilled off under reduced pressure and column chromatography was used to obtain carbamic acid 3-[4-(3,4,5-trihydroxy-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.

[767] 1H-NMR (CD30D, 200ΜΗζ) δ 7.5(d, 2Η), 6.65(s, 1Η), 6.6(d, 2Η), 6.4(s, 2Η), 5.2(s, 2Η), 4.2(s, 2Η)

[768]

[769] Example 117: Synthesis of carbamic acid

1- [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-ethyl ester

[770]

[771] The compound was synthesized using 3-butyn-2-ol instead of propargyl alcohol in the same manner as in Example 1.

[772] 1H-NMR (CD30D, 200ΜΗζ) δ 7.6(d, 2Η), 7.3(m, 5Η), 7.0(d, 2Η), 6.4(s, 1Η), 5.8(q, 1Η), 5.0(s, 2Η), 1.5(d, 3Η)

[773]

[774] Example 118: Synthesis of carbamic acid

2- [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-ethyl ester

[775]

[776] The compound was synthesized using 3-butyn-l-ol instead of propargyl alcohol in the same manner as in Example 1.

[777] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.1(d, 2Η), 6.35(s, 1Η), 5.1(s, 2Η), 4.6(brs, 2Η), 4.4(t, 2Η), 3.1(t, 2Η)

[778]

[779] Example 119: [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-prop-2-ynyl-amine 119.1 Synthesis of 3-(4-benzyloxy-phenyl)-isoxazol-5-carbaldehyde

[783] [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (1.0 g, 3.5 mmol) was dissolved in 60 mi of DMSO/methylene chloride (1:2), to which solution were added dropwise sulfur trioxide-pyridine complex (1.6 g, 10.5 mmol) and triethylamine(2.44 mi, 17.5 mmol), and stirred at 0°C for about 2 hours. The completion of the reaction was confirmed by TLC, and 10 mf of NH4C1 was added to the solution. The residual solvent was distilled under reduced pressure, and then extracted three times with water and methylene chloride. An organic layer was washed with saline solution. The obtained organic layer was distilled under reduced pressure, followed by column chromatography (ethyl acetate/Hexane = 1:2) to obtain 3-(4-benzyloxy-phenyl)-isoxazol-5-carbaldehyde as a desired solid compound.

[784]

[785] 119.2 Synthesis of [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-prop-2-ynyl-amine 3-(4-benzyloxy-phenyl)-isoxazol-5-carbaldehyde (150 mg, 0.53 mmol) andpropargyl amine (51 /if, 0.8 mmol) were dissolved in Μ℮ΟΗ and stirred at room temperature for about 2 hours. The production of an imine was confirmed by TLC, NaBH3CN (50 mg, 0.8 mmol) was placed to the mixture at 0°C, the temperature was increased to room temperature, and the mixture was stirred for 12 hours. The Μ℮ΟΗ was distilled off under reduced pressure and 10 mf of a NaHC03 aqueous solution was added to the mixture, followed by extraction three times with water and ethyl acetate. The obtained organic layer was distilled under reduced pressure, followed by column chromatography to obtain 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-prop-2-ynyl-amine as a desired solid compound.

[787] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.1(d, 2Η), 6.5(s, 1Η), 5.1(s, 2Η), 4.1(s, 2Η), 3.5(s, 2Η), 2.3(m, 1Η)

[788]

[789] Example 120: Imidazole-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[790]

[791] 120.1 Synthesis of 3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol

[792] [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol was synthesized in the same manners as in Examples 1.1 and 1.2.

[793]

[794] 120.2 Imidazole-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (500 mg, 1.77 mmol) was dissolved in 10 imi of THF, to which solution was added l,l'-carbonyldiimidazole (576 mg, 3.55 mmol), and stirred at room temperature for 1 hour. The THF was distilled off under reduced pressure and extracted three times with water and ethyl acetate. An obtained organic layer was distilled under reduced pressure and recrystallized from hexane/ethyl acetate (1/4) conditions to obtain imidazole-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a desired solid compound.

[796] 1H-NMR (CDC13, 200ΜΗζ) δ 8.3(brs, 1Η), 7.7(d, 2Η), 7.5(m, 6Η), 7.1(d, 3Η), 6.7(s, 1Η), 5.6(s, 2Η), 5.1(s, 2Η)

[797]

[798] Example 121: Synthesis of methyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[799]

[800] 0.5 g of the compound [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol in Example 1 was dissolved in 10 mi of THF, to which solution was added 0.49 g (1.7 equivalents) of l,l'-carbonyldiimidazole. The consumption of all the reactants was confirmed by TLC, and 2 equivalents of methyl amine were added to the reaction solution. 2 hours later, the solvent was distilled off under reduced pressure, 50 mi of a 1N-HC1 aqueous solution was placed in the reactants, and the mixture was extracted three times with 30 mi of ethyl acetate. An obtained organic layer was distilled under reduced pressure, followed by column chromatography to obtain methyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a desired compound.

[801] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 4.8(brs, 1Η), 2.8(d, 3Η)

[802]

[803] Example 122: Synthesis of dimethyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[804]

[805] The compound was synthesized using diethyl amine in the same manner as in Example 121.

[806] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.0(s, 6Η)

[807]

[808] Example 123: Synthesis of diethyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[809]

[810] The compound was synthesized using diethyl amine in the same manner as in Example 121.

[811] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.3(q, 4Η), 1.2(t, 6Η)

[813] Example 124: Synthesis of ethyl-methyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[814]

[815] The compound was synthesized using N-ethylmethylamine amine in the same manner as in Example 121.

[816] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.3(q, 2Η), 2.9(s, 3Η), 1.15(t, 3Η)

[817]

[818] Example 125: Synthesis of pyrrolidine-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[819]

[820] The compound was synthesized using pyrrolidine in the same manner as in Example 121.

[821] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.4(m, 4Η), 1.9(m, 2Η), 1.6(m, 2Η)

[822]

[823] Example 126: Synthesis of piperidine-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[824]

[825] The compound was synthesized using piperidine in the same manner as in Example 121.

[826] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.5(m, 4Η), 1.6(m, 6Η)

[827]

[828] Example 127: Synthesis of morpholine-4-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[829]

[830] The compound was synthesized using morpholine in the same manner as in Example 121.

[831] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.7(m, 2Η), 3.5(m, 4Η), 1.6(m, 2Η)

[832]

[833] Example 128: Piperazine-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[834]

[835] N-boc-piperazin-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester was obtained using N-boc piperazine in the same manner as in Example 121. The compound was dissolved in methylene chloride (5 mf ), to which solution was added 5 ηΐ/ of 0.2 N HC1 (in ether), and stirred for 3 hours or more. The thus-obtained white solid compound was filtered to obtain piperazine-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester hydrochloride.

[836] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 4Η), 7.0(d, 2Η), 6.6(d, 1Η), 5.3(s, 2Η), 5.1(s, 2Η), 3.9(brs, 4Η), 3.2(brs, 4H)-NMR solvent confirmation

[837]

[838] Example 129: Synthesis of N',N'-dimethyl-hydrazinecarboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[839]

[840] The compound was synthesized using l,l'-dimethylhydrazine in the same manner as in Example 121.

[841] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.0(s, 6Η)

[842]

[843] Example 130: (3-amino-propyl)-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[844]

[845] [3-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethoxycarbonylamino]-propyl]-carbamic acid tert-butyl ester was synthesized using t-butyl N-(3-aminopropyl)carbamate in the same manner as in Example 121, and then a boc-deprotection of the compound was performed to synthesize (3-amino-propyl)-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a desired compound.

[846] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(m, 2Η), 7.4(m, 5Η), 7.1(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.2(m, 4Η), 1.7(m, 2Η)

[847]

[848] Example 131: (2-amino-ethyl)-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[849]

[850] The compound was synthesized using t-butyl N-(2-aminoethyl)carbamate in the same manner as in Example 130.

[851] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.7(brs, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.3(brs, 4Η)

[852]

[853] Example 132: Synthesis of piperidine- 1-yl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[854]

[855] The compound was synthesized using 1-aminopiperidine in the same manner as in Example 121.

[856] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.5(m, 4Η), 1.6(m, 6Η)

[857]

[858] Example 133: Synthesis of (4-methyl-piperazin-l-yl)-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[859]

[860] The compound was synthesized using 1-amino 4-methylpiperazine in the same manner as in Example 121.

[861] 1H-NMR (CDC13, 200ΜΗζ) δ 7.8(d, 2Η), 7.4(m, 5Η), 7.1(d, 2Η), 6.6(s, 1Η), 5.3(s, 2Η), 5.1(s, 2Η), 3.6(m, 4Η), 2.5(m, 4Η), 2.4(s, 3Η)

[862]

[863] Example 134: 4-methyl-piperazin-l-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[864]

[865] An experiment was performed using 1-methylpiperazine in the same manner as in Example 121.

[866] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.6(s, 1Η), 5.3(brs, 2Η), 5.2(s, 2Η), 4.2(brs, 2Η), 3.8(brs, 2Η), 3.4(brs, 2Η), 2.8(s, 3Η)

[867]

[868] Example 135: Piperidine-4-yl-carbamic acid

3- (4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[869]

[870] An experiment was performed using 4-amino-1-boc-piperidine in the same manner as in Example 130.

[871] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.3(m, 5Η), 7.0(d, 2Η), 6.5(s, 1Η), 5.1(s, 2Η), 5.0(s, 2Η), 3.6(brs, 2Η), 2.9(brs, 2Η), 2.1(brs, 2Η), 1.8(brs, 2Η)

[872]

[873] Example 136:

4- [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethoxycarbonyl] - [ 1,4]diazepan-1 -ium chloride

[874]

[875] An experiment was performed using 1-boc-homopiperazine in the same manner as in Example 130.

[876] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 4.4(s, 2Η), 3.6(m, 4Η), 2.9(m, 4Η), 1.8(m, 2Η)

[877]

[878] Example 137: l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-piperidin-4-ol

[881] 137.1 Synthesis of methanesulfonic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[882] [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (3.0 g, 10.6 mmol) was dissolved in methylene chloride (50 mi, 0.2 Μ), to which solution were added dropwise MsCl(1.23 mi, 15.9 mmol) and triethylamine (2.23 mi, 16 mmol-), and a reaction was performed at room temperature for 4 hours. The completion of the reaction was confirmed by liquid chromatography, 5 mi of water was added to the mixture, and the resulting solution was extracted with water and methylene chloride. The organic solvent layer was distilled under reduced pressure to obtain a crude solid compound.

This was recrystallized from hexane: ethyl acetate (5:1) to obtain methanesulfonic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a white solid compound.

[883]

[884] 137.2 Synthesis of l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-piperidin-4-ol Methanesulfonic acid-3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.42 mmol), 4-hydroxypiperidine (64 mg, 0.63 mmol), potassium carbonate (87 mg, 0.63 mmol), and TBAI (96 mg, 0.26 mmol) were placed in 10 mf of DMF and stirred at room temperature overnight. The completion of the reaction was confirmed by LC, and then a crude solid compound obtained from distillation of the DMF under reduced pressure was extracted with ethyl acetate and water. The ethyl acetate was distilled off under reduced pressure to obtain a white solid compound. The compound was recrystallized from methylene chloride: Μ℮ΟΗ (9:1) to obtain l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-piperidin-4-ol as a white solid compound.

[886] 1H-NMR (CDC13, 200ΜΗζ) δ 7.65(d, 2Η), 7.35(m, 5Η), 6.94(d, 2Η), 6.53(d.2H), 5.38(s, 1Η), 5.19(s, 2Η), 4.84(brs, 2Η), 1.67(s, 3Η)

[887]

[888] Example 138: Carbamic acid

1 -[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-piperidin-4-yl ester

[889]

[890] An experiment was performed using the compound in Example 137 as a starting material in the same manner as in Example 74.5.

[891] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.5(s, 1Η), 5.1(s, 2Η), 4.6(brs, 2Η), 3.8(s, 2Η), 2.8(brs, 2Η), 2.4(brs, 2Η), 2.0(brs, 2Η), 1.8(brs, 2Η)

[893] Example 139: 3-(4-benzyloxy-phenyl)-5-imidazol-l-ylmethyl-isoxazole

[894]

[896] 139.1 Synthesis of methanesulfonic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester

[897] Methanesulfonic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester was synthesized in the same manner as in Example 137.1.

[898]

[899] 139.2 Synthesis of 3-(4-benzyloxy-phenyl)-5-imidazol-l-ylmethyl-isoxazole Methanesulfonic acid-3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (600 mg, 1.67 mmol), imidazole (170 mg, 2.50 mmol), potassium carbonate (460 mg, 3.34 mmol), and TBAI (200 mg, 0.54 mmol) were placed in 20 mf of DMF and stirred for 2 hours. The completion of the reaction was confirmed by LC, and then a crude solid compound obtained from distillation of the DMF under reduced pressure was extracted with ethyl acetate and water. The ethyl acetate was distilled off under reduced pressure to obtain a white solid compound. The compound was purified by silica chromatography (methylene chloride: Μ℮ΟΗ = 20:1) to obtain 3-(4-benzyloxy-phenyl)-5-imidazol-l-ylmethyl-isoxazole as a white solid compound.

[901] 1H-NMR (DMSO, 200ΜΗζ) δ 9.36(s, 1Η), 7.82(m, 4Η), 7.40(m, 5Η), 7.12(t, 3Η), 5.80(s, 2Η), 5.17(s, 2Η)

[902]

[903] Example 140: 3-(4-benzyloxy-phenyl)-5-(2-methyl-imidazol-l-ylmethyl)-isoxazole

[905] An experiment was performed using 2-methylimidazole in the same manner as in Example 139.

[906] 1H-NMR (CDC13, 200ΜΗζ) δ 7.67(d, 2Η), 7.38(m, 5Η), 7.01(m, 4Η), 6.26(s, 1Η), 5.16(s, 2Η), 5.08(s, 2Η), 2.45(s, 3Η)

[907]

[908] Example 141: 3-(4-benzyloxy-phenyl)-5-(4-methyl-imidazol-l-ylmethyl)-isoxazole

[910] An experiment was performed using 4-methylimidazole in the same manner as in Example 139.

[911] 1H-NMR (DMSO, 200ΜΗζ) δ 9.25(s, 1Η), 7.80(d, 2Η), 7.56(m, 6Η), 7.12(t, 3Η), 5.75(s, 2Η), 5.17(s, 2Η), 2.28(s, 3Η)

[912]

[913] Example 142: 3-[4-(3-fluoro-benzyloxy)-phenyl]-5-imidazol-l-ylmethyl-isoxazole

[915]

[916] 142.1 Synthesis of 4-(5-imidazol-l-ylmethyl-isoxazol-3-yl)-phenol

[917] 3-(4-benzyloxy-phenyl)-5-imidazol-l-ylmethyl-isoxazol was obtained in the same manners as in Examples 139-1 and 139-2 in Example 139. The compound was dissolved in Μ℮ΟΗ, and a hydrogenation of the resulting solution was performed using 10 wt% Pd/C to synthesize 4-(5-imidazol-l-ylmethyl-isoxazol-3-yl)-phenol as a debenzyl compound.

[918]

[919] 142.2 Synthesis of

3 - [4- (3 -fluoro-benzyloxy ) -phenyl] - 5 -imidazol-1 -ylmethyl-isoxazole

[920] 4-(5-imidazol-l-ylmethyl-isoxazol-3-yl)-phenol (150 mg, 0.62 mmol) and potassium carbonate (172 mg, 1.25 mmol) were placed in 10 mi of DMF, to which solution was added dropwise 3-fluorobenzyl bromide (89 μΑ, 0.75 mmol), and the mixture was stirred at room temperature for 4 hours. The completion of the reaction was confirmed by LC, and then DMF was distilled off under reduced pressure. A crude solid compound was extracted with ethyl acetate and water, and the organic solvent was distilled off under reduced pressure to obtain a white solid compound. The compound was purified by silica chromatography (methylene chloride: Μ℮ΟΗ = 20:1) to obtain 3-[4-(3-fluoro-benzyloxy)-phenyl]-5-imidazol-l-ylmethyl-isoxazole as a desired white solid compound.

[921] 1H-NMR (DMSO, 200ΜΗζ) δ 9.37(s, 1Η), 7.85(m, 4Η), 7.33(m, 7Η), 5.80(s, 2Η), 5.21(s, 2Η)

[922]

[923] Example 143:

3-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-imidazol-l-ylmethyl-isoxazole

[924]

[925] An experiment was performed using 2,6-difluorobenzyl bromide in the same manner as in Example 142.

[926] 1H-NMR (DMSO, 200ΜΗζ) δ 9.32(s, 1Η), 7.85(q, 4Η), 7.56(m, 1Η), 7.20(m, 5Η), 5.79(s, 2Η), 5.19(s, 2Η)

[927]

[928] Example 144: l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-lH-[l,2,4]triazole

[930] An experiment was performed using 1,2,4-triazole in the same manner as in Example 139.

[931] 1H-NMR (CDC13, 200ΜΗζ) δ 8.26(s, 1Η), 8.02(s, 1Η), 7.68(d, 2Η), 7.36(m, 5Η), 7.02(d, 2Η), 6.50(s, 1Η), 5.50(s, 2Η), 5.09(s, 2Η)

[932]

[933] Example 145: l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-lH-[l,2,3]triazole

[935] An experiment was performed using 1,2,3-triazole in the same manner as in Example Example 146: 2-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-2H-tetrazole

[939]

[940] A separation of the upper spot in the two compounds obtained by reaction using tetrazole in the same manner as in Example 139 was performed by column chromatography to obtain 2-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-2H-tetrazole as a desired compound.

[941] 1H-NMR (CDC13, 200ΜΗζ) δ 8.6(s, 1Η), 7.7(d, 2Η), 7.5(m, 5Η), 7.1(d, 2Η), 6.6(s, 1Η), 6.0(s, 2Η), 5.2(s, 2Η), 5.11(s, 2Η)

[942]

[943] Example 147: l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-2H-tetrazole

[944]

[945] The lower compound in Example 146 was separated by column chromatography to obtain l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-2H-tetrazole as a desired compound.

[946] 1H-NMR (CDC13, 200ΜΗζ) δ 8.6(s, 1Η), 7.7(d, 2Η), 6.6(s, 1Η), 5.8(s, 2Η), 5.1(s, 2Η), 5.11 (s, 2Η)

[947]

[948] Example 148: 3-(4-benzyloxy-phenyl)-5-pyrrolidin-l-ylmethyl-isoxazole

[949]

[950] An experiment was performed using pyrrolidine in the same manner as in Example 139.

[951] 1H-NMR (CDC13, 200ΜΗζ) δ 7.76(d, 2Η), 7.39(m, 5Η), 7.02(d, 2Η), 6.45(s, 1Η), 5.10(s, 2Η), 3.82(s, 2Η), 2.64(s, 4Η), 1.82(s, 4Η)

[952]

[953] Example 149: l-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-piperidine

[954]

[955] An experiment was performed using piperidine in the same manner as in Example 139.

[956] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.0(d, 2Η), 6.4(s, 1Η), 5.3(s, 2Η), 5.1(s, 2Η), 4.6(s, 2Η), 2.5(d, 4Η), 1.6(d, 4Η)

[957]

[958] Example 150: [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-dimethyl-amine

[960] An experiment was performed using dimethylamine in the same manner as in Example 139.

[961] 1H-NMR (CDC13, 200ΜΗζ) δ 7.76(ά, 2Η), 7.42(m, 5Η), 7.02(ά, 2Η), 6.45(s, 1Η), 5.1 l(s, 2Η), 3.66(s, 2Η), 2.34(s, 6Η)

[962]

[963] Example 151: [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-diethyl-amine

[964]

[965] An experiment was performed using diethylamine in the same manner as in Example 139.

[966] 1H-NMR (CDC13, 200ΜΗζ) δ 7.79(d, 2Η), 7.43(m, 5Η), 7.05(d, 2Η), 6.46(s, 1Η), 5.12(s, 2Η), 3.87(s, 2Η), 2.63(q, 4Η), 1.45(t, 6Η)

[967]

[968] Example 152: Synthesis of [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-urea

[970]

[971] 152.1 3-(4-benzyloxy-phenyl)-5-chloromethyl-isoxazole

[972] 0.3 g of [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol in Example 1 was dissolved in 10 mi of benzene, to which solution was added 0.15 mi (2 equivalents) of SOC12, and the mixture was refluxed for 4 hours.

3-(4-benzyloxy-phenyl)-5-chloromethyl-isoxazole obtained after drying and removal of the solvent under reduced pressure was used in the next reaction without further purification.

[973]

[974] 152.2 C-[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methylamine

[975] 0.13 g of 3-(4-benzyloxy-phenyl)-5-chloromethyl-isoxazole was dissolved in 10 mi of DMF, to which solution was added 85 mg (3 equivalents) of NaN3, and the mixture was stirred for 12 hours. The solvent was dried off under reduced pressure and removed, followed by column chromatography to obtain 5-azidomethyl-3-(4-benzyloxy-phenyl)-isoxazole. A reduction of the compound was performed under NaBH4 conditions to obtain C[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methylamine as a desired compound.

[976]

[977] 152.3 [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-urea

[978] C-[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methylamine was dissolved in 10 mi of THF, to which solution was added 1.7 equivalents of 1,1-carbonyldiimidazole. The consumption of all the reactants was confirmed by TLC, followed by addition of 2 equivalents of aqueous ammonia to the reaction solution. 2 hours later, the solvent was distilled off under reduced pressure and 50 mi of 1N-HC1 aqueous solution was added to the reactants, followed by extraction three times with 30 mi of ethyl acetate. The obtained organic layer was distilled under reduced pressure, followed by column chromatography to obtain [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-urea as a desired compound.

[979] 1H-NMR (CD30D, 200ΜΗζ) δ 7.7 (d, 2Η), 7.4 (m, 5Η), 7.1(d, 2Η), 6.6(s, 1Η), 5.1(s, 2Η), 4.5(s, 2Η),2.63

[980]

[981] Example 153: N-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-guanidine

[982]

[983]

[984] 153.1 N-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-N,N'-di-BOC-guanidine 0.52 g of di-BOC-guanidine and 0.393 g of triphenylphosphine were dissolved in 5 mi of THF, to which solution was slowly added a solution of 0.281 g (1 mmol) of [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol dissolved in 5 mi of THF. The temperature of the reactants was reduced to 0°C, 0.3 mi of diisopropyl azodicarboxylate was slowly added to the solution, and the resulting mixture was stirred at room temperature for another 3 hours. Subsequently, the reactants were distilled under reduced pressure to remove the solvent, followed by column chromatography to obtain Ν[3-(benzyloxy-phenyl)-isoxazol-5-ylmethyl]-N,N'-di-BOC-guanidine as a desired compound.

[986]

[987] 153.2 N-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-guanidine

[988] The compound Ν[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-N,N'-di-BOC-guanidine obtained above was dissolved in 10 mi of methylene chloride, to which solution was added 5 mi of trifluoroacetic acid, and the mixture was stirred at room temperature for 5 hours. The reactants were distilled under reduced pressure to remove the solvent and pH of the reactants was regulated to 8 with aqueous ammonia, followed by extraction three times with 20 mi of chloroform. The organic layer was dried and distilled under reduced pressure to obtain N-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-guanidine as a desired compound.

[989] 1H-NMR (CD30D, 200ΜΗζ) δ 7.8 (d, 2Η), 7.4 (m, 5Η), 7.1(d, 2Η), 6.8(s, 1Η), 5.2(s, 2Η), 4.6(s, 2Η)

[990]

[991] Example 154:

3-[4-(2,4-difluoro-benzyloxy)-phenyl]-5-imidazol-l-ylmethyl-isoxazole

[992]

[993] The compound was synthesized using 2,4-difluorobenzyl bromide in the same manner as in Example 142.

[996] Example 155:

5-imidazol-l-ylmethyl-3-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-isoxazole

[997]

[998] The compound was synthesized using 2,4,6-trifluorobenzyl bromide in the same manner as in Example 142.

[999] 1H-NMR (CDC13, 200ΜΗζ) δ 7.67(t, 3Η), 7.27(m, 4Η), 7.00(t, 2Η), 6.35(s, 1Η), 5.28(s, 2Η), 5.09(s, 2Η)

[1000]

[1001] Example 156: 3-[4-(4-fluoro-benzyloxy)-phenyl]-5-imidazol-l-ylmethyl-isoxazole

[1003] The compound was synthesized using 4-fluorobenzyl bromide in the same manner as in Example 142.

[1004] 1H-NMR (CDC13, 200ΜΗζ) δ 7.69(t, 3Η), 7.62(m, 1Η), 7.39(m, 2Η), 7.03(m, 6Η), 5.27(s, 2Η), 5.05(s, 2Η)

[1005]

[1006] Example 157: 3-[4-(4-chloro-benzyloxy)-phenyl]-5-imidazol-l-ylmethyl-isoxazole

[1008] The compound was synthesized using 4-chlorobenzyl bromide in the same manner as in Example 142.

[1009] 1H-NMR (CDC13, 200ΜΗζ) δ 7.66(t, 3Η), 7.62(m, 1Η), 7.36(m, 4Η), 7.14(s, 1Η), 7.03(d, 2Η), 5.28(s, 2Η), 5.07(s, 2Η)

[1010]

[1011] Example 158:

3 - [4- (4-fluoro-benzyloxy ) -phenyl] - 5 - (4-methyl-imidazol-1 -ylmethyl) -isoxazole

[1013] An experiment was performed in the same manner as in Example 139 to synthesize 4-[5-(4-methyl-imidazol-l-ylmethyl)-isoxazol-3-yl]-phenol as an intermediate, and then a synthesis was performed using 4-fluorobenzyl bromide in the same manner as in Example 142.

[1014] 1H-NMR (CDC13, 200ΜΗζ) δ 7.73(d, 2Η), 7.60(s, 1Η), 7.43(m, 2Η), 7.06(m, 4Η), 6.77(s, 1Η), 6.37(s, 1Η), 5.23(s, 2Η), 5.08(s, 2Η), 2.63(s, 3Η)

[1015]

[1016] Example 159:

3 - [4- (3 -fluoro-benzyloxy ) -phenyl] - 5 - (4-methyl-imidazol-1 -ylmethyl) -isoxazole

[1018] The compound was synthesized using 3-fluorobenzyl bromide in the same manner as in Example 158.

[1019] 1H-NMR (CDC13, 200ΜΗζ) δ 7.73(d, 2Η), 7.61(s, 1Η), 7.38(m, 2Η), 7.22(m, 4Η), 6.77(s, 1Η), 6.37(s, 1Η), 5.22(s, 2Η), 5.1 l(s, 2Η), 2.26(s, 3Η)

[1020]

[1021] Example 160:

3-[4-(2,4-difluoro-benzyloxy)-phenyl]-5-(4-methyl-imidazol-l-ylmethyl)-isoxazole

[1023] The compound was synthesized using 2,4-difluorobenzyl bromide in the same manner as in Example 158.

[1024] 1H-NMR (CDC13, 200ΜΗζ) δ 7.96(s, 1Η), 7.73(d, 2Η), 7.29(m, 1Η), 7.06(d, 2Η), 6.96(m, 2Η), 6.82(s, 2Η), 6.49(s, 2Η), 5.33(s, 2Η), 5.17(s, 2Η), 2.28(s, 3Η)

[1025]

[1026] Example 161: Carbamic acid 3-[4-(l-oxy-pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[1027]

[1028] 0.28 g of carbamic acid 3-[4-(pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester in Example 65 was dissolved in 10 mf of dichloromethane, to which solution was added 0.22 g of m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by TLC and 10 mf of water was added to the reactants to separate an organic layer. A crude material obtained after drying and distillation of the organic layer under reduced pressure was separated by column chromatography to synthesize carbamic acid 3-[4-(l-oxy-pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.

[1029] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 8.35(d, 1Η), 7.8(d, 2Η), 7.6(d, 1Η), 7.4(d, 2Η), 7.2(d, 2Η), 7.0(s, 1Η), 6.8(brs, 2Η), 5.3(s, 2Η), 5.1(s, 2Η)

[1030]

[1031] Example 162: 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-acetamide

[1033] The compound was synthesized using glycinamide instead of propargyl amine in the same manner as in Example 119.

[1034] 1H-NMR (CDC13, 200ΜΗζ) δ 7.75(d, 2Η), 7.42(m, 5Η), 7.05(d, 2Η), 6.96(brs, 1Η), 6.45(s, 1Η), 5.5(brs, 1Η), 5.17(s, 2Η), 4.0(s, 2Η), 3.39(s, 2Η)

[1035]

[1036] Example 163:

2- {[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl] -amino} -propionamide

[1037]

[1038] The compound was synthesized using alaninamide in the same manner as in Example 119.

[1039] 1H-NMR (CDC13, 200ΜΗζ) δ 7.75(d, 2Η), 7.42(m, 5Η), 7.04(d, 2Η), 6.99(brs, 1Η), 6.43(s, 1Η), 5.6(brs, 1Η), 5.13(s, 2Η), 3.96(s, 2Η), 3.3(q, 1Η), 1.38(d, 3Η)

[1040]

[1041] Example 164:

2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-2-methyl-propionamide

[1043] The compound was synthesized using 2-amino-2-methylpropionamide in the same manner as in Example 119.

[1044] 1H-NMR (CDC13, 200ΜΗζ) δ 7.75(d, 2Η), 7.43(m, 5Η), 7.2(brs, 1Η), 7.05(d, 2Η), 6.44(s, 1Η), 5.2(brs, 1Η), 5.14(s, 2Η), 3.9 (s, 2Η), 1.45(s, 6Η)

[1045]

[1046] Example 165: Synthesis of carbamic acid

1- [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-1-methyl-ethyl ester

[1047]

[1048] The compound was synthesized using 2-methyl-but-3-yn-2-ol instead of propargyl alcohol in the same manner as in Example 1.

[1049] 1H-NMR (CD30D, 200ΜΗζ) δ 7.75(d, 2Η), 7.45(m, 5Η), 7.0(d, 2Η), 6.4(s, 1Η), 5.12(s, 2Η), 4.6(brs, 2Η), 1.87(s, 6Η)

[1050]

[1051] Example 166: Carbamic acid

2- { [3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-propyl ester hydrochloride

[1053] The compound was synthesized using carbamic acid 2-amino-propyl ester in the same manner as in Example 119.

[1054] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 9.9(brs, 2Η), 7.8(d, 2Η), 7.44(m, 5Η), 7.2(d, 2Η), 6.7(s, 2Η), 5.17(s, 2Η), 4.5(s, 2Η), 4.17 (s, 2Η), 3.5(m, 1Η), 1.3 (s, 3Η)

[1055]

[1056] Example 167:

2- {[3 - (4-benzyloxy-phenyl) -isoxazol-5 -ylmethyl] - amino} - 3 -hydroxy-propionamide

[1058] The compound was synthesized using L-serinamide in the same manner as in Example 119.

[1059] 1H-NMR (CDC13, 200ΜΗζ) δ 7.72(d, 2Η), 7.4(m, 5Η), 7.1(d, 2Η), 6.46(s, 1Η), 5.1 (s, 2Η), 4.01(s, 2Η), 3.86(brs, 1Η), 3.4(m, 1Η)

[1060]

[1061] Example 168: 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-ethanol The compound was synthesized using 2-aminoethanol in the same manner as in Example 119.

[1064] 1H-NMR (CDC13, 200ΜΗζ) 7.75(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.44(s, 2Η), 5.13(s, 2Η), 4.0 (s, 2Η), 3.71(t, 2Η), 2.9 (t, 2Η)

[1065]

[1066] Example 169: 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-propan-l-ol

[1068] The compound was synthesized using 2-aminopropanol in the same manner as in Example 119.

[1069] 1H-NMR (CDC13, 200ΜΗζ) 7.75(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.45(s, 2Η), 5.13(s, 2Η), 4.0 (dd, 2Η), 3.6(dd, 1Η), 3.4(dd, 1Η), 2.9 (m, 1Η), 2.1(brs, 1Η), 1.1 (d, 3Η)

[1070]

[1071] Example 170: 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-butan-l-ol

[1073] The compound was synthesized using 2-aminobutanol in the same manner as in Example 119.

[1074] 1H-NMR (CDC13, 200ΜΗζ) 7.75(d, 2Η), 7.42(m, 5Η), 7.05(d, 2Η), 6.45(s, 2Η), 5.13(s, 2Η), 4.0 (dd, 2Η), 3.7(dd, 1Η), 3.4(dd, 1Η), 2.7 (m, 1Η), 1.5(m, 2Η), 0.95(t, 3Η)

[1075]

[1076] Example 171:

2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-2-methyl-propan-l-ol

[1078] The compound was synthesized using 2-amino2-methylpropanol in the same manner as in Example 119.

[1079] 1H-NMR (CDC13, 200ΜΗζ) 7.75(d, 2Η), 7.42(m, 5Η), 7.05(d, 2Η), 6.45(s, 2Η), 5.13(s, 2Η), 3.9 (s, 2Η), 3.4(s, 2Η), 1.16(s, 6Η)

[1080]

[1081] Example 172:

2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-3-methyl-butan-l-ol

[1083] The compound was synthesized using 2-amino3-methylbutanol in the same manner as in Example 119.

[1084] 1H-NMR (CDC13, 200ΜΗζ) 7.75(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.45(s, 2Η), 5.12(s, 2Η), 4.0 (dd, 2Η), 3.7(dd, 1Η), 3.4(dd, 1Η), 2.5 (m, 1Η), 2.2(brs, 1Η), 1.8(m, 1Η), 0.95(dd, 6Η)

[1086] Example 173:

2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino]-propan-l,3-diol

[1087]

[1088] The compound was synthesized using L-serinol in the same manner as in Example 119.

[1089] 1H-NMR (CDC13, 200ΜΗζ) 7.72(d, 2Η), 7.45(m, 5Η), 7.04(d, 2Η), 6.48(s, 2Η), 5.13(s, 2Η), 4.04 (dd, 2Η), 3.67(m, 4Η), 2.9 (m, 1Η), 2.2(brs, 1Η)

[1090]

[1091] Example 174:

[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-(2-methoxy-ethyl)-amine

[1092]

[1093] The compound was synthesized using 2-methoxyethalamine in the same manner as in Example 119.

[1094] 1H-NMR (CDC13, 200ΜΗζ) 7.75(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.44(s, 2Η), 5.12(s, 2Η), 4.0 (s, 2Η), 3.53(t, 2Η), 3.38(s, 3Η), 2.9 (t, 2Η)

[1095]

[1096] Example 175: Carbamic acid

1 - {3-[4-(pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-yl}-ethyl ester

[1097]

[1098] The compound was synthesized using carbamic acid

1- [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-ethyl ester of example 117 in the same manner as in Exmaple 10 by débenzylation following reaction with

2- bromomethylpyridine.

[1099]

[1100] 1H-NMR (CDC13, 200ΜΗζ) δ 8.63(d, 1Η), 7.74(d, 3Η), 7.5(d, 1Η), 7.2(d, 1Η), 7.1(d, 2Η), 6.5(s, 1Η), 6.0(q, 1Η), 5.3(s, 2Η), 4.8(brs, 2Η), 1.68(d, 3Η)

[1101]

[1102] Example 176: Allyl-[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amine

[1103]

[1104] A side product obtained after reaction in the same manner as in Example 119 was separated by column chromatography using a solvent of ethyl acetate:hexane (1:2) as a mobile phase to obtain a desired compound.

[1105] 1H-NMR (CDC13, 200ΜΗζ) δ 7.77(d, 2Η), 7.45(m, 5Η), 7.05(d, 2Η), 6.44(s, 1Η), 5.9(m, 1Η), 5.2(dd, 2Η), 5.1(s, 2Η), 3.9(s, 2Η), 3.35(d, 2Η)

[1106]

[1107] Example 177: Carbamic acid 2-{[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-amino}-ethyl ester

[1109] The compound was synthesized using carbamic acid 2-amino-ethyl ester in the same manner as in Example 119.

[1110] 1H-NMR (DMSO-d6, 200ΜΗζ) 9.83(brs, 2Η), 7.8 l(d, 2Η), 7.47(m, 5Η), 7.2(s, 1Η), 7.15(d, 2Η), 6.68(s, 2Η), 5.19(s, 2Η), 4.5 (t, 2Η), 4.23(t, 2Η)

[1111]

[1112] Example 178:

[3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl]-methyl-prop-2-ynyl-amine

[1113]

[1114] The compound was synthesized using N-methylpropargylamine in the same manner as in Example 139.

[1115] 1H-NMR (CDC13, 200ΜΗζ) δ 7.75(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.49(s, 1Η), 5.13(s, 2Η), 3.82(s, 2Η), 3.43(d, 2Η), 2.44(s, 3Η), 2.33(d, 1Η)

[1116]

[1117] Example 179:

3-(4-benzyloxy-phenyl)-5-(2-isopropyl-imidazol-l-ylmethyl)-isoxazole

[1118]

[1119] The compound was synthesized using 2-isopropylimidazole in the same manner as in Example 139.

[1120] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.05(m, 4Η), 6.2(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η), 3.0(m, 1Η), 1.3 (d, 6Η)

[1121]

[1122] Example 180: 3-(4-benzyloxy-phenyl)-5-(4-bromo-imidazol-l-ylmethyl)-isoxazole

[1124] The compound was synthesized using 4-bromoimidazole in the same manner as in Example 139.

[1125] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 6Η), 7.0(m, 3Η), 6.4(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η)

[1126]

[1127] Example 181:

3 - (4-benzyloxy-phenyl) -5 - (4,5 -dichloro-imidazol-1 -ylmethyl) -isoxazole

[1128]

[1129] An experiment was performed using 4,5-dichloroimidazole in the same manner as in Example 139.

[1130] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.5(m, 6Η), 7.0(m, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 5.1(s, 2Η)

[1131]

[1132] Example 182:

3-(4-benzyloxy-phenyl)-5-(2-methyl-4,5-dichloro-imidazol-l-ylmethyl)-isoxazole

[1134] An experiment was performed using 2-methyl-4,5-dichloroimidazole in the same manner as in Example 139.

[1135] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 6Η), 7.05(m, 2Η), 6.35(s, 1Η), 5.18(s, 2Η), 5.12(s, 2Η), 2.48(s, 3Η)

[1136]

[1137] Example 183: 3-(4-benzyloxy-phenyl)-5-(2-nitro-imidazol-l-ylmethyl)-isoxazole

[1139] An experiment was performed using 2-nitroimidazole in the same manner as in Example 139.

[1140] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.2(dd, 2Η), 7.05(m, 2Η), 6.6(s, 1Η), 5.78(s, 2Η), 5.12(s, 2Η)

[1141]

[1142] Example 184: 3-(4-benzyloxy-phenyl)-5-(4-phenyl-imidazol-l-ylmethyl)-isoxazole

[1144] An experiment was performed using 4-phenylimidazole in the same manner as in Example 139.

[1145] 1H-NMR (CDC13, 200ΜΗζ) δ 1.1 (m, 5Η), 7.4(m, 9Η), 7.2(dd, 2Η), 7.05(m, 2Η), 6.4(s, 1Η), 5.3(s, 2Η), 5.12(s, 2Η)

[1146]

[1147] Example 185: 3-(4-benzyloxy-phenyl)-5-(4-nitro-imidazol-l-ylmethyl)-isoxazole

[1149] An experiment was performed using 4-nitroimidazole in the same manner as in Example 139.

[1150] 1H-NMR (CDC13, 200ΜΗζ) δ 7.92(s, 1Η), 7.7(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.56(s, 1Η), 5.37(s, 2Η), 5.13(s, 2Η)

[1151]

[1152] Example 186:

3-(4-benzyloxy-phenyl)-5-(2-ethyl-4-methyl-imidazol-l-ylmethyl)-isoxazole

[1154] An experiment was performed using 2-ethyl-4-methylimidazole in the same manner as in Example 139.

[1155] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.64(s, 1Η), 6.23(s, 1Η), 5.12(s, 4Η), 2.7(q, 2Η), 2.22(s, 3h), 1.3(t, 3Η)

[1156]

[1157] Example 187: 3-(4-benzyloxy-phenyl)-5-(2-chloroimidazol-l-ylmethyl)-isoxazole

[1159] An experiment was performed using 2-chloroimidazole in the same manner as in Example 139.

[1160] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.05(m, 4Η), 6.4(s, 1Η), 5.26 (s, 2Η), 5.12(s, 2Η)

[1161]

[1162] Example 188: 3-(4-benzyloxy-phenyl)-5-(2-bromoimidazol-l-ylmethyl)-isoxazole

[1164] An experiment was performed using 2-bromoimidazole in the same manner as in Example 139.

[1165] 1H-NMR (CDC13, 200ΜΗζ) δ 7.71(d, 2Η), 7.4(m, 5Η), 7.1(m, 4Η), 6.38(s, 1Η), 5.26 (s, 2Η), 5.12(s, 2Η)

[1166]

[1167] Example 189:

3 - (4-benzyloxy-phenyl) -5 - (2-bromo-4,5 -dichloroimidazol-1 -ylmethyl) -isoxazole

[1169] An experiment was performed using 2-bromo-4,5-dichloroimidazole in the same manner as in Example 139.

[1170] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.43(s, 1Η), 5.3 (s, 2Η), 5.13(s, 2Η)

[1171]

[1172] Example 190:

3- (4-benzyloxy-phenyl)-5- (2,4,5-tribromo-imidazol-1 -ylmethyl)-isoxazole

[1173]

[1174] An experiment was performed using 2,4,5-tribromoimidazole in the same manner as in Example 139.

[1175] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7(d, 2Η), 7.4(m, 5Η), 7.05(d, 2Η), 6.41(s, 1Η), 5.35 (s, 2Η), 5.13(s, 2Η)

[1176]

[1177] Example 191: 3-(4-benzyloxy-phenyl)-5-(2-ethyl-imidazol-l-ylmethyl)-isoxazole

[1179] An experiment was performed using 2-ethylimidazole in the same manner as in Example 139.

[1180] 1H-NMR (CDC13, 200ΜΗζ) δ 7.69(d, 2Η), 7.38(m, 5Η), 7.02(m, 4Η), 6.241(s, 1Η), 5.19 (s, 2Η), 5.1 l(s, 2Η), 2.81(q, 2Η), 1.33(t, 3Η)

[1181]

[1182] Example 192:

2-[4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxymethyl]-l-methyl-pyridinium iodide

[1184] 2 ηΐ/ of iodomethane was added to 0.3 g of the compound carbamic acid

3- [4-(pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester in Example 65 and stirred at 80°C for 10 hours. A crude solid compound obtained after distillation of the solution under reduced pressure to remove an excess of Mel was recrystallized from ethyl acetate/hexane/methylene chloride to obtain

2- [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxymethyl]-l-methyl-pyridinium iodide as a desired compound.

[1185] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 9.1(d, 2Η), 8.63(t, 1Η), 8.26(d, 1Η), 8.14(t, 1Η), 7.9(d, 2Η), 7.36(d, 2Η), 7.06(s, 1Η), 6.8(brs, 1Η), 5.68 (s, 2Η), 5.14(s, 2Η), 4.36(s, 3Η)

[1186]

[1187] Example 193: Carbamic acid 3-(4-cyclopentylmethoxy-phenyl)-isoxazol-5-ylmethyl ester

[1188]

[1189] [3-(4-cyclopentylmethoxy-phenyl)-isoxazol-5-yl]-methanol was synthesized using 4- (5-hydroxymethyl-isoxazol-3-yl)-phenol and toluene-4-sulfonic acid cyclopentylmethyl ester in the same manner as in Example 10, and then a carbamoylation of the compound was performed to obtain carbamic acid

3- (4-cyclopentylmethoxy-phenyl)-isoxazol-5-ylmethyl ester as a desired compound.

[1190] 1H-NMR (CdC13, 200ΜΗζ) δ 7.7(d, 2Η), 6.95(d, 2Η), 6.6(s, 1Η), 5.25 (s, 2Η), 4.8(brs, 2Η), 3.88(d, 2Η), 2.4(m, 1Η), 1.87(m, 2Η), 1.63(m, 4Η), 1.35(m, 2Η)

[1191]

[1192] Example 194: Carbamic acid 3-[4-(benzyl-ethyl-amino)-phenyl]-isoxazol-5-ylmethyl ester

[1193]

[1194] An experiment was performed using carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester in Example 74 as a starting material and acetaldehyde in the same manner as in Example 74.4 to obtain carbamic acid 3 - [4- (benzyl-ethyl- amino)-phenyl] -isoxazol- 5 -ylmethyl ester.

[1195] 1H-NMR (CDC13, 200ΜΗζ) δ 7.63(d, 2Η), 7.3(m, 5Η), 6.7(d, 2Η), 6.5(s, 1Η), 5.2(s, 2Η), 4.9(brs, 2Η), 4.6(s, 2Η), 3.6(q, 2Η), 1.25(t, 3Η)

[1196]

[1197] Example 195: Carbamic acid

3- [4-(benzyl-propyl-amino)-phenyl] -isoxazol-5-ylmethyl ester

[1198]

[1199] An experiment was performed using the compound carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester in Example 74 as a starting material and propionaldéhyde in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(benzyl-propyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.

[1200] 1H-NMR (CDC13, 200ΜΗζ) δ 7.6(d, 2Η), 7.34(m, 5Η), 6.7(d, 2Η), 6.52(s, 1Η), 5.22(s, 2Η), 4.8(brs, 2Η), 4.6(s, 2Η), 3.43(t, 2Η), 1.75(m, 2Η), 0.98(t, 3Η)

[1201]

[1202] Example 196: Synthesis of carbamic acid 3-[4-(2,4-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[1203]

[1204] The compound was synthesized using 2,4-di-fluorobenzyl bromide in the same manner as in Example 10.

[1205] 1H-NMR (CDC13, 200ΜΗζ) δ 7.77(d, 2Η), 7.47(q, 1Η), 7.06(d, 2Η), 6.91(dd, 2Η), 6.59(s, 1Η), 5.21(s, 2Η), 5.12(s, 2Η), 4.81(brs, 2Η)

[1206]

[1207] Example 197: Synthesis of carbamic acid 3-[4-(2,5-difluoro-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[1208]

[1209] The compound was synthesized using 2,5-di-fluorobenzyl bromide in the same manner as in Example 10.

[1210] 1H-NMR (CDC13, 200ΜΗζ) δδ 7.76(d, 2Η), 7.26(s, 1Η), 7.10(m, 4Η), 6.59(s, 1Η), 5.21(s, 2Η), 5.16(s, 2Η), 4.78(brs, 2Η)

[1211]

[1212] Example 198: Synthesis of carbamic acid 3-[4-(2,4-dichlorobenzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[1213]

[1214] The compound was synthesized using 2,4-chlorobenzylbromide in the same manner as in Example 10.

[1215] 1H-NMR (CDC13, 200ΜΗζ) δ 7.78(d, 2Η), 7.53(m, 2Η), 7.45(d, 1Η), 7.04(d, 2Η), 6.59(s, 1Η), 5.22(s, 2Η), 5.17(s, 2Η), 4.89(brs, 2Η)

[1216]

[1217] Example 199: Carbamic acid

3- [4-(2-chloro-6-fluorobenzyloxy)-phenyl] -isoxazol-5-ylmethyl ester

[1218]

[1219] The compound was synthesized using 2-chloro-6-fluorobenzyl bromide in the same manner as in Example 10.

[1220] 1H-NMR (CDC13, 200ΜΗζ) δ 7.78(d, 2Η), 7.29(m, 2Η), 7.12 (m, 3Η), 6.60(s, 1Η), 5.24(s, 4Η), 4.89(brs, 2Η)

[1221]

[1222] Example 200: Synthesis of carbamic acid 3-[4-(3-methyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[1223]

[1224] The compound was synthesized using 3-methylbenzyl bromide in the same manner as in Example 10.

[1225] 1H-NMR (DMSO-d6, 200ΜΗζ) δ 7.8(d, 2Η), 7.28(m, 3Η), 7.18(d, 3Η), 6.99(s, 1Η), 6.8(brs, 2Η), 5.13(s, 4Η), 2.33(s, 3Η)

[1226]

[1227] Example 201: Synthesis of carbamic acid 3-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[1228]

[1229] The compound was synthesized using 2-trifluoromethylbenzyl bromide in the same manner as in Example 10.

[1230] 1H-NMR (CDC13, 200ΜΗζ) δ 7.7~7.4(m, 6Η), 7.07(d, 2Η), 6.59(s, 1Η), 5.33(s, 2Η), 5.22(s, 2Η), 4.8(brs, 2Η)

[1231] Example 202: Synthesis of carbamic acid 3-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester

[1232]

[1233] The compound was synthesized using 4-trifluoromethylbenzyl bromide in the same manner as in Example 10.

[1234] 1H-NMR (CDC13, 200ΜΗζ) δ 7.79(d, 2Η), 7.68(d, 2Η), 7.58(d, 2Η), 7.05(d, 2Η), 6.60(s, 1Η), 5.23(s, 2Η), 5.20(s, 2Η), 4.8(brs, 2Η)

[1235]

[1236] Example 203: Synthesis of carbamic acid 3-[4-(benzo[l,3]dioxol-5-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester

[1237]

[1238] The compound was synthesized using 5-bromomethyl-benzo[l,3]dioxole in the same manner as in Example 10.

[1239] 1H-NMR (CDC13, 200ΜΗζ) δ 7.76(d, 2Η), 7.05(d, 2Η), 6.89(m, 3Η), 6.59(s, 1Η), 6.0(s, 2Η), 5.22(s, 2Η), 5.01(s, 2Η), 4.8(brs, 2Η)

[1240]

[1241] Example 204: Synthesis of carbamic acid

3- {4-[3-(t-butylnitronyl)-benzyloxy]-phenyl}-isoxazol-5-ylmethyl ester

[1242]

[1243] An oxime reaction of the 4-carbamic acid 3-[4-(3-formyl-benzyloxy)-phenyl]-isoxazol-5-ylmethyl ester obtained above with Ν-t-butyl hydroxylamine was performed in the same manner as in Example 1-1 to obtain carbamic acid 3-{4-[3-(t-butylnitronyl)-benzyloxy]-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.

[1246] Analyses of behavioral changes, brain tissue lesions, dopamine concentrations, etc.

were performed using ΜΑΟ-Β inhibitory effects and the ΜΡΤΡ mouse model and 6-OHDA rat model as an animal model of Parkinson's disease in order to verify the efficacy of the compound for treatment of Parkinson's disease.

[1247]

[1248] Hereinafter, what is mentioned above will be described in more detail.

[1249]

[1250] In the following Examples, IP refers to intraperitoneal administration, ΡΟ to oral administration, IC50 to concentration at which 50% of the disease is inhibited, ED50 to the dose at which 50% of efficacy is shown, ΜΑΟ-Α to MonoamineOxidase A, and ΜΑΟ-Β to MonoamineOxidase Β.

[1251]

[1253]

[1254] (1) Materials and Methods

[1255] MonoamineOxidase A or Β type human-derived enzyme (5 mg/mf) was each diluted with 0.05 Μ sodium phosphate buffer (pH 7.4) to yield a dilution of 1:200, and then 100 !ii of an enzyme buffer containing 2 >01 of a compound 1 solution at the corresponding concentration was placed in a test plate (flat-bottom) and incubated for 30 minutes.

[1256]

[1257] 100 [Â of a working buffer containing 400 μΜ of Amplex Red reagent, 2 U/mf horseradish peroxidase, and 2 mM substrate (tyramine for ΜΑΟ-Α and benzylamine for ΜΑΟ-Β) in 0.05 Μ sodium phosphate buffer (pH 7.4) was mixed with a preincubated enzyme buffer at 1:1 and measured using fluorescence (EX: 563 nm & EM:

587 nm) for 30 minutes.

[1258]

[1259] Because ΜΑΟ-Α has high homology with ΜΑΟ-Β and is different from ΜΑΟ-Β in function, the selectivity of ΜΑΟ-Α/Β has an influence on the safety of a drug, playing an important role in evaluation of the drug.

[1260]

[1261] (2) Results

[1262] 1) ΜΑΟ-Β

[1263] The following Table 1 shows ΜΑΟ-Β inhibitory effects according to treatment concentrations of each compound in Examples in the same manner as in the methods described above

[1264]

[1265] Table 1

[Table 1]

[Table ]

Inhibitory effects on the activity of ΜΑΟ-Β

02751343 2011-08-02

[1267] It was confirmed that the azole derivatives to be subjected to experiments as above had potent inhibitory effects on the activity of ΜΑΟ-Β at the treatment concentration of 10 ηΜ or 100ηΜ, showing the availability as a therapeutic agent for Parkinson's disease.

[1268]

[1269] 2) ΜΑΟ-Α

[1270] All the compounds described in Examples, etc. showed 30% or less inhibitory effects of ΜΑΟ-Α at 10 μΜ or 100ηΜ. Thus, it was confirmed that the azole derivatives had high ΜΑΟ-Α/Β selectivity, compared to potent inhibitory effects of ΜΑΟ-Β, which the compounds of the present invention showed.

[1273]

[1274] It was confirmed that the azole derivative of Formula (I) exhibited protective effects against dopamine neuronal damage by administration of ΜΡΤΡ (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in an animal model of Parkinson's disease.

[1275]

[1276] An acute administration model of ΜΡΤΡ generally used was constructed by administration of ΜΡΤΡ (free base) at 15-25 mg/kg four times at the interval of 2 hours for a day (Breidert et al., 2002, Protective action of the peroxisome proliferator-activated receptor-c agonist pioglitazone in a mouse model of Parkinson’s disease, J.

Neurochem. 82(3):615-624), and it was known that at 3 to 7 days after administration of ΜΡΤΡ, the administration model showed 70-80% in brain damage, 40-50% in behavioral dysfunction, and a decrease in dopamine concentration in the brain by 70% or more, respectively compared to a control group (Sham) in which ΜΡΤΡ was not administered, and was gradually recovered at 7 to 8 days after ΜΡΤΡ treatment (Khaldy et al., 2003, Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion, Neurobiol. Aging 24(3):491-500; Bezard et al., 2000, Adaptive changes in the nigrostriatal pathway in response to increased 1 -methyl-4-phenyl-l,2,3,6-tetrahydropyridine-induced neurodegeneration in the mouse, Eur. J. Neurosci. 12:2892-2900; Muramatsu et ah, 2002, Therapeutic effect of neuronal nitric oxide synthase inhibitor (7-Nitroindazole) against ΜΡΤΡ neurotoxicity in mice, Met. Brain Dis. 17(3): 169-182).

[1277]

[1278] (1) Materials and Methods

[1279]

[1280] A. ΜΡΤΡ (l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) and drug treatment ΜΡΤΡ (20 mg/kg, free base; Sigma, St. louis, MO) was administered to an 8 week old (20-25 g) male C57BL/6 test mouse intraperitoneally three times a day at the interval of 2 hours to construct a model (Yang et al., 2003, Minocycline enhances ΜΡΤΡ toxicity to dopaminergic neurons. J. Neurosci. Res. 74:278-285). In order to observe the protective effects of the compound as a candidate drug, the compound was dissolved in a solution containing 10% dimethylsulfoxide (DMSO), 10% Cremophor, and 40% polyethyleneglycol (PEG), and the resulting solution was orally administered at doses REPLACEMENT SHEET

of 5 mg/kg, 0.5 mg/kg, 0.1 mg/kg, and 0.05 mg/kg 1 hour before and after ΜΡΤΡ treatment. Rasagiline as a control drug was also dissolved in the same solution, and the resulting solution was administered at the same doses in the same manner as above. A control group (Sham) in which ΜΡΤΡ was not administered was constructed by intraperitoneally administering saline solution to the group instead of ΜΡΤΡ in the same manner as above and orally administering the same solution 1 hour before and after PBS treatment.

[1282]

[1283] Β. Behavior analysis through a tail suspension test

[1284] A tail suspension test was performed in order to measure the induction degree of behavioral dysfunctions in accordance with administration of ΜΡΤΡ and a drug. At 7 days after administration of the drug, a round stainless steel rod (width: 1 cm) was affixed to a cage (width: 16 cm, height: 40 cm) 35 cm above from the surface shielded by black wooden structures in the left and right sides to perform experiments. The time for which the animal moved for a total period of 6 minutes was measured in seconds to evaluate the drug action.

[1285]

[1286] C. Measurement of contents of dopamine in the striatum and metabolites thereof The changes of contents of dopamine and dopamine metabolites in the striatum in accordance with administrations of ΜΡΤΡ and the drug were measured by high performance liquid chromatography (HPLC). At 7 days after administration of the drug, the animal was sacrificed by cervical vertebra dislocation and the brain tissues were immediately isolated from the animal. 0.5 mi of iced solution for HPLC analysis (0.1 Μ perchloric acid and 0.1 mM EDTA) was added to a striatum obtained from the isolated brain tissues, and an ultrasonic grinder was used to prepare a tissue homogenate. The tissue homogenate was centrifuged at 12,000 rpm for 15 minutes, and its supernatant was filtered through nitrocellulose membrane filter (0.2 um, Millipore).

For HPLC analysis, uBondapakTM C18 column (4.6 χ 150 mm, particle size 10 pm:

Shisheido, Japan) was used, the flow rate of the mobile phase (0.07 Μ monobasic sodium phosphate), 1 mM sodium octasulfonic acid, 0.1 uM EDTA, 5% acetonitrile, pH 3.2) was maintained at 0.7 mf/min, and the electrode potential of the electrochemical detector (ICA-5000, Japan) was set at 700 mV.

[1288]

[1289] D. Statistical analysis

[1290] In order to confirm the damage and protective effects of dopamine neuron cells in accordance with administrations of ΜΡΤΡ and the drug, results from experiments performed five times or more were used and experimental data were expressed as the mean ± standard error mean (SEM). Statistical analysis showed that the data were significant when the ρ value was 0.05 or less by a Student's t-test after a 1-way ANOVA test.

[1291]

[1292] (2) Results

[1293] A. Behavior analysis through a tail suspension test

[1294] A tail suspension test was performed at 7 days after administration of ΜΡΤΡ in order to review the behavioral dysfunction preventive effects of a drug against the ΜΡΤΡ toxicity, and the results were shown in the following Table 2.

Table 2

[Table 2]

[Table ]

tests for the azole derivatives

Mobilityto an expression of the measurement oftime for which the animal moved withtail hung high as a percentage comparedmeasurement of a controlΜΡΤΡ single administration groupabout 50-70% in mobilitya control group (Sham) in which ΜΡΤΡnot administered because group70 to 80% in brain damage, 40 to 50%behavioral dysfunction, ain dopamine concentration in the brain byor more, respectively compared tocontrol group (Sham), at 3 to 7 daysof ΜΡΤΡ.

from the above results, it can bethat a group to which the azole derivative of Formula (I) was administered showed a mobility of 70.3-114 against a control group at an administration concentration of 10 mg/kg, compared to the ΜΡΤΡ single administration group showing behavioral dysfunctions against the control group.

[1300]

[1301] Β. Changes of contents of dopamine and its metabolites in the striatum

[1302] In order to review protective effects of the drug against ΜΡΤΡ toxicity, changes of contents of dopamine and its metabolites in the striatum were measured at 7 days after administration of ΜΡΤΡ.

[1303]

[1304] Table 3

[Table 3]

[Table ]

Levels of dopamine (DA) in the striata of MPTP-treated mice (% compared to a control group)

[1305] The protective effects by the azole derivatives of Formula (I) against dopamine neuronal cell damage using an acute administration model of ΜΡΤΡ were observed.

The observation showed that the ΜΡΤΡ single administration group exhibited a dopamine level in the striatum at 20 to 40% compared to the control group while a group to which the azole derivative of Formula (I) was administered showed a recovery of dopamine level at an administration concentration of 10 mg/kg to the level of the control group.

[1306]

[1307] That is, for reduction in dopamine level in the striatum by ΜΡΤΡ and dopamine neuronal cell damage by ΜΡΤΡ, it was determined that the azole derivatives had neuron protective effects from the results of a dopamine level at an administration concentration of 10 mpk at up to 111.5% compared to the control group. The dopamine level reduced by ΜΡΤΡ was concentration-dependently recovered to show inhibitory effects against ΜΑΟ-Β. It can be confirmed that the azole derivatives substituted as above show inhibitory effects against dopamine neuronal cell damage, and are useful as a therapeutic agent for treating Parkinson's disease.

[1308]

[1310]

[1311] An acute administration model of ΜΡΤΡ generally used was constructed by administration of ΜΡΤΡ (free base) at 15-25 mg/kg four times at the interval of 2 hours for a day (Breidert et ah, 2002), and it was known that at 3 to 7 days after administration of ΜΡΤΡ, the administration model showed 70-80% in brain damage, 40-50% in behavioral dysfunction, and a decrease in dopamine concentration in the brain by 70% or more, respectively compared to a control group (Sham) in which ΜΡΤΡ was not administered, and was gradually recovered at 7 to 8 days after ΜΡΤΡ treatment (Khaldy et ah, 2003; Bezard et ah, 2000; Muramatsu et ah, 2002).

[1312]

[1313] In the case of Levodopa which is a gold standard of a drug for treating Parkinson's disease, various side effects have been reported after prolonged use of the drug, and the duration time of efficacy decreases. In order to prevent the limitations, coadministration therapies using ΜΑΟ-Β or COMT inhibitors, etc. have been widely used.

[1314]

[1315] In the present invention, it is intended to know whether a composition containing the azole derivative of the present invention when co-administered with L-dopa is available as a drug for treating Parkinson's disease by using an animal mode in which Parkinson's disease was induced by administration of ΜΡΤΡ

( 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

[1316]

[1317] ( 1 ) Materials and Methods

[1318] A. ΜΡΤΡ (l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) and drug treatment ΜΡΤΡ (20 mg/kg, free base; Sigma, St. louis, MO) was administered to an 8 week old (20-25 g) male C57BL/6 test mouse intraperitoneally at the interval of 2 hours to construct a model.

[1320]

[1321] In order to observe the effects of combined administration of a compound of the present invention and Levodopa, the compound of the present invention was dissolved in a solution containing 0.02 mi of dimethylsulfoxide (DMSO), 0.02 mi of Cremophor, 0.08 mi of polyethyleneglycol (PEG), and 0.08 mi of physiological saline. The resulting solution was orally administered at doses of 1 mg/kg one week after the ΜΡΤΡ treatment, and a Levodopa group containing Levodopa at 50 mg/kg and Β℮ηzerazide at 25 mg/kg was intraperitoneally administered 1 hour later.

[1322]

[1323] Instead of ΜΡΤΡ, physiological saline was intraperitoneally administered in the same manner as above and the same solution was orally administered 1 hour before Phosphate Buffered Saline (PBS) treatment to construct a control group (Sham) in which ΜΡΤΡ was not administered.

[1324]

[1325] A single administration of the Levodopa group in the following Table 4 indicates values resulting from a ΜΡΤΡ (toxin) treatment followed by an administration of the Levodopa group compared to the treatment results of a Levodopa single administration group of Levodopa and Benzerazide.

[1326]

[1327] Β. Measurement of contents of dopamine in the striatum and metabolites thereof The changes of contents of dopamine and dopamine metabolites in the striatum in accordance with administrations of ΜΡΤΡ and the drug were measured by high performance liquid chromatography (HPLC).

[1329]

[1330] At 1 hour and 3 hours after administration of Levodopa, the animals were sacrificed by cervical vertebra dislocation and the brain tissues were immediately isolated from the animals. 0.5 mi of iced solution for HPLC analysis (0.1 Μ perchloric acid and 0.1 mM EDTA) was added to a striatum obtained from the isolated brain tissues, and an ultrasonic grinder was used to prepare a tissue homogenate. The tissue homogenate was centrifuged at 12,000 rpm for 15 minutes, and its supernatant was filtered through nitrocellulose membrane filter (0.2 um, Millipore). Lor HPLC analysis, uBondapakTM C18 column (4.6 χ 150 mm, particle size 10 μΐη: Shisheido, Japan) was used, the flow rate of the mobile phase (0.07 Μ monobasic sodium phosphate, 1 mM sodium octasulfonic acid, 0.1 uM EDTA, 5% acetonitrile, pH 3.2) was maintained at 0.5 mf/min, and the electrode potential of the electrochemical detector (CouloChem III, ESA, Japan) was set at 350 mV.

[1331]

[1332] (2) Results

[1333] A. The changes of contents of dopamine and dopamine metabolites in the striatum In order to review the effects of combined administration of Levodopa group, the changes of contents of dopamine and metabolites thereof in the striatum were measured at 1 hour and 3 hours after administration of a Levodopa group. The results are summarized in the following Table 4.

[1335]

[1336] Table 4

[Table 4]

[Table ]

Concentration of dopamine (DA) in the striatum of a MPTP-treated mouse ExamAdministrati Concentration of Exam Administration Concentration of

[1337] After observing whether a composition containing the azole derivative of the present invention when co-administered with L-dopa is available as a drug for treating Parkinson's disease by using an animal mode in which Parkinson's disease was induced by administration of ΜΡΤΡ (l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine), it can be confirmed that a composition containing the azole derivative of the present invention at 1 mg/kg was co-administered at 1 hour and 3 hours, respectively, after administration of the Levodopa group to increase the amounts of dopamine in the striatum compared to a single administration of the Levodopa group.

[1338]

[1339] When a compound of the present invention was administered in combination with Levodopa at 1 mg/kg, the amount of dopamine in the striatum to be reduced by ΜΡΤΡ administration exhibits an increase much more than that to be recovered by a single administration of Levodopa. Thus, it can be confirmed that a compound containing the azole derivative as substituted above has therapeutic effect of Parkinson's disease when it is administered in combination with Levodopa.