RU2152935C2 - N-hydroxylureas as anti-inflammatory agents - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to derivatives of N-hydroxylurea of the formula (I)

or their pharmaceutically acceptable salts where A is C_1-4-alkylene, CH(R), CH(R)-CH₂ or CH(R)-CH₂CH₂; R is methyl or ethyl; m = 1; n = 0 or 1; R¹, R² are hydrogen atom, C_1-4-alkyl or C_2-6-alkenyl; X means O or S; Y means O, C≡C; Ar¹ means phenyl or phenyl monosubstituted with halogen atom; Ar² means phenylene, pyridylene or phenylene monosubstituted with halogen atom, C_1-4-alkyl, C_1-4-alkoxy-group. These compounds can be used for treatment of allergic or inflammatory state in mammalian. EFFECT: valuable medicinal properties of compounds. 11 cl, 1 tbl, 40 ex

Description

FIELD OF THE INVENTION
The invention relates to new compounds of N-hydroxyurea. The compounds of the present invention inhibit the action of the lipoxygenase enzyme and are useful for treating or alleviating inflammatory diseases, allergies, and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION
Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins, including prostacyclins, thromboxanes and leukotrienes. The first stage of arachidonic acid metabolism is the secretion of arachidonic acid and related unsaturated fatty acids from membrane phospholipids through the action of phospholipase A2. Arachidonic acid is then metabolized either by cyclooxygenase to produce prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids, which can then be metabolized to leukotrienes. Leukotrienes are involved in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemic damage during reperfusion, psoriasis and inflammatory bowel diseases and are the subject of several review articles. It is believed that any drug that inhibits lipoxygenase will provide significant new therapy for both acute and chronic inflammatory conditions (See H. Masamune and LS Melvin, Sr., Annual Reports in Medicinal Chemistry: 24 (1989) pp 71-80 ( Academic), BJ Fitzsimmons and J. Rokach, Leukotrienes and Lipoxygenases (1989) pp 427-502 (Elsevier)) and DGBatt, Progress in Med. Chem. 29 (1992) p. 1.

 WO 92/22543 (1992) describes N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme.

и их фармацевтически приемлемым солям, где A представляет C₁-C₄алкилен, CH(R), CH(R) CH₂ или CH(R) CH₂CH₂, где R представляет метил или этил; m и n равны нулю или единице; каждый из R¹ и R² представляет водород, C₁-C₄алкил или C₂-C₆алкенил; X представляет О или S, Y представляет О, S, CH=CH или C≡C; Ar¹ представляет фенил или фенил, монозамещенный галогеном, C₁-C₄алкилом, C₄-C₄алкокси, C₁-C₄ галогензамещенным алкилом или C₁-C₄ галогензамещенным алкокси; и Ar² представляет фенилен, пиридилен или фенилен, моно- или дизамещенный галогеном, C₁-C₄алкилом, C₄-C₄алкокси, C₁-C₄галогензамещенным алкилом или C₁-C₄галогензамещенным алкокси.SUMMARY OF THE INVENTION
The present invention relates to new N-hydroxyurea compounds of the following chemical formula (I):

and their pharmaceutically acceptable salts, where A is C ₁ -C ₄ alkylene, CH (R), CH (R) CH ₂ or CH (R) CH ₂ CH ₂ , where R is methyl or ethyl; m and n are zero or one; each of R ¹ and R ² represents hydrogen, C ₁ -C ₄ alkyl or C ₂ -C ₆ alkenyl; X represents O or S, Y represents O, S, CH = CH or C≡C; Ar ¹ is phenyl or phenyl monosubstituted with halogen, C ₁ -C ₄ alkyl, C ₄ -C ₄ alkoxy, C ₁ -C ₄ halogen-substituted alkyl or C ₁ -C ₄ halogen-substituted alkoxy; and Ar ² is phenylene, pyridylene or phenylene mono- or disubstituted with halogen, C ₁ -C ₄ alkyl, C ₄ -C ₄ alkoxy, C ₁ -C ₄ halogen-substituted alkyl or C ₁ -C ₄ halogen-substituted alkoxy.

 The compounds of formula (I) inhibit the enzyme 5-lipoxygenase. Therefore, these compounds are useful for treating a medical condition that requires a 5-lipoxygenase inhibitor in a mammalian subject, such as a human subject. The compounds are especially useful for the treatment of allergic and inflammatory conditions. The invention also includes pharmaceutical compositions that comprise a compound of formula (I) and a pharmaceutically acceptable carrier.

A preferred group of compounds of the invention includes compounds of formula (I), wherein n is zero, each of R ¹ and R ² is hydrogen; X represents O; Ar ² is phenyl or 4-fluorophenyl and Ar ² is 1,3-phenylene or 1,3-phenylene having one substituent selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halogen-substituted alkyl; and C ₁ -C ₄ halogen-substituted alkoxy.

Within this preferred group, a particularly preferred subgroup of compounds are compounds wherein A is CH ₂ , CH ₂ CH ₂ , CH (CH ₃ ) or CH (CH ₃ ) CH ₂ ; Ar ² is 1,3-phenylene or 1,3-phenylene having one fluorine as a substituent; m is unity and Y is O. Within this particularly preferred subgroup, Ar ^{1 is} preferably attached at the 4-position of the oxazoline ring and the carbon atom to which Ar ¹ is attached preferably has a (R) configuration.

The most preferred individual compounds are:
(+) - N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxy-N'-methylurea ;
(+) - N- [3- [3- [4,5-Dihydro-4 (R) - (4-fluorophenyl) oxazol-2-yl] phenyl] -2-propin-1-yl] -N-hydroxyurea ;
(-) - N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -2-fluorophenyl] -2-propin-1-yl] -N-hydroxyurea;
N- [4- [3- (4,5-Dihydro-5-phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] -N-hydroxyurea;
(-) - N-1- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethyl] -N-hydroxyurea;
(+) - N-1- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -5-fluorophenoxy] ethyl] -N-hydroxyurea; and
N-1- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl] -2-fluorophenoxy] ethyl] -N-hydroxyurea.

DETAILED DESCRIPTION OF THE INVENTION
The term "halogen" is used in the description to refer to radicals formed from fluorine, chlorine, bromine or iodine elements.

 The term "pharmaceutically acceptable salts" refers to (1) the basic salts of the compounds of this invention containing non-toxic cations, including, but not limited to, cations of alkali or alkaline earth metals such as sodium, lithium, potassium, magnesium and the like, as well as non-toxic ammonium, substituted ammonium and quaternary ammonium cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylammonium, diethylammonium, trimethylammonium, triethylammonium and the like, or refers to (2) acid to the additive salts of the compounds of this invention containing non-toxic acids, including, but not limited to, hydrochloride, sulfate or bisulfate, phosphate or acid phosphate, acetate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulfonate, formate salts.

 The term “halogen-substituted alkyl” refers to an alkyl radical substituted with one or more halogens, including, but not limited to, chloromethyl, 1-fluoroethyl, trifluoromethyl and the like. A preferred halogen-substituted alkyl group is trifluoromethyl.

 The term “halogen-substituted alkoxy” is used to mean an alkoxy radical substituted with one or more halogens, including, but not limited to, chloromethoxy, 2-chloroethoxy, difluoromethoxy, trifluoromethoxy and the like.

 A preferred halogen-substituted alkoxy group is trifluoromethoxy.

 New hydroxyureas of the formula (I) can be obtained by a number of synthetic methods that are well known to specialists in this field.

В одном варианте осуществления изобретения соединения (I) получают в соответствии с реакционной схемой, изображенной на схеме 1.

In one embodiment of the invention, compounds (I) are prepared according to the reaction scheme depicted in scheme 1.

В приведенной выше схеме Q представляет

и R¹, R², Ar¹, Ar², X, Y, A, n и m такие, как определены ранее.Scheme 1

In the above diagram, Q represents

and R ¹ , R ² , Ar ¹ , Ar ² , X, Y, A, n and m are as previously defined.

According to the reaction of Scheme 1, compounds (I) are obtained by treating hydroxylamine (II) with a trialkylsilyl isocyanate, such as trimethylsilyl isocyanate, or an alkyl or alkenyl isocyanate of the formula R ⁶ —N═C═ Ob in a reaction inert solvent. Suitable solvents that do not react with reagents and / or products are, for example, tetrahydrofuran (THF), dioxane, dichloromethane (CH ₂ CL ₂ ) or benzene. The preferred temperature is in the range from room temperature to the boiling point of the solvent, for example from 15 to 80 ^o C, but if necessary, you can choose lower or higher temperatures. The progress of the reaction is easily monitored by thin layer chromatography (TLC). The reaction time is usually from several minutes to several hours.

In an alternative method, treatment of (II) with hydrogen chloride gas in a reaction inert solvent such as benzene or toluene, followed by treatment with phosgene, is used. The reaction temperature usually ranges from room temperature to the boiling point of the solvent, for example from 15 to 100 ^o C, but if necessary, you can choose lower or higher temperatures. Intermediate chloroformamide is not isolated, but is subjected (for example, in situ) to a reaction with a suitable amine (HNR ¹ R ² ), for example ammonia or methylamine. The progress of the reaction is easily monitored by TLC, and the reaction time is usually from several minutes to several hours.

In addition, the hydroxylamine (II) addition salt can be reacted with an alkali metal cyanate, such as potassium cyanate, for example, in water, to give a compound of formula (I), wherein R ¹ and R ² are hydrogen.

 The aforementioned hydroxylamine (II) can be easily obtained by standard synthetic methods from the corresponding carbonyl compound, for example, a ketone or aldehyde, an alcohol compound and a halogen-containing compound. For example, a suitable carbonyl compound is converted to its oxime and then reduced to the desired hydroxylamine (II) with a suitable reducing agent (see e.g. RF Borch et al, J. Amer. Chem. Soc., 1971, 93, p 2897). Selected reducing agents include, but are not limited to, sodium cyanoborohydride and borane complexes such as borane-pyridine, borane-triethylamine, and borane-dimethyl sulfide. However, trimethylsilane in trifluoroacetic acid (TFA) can also be used.

Alternatively, hydroxylamine (II) can be easily obtained by treating the corresponding alcohol (Q-OH), for example, N, O-bis (tert-butoxycarbonyl) with hydroxylamine according to a Mitsunobu type reaction followed by acid-catalyzed hydrolysis (for example, using TFA or HCI-MeOH solution ) N, O-protected intermediate (see Japanese Patent (KOKAI) 45344/1989). A suitable condensing reagent in the Mitsunobu reaction is di- (C ₁ -C ₄ ) alkyl azodicarboxylate in the presence of triarylphosphine, for example diethyl azodicarboxylate in the presence of triphenylphosphine. Selected reaction inert solvents include CH ₂ Cl ₂ , THF, dimethylformamide or toluene. The reaction temperature is preferably in the range from 0 ^° C. to the boiling point of the solvent, for example from 0 to 100 ^° C., but if necessary, lower or higher temperatures can be selected. The progress of the reaction is easily monitored by TLC. The reaction time is usually from several minutes to several hours.

 The aforementioned hydroxylamine (II) can also be obtained from a suitable halogen-containing compound (e.g. Q-CI) by reacting with O-protected hydroxylamine and then removing the protecting group (see WPJackson et al., J. Med. Chem., 1989, 31, p 499).

 The hydroxylamine of formula (II) thus obtained by the aforementioned method is isolated using standard procedures and can be purified by conventional methods such as recrystallization and chromatography.

In another embodiment, the compounds of formula (I) are prepared as shown in Scheme 2. Q is as previously defined and R ³ is phenyl, monosubstituted phenyl or C ₁ -C ₄ alkyl, and R ⁴ is phenyl or monosubstituted phenyl.

В реакционной последовательности на схеме 2 соединения (I) получают обработкой спирта (III) в условиях реакции Мицунобу проходящим N,O-бис-(карбокси)гидроксиламином, предпочтительно N,O-бис-(феноксикарбонил)гидроксиламином, и последующим превращением полученного продукта (IV) в (I) обработкой подходящим амином (HNR¹R²), таким как аммиак, метиламин или диметиламин (A.O. Stewart and D.W.Brooks, J.Org. Chem., 1992, 57, p 5020) в отсутствии или присутствии инертного в реакции растворителя. Выбранные, инертные в условиях реакции растворители включают воду, метанол, этанол, ТГФ и бензол. Температура реакции предпочтительно находится в диапазоне от -78^oC до температуры кипения растворителя, но, если необходимо, можно выбрать более низкие или более высокие температуры. Ход реакции легко контролируют с помощью ТСХ. Время реакции обычно составляет от нескольких минут до нескольких часов. Подходящим конденсирующим реагентом в реакции Мицунобу является ди-(C₁-C₄) алкилазодикарбоксилат в присутствии триарилфосфина, например диэтилазодикарбоксилат в присутствии трифенилфосфина.Scheme 2

In the reaction sequence in Scheme 2, compounds (I) are obtained by treating the alcohol (III) under the Mitsunobu reaction with N, O-bis (carboxy) hydroxylamine, preferably N, O-bis (phenoxycarbonyl) hydroxylamine, and then converting the resulting product ( Iv) in (I) treatment with a suitable amine (HNR ¹ R ² ) such as ammonia, methylamine or dimethylamine (AO Stewart and DW Brooks, J. Org. Chem., 1992, 57, p 5020) in the absence or presence of an inert reaction solvent. Selected inert reaction solvents include water, methanol, ethanol, THF, and benzene. The reaction temperature is preferably in the range of -78 ^° C. to the boiling point of the solvent, but lower or higher temperatures can be selected if necessary. The progress of the reaction is easily monitored by TLC. The reaction time is usually from several minutes to several hours. A suitable condensing reagent in the Mitsunobu reaction is di- (C ₁ -C ₄ ) alkyl azodicarboxylate in the presence of triarylphosphine, for example diethyl azodicarboxylate in the presence of triphenylphosphine.

In the case where (Y) _m is C≡C, the hydroxylamine intermediate (II) can be obtained from a suitable aryl halide compound (VI, Z represents Br or I) or a triflate derivative (VI, Z represents OSO ₂ CF ₃ ) and the corresponding N , O-protected alkynylhydroxylamine (e.g. N, O-bis (tert-butoxycarbonyl) prop-2-yn-1-ylhydroxylamine and the like) by coupling reaction in the presence of a palladium catalyst (e.g. Pd (PPh ₃ ) ₂ Cl ₂ , Pd ( PPh ₃ ) ₄ , Pd (PPh ₃ ) ₂ Cl ₂ -CuI, etc.). Subsequent removal of the protective group. Alternative hydroxylamine intermediate (II) can be obtained from a suitable aryl halide compound (e.g. bromaryl or iodaryl derivative and the like) or a triflate derivative and the corresponding alkynyl alcohol (e.g. propargyl alcohol and the like) by coupling in the presence of a palladium catalyst (e.g. Pd (PPh) ) ₃ ) ₂ Cl ₂ , Pd (PPh ₃ ) ₄ , Pd (PPh ₃ ) ₂ Cl ₂ CuI, etc. ) The resulting alcohol can be converted to (II) as previously described.

In the case where (Y) _m is oxygen or sulfur, the hydroxylamine intermediate (II) can be obtained by an alkylation reaction from a suitable phenol or thiophenol compound (VI, Z represents OH or SH) and a suitable alkyl halide or alkyl sulfonyloxy compound (e.g. 2- (protected hydroxy) ethyl bromide) followed by removal of the protecting group to give (III). The resulting alcohol can be converted to (II) as described above. When the alkyl halide or alkyl sulfonyloxy compound is reacted with phenol or thiophenol, an alkali metal or alkaline earth metal carbonate, hydroxide or hydride, such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, is usually used.

Suitable solvents that do not react with reagents and / or products are, for example, N, N-dimethylformamide, dimethyl sulfoxide, acetone or THF. The reaction temperature is preferably in the range from room temperature to the boiling point of the solvent, for example from 15 to 150 ^o C, but if necessary, you can choose lower or higher temperatures. The progress of the reaction is easily monitored by thin layer chromatography (TLC). The reaction time is usually from several minutes to several hours.

 Pharmaceutically acceptable base salts of the compounds of formula (I) can be prepared by methods well known to those skilled in the art, for example by contacting the compound with a stoichiometric amount of a suitable alkali or alkaline earth metal hydroxide or alkoxide (sodium, lithium, potassium, calcium and magnesium) in water or a suitable organic solvent, such as ethanol, isopropanol or the like. Some compounds of formula (I) can form acid addition salts by contacting this compound with a suitable non-toxic acid. Examples of suitable acid addition salts are hydrochloride, sulfate or bisulfate, phosphate or acid phosphate, acetate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfate. Pharmaceutically acceptable salts of the compounds of formula (I) can be isolated by subsequent precipitation or removal of the solvent by evaporation.

Intermediates (VI) can be used to prepare compounds of formula (I), wherein Ar ¹ , Ar ² , X and n are as previously defined, and Z is halogen (preferably bromine or iodine) OH, SH, SR ⁵ , OR ⁵ or CH ₂ OR ⁵ , where R ⁵ represents a suitable protecting group, preferably a benzyl, 4-methoxyphenyl or tert-butyldimethylsilyl group.

Этот промежуточный продукт (VI), где Z представляет галоген, SR⁵, OR⁵ или CH₂OR⁵, можно получить реакцией соединения формулы (V) с дегидратирующим агентом, таким как ди-(C₁-C₄)-алкилазодикарбоксилат в присутствии триарилфосфина, например диэтилазодикарбоксилат в присутствии трифенилфосфина или альтернативно тионилхлорида. Подходящими растворителями, которые не реагируют с реагентами и/или продуктами являются, например, ТГФ, CH₂Cl₂ или бензол. Предпочтительно температура реакции находится в диапазоне от 0^oC до температуры кипения растворителя, например от 0^oC до 80^oC, но если необходимо, можно выбрать более низкие или более высокие температуры. Ход реакции легко контролируют способами тонкослойной хроматографии (ТСХ). Время реакции обычно составляет от нескольких минут до нескольких часов.Scheme 3

This intermediate (VI), where Z is halogen, SR ⁵ , OR ⁵ or CH ₂ OR ⁵ , can be prepared by reacting a compound of formula (V) with a dehydrating agent such as di- (C ₁ -C ₄ ) -alkyl azodicarboxylate in the presence of triarylphosphine, for example diethyl azodicarboxylate in the presence of triphenylphosphine or alternatively thionyl chloride. Suitable solvents that do not react with reagents and / or products are, for example, THF, CH ₂ Cl ₂ or benzene. Preferably, the reaction temperature is in the range from 0 ^° C. to the boiling point of the solvent, for example from 0 ^° C. to 80 ^° C., but if necessary, lower or higher temperatures can be selected. The progress of the reaction is easily monitored by thin layer chromatography (TLC). The reaction time is usually from several minutes to several hours.

The method for removing a suitable protecting group R ^{5 is} selected depending on the choice of protecting group. Thus, for example, an arylmethyl group, such as a benzyl group, can be removed, for example, by hydrogenolysis over a catalyst, such as palladium on carbon. Alternatively, the protecting group, such as the 4-methoxyphenyl group, can be removed by oxidation, for example with mixed cerium (IV) nitrate and ammonium nitrate. A trialkylsilyl or aryl dialkylsilyl group, such as a tert-butyldimethylsilyl or dimethylphenylsilyl group, can be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or TFA, or alkali metal fluoride or ammonium fluoride, such as, for example, sodium fluoride or preferably ammonium fluoride.

 The compounds of formula (I) and their various intermediates are isolated by standard methods, and they can be purified by conventional methods, for example, recrystallization and chromatography.

 The compounds of formula (I) contain one or more asymmetric centers and therefore they are able to exist in various stereoisomeric forms. The present invention includes all such possible stereoomers, both in their pure state and in the form of mixtures thereof.

The compounds of the present invention inhibit the activity of the enzyme 5-lipoxygenase. This inhibition can be shown in vitro assays using human heparinized whole blood (HWB) in accordance with the method described in Br. J. Pharmacol .: 99, pp 113-118 (1990), which determines the effect of these compounds on the metabolism of arachidonic acid. In these tests, some preferred compounds show IC ₅₀ values of 0.1 to 5 μM in the HWB assay relative to lipoxygenase activity.

In vivo activity in mice (males) of ICR after oral administration of the compounds of the invention can be determined using a PAF-induced mortality assay by a technique similar to that described in JM Young et al. (JM Young, PJ Maloney, SNJubb and JSClark, Prostaglandins, 30, p 545 (1985); M. Criscuoli and A. Subissi, Br. J. Pharmac., 90, p 203 (1987): H. Tsunoda, S. Abe, Y. Sakuma, S. Katayama and K. Katayama, Prostaglandins, Leukotriens and Essential Fatty Acids, 39, p 291 (1990)). In this test, some preferred compounds show ED ₅₀ values in the range of 1 to 10 mg / kg.

 The ability of the compounds of the present invention to inhibit the 5-lipoxygenase enzyme makes them useful for regulating the symptoms induced by endogenous metabolites arising from arachidonic acid in a mammalian subject. These compounds are therefore valuable for the prevention and treatment of disease states in which the accumulation of metabolites of arachidonic acid is a causative factor of the disease, for example, allergic bronchial asthma, skin diseases of rheumatoid arthritis and osteoarthritis. Thus, the compounds of the present invention and their pharmaceutically acceptable salts are particularly suitable for the treatment or prevention of inflammatory diseases in a human subject.

 For the treatment or prevention of various diseases described above, the compounds of formula (I) of this invention can be administered to a human subject either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents in the form of a pharmaceutical composition in accordance with standard pharmaceutical practice.

 The compounds can be administered to human subjects by various conventional routes of administration, including oral and parenteral. When the compounds are administered orally to humans to treat or prevent an inflammatory disease, the dose range is from about 0.1 to 20 mg / kg body weight of the subject being treated per day, preferably from about 0.5 to 15 mg / kg body weight per day in single or divided doses. If parenteral administration is desired, the effective dose is from about 0.05 to 5 mg / kg body weight of the human subject being treated per day. In some cases, it may be necessary to use doses outside these limits, since the doses necessarily vary depending on the age, weight and response of the individual patient, as well as the severity of the patient's disease symptoms and the activity of the particular compound being administered.

 For oral administration, the compounds of the present invention and their pharmaceutically acceptable salts can be administered, for example, in the form of tablets, powders, lozenges, syrups or capsules, or as an aqueous solution or suspension. In the case of tablets for oral administration, commonly used carriers include lactose and corn starch. Additionally, lubricating agents such as magnesium stearate are usually added. In the case of capsules, useful diluents are lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with an emulsifying or suspending agent. If desired, sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually obtained, after which it is necessary to establish the appropriate pH values of the solutions and buffer the solutions. For intravenous use, the total solute concentration should be adjusted to make the drug isotonic.

Examples
The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance (NMR) spectra were measured at 270 MHz, unless otherwise stated, and peak positions are expressed in parts per million (ppm) relative to tetramethylsilane. The shape of the peaks is indicated as follows: c - singlet, d - doublet, t - triplet, m - multiplet and width. - wide.

Example 1 (+) - N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxyurea
A. (+) - 2- (3-Iodbenzamido) -2 (R) -phenylethan-1-ol
To a vigorously stirred solution of 3-iodobenzoyl chloride (16.79 g, 63 mmol) in dichloromethane (300 ml), a solution of (R) - (-) - 2-phenylglycinol (8.64 g, 63 mmol) in dichloromethane (50 ml) is quickly added ) The reaction mixture was stirred for 3 hours and the crude product was collected by filtration. Recrystallization from isopropyl alcohol gave (+) - 2- (3-iodobenzamido) -2 (R) -phenylethan-1-ol as white needles (14.74 g, 64%).

Mp: 154-156 ^o C
IR (KBr) ν: 3400, 3300, 1635, 1538, 700 cm ^-1 .

¹ H NMR (CDCl ₃ ) δ: 8.14 (t, J = 1.5 Hz, 1H), 7.85 (d, J = 7 Hz, 1H), 7.77 (d, J = 7 Hz, 1H), 7.4 - 7.3 (m, 5H), 7, 19 (t, J = 7 Hz, 1H), 6.78 (br s, 1H), 5.3 - 5.2 (m , 1H), 4.02 (d, J = 5 Hz, 2H), 2.35 (br s, 1H).

[α] _D : +52.3 ^° (c = 0.44, DMF).

B. (+) - 4,5-Dihydro-2- (3-iodophenyl) -4 (R) -phenyloxazole
To a mixture of (+) - 2- (3-iodobenzamido) -2 (R) -phenylethan-1-ol (14.70 g, 40 mmol) and triphenylphosphine (13.64 g, 52 mmol) in dry tetrahydrofuran (350 ml ) a solution of diethyl azodicarboxylate (10.52 g, 52 mmol) in dry tetrahydrofuran (15 ml) is added dropwise. The reaction mixture was stirred for 18 hours and the readily volatile components were removed by evaporation. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 8), to give (+) - 4,5-dihydro-2- (3-iodophenyl) -4 (R) -phenyloxazole (7.81 g, 56 %) as a liquid.

IR (film) ν: 3080, 3020, 2960, 2900, 1645, 1560, 1355, 955, 820, 800 cm ^-1 .

¹ H NMR (CDCl ₃ ) δ: 8.41 (t, J = 1.5 Hz, 1H), 7.98 (dd, J = 8, 1.5 Hz, 1H), 7.83 (dd, J = 8, 1.5 Hz, 1H), 7.42 - 7.24 (m, 5H), 7.18 (t, J = 8 Hz, 1H), 5.39 (dd, J = 10, 8, 5 Hz, 1H), 4.80 (dd, j = 10, 8.5 Hz, 1H), 4.29 (t, J = 8.5 Hz, 1H).

[α] _D : = + 11.42 ^° (c = 0.42, CH ₂ Cl ₂ ).

B. N, O-Di (tert-butoxycarbonyl) - [3- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -2-propin-1-yl] hydroxylamine
A mixture of (+) - 4,5-dihydro-2- (3-iodophenyl) -4 (R) -phenyloxazole (7.76 g, 22.2 mmol), [N, O-di (tert-butoxycarbonyl) -2 -propin-1-yl] hydroxyamine (9.03 g, 33.3 mmol) and bis (triphenylphosphine) palladium (II) chloride (780 mg, 1.1 mmol) in triethylamine (30 ml) are stirred for 1 h under nitrogen, CuI (420 mg, 2.2 mmol) was added and the reaction mixture was stirred for an additional 16 hours. Insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane = 1: 7, to obtain N, O-di (tert-butoxycarbonyl) - [3- [3- (4,5-dihydro-4 (R) -phenyloxazole- 2-yl) phenyl] -2-propin-1-yl] hydroxylamine (7.6 g, 70%) as brittle, off-white flakes.

¹ H NMR (CDCl ₃ ) δ: 8.11 (t, J = 1.5 Hz, 1H), 7.99 (dd, J = 8, 1.5 Hz, 1H), 7.55 (dd, J = 8, 1.5 Hz, 1H), 7.40 - 7.28 (m, 6H), 5.39 (dd, J = 10.7 Hz, 1H) 4.80, (dd, J = 10, 7 Hz, 1H), 4.56 (br s, 2H), 4.28 (t, J = 10 Hz, 1H), 1.53 (s, 9H), 1.51 (s, 9H).

G. (+) - N- [3- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxyurea
To a solution of N, O-di (tert-butoxycarbonyl) - [3- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -2-propin-1-yl] hydroxylamine ( 1.99 g, 4 mmol) in dichloromethane (30 ml), cooled to 0 ^° C., trifluoroacetic acid (10 ml) is slowly added. The reaction mixture was allowed to warm to room temperature, stirred for an additional 30 minutes, and then poured into a saturated aqueous solution of NaHCO ₃ (100 ml). The mixture was extracted with dichloromethane (3 x 30 ml) and the organic phase was washed with brine (20 ml), dried (MgSO ₄ ) and evaporated. The resulting residue was dissolved in tetrahydrofuran (20 ml) and trimethylsilyl isocyanate (0.84 ml, 6.3 mmol) was added. After stirring for 10 minutes, the product is precipitated. Methanol (1 ml) was added and the solvent was removed by evaporation. The resulting solid was recrystallized from ethyl acetate to give the title compound (0.98 g, 72%) as a white solid.

Mp: 182-183.5 ^o C (decomposition)
IR (KBr) ν: 3800, 3500, 1640, 1440, 1100, 995, 950, 700 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.65 (s, 1H), 7.94 (s, 1H), 7.92 (d, J = 8 Hz, 1H), 7.62 (d, J = 8 Hz, 1H), 7.53 (t, J = 8 Hz, 1H), 7.46-7.28 (m, 5H), 6.58 (s, 2H), 5.42 (dd, J = 8.5, 10 Hz, 1H), 4.86 (dd, J = 8.5, 10 Hz, 1H), 4.33 (s, 2H), 4.21 (t, J = 8.5 Hz , 1H).

[α] _D : + 1.7 ^° (c = 0.18, DMF).

Elemental analysis:
Calculated: C 67.33%; H 5.14%; N 12.4%
Found: C 67.57%; H 5.17%; N, 12.17%.

Example 2
(+) - N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -2-propin-1-yl] and hydroxy-N'-methylurea :
The title compound was prepared analogously to the method of Example 1, using methyl isocyanate instead of trimethylsilyl isocyanate as a white solid (recrystallized from ethyl acetate / methanol).

Mp: 173.1 - 174.8 ^o C
IR (KBr) ν: 3360, 3100, 2850, 1670, 1640, 1540, 1410, 1340, 1100, 990, 950 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.59 (s, 1H), 7.92 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 7.7 Hz, 1H ), 7.52 (t, J = 7.3 Hz, 1H), 7.39 - 7.31 (m, 1H), 7.29 - 7.28 (m, 5H), 5.42 (dd, J = 8.10 Hz, 1H), 4.90 - 4.82 (m, 1H, 4.34 (s, 2H), 4.25 - 4.18 (m, 1H), 2.61 (d, J = 4.8 Hz, 3H).

[α] _D : = + 11.0 ^° (c = 0.2, methanol).

Example 3
(+) - N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -2-propin-1-yl] -N'-ethyl-N-hydroxyurea
The title compound was prepared analogously to the method of Example 1, using ethyl isocyanate instead of trimethylsilyl isocyanate as a white solid (recrystallized from ethyl acetate / hexane).

Mp: 141.2 - 143.0 ^o C
IR (KBr) ν: 3330, 3150-2850, 1670, 1660, 1530, 1440, 1340, 1240, 1100, 990, 950 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.59 (s, 1H), 7.92 (d, J = 9 Hz, 2H), 7.62 - 7.17 (m, 8H), 5.42 (t, J = 8 Hz, 1H), 4.86 (t J = 8.8 Hz, 1H), 4.33 (s, 2H), 4.21 (t, J = 8 Hz, 1H), 3 13 - 3.03 (m, 2H); 1.01 (t, 7.3 Hz, 3H).

[α] _D : + 8.0 ^° (c = 0.2, methanol).

Example 4
(+) - N- [3- [3- (4,5-Dihydro-4R) -Phenyloxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxy-N'isopropylurea
The title compound was prepared analogously to the method of Example 1, using isopropylisocyanate instead of trimethylsilyl isocyanate as a white solid (recrystallized from ethyl acetate / hexane).

Mp: 111.8-112.9 ^o C (decomposition)
IR (KBr) ν: 3420, 3250, 2970, 1670, 1640, 1510, 1350, 1230, 1100, 1000, 950 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.61 (s, 1H), 7.94-7.90 (m, 3H), 7.61-7.52 (m, 1H), 7.49- 7.28 (m, 5H), 6.85 (d, J = 8.4 Hz, 1H), 5.42 (dd, J = 8.4, -9.9 Hz, 1H), 4.86 ( dd, J = 8.4, 9.90 Hz, 1H), 4.33 (s, 2H), 4.20 (t, J = 8.4 Hz, 1H), 3.81-3.73 (m , 1H), 1.08 (d, J = 6.6 Hz, 6H).

[α] _D : = + 12.0 ^° (c = 0.2, methanol).

Example 5
(-) N- [3- [3- (4,5-Dihydro-4 (S) -phenyloxazol-2-yl) phenyl] - 2-propin-1-yl] -N-hydroxyurea
The title compound was prepared analogously to the method of Example 1 using (S) - (+) - 2-phenylglycinol instead of (R) - (-) - 2-phenylglycinol as a white solid (recrystallized from ethanol).

M.p ^. : 186.7 - 188.0 ^o C (decomposition)
IR (KBr) ν: 3380, 3500, 1640, 1440, 1100, 995, 950, 700 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.65 (s, 1H), 7.94 (s, 1H), 7.92 (d, J = 6 Hz, 1H), 7.62 (d, J = 8 Hz, 1H), 7.53 (t, J = 8 Hz, 1H), 7.46 - 7.28 (m, 5H), 6.58 (s, 2H), 5.42 (dd, J = 8.5, 10 Hz, 1H), 4.86 (dd, J = 8.5, 10 Hz, 1H), 4.33 (s, 2H), 4.21 (t, J = 8.5 Hz , 1H).

Example 6
(-) - N- [3- [3- (4,5-Dihydro-4 (S) -phenyloxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxy-N'-methylurea
The title compound was prepared analogously to the method of Example 5 using methyl isocyanate instead of trimethylsilyl isocyanate as white needles (recrystallized from ethyl acetate).

Mp: 163-165 ^o C
IR (KBr) ν: 3400, 1670, 1640, 700 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.56 (s, 1H), 7.94 (s, 1H), 7.93 (d, J = 8 Hz, 1H), 7.58 (t, J = 8 Hz, 1H), 7.52 (t, J = 8 Hz, 1H), 7.44 - 7.28 (m, 5H), 7.14 (q, J = 5 Hz, 1H), 5, 41 (dd, J = 8.5, 10 Hz, 1H), 4.89 (dd, J = 8.5, 10 Hz, 1H), 4.34 (s, 2H), 4.21 (t, J = 8.5 Hz, 1H); 2.61 (d, J = 5 Hz, 3H).

Example 7
(+) - N- [3- [3- (4,5-Dihydro-4 (R) - (4-fluorophenyl) oxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxyurea
The title compound was prepared analogously to the method of Example 1 using (R) - (-) - 2- (4-fluorophenyl) glycinol instead of (R) - (-) - 2-phenylglycinol as a white solid (recrystallized from ethyl acetate / methanol).

Mp: 180.9 - 181.4 ^o C
IR (KBr) ν: 3420, 3200-3300, 2850, 1640, 1510, 1440, 1240, 1100, 990, 950 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.64 (s, 1H), 7.94-7.91 (m, 2H), 7.63-7.61 (m, 1H), 7.52 ( t, J = 7.7 Hz, 1H), 7.35 (dd, J = 5.5, 8.8 Hz, 2H), 7.19 (t, J = 8.8 Hz, 2H), 6, 58 (s, 2H), 5.44 (t, J = 8.4 Hz, 1H), 4.86 (t, J = 8.4 Hz, 1H), 4.34 (s, 2H), 4, 19 (t, J = 8.4 Hz, 1H).

[α] _D : = + 6.5 ^° (c = 0.2, methanol).

Example 8
(-) - N- [3- [3- (4,5-Dihydro-4 (R) phenylthiazol-2-yl) phenyl] -2-propin-1-yl] - N-hydroxyurea
A. N- (1-tert-Butyldimethylsilyloxy-2 (R) -phenylethan-2-yl) -3-iodobenzamide
To a mixture of (+) - 2- (3-iodobenzamido) -2 (R) -phenylethan-1-ol (10 g, 27.2 mmol, obtained by the method of example 1) and imidazole (4.6 g, 68 mmol) in N, N-dimethylformamide (50 ml), tert-butyldimethylchlorosilane (6.2 g, 41 mmol) is added in one portion. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was separated and extracted with ethyl acetate (3 x 50 ml). The combined organic phase is washed with 1 N. HCl (100 ml), aqueous saturated NaHCO ₃ solution (100 ml) and brine (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 8), to obtain N- (1-tert-butyldimethylsilyloxy-2 (R) -phenylethan-2-yl) -3-iodobenzamide (13.1 g, quant.) in the form of a pale yellow liquid.

¹ H NMR (CDCl ₃ ) δ: 8.19 (s, 1H), 7.88 (d, J = 8 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 7.39- 7.20 (m, 6H), 6.99 (br s, 1H), 5.24-5.21 (m, 1H), 4.06 (dd, J = 4.4, 10 Hz, 1H) 3.94 (dd, J = 4.0, 10 Hz, 1H); 0.92 (s, 9H); 0.04 (s, 6H).

B. N- (1-tert-Butyldimethylsilyloxy-2 (R) -phenylethan-2-yl) -3-iodobenzothiamide
To a solution of N- (1-tert-butyldimethylsilyloxy-2 (R) -phenylethan-2-yl) -3-iodobenzamide (13.1 g, 27.2 mmol) in 1,2-dimethoxyethane (80 ml), Lawesson's reagent (8.2 g, 20 mmol). The reaction mixture was stirred at room temperature for 1 hour and then at 60 ^° C. for 2 hours, cooled and poured into water (100 ml). The mixture was extracted with CH ₂ Cl ₂ (2 x 50 ml), washed with brine (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 7), to obtain N- (1-tert-butyldimethylsilyloxy-2 (R) -phenylethan-2-yl) -3-iodobenzethiamide (4.99 g, 50%) as a yellow liquid.

¹ H NMR (CDCl ₃ ) δ: 8.30 (d, J = 1.8 Hz, 1H), 7.87-7.79 (m, 2H), 7.39-7.32 (m, 5H) , 7.17 (t, J = 7.7 Hz, 1H), 5.71 (t, J = 9.1 Hz, 1H), 3.87-3.79 (m, 2H), 3.35 ( dd, J = 9.5, 11 Hz, 1H), 0.9 (s, 6H), 0.3 (s, 9H).

B. 4,5-Dihydro-2- (3-iodophenyl) -4 (R) -phenylthiazole
To a solution of N- (1-tert-butyldimethylsilyloxy-2 (R) -phenylethan-2-yl) -3-iodobenzethiamide (8.1 g, 16 mmol) in THF (70 ml) was added dropwise tetrabutylammonium fluoride (1 M in THF, 21 ml). The reaction mixture was stirred at room temperature for 4 hours, the solvent was removed by evaporation and the resulting residue was purified.
silica gel column chromatography, eluting with ethyl acetate / n. hexane (1: 7) to give 4,5-dihydro-2- (3-iodophenyl) -4 (R) -phenylthiazole (2.46 g, 41%).

¹ H NMR (CDCl ₃ ) δ: 8.30 (s, 1H), 7.88-7.80 (m, 2H), 7.39-7.31 (m, 5H), 7.17 (t, J = 8 Hz, 1H), 5.70 (t, J = 9 Hz, 1H), 3.83 (dd, J = 9.11 Hz, 1H), 3.34 (dd, J = 9.5, 11 Hz, 1H).

Additional elution with ethyl acetate / n-hexane (1: 1) gave 2-amino-N- (3-iodobenzothiazoyl) -2 (R) -phenylethan-1-ol (0.75 g, 12%),
¹ H NMR (CDCl ₃ ) δ: 8.28 (br s, 1H), 8.12 (t, J = 1.8 Hz, 1H), 7.82-7.72 (m, 2H), 7 44-7.30 (m, 5H), 7.14 (t, J = 8 Hz, 1H), 5.86-5.80 (m, 1H), 4.17-4.07 (m, 3H )

G. (-) - N- [3- [3- (4,5-Dihydro-4 (R) -phenylthiazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 1, from 4,5-dihydro-2- (3-iodophenyl) -4 (R) -phenylthiazole, as a pale yellow solid (recrystallized from ethyl acetate / hexane).

Mp: 154.6-156.8 ^o C
IR (KBr) ν: 3400, 3300, 1640, 1440, 1090, 940 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.65 (s, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.62-7.46 (m, 2H), 7 , 39-7.33 (m, 5H), 6.59 (s, 2H), 5.78 (t, J = 8.8 Hz, 1H), 4.35 (s, 2H), 3.99 ( t, J = 9.2 Hz, 1H), 3.34-3.32 (m, 1H).

[α] _D : = -79 ^° (c = 0.2, methanol).

Elemental analysis:
Calculated: C 64.94%; H 4.88%; N 11.96%
Found: C 65.04%; H 4.74%; N, 11.98%.

Example 9
N'-Allyl-N- [3- [3- (4,5-dihydro-4 (R) -phenylthiazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 8, using allyl isocyanate instead of trimethylsilyl isocyanate.

T. pl .: amorphous
IR (KBr) ν: 3450, 3200, 1660, 1540, 1420, 910 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.66 (s, 1H), 7.85-7.82 (m, 2H), 7.61-7.30 (m, 8H), 5.85- 5.74 (m, 2H), 5.14-4.98 (m, 2H), 4.35 (s, 2H), 3.99 (dd, J = 9, 11 Hz, 1H), 3.68 (t, J = 5 Hz, 2H); 3.33 - 3.27 (m, 1H).

Example 10
(-) - N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -2-fluorophenyl] -2-propyn-yl] -N-hydroxyurea
A. 4,5-dihydro-2- (2-fluoro-3-iodophenyl) -4 (R) -phenyloxazole
4,5-dihydro-2- (2-fluoro-3-iodophenyl) -4 (R) - phenyloxazole is obtained from 2-fluoro-3-iodobenzoyl chloride in the same way as for the preparation of (+) - 4,5-dihydro-2- (3 iodophenyl) -4 (R) -phenyloxazole according to the procedure of Example 1.

¹ H NMR (CDCl ₃ ) δ: 7.96-7.85 (m, 2H), 7.39-7.28 (m, 5H), 6.97 (t, J = 8 Hz, 1H), 5 43 (t, J = 10 Hz, 1H), 4.80 (dd J = 8, 10 Hz, 1H), 4.29 (t, J = 8 Hz, 1H).

B. 3- [3- [4,5-Dihydro-4 (R) -phenyloxazol-2-yl] -2-fluorophenyl] -2-propin-1-ol
A mixture of 4,5-dihydro-2- (2-fluoro-3-iodophenyl) -4 (R) -phenyloxazole (2.28 g, 6.2 mmol), propargyl alcohol (0.22 g, 12.4 mmol) and bis (triphenylphosphine) palladium (II) chloride (220 mg, 1.1 mmol) in triethylamine (50 ml) was stirred for 1 h under nitrogen atmosphere, Cul (420 mg, 2.2 mmol) was added and the reaction mixture was stirred in for an additional 16 hours. Insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1:14), to give 3- [3- [4,5-dihydro-4 (R) -phenyloxazol-2-yl] -2-fluorophenyl] -2 -propin-1-ol (1.41 g, 77%) as an off-white solid.

¹ H NMR (CDCl ₃ ) δ: 7.92 (t, J = 7 Hz, 1H), 7.55 (t, J = 7 Hz, 1H), 7.36-7.25 (m, 5H), 7.16 (t, J = 7 Hz, 1H), 5.34 (t, J = 10 Hz, 1H), 4.81 (t, J = 8 Hz, 1H), 4.50 (d, J = 6 Hz, 2H), 4.32 (dd, J = 8, 10 Hz, 1H), 2.05 (t, J = 6 Hz, 1H).

B. N, O-Di (tert-butoxycarbonyl) - [3- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) - 2-fluorophenyl] -2-propin-1-yl ] hydroxylamine
To a mixture of 3- [3- [4,5-dihydro-4 (R) -phenyloxazol-2-yl] -2-fluorophenyl] -2-propin-1-ol (1.41 g, 4.8 mmol), N, O-bis (tert-butoxycarbonyl) hydroxylamine (1.11 g, 4.8 mmol) and triphenylphosphine (1.63 g, 6.2 mmol) in dry tetrahydrofuran (350 ml) is added dropwise a solution of diethyl azodicarboxylate (1, 08 g, 6.2 mmol) in dry tetrahydrofuran (15 ml). The reaction mixture was stirred for 2 hours and the volatiles were removed by evaporation. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 10), to obtain N, O-di (tert-butoxycarbonyl) - [3- [3- (4,5-dihydro-4 (R) -phenyloxazole- 2-yl) -2-fluorophenyl] -2-propin-1-yl] hydroxylamine (1.64 g 67%) as pale yellow plates.

¹ H NMR (CDCl ₃ ) δ: 7.89 (dt, J = 2.6 Hz, 1H), 7.55 (dt, J = 2.6 Hz, 1H), 7.40-7.28 (m , 5H), 7.14 (t, J = 7 Hz, 1H), 5.42 (dd, J = 8, 10 Hz, 1H), 4.80 (dd, J = 8, 10 Hz, 1H), 4.59 (br s, 2H), 4.28 (t, J = 8 Hz, 1H), 1.53 (s, 9H), 1.51 (s, 9H).

G. (-) - N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) 2-fluorophenyl] -2-propin-1-yl] -N-hydroxyurea
N, O-Di (tert-butoxycarbonyl) - [3- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) -2-fluorophenyl] -2-propin-1-yl] hydroxylamine converted to the title compound according to the procedure for Example 1, as a pale yellow solid (recrystallized from ethyl acetate).

Mp: 165.5-167.2 ^o C
IR (KBr) ν: 3400, 3250, 1640, 1000, 740, 700 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.64 (s, 1H), 7.91 (dt, J = 7.2 Hz, 1H), 7.67 (dt, J = 7.2 Hz, 1H ), 7.41-7.30 (m, 6H), 6.58 (s, 2H), 5.44 (dd, J = 10.8 Hz, 1H), 4.84 (dd, J = 10, 8 Hz, 1H), 4.38 (s, 2H), 4.19 (t, J = 8 Hz, 1H).

[α] _D : = -18 ^° (c = 0.2 methanol).

Elemental analysis:
Calculated: C 64.58%; H 4.56%; N 11.89%
Found: C 64.37%; H 4.47%; N, 11.49%.

Example 11
N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -4-fluorophenyl] -2-propin-1-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 10 using 2-fluoro-5-iodobenzoyl chloride instead of 2-fluoro-3-iodobenzoyl chloride as a white solid (recrystallized from ethyl acetate).

Mp: 172.6-173.8 ^o C
IR (KBr) ν: 3400, 3200 (br.), 1640 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.63 (s, 1H), 7.95 (dd, J = 7.2 Hz, 1H), 7.69-7.63 (m, 1H), 7 44-7.30 (m, 6H), 6.56 (s, 2H), 5.43 (dd, J = 10.8 Hz, 1H), 4.84 (dd, J = 10.8 Hz, 1H), 4.33 (s, 2H), 4.20 (t, J = 8 Hz, 1H).

Example 12
N- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -4-fluorophenyl] -2-propin-1-yl] -N-hydroxy-N'-methylurea
The title compound was prepared according to the procedure for Example 10, using methyl isocyanate instead of trimethylsilyl isocyanate, as a white solid (recrystallized from ethyl acetate).

Mp: 164.5-166 ^o C (decomposition)
IR (KBr) ν: 3360, 3100, 2850, 1670, 1635, 1495 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.57 (s, 1H), 7.93 (dd, J = 8.2 Hz, 1H), 7.66-7.62 (m, 1H), 7 , 43-7.25 (m, 6H), 7.10 (q, J = 5 Hz, 1H), 5.43 (dd, J = 8, 10 Hz, 1H), 4.8 (dd, J = 8, 10 Hz, 1H), 4.32 (s, 2H), 4.19 (t, J = 8 Hz, 1H), 2.61 (d, J = 5 Hz, 3H).

Example 13
N- [3- [5- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -2-methoxyphenyl] -2-propin-1-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 10, using 3-iodo-4-methoxybenzoyl chloride instead of 2-fluoro-3-iodobenzoyl chloride, as a white solid (recrystallized from ethyl acetate).

Mp: 189.5-192.0 ^o C
IR (KBr) ν: 3470, 2850, 1660, 1640, 1610, 1550, 1280, 1150, 1090, 950 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.54 (s, IH), 7.92-7.88 (m, 2H), 7.39-7.28 (m, 5H), 7.17 ( d, J = 9 Hz, 1H), 7.10 (d, J = 4.4 Hz, 1H), 5.37 (dd, J = 8, 9.5 Hz, 1H), 4.82 (dd, J = 8.4, 9.9 Hz, 1H), 4.34 (s, 2H), 4.17 (t, J = 8.4 Hz, 1H), 3.88 (s, 3H), 2, 61 (d, J = 5 Hz, 3H).

Example 14
N- [3- [5- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -2-methoxyphenyl] -2-propine -1-yl] -N-hydroxy-N'-methylurea
The title compound was prepared according to the procedure for Example 13, using methyl isocyanate instead of trimethylsilyl isocyanate, as a white solid (recrystallized from ethyl acetate).

Mp: 168.5-170.0 ^o C
IR (KBr) ν: 3000-3500, 2850, 1650, 1510, 1350, 1280, 1040, 950 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.59 (s, 1H), 7.91-7.88, (m, 2H), 7.39-7.28 (m, 5H), 7.17 (d, J = 9 Hz, 1H), 6.55 (s, 2H), 5.38 (dd, J = 8, 9.9 Hz, 1H), 4.78 (dd, J = 8.4, 9.9 Hz, 1H), 4.34 (s, 2H), 4.17 (t, J = 8.4 Hz, 1H), 3.89 (s, 3H).

Example 15
N- [3- [5- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -2-methylphenyl] -2-propin-1-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 10 using 3-iodo-4-methylbenzoyl chloride instead of 2-fluoro-3-iodobenzoyl chloride as a white solid (recrystallized from ethyl acetate).

Mp: 169.0-169.5 ^o C
IR (KBr) ν: 3480, 3350, 3200, 2900, 1640, 1580 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.61 (s, 1H), 7.90 (s, 1H), 7.81 (dd, J = 8.2 Hz, 1H), 7.43-7 26 (m, 6H), 6.58 (s, 2H), 5.39 (dd, J = 10.8 Hz, 1H), 4.36 (s, 2H), 4.19 (t, J = 8 Hz, 1H); 2.43 (s, 3H).

Example 16
N- [3- [5- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -2-methylphenyl] -2-propine -1-yl] -N-hydroxy-N'-methylurea
The title compound was prepared according to the procedure for Example 15 using methyl isocyanate instead of trimethylsilyl isocyanate as a white solid (recrystallized from ethyl acetate).

Mp: 175.8-176.4 ^o C (decomposition)
IR (KBr) ν: 3350, 3100, 2800, 1675, 1640, 1515, 1370 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.56 (s, 1H), 7.89 (d, J = 2 Hz, 1H), 7.81 (dd, J = 8.2 Hz, 1H), 7.43-7.26 (m, 6H), 7.14 (q, J = 5 Hz, 1H), 5.40 (dd, J = 8, 10 Hz, 1H), 4.84 (dd, J = 8, 10 Hz, 1H), 4.36 (s, 2H), 4.19 (t, J = 8 Hz, 1H), 2.62 (d, J = 5 Hz, 3H), 2.42 ( s, 3H).

Example 17
N- [3- [3- (4 (S) -Benzyl-4,5-dihydrooxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 1 using (S) - (-) - 2-amino-3-phenyl-1-propanol instead of (R) - (-) - 2-phenylglycinol as a white solid (recrystallized from ethanol).

Mp: 167.5-168.9 ^o C (decomposition)
IR (KBr) ν: 3400, 3250, 2850, 1630, 1440, 1350, 1100, 1000, 960, 800 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.64 (s, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 7.7 Hz, 1H ), 7.48 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 4.4 Hz, 4H), 7.24-7.21 (m, 1H), 6.59 (s, 2H), 4.59-4.53 (m, 1H), 4.43 (t, J = 8 Hz, 1H), 4.34 (s, 2H), 4.11 (t, J = 7.7 Hz, 1H), 2.99 (dd, J = 6, 13.5 Hz, 1H), 2.79 (dd, J = 7, 13.5 Hz, 1H).

Example 18
N- [3- [3- (4 (S) -Benzyl-4,5-dihydrooxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxy-N'-methylurea
The title compound was prepared according to the procedure for Example 17, using methyl isocyanate instead of trimethylsilyl isocyanate as a white solid (recrystallized from ethyl acetate / methanol).

Mp: 169.6 - 170.9 ^o C
IR (KBr) ν: 3420, 3250, 1660, 1540, 1360, 1240, 1100, 990, 800 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.59 (s, 1H), 7.82 (d, J = 7 Hz, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 7.29 (d, J = 4 Hz, 4H), 7.23-7.20 (m, 1H), 7.13 (d, J = 4 , 8 Hz, 1H), 4.56-4.53 (m, 1H), 4.43 (t, J = 8.4 Hz, 1H), 4.34 (s, 2H), 4.11 (t , J = 8 Hz, 1H), 3.16 (dd, J = 6, 13.5 Hz, 1H), 2.79 (dd, J = 7, 13.5 Hz, 1H), 2.62 (d , J = 4.7 Hz, 3H).

Example 19
N- [3- [3- (4 (R) -Benzyl-4,5-dihydrooxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 1 using (R) - (+) - 2-amino-3-phenyl-1-propanol instead of (R) - (-) - 2-phenylglycinol as a white solid (recrystallized from ethanol).

Mp: 164.3-166.0 ^o C
IR (KBr) ν: 3400, 3250, 2850, 1630, 1440, 1250, 1100, 1000, 960 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.65 (s, 1H), 7.84-7.80 (m, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7 48 (t, J = 7.3 Hz, 1H), 7.30-7.20 (m, 5H), 6.58 (s, 2H), 4.59-4.53 (m, 1H), 4.43 (t, J = 8.8 Hz, 1H), 4.33 (s, 2H), 4.11 (t, J = 7.7 Hz, 1H), 2.99 (dd, J = 6 , 13.5 Hz, 1H); 2.79 (dd, J = 7, 13.5 Hz, 1H).

Example 20
N- [3- [3- (4 (R) -Benzyl-4,5-dihydrooxazol-2-yl) phenyl] -2-propin-1-yl] -N-hydroxy-N'-methylurea
The title compound was prepared according to the procedure for Example 19, using methyl isocyanate instead of trimethylsilyl isocyanate as a white solid.

Mp: 160.2-161.2 ^o C
IR (KBr) ν: 3450, 3200, 2850, 1660, 1530, 1360, 1230, 1100, 990, 960 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.60 (s, 1H), 7.82 (d, J = 6.6 Hz, 2H), 7.57 (d, J = 7.7 Hz, 1H ), 7.48 (t, J = 8 Hz, 1H), 7.31-7.12 (m, 6H), 4.59-4.51 (m, 1H), 4.43 (t, J = 8 Hz, 1H), 4.34 (s, 2H), 4.41 (t, J = 7.7 Hz, 1H), 2.99 (dd, J = 6, 13.5 Hz, 1H), 2 80 (dd, J = 7, 13.5 Hz, 1H); 2.62 (d, J = 4.8 Hz, 3H).

Example 21
N- [4- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] -N-hydroxyurea
A. 2- (3-Bromobenzamido) -2 (R) -phenylethan-1-ol
To a vigorously stirred solution of 3-bromobenzoyl chloride (13 g, 58 mmol) in dichloromethane (500 ml), a solution of (R) - (-) - 2-phenylglycinol (10.5 g, 76 mmol) in dichloromethane (50 ml) is quickly added. The reaction mixture was stirred for 3 hours and insoluble material was removed by filtration. Concentration of the filtrate gives 2- (3-bromobenzamido) - 2 (R) -phenylethan-1-ol as a colorless solid (18.5 g, amounts).

¹ H NMR (CDCl ₃ ) δ: 7.95 (t, J = 1.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.39-7.29 (m, 7H), 6.83 (br s, 1H), 5.28-5.23 (m, 1H), 4.02 (d, J = 4.4 Hz, 2H).

B. 2- (3-Bromophenyl) -4,5-dihydro-4 (R) -phenyloxazole
To a mixture of 2- (3-bromobenzamido) -2- (R) -phenylethan-1-ol (18 g, 56 mmol) and triphenylphosphine (19.2 g, 73 mmol) in dry tetrahydrofuran (350 ml), cooled to -60 ^° C., diethyl azodicarboxylate (12 ml, 73 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 18 hours and the volatiles were removed by evaporation. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 7), to give 2- (3-bromophenyl) -4,5-dihydro-4 (R) -phenyloxazole (10.9 g, 65%) as pink liquid.

¹ H NMR (CDCl ₃ ) δ: 8.21 (t, J = 1.8 Hz, 1H), 7.98-7.94 (m, 1H), 7.66-7.61 (m, 1H) , 7.39-7.28 (m, 6H), 5.39 (dd, J = 8, 10 Hz, 1H), 4.81 (dd, J = 8, 10 Hz, 1H), 4.29 ( t, J = 8 Hz, 1H).

B. N- [4- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] hydroxylamine
A mixture of 2- (3-bromophenyl) -4,5-dihydro-4 (R) -phenyloxazole (4.5 g, 15 mmol), [N, O-di (tert-butoxycarbonyl) -3-butyn-2-yl ] hydroxylamine (6.4 g, 22 mmol) and bis (triphenylphosphine) palladium (II) chloride (522 mg, 0.75 mmol) in triethylamine (15 ml) were stirred at 75 ^° C. for 3 hours under nitrogen atmosphere. The reaction mixture was cooled and concentrated under reduced pressure. The residue was extracted with ethyl acetate (3 x 50 ml) and washed with 1N. HCl (100 ml), aqueous 4% NaHCO ₃ solution (100 ml) and brine (100 ml). The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 7), to obtain crude N, O-di (tert-butoxycarbonyl) - [3- [3- (4,5-dihydro-4 (R) - phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] hydroxylamine (4.1 g).

Trifluoroacetic acid (6.1 ml, 79 mmol) was slowly added to a solution of the obtained protected hydroxylamine in dichloromethane (40 ml) cooled to 0 ^° C. The reaction mixture was allowed to warm to room temperature, stirred for an additional 30 minutes, and then poured into a saturated aqueous solution of NaHCO ₃ (100 ml). The mixture was extracted with dichloromethane (2 x 50 ml) and the organic phase was washed with water (100 ml), brine (120 ml), dried (MgSO ₄ ) and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 1), to obtain N- [4- [3- (4,5-dihydro- (R) -phenyloxazol-2-yl) phenyl] -3- butyn-2-yl] hydroxylamine (1.4 g, 58%) as an orange oil.

¹ H NMR (CDCl ₃ ) δ: 8.14 (s, 1H), 7.97 (d, J = 8 Hz, 1H), 7.56 (d, J = 8 Hz, 1H), 7.40- 7.28 (m, 7H), 5.42-5.35 (m, 1H), 5.25 (br s, 1H), 4.80 (t, J = 8.5 Hz, 1 H), 4.31-4.25 (m, 1H); 4.13-4.02 (m, 1H); 1.43 (d, J = 7 Hz, 3H).

G. N- [4- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] -N- hydroxyurea
To a solution of N- [4- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] hydroxylamine (1.3 g, 4.2 mmol ) in THF (13 ml), trimethylsilyl isocyanate (0.84 ml, 6.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. Methanol (10 ml) was added and after 10 minutes the solvent was removed by evaporation. The resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate, to obtain the title compound (0.9, 64%) as a colorless amorphous solid.

Mp: amorphous
IR (KBr) ν: 3500, 3400, 2900, 1650, 1560, 1360, 960 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.36 (s, 1H), 7.91 (d, J = 1.4 Hz, 2H), 7.59 (d, J = 8 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.39-9.29 (m, 5H), 6.57 (s, 2H), 5.42 (t, J = 10 Hz, 1H ), 5.14 (dd, J = 6.6, 14 Hz, 1H), 4.86 (t, J = 10 Hz, 1H), 4.21 (t, J = 8 Hz, 1H), 1, 37 (d, J = 7 Hz, 3H).

Example 22
N- [4- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] -N-hydroxyurea (first enantiomer)
N- [4- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl-3-butyn-2-yl] -N-hydroxyurea (Example 21) was separated on a chiral stationary substrate ( CHIRALPAK OJ (Daicel Chemical Industries) 0.46 x 25 cm; mobile phase: ethanol / hexane (20:80); flow rate 1 ml / min; temperature equal to room temperature; 1 = 230 nm) to obtain the title compound ( Example 22, retention time = 21.4 min).

¹ H NMR (DMSO-d ₆ ) δ: 9.36 (s, 1H), 7.91 (d, J = 1.4 Hz, 2H), 7.59 (d, J = 8 Hz, 1H), 7, 51 (t, J = 7.3 Hz, 1H), 7.39-9.29 (m, 5H), 6.57 (s, 2H), 5.42 (t, J = 10 Hz, 1H), 5.14 (dd, J = 6.6, 14 Hz, 1H), 4.86 (t, J = 10 Hz, 1H), 4.21 (t, J = 8 Hz, 1H), 1.37 ( d, J = 7 Hz, 3H).

Example 23
N- [4- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] -N- hydroxyurea (second enantiomer)
N- [4- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenyl-3-butyn-2-yl] -N-hydroxyurea (Example 21) was separated on a chiral stationary substrate ( CHIRALPAK OJ (Daicel Chemical Industries) 0.46 x 25 cm; mobile phase: ethanol / hexane (20:80); flow rate 1 ml / min; temperature equal to room temperature; 1 = 230 nm) to obtain the title compound ( Example 23, retention time = 36.5 min).

¹ H NMR (DMSO-d ₆ ) δ: 9.36 (s, 1H), 7.91 (d, J = 1.4 Hz, 2H), 7.59 (d, J = 8 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.39-9.29 (m, 5H), 6.57 (s, 2H), 5.42 (t, J = 10 Hz, 1H ), 5.14 (dd, J = 6.6, 14 Hz, 1H), 4.86 (t, J = 10 Hz, 1H), 4.21 (t, J = 8 Hz, 1H), 1, 37 (d, J = 7 Hz, 3H).

Example 24
N- [4- [3- (4,5-Dihydro-5-phenyloxazol-2-yl) phenyl] -3-butyn-2-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 21, using 2-amino-1-phenylethanol in place of (R) - (-) - 2-phenylglycinol as a white solid (recrystallized from ethyl acetate).

Mp: 145.1-146.4 ^o C
IR (KBr) ν: 3400, 3200, 2900, 1640, 1590, 1420, 1080, 1000, 960 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.38 (s, 1H), 7.93-7.89 (m, 2H), 7.60-7.35 (m, 7H), 6.56 ( s, 2H), 5.79 (t, J = 6.7 Hz, 1H), 5.13 (m, 1H), 4.45 (dd, J = 10, 15 Hz, 1H), 3.84 ( dd, J = 7.15 Hz, 1H); 1.37 (d, J = 7 Hz, 3H).

Example 25
N- [4- [3- (4 (S) -Benzyl-4,5-dihydrooxazol-2-yl) phenyl] -3-butyn-2-yl] -N-hydroxy-N'-methylurea
The title compound was prepared according to the procedure for Example 21, using (S) - (-) - 2-amino-3-phenyl-1-propanol instead of (R) - (-) - 2-phenylglycinol and methyl isocyanate instead of trimethylsilyl isocyanate as white solid product (recrystallized from ethyl acetate).

Mp: 153.8-155.0 ^o C
IR (KBr) ν: 3390, 2900, 1660, 1540, 1360, 1210, 1070, 960, 910 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.32 (s, 1H), 7.81 (d, J = 6 Hz, 2H), 7.54-7.46 (m, 2H), 7.30 -7.13 (m, 6H), 5.12 (q, J = 7 Hz, 1H), 4.59-4.51 (m, 1H), 4.43 (t, J = 8 Hz, 1H) , 4.10 (t, J = 8 Hz, 1H), 2.99 (dd, J = 6, 13.5 Hz, 1H), 2.79 (dd, J = 7, 13.5 Hz, 1H) 2.63 (d, J = 4 Hz, 3H); 1.37 (d, J = 7 Hz, 3H).

Example 26
N- [4- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) pyridin-5-yl] -3-butyn-2-yl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 21, using 5-bromonicotinoyl chloride hydrochloride instead of 3-bromobenzoyl chloride.

T. pl.: Amorphous
IR (KBr) ν: 3000-3500, 2950, 1650, 1500, 1420, 1160 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.40 (s, 1H), 9.20 (s, 1H), 8.76 (s, 1H), 8.23 (s, 1H), 7.40 -7.31 (m, 5H), 6.60 (s, 2H), 5.45 (t, J = 9 Hz, 1H), 5.18 (dd, J = 7, 13.5 Hz, 1H) 4.90 (t, J = 9.5 Hz, 1H); 4.25 (t, J = 8.4 Hz, 1H); 1.38 (d, J = 6.6 Hz, 3H).

Example 27
N- [4- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) pyridin-5-yl] -3-butyn-2-yl] -N-hydroxy-N'-methylurea
The title compound was prepared according to the procedure for Example 26, using methyl isocyanate instead of trimethylsilyl isocyanate as a white solid (recrystallized from ethyl acetate).

Mp: amorphous
IR (KBr) ν: 3000-3400, 2900, 1650, 1530, 1360, 1080 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.35 (s, 1H), 9.20 (d, J = 2 Hz, 1H), 8.76 (d, J = 2 Hz, 1H), 8, 22 (s, 1H), 7.38-7.31 (m, 5H), 7.14-7.13 (m, 1H), 5.46 (t, J = 8.8 Hz, 1H), 5 , 17-5.14 (m, 1H), 4.90 (t, J = 8.8 Hz, 1H), 4.25 (t, J = 8.4 Hz, 1H), 2.62 (d, J = 4.7 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H).

Example 28
(-) - Nl- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethyl] -N-hydroxyurea
A. 2- (3-Benzyloxybenzamido) -2 (R) -phenylethan-1-ol
Thionyl chloride (14.1 ml, 19 mmol) was added dropwise to a solution of 3-benzyloxybenzoic acid (22 g, 96 mmol) in toluene (200 ml). The reaction mixture was heated at 90 ^° C. for 2 hours, cooled to room temperature and the volatiles removed under reduced pressure to give crude 3-benzyloxybenzoyl chloride (32 g, quant.). The crude 3-benzyloxybenzoyl chloride was dissolved in CH ₂ Cl ₂ and added dropwise to the vigorously stirred solution of (R) - (-) - 2-phenylglycinol (15.8 g, 115 mmol) and triethylamine (16 ml, 15 mmol) over 30 minutes. ) in CH ₂ Cl ₂ (200 ml), cooled to 0 ^o C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (1 L) and water (1 L).

The aqueous layer was separated, extracted with ethyl acetate (2 x 500 ml) and the combined organic phase was washed with 1 N HCl (500 ml), aqueous 4% NaHCO ₃ solution (500 ml) and brine (500 ml), dried over MgSO ₄ and concentrated under reduced pressure to obtain 2- (3-benzyloxybenzamido) -2 (R) -phenylethane- 1-ol (29 g, 88%) as a pale yellow solid.

¹ H NMR (CDCl ₃ ) δ: 7.46-7.29 (m, 9H), 7.04-7.01 (m, 1H), 5.34 (t, J = 8.8 Hz, 1H) 4.89-4.79 (m, 1H); 4.31 (t, J = 8 Hz, 1H).

B. 2- (3-Benzyloxyphenyl) -4,5-dihydro-4 (R) -phenyloxazole
To a mixture of 2- (3-benzyloxybenzamido) -2 (R) -phenylethan-1-ol (29 g, 83 mmol) and triphenylphosphine (28.4 g, 108 mmol) in dry tetrahydrofuran (200 ml) is added dropwise a solution of diisopropylazodicarboxylate (19.6 ml, 108 mmol) in dry tetrahydrofuran (30 ml). The reaction mixture was stirred for 4 hours and the volatiles were removed by evaporation. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 9), to give 2- (3-benzyloxyphenyl) -4,5-dihydro-4 (R) -phenyloxazole (23.5 g, 85%) as a pale yellow solid.

¹ H NMR (CDCl ₃ ) δ: 7.70-7.63 (m, 2H), 7.46-7.28 (m, 11H), 7.15-7.11 (m, 1H), 5, 39 (dd, J = 8, 9.9 Hz, 1H), 5.11 (s, 2H), 4.80 (dd, J = 8.4, 9.9 Hz, 1H), 4.27 (t , J = 8 Hz, 1H).

B. 4,5-dihydro-2- (3-hydroxyphenyl) -4 (R) -phenyloxazole
2- (3-Benzyloxyphenyl) -4,5-dihydro-4 (R) -phenyloxazole (3 g, 8.9 mmol) was dissolved in ethyl acetate (15 ml) and hydrogenated in the presence of 10% palladium on charcoal (300 mg). Recrystallization from ethyl acetate / n-hexane gave 4,5-dihydro-2- (3-hydroxyphenyl) -4 (R) -phenyloxazole (1.03 g, 48%) as colorless needles.

¹ H NMR (CDCl ₃ ) δ: 7.56-7.53 (m, 2H), 7.38-7.28 (m, 6H), 6.98-6.95 (m, 1H), 6, 37 (br s, 1H), 5.38 (dd, J = 8, 9.9 Hz, 1H), 4.80 (dd, J = 8.4, 9.9 Hz, 1H), 4.29 (t, J = 8 Hz, 1H).

G. 1- (tert-Butyldimethylsilyloxy) -2- [3- (4,5, -dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethane
To a stirred solution of 4,5-dihydro-2- (3-hydroxyphenyl) -4 (R) -phenyloxazole (3.3 g, 13.8 mmol) in N, N-dimethylformamide (30 ml) was added in parts over 5 minutes at room temperature, sodium hydride (60% in mineral oil, 0.62 g, 16 mmol). The mixture was stirred for 1 h and then a solution of 2-bromo-1- (tert-butyldimethylsilyloxy) ethane (4.94 g, 21 mmol) in N, N-dimethylformamide (5 ml) was added dropwise over 5 min and the reaction mixture leave overnight. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml), the aqueous layer was separated, extracted with ethyl acetate (2 x 50 ml) and the combined organic phase was washed with 1 N HCl (100 ml), aqueous 4% NaHCO ₃ solution (100 ml) and brine (100 ml), dried (MgSO ₄ ) and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate / n-hexane (1: 6), to obtain 1- (tert-butyldimethylsilyloxy) -2- [3- (4,5-dihydro-4 (R) - phenyloxazole-2 -yl) phenoxy] ethane (4.7 g, 86%) as a colorless oil.

¹ H NMR (CDCl ₃ ) δ: 7.54-7.48 (m, 2H), 7.29-7.15 (m, 6H), 6.99-6.95 (m, 1H), 5, 28 (dd, J = 8, 9.9 Hz, 1H), 4.69 (dd, J = 8.4, 9.9 Hz, 1H), 4.16 (t, J = 8 Hz, 1H), 4.01-3.97 (m, 2H), 3.89-3.85 (m, 2H), 0.80 (s, 9H), 0.01 (s, 6H).

D. 2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethan-1-ol
To a solution of 1- (tert-butyldimethylsilyloxy) -2- [3- (4,5-dihydro-4-R) phenyloxazol-2-yl) phenoxy] ethane (4.4 g, 11 mmol) in THF (35 ml ) tetrabutylammonium fluoride (1 M in THF, 14 ml) is added dropwise. The reaction mixture was stirred at room temperature for 45 minutes, the solvent was removed by evaporation, and the obtained residue was purified by silica gel column chromatography, eluting with ethyl acetate / n-hexane (1: 2), to give 2- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethan-1-ol (2.8 g, 91%) as a colorless oil.

¹ H NMR (CDCl ₃ ) δ: 7.66-7.60 (m, 2H), 7.39-7.29 (m, 6H), 7.10-7.07 (m, 1H), 5, 34 (dd, J = 8, 10 Hz, 1H), 4.80 (dd, J = 8.4, 10 Hz, 1H), 4.28 (t, J = 8.4 Hz, 1H), 4, 14 (t, J = 4.4 Hz, 2H), 3.96 (br s, 2H), 2.04 (br s, 1H).

E. (-) - N-1- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethyl] -N-hydroxyurea
2- [3- (4,5-Dihydro-4 (R) - phenyloxazol-2-yl) phenoxy] ethan-1-ol is converted to the title compound according to the procedure for Example 10, as a colorless solid (recrystallized from a mixture ethyl acetate / hexane).

Mp 135.7-137.4 ^o C
IR (KBr) ν: 3500, 3400, 2900, 1640, 1580, 1220, 1060, 990 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.45 (d, J = 1.1 Hz, 1H), 7.54-7.29 (m, 8H), 7.18-7.15 (m, 1H), 6.37 (s, 2H), 5.41 (t, J = 9 Hz, 1H), 4.85 (t, J = 10 Hz, 1H), 4.23-4.14 (m, 3H), 3.72 (t, J = 5.5 Hz, 2H).

[α] _D : = −1 ^° (c = 0.2, methanol).

Elemental analysis:
Calculated: C 63.33%; H 5.61%; N 12.31%
Found: C 63.29%; H 5.54%; N, 12.27%.

Example 29
N-1- [3- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] propyl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 28 using 3-bromo-1- (tert-butyldimethylsilyloxy) propane instead of 2-bromo-1- (tert-butyldimethylsilyloxy) ethane, as a white solid (recrystallized from ethyl acetate / hexane) .

Mp: 149.5-150.8 ^o C
IR (KBr) ν: 3500, 3350, 3200, 1640, 1580, 1450, 1100, 980 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.29 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.44-7.28 (m, 7H), 7 , 16-7.12 (m, 1H), 6.29 (s, 2H), 5.40 (dd, J = 8.4, 10 Hz, 1H), 4.84 (dd, J = 8.4 10 Hz, 1H), 4.19 (t, J = 8.4 Hz, 1H), 4.05 (t, J = 6.6 Hz, 2H), 3.49 (t, J = 7 Hz, 2H ), 1.98-1.93 (m, 2H).

Example 30
N-1- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethyl] -N-hydroxy-N'-methylurea
The title compound was prepared according to the procedure for Example 28, using methyl isocyanate instead of trimethylsilyl isocyanate as a white solid (recrystallized from ethyl acetate / hexane).

Mp 132.5-133.6 ^o C
IR (KBr) ν: 3390, 3100, 2900, 1660, 1530, 1450, 1320, 1090, 1000, 950 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.39 (s, 1H), 7.54-7.29 (m, 8H), 7.17-7.14 (m, 1H), 6.93- 6.92 (m, 1H), 5.41 (t, J = 8 Hz, 1H), 4.84 (dd, J = 8.4, 10 Hz, 1H), 4.34-4.13 (m , 3H), 3.71 (t, J = 5.5 Hz, 2H), 2.60 (d, J = 5 Hz, 3H).

Example 31
(+) - N-1- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) 5-fluorophenoxy] ethyl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 28 using 3-benzyloxy-5-fluorobenzoic acid instead of 3-benzyloxybenzoic acid as a white solid (recrystallized from ethyl acetate / hexane).

Mp: 122.4-123.7 ^o C
IR (KBr) ν: 3500, 3400, 3200, 1660, 1580, 1440, 1150, 1030, 930 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.45 (s, 1H), 7.40-7.25 (m, 7H), 7.12-7.07 (m, 1H), 6.38 ( s, 2H), 5.42 (dd, J = 8.4, 9.9 Hz, 1H), 4.86 (dd, J = 8.4, 9.9 Hz, 1H), 4.25-4 16 (m, 3H); 3.70 (t, J = 5.5 Hz, 2H).

[α] _D : = +3.5 (c = 0.2, methanol).

Example 32
(+) - N-1- [2- [3- (4,5-Dihydro-4 (R) - (4-fluorophenyl) oxazol-2-yl) phenoxy] ethyl] -N-hydroxyheucene
The title compound was prepared according to the procedure for Example 28 using (R) - (-) - 2- (4-fluorophenyl) glycinol instead of (R) - (-) - 2-phenylglycinol as a white solid (recrystallized from methanol / ethyl acetate).

Mp: 150.3-151.9 ^o C
IR (KBr) ν: 3500, 3320, 2900, 1630, 1510, 1210, 1070, 990 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.45 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.45-7.32 (m, 4H), 7 22-7.16 (m, 3H), 6.38 (s, 2H), 5.42 (t, J = 9.2 Hz, 1H), 4.84 (t, J = 9.2 Hz, 1H), 4.21-4.13 (m, 3H), 3.71 (t, J = 6 Hz, 2H).

[α] _D : = +0.5 ^° (c = 0.2, methanol).

Example 33
N-1- [2 (R) - [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] propyl] -N- hydroxyurea
A. 1- (tert-Butyldimethylsilyloxy) -2 (R) - [3 [(4,5-dihydro-4 (R) - phenyloxazol-2-yl) phenoxy] propane
To a mixture of 4,5-dihydro-2- (3-hydroxyphenyl) -4 (R) -phenyloxazole (5.0 g, 20.9 mmol), 1- (tert-butyldimethylsilyloxy) propan-2 (S) -ol ( 4.76 g, 25 mmol) and triphenylphosphine (6.58 g, 25 mmol) in dry tetrahydrofuran (30 ml) was added dropwise a solution of diethyl azodicarboxylate (3.9 ml, 25 mmol) in dry tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature for 1 hour and then at 50 ^° C. for 5 hours. Volatiles were removed by evaporation and the resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane (1: 6), to give 1- (tert -butyldimethylsilyloxy) -2 (R) - [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -phenoxy] propane (8.7 g, quant.) as a colorless oil.

¹ H NMR (CDCl ₃ ) δ: 7.62-7.59 (m, 2H), 7.38-7.29 (m, 6H), 7.08-7.05 (m, 1H), 5, 38 (t, J = 10 Hz, 1H), 4.78 (dd, J = 8.4, 10 Hz, 1H), 4.55-4.8 (m, 1H), 4.26 (t, J = 8 Hz, 1H), 3.80 (dd, J = 5.9, 10.6 Hz, 1H), 3.65 (dd, J = 5.1, 10.6 Hz, 1H), 1.57 (d, J = 8 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H).

B. N-1- [2 (R) - [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] propyl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 28 using 1- (tert-butyldimethylsilyloxy) -2 (R) - [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] propane instead of 1 - (tert-butyldimethylsilyloxy) -2- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethane, as an amorphous product.

IR (Nujol) ν: 3200, 2900, 1650, 1580, 1450, 980 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.47 (s, 1H), 7.52-7.28 (m, 8H), 7.16 (d, J = 8 Hz, 1H), 6.31 (s, 2H), 5.40 (t, J = 8.4 Hz, 1H), 4.84 (t, J = 8.8 Hz, 1H), 4.72-4.66 (m, 1H) , 4.19 (t, J = 8.4 Hz, 1H), 3.71 (dd, J = 6, 14 Hz, 1H), 3.38 (dd, J = 6.14 Hz, 1H), 1 25 (d, J = 6 Hz, 3H).

Elemental analysis:
Calculated: C 63.32%; H 5.96%; N 11.82%
Found: C 63.11%; H 6.11%; N 11.47%
Example 34
N-1- [2 (S) - [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] propyl] - N-hydroxyurea
The title compound was prepared according to the procedure for Example 28 using 1- (tert-butyldimethylsilyloxy) -2 (S) - [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] propane instead of 1 - (tert-butyldimethylsilyloxy) -2- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) phenoxy] ethane, as a white solid (recrystallized from ethyl acetate / hexane).

Mp: 163.4-164.7 ^o C.

IR (Nujol) ν: 3450, 3200, 2850, 1620, 1580, 1450, 1210, 1080, 980 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.47 (s, 1H), 7.53-7.14 (m, 9H), 6.32 (s, 2H), 5.40 (t, J = 9.9 Hz, 1H), 4.84 (t, J = 8.4 Hz, 1H), 4.70 (k, J = 5.8 Hz, 1H), 4.19 (t, J = 8, 4 Hz, 1H), 3.70 (dd, J = 6.14 Hz, 1H), 3.41 (dd, J = 6.14 Hz, 1H), 1.26 (d, J = 6 Hz, 3H )

Elemental analysis:
Calculated: C 63.32%; H 5.96%; N 11.82%
Found: C 64.42%; H 6.09%; N 11.80%.

Example 35
(+) - N-1- [2- [3- (4,5-Dihydro-4 (S) -phenyloxazol-2-yl) phenoxy] ethyl] -N- hydroxyurea
A. 4,5-dihydro-2- (3-hydroxyphenyl) -4 (S) phenyloxazole
4,5-dihydro-2- (3-hydroxyphenyl) -4 (S) phenyloxazole was prepared according to the procedure for Example 28 B using (S) - (+) - phenylglycinol instead of (R) - (-) - phenylglycinol.

¹ H NMR (CDCl ₃ + 2 drops DMSO-d ₆ ) δ: 8.8 (s, 1H), 7.53-7.50 (m, 2H), 7.36 - 7.18 (m, 6H) , 7.00 (d, J = 7 Hz, 1H), 5.33 (t, J = 8 Hz, 1H), 4.77 (t, J = 10 Hz, 1H), 4.24 (t, J = 8 Hz, 1H).

B. Ethyl 3- (4,5-dihydro-4 (S) -phenyloxazol-2-yl) phenoxyacetate
To a vigorously stirred mixture of 4,5-dihydro-2- (3-hydroxyphenyl) -4 (3) -phenyloxazole (2.04 g, 8.5 mmol) and potassium carbonate (2.36 g, 17 mmol) in DMF ( 40 ml), a solution of ethyl bromoacetate (1.71 g, 10.2 mmol) in DMF (5 ml) was added dropwise over 5 minutes at room temperature. The reaction mixture was stirred for 12 hours and then poured into water (100 ml). The mixture was extracted with diethyl ether (3 x 50 ml) and the combined extracts washed with brine (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to obtain the title compound (2.77 g, quant.) As a pale yellow fluid.

¹ H NMR (CDCl ₃ ) δ: 7.68 (d, J = 7 Hz, 1H), 7.57 (d, J = 2 Hz, 1H), 7.39-7.28 (m, 6H), 7.12 (dd, J = 7 and 2 Hz, 1H), 5.38 (dd, J = 8 and 10 Hz, 1H), 4.79 (t, J = 8 Hz, 1H), 4.67 ( s, 2H), 4.31-4.23 (m, 3H), 1.29 (t, J = 7 Hz, 3H).

B. 2- [3- [4,5-Dihydro-4 (S) -phenyloxazol-2-yl] phenoxy] ethan-1-ol
To a solution of ethyl 3- (4,5-dihydro-4 (S) -phenyloxazol-2-yl) phenoxyacetate (2.77 g, 8.5 mmol) in a THF solution (40 ml), LiBH ₄ (0.37) was added g, 17 mmol) in one portion. After stirring for 4 hours, water (40 ml) was added and the mixture was diluted with diethyl ether (40 ml). The aqueous solution was separated and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts are washed with 0.5 N. aqueous HCl (20 ml), brine (20 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with hexane / ethyl acetate (2: 1), to give the title compound (0.95 g, 40%) as a colorless liquid.

¹ H NMR (CDCl ₃ ) δ: 7.66-7.59 (m, 2H), 7.39-7.26 (m, 6H), 7.06 (dd, J = 2 and 7 Hz, 1H) , 5.39 (dd, J = 10 and 8 Hz, 1H), 4.80 (dd, J = 10 and 8 Hz, 1H), 4.28 (t, J = 8 Hz, 1H), 4.16 -4.12 (m, 2H), 3.98-3.92 (m, 2H), 2.18 (br s, 1H).

G. (+) - N-1- [2- [3- (4,5-Dihydro-4 (S) -phenyloxazol-2-yl) phenoxy] ethyl] -N-hydroxyurea
2- [3- [4,5-Dihydro-4 (S) -phenyloxazol-2-yl] phenoxy] ethan-1-ol was converted to the title compound according to the procedure for EXAMPLE 28 E. It was recrystallized from ethyl acetate to give a white solid. product.

Mp: 146.5-147.1 ^o C.

IR (KBr) ν: 3490, 3320, 2875, 1630, 1590, 1580, 1220, 700 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.47 (s, 1H), 7.52 (d, J = 8 Hz, 1H), 7.45-7.25 (m, 7H), 7.16 (dd, J = 8 and 2 Hz, 1H), 6.40 (s, 2H), 5.41 (t, J = 10 Hz, 1H), 4.85 (t, J = 8.5 Hz, 1H ), 4.23-4.13 (m, 3H), 3.71 (t, J = 5.5 Hz, 2H).

[α] _D : = +7.65 ^° (c = 0.2, methanol).

Elemental analysis:
Calculated: C 63.33%; H 5.61%; N 12.31%
Found: C 62.83%; H 5.60%; N, 12.24%.

Example 36
N-1- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -2-fluorophenoxy] ethyl] -N- hydroxyurea
N-1- [2- [3- (4,5-Dihydro-4 (R) -phenyloxazol-2-yl) -2-fluorophenoxy] ethyl] -N-hydroxyurea was prepared according to the procedure for Example 35 using 4,5- dihydro-2- (2-fluoro-3-hydroxyphenyl) - 4 (R) -phenyloxazole instead of 4,5-dihydro-2- (3-hydroxyphenyl) -4 (S) - phenyloxazole, as a white solid (amorphous) .

IR (KBr) ν: 3500, 3320, 2800, 1630, 1590, 700 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.51 (s, 1H), 7.45-7.20 (m, 8H), 6.40 (s, 2H), 5.42 (t, J = 9 Hz, 1H), 4.81 (t, J = 9 Hz, 1H), 4.30-4.10 (m, 3H), 3.80-3.70 (br s, 2H).

Elemental analysis:
Calculated: C 60.16%; H 5.05%; N 11.69%
Found: C 57.92%; H 5.10%; N, 11.36%.

Starting material, 4,5-dihydro-2- (2-fluoro-3-hydroxyphenyl) -4 (R) -phenyloxazole is prepared as follows:
A. 3-tert-Butyldimethylsilyloxy-2-fluorophenol
To a solution of 2-fluorophenol (10.35 g, 9.2 mmol) and tert-butyldimethylsilyl chloride (101 mmol) in DMF (180 ml), imidazole (7.54 g, 110 mmol) is added in one portion. After stirring for 3 hours, the reaction mixture was poured into water (330 ml) and extracted with diethyl ether (3 x 100 ml). The combined extracts were washed with 10% aqueous citric acid (100 ml), brine (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to obtain the title compound (20.63 g, quant.) As a colorless liquid.

¹ H NMR (CDCl ₃ ) δ: 7.10-6.84 (m, 4H), 0.98 (s, 9H), 0.20 (s, 6H).

B. 3-tert-Butyldimethylsilyloxy-2-fluorobenzoic acid
To a solution of 3-tert-butyldimethylsilyloxy-2-fluorophenol (10.59 g, 46.8 mmol) in THF (150 ml), cooled to -70 ^° C., sec-butyl lithium (42 ml, 1.12 M in cyclohexane). The reaction mixture was stirred at -70 ^° C for 1 h and then poured into a suspension of dry ice / diethyl ether. Water (200 ml) is carefully added and the organic layer is separated and discharged. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give the title compound (7.90 g, 70%) as a white solid.

¹ H NMR (DMSO-d ₆ ) δ: 7.45-7.37 (m, 1H), 7.25-7.11 (m, 2H), 0.98 (s, 9H), 0.20 ( s, 6H).

B. Benzyl-3-benzyloxy-2-fluorobenzoate
To a mixture of 3-tert-butyldimethylsilyloxy-2-fluorobenzoic acid (7.74 g, 29 mmol), potassium carbonate (24.0 g, 174 mmol) and sodium iodide (25.9 g, 174 mmol) in DMF (180 ml ) benzyl chloride (8.33 ml, 72.4 mmol) is added dropwise over 5 minutes. After stirring for 2 days, the reaction mixture was poured into water (400 ml) and extracted with diethyl ether (3 x 200 ml). The combined extracts were washed with brine (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting crude product was recrystallized from 2-propanol to give the title compound (7.19 g, 74%) as white flakes.

¹ H NMR (CDCl ₃ ) δ: 7.51-7.32 (m, 11H), 7.16 (t, J = 7 Hz, 1H), 7.05 (t, J = 7 Hz, 1H), 5.38 (s, 2H); 5.15 (s, 2H).

G. 3-Benzyloxy-2-fluorobenzoic acid
To a solution of benzyl 3-benzyloxy-2-fluorobenzoate (7.13 g, 21 mmol) in methanol (40 ml) was added an aqueous solution of potassium hydroxide (2.38 g, 42 mmol in 40 ml of water) and the mixture was heated under reflux within 30 minutes The reaction mixture was cooled, washed with diethyl ether (20 ml) and the ether layer was discharged. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate (3 x 40 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO ₄ ) and evaporated to give the title compound (4.83 g, 85%) as a white solid.

¹ H NMR (DMSO-d ₆ δ: 13.2 (br s, 1H), 7.50-7.30 (m, 7H), 7.18 (t, J = 7 Hz, 1H), 5, 21 (s, 2H).

D. 4,5-dihydro-2- (2-fluoro-3-hydroxyphenyl) -4 (R) -phenyloxazole
3-Benzyloxy-2-fluorobenzoic acid was converted to the title compound according to the procedure for Example 28.

¹ H NMR (CDCl ₃ + 1 drop of DMSO-d ₆ ) δ: 8.40 (br s, 1H), 7.45-7.18 (m, 6H), 7.10 (t, J = 8 Hz , 1H), 7.02 (t, J = 8 Hz, 1H), 5.39 (t, J = 8 Hz, 1H), 4.75 (t, J = 8 Hz, 1H), 4.22 ( t, J = 8 Hz, 1H).

Example 37
(-) - N-1- [2- [3- (4,5-Dihydro-5 (R) -phenyloxazol-2-yl) -2-fluorophenoxy] ethyl] -N-hydroxyurea
A. 2- (3-tert-Butyldimethylsilyloxy-2-fluorobenzamido) -1- (S-phenylethanol
To a solution of 3-tert-butyldimethylsilyloxy-2-fluorobenzoic acid (3.3 g, 12 mmol, example 36 (B) in toluene (30 ml), thionyl chloride (1.3 ml, 18 mmol) is carefully added at room temperature. The reaction mixture was refluxed for 40 minutes, then cooled and concentrated in vacuo.The remaining oil was dissolved in CH ₂ Cl ₂ (20 ml) and added dropwise to the solution (+) - 2-amino-1 (S) - phenylethanol (1.7 g, 12 mmol, see AI Meyers and J. Slade. J Org. Chem. 1980, 45, 2785) and triethylamine (2.0 ml, 15 mmol) in CH ₂ Cl ₂ (20 ml), chilled to 0 ^o C. The reaction mixture allowed to warm to room temperature and stirred for an additional 30 minutes, the mixture was poured into water (100 ml) and extracted with CH ₂ Cl ₂ (3 x 10 ml). The combined organic extracts were washed with saturated aqueous NaHCO ₃ (100 ml), dried (MgSO ₄ ) and the crude product was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (3: 2), to give the title compound (4.6 g, 97%) as a pale yellow liquid.

¹ H NMR (CDCl ₃ ) δ: 7.70-7.01 (m, 8H), 5.00 (m, 1H), 4.00-3.85 (m, 1H), 3.70-3, 55 (m, 1H), 3.25 (br s, 1H), 1.02 (s, 9H), 0.22 (s, 6H).

B. 2- (3-tert-Butyldimethylsilyloxy-2-fluorophenyl) -4,5-dihydro-5 (R) -phenyloxazole
To a solution of 2- (3-tert-butyldimethylsilyloxy-2-fluorobenzamido) -1 (S) -phenylethanol (4.6 g, 12 mmol) and triphenylphosphine (3.7 g, 14 mmol) in THF (50 ml) dropwise add a solution of diethyl azodicarboxylate (2.2 ml, 42 mmol) in THF (20 ml). After stirring for 1 h, volatiles were removed by evaporation. The residue was purified by silica gel column chromatography, eluting with hexane / ethyl acetate (13: 1 to 9: 1), to give the title compound (2.2 g, 50%) as a pale yellow liquid.

¹ H NMR (CDCl ₃ ) δ: 7.60-6.98 (m, 8H), 5.63 (dd, J = 10 and 8 Hz, 1H), 4.53 (dd, J = 15.0 and 8 Hz, 1H), 1.01 (s, 9H), 0.21 (s, 6H).

B. 4,5-Dihydro-2- (2-fluoro-3-hydroxyphenyl) -5 (R) -phenyloxazole
To a solution of 2- (3-tert-butyldimethylsilyloxy-2-fluorophenyl) -4,5-dihydro-5 (R) -phenyloxazole (2.2 g, 5.8 mmol) in THF (20 ml) was added dropwise tetrabutylammonium fluoride (1 M in THF, 7 ml). The reaction mixture was stirred at room temperature for 10 minutes, the volatiles were removed by evaporation, and the resulting residue was purified by silica gel column chromatography, eluting with hexane / ethyl acetate (3: 2), to give the title compound (1.3 g, 86%) in as a colorless solid.

¹ H NMR (CDCl ₃ ) δ: 10.70-9.50 (br 1H), 7.58-7.03 (m, 8H), 5.74 (m, 1H), 4.43 (m, 1H), 3.78 (m, 1H).

G. 2- [3- (4,5-Dihydro-5 (R) -phenyloxazol-2-yl) -2-fluorophenoxy] ethyl methacrylate
To a solution of 4,5-dihydro-2- (2-fluoro-3-hydroxyphenyl) -5 (R) -phenyloxazole (0.97 g, 3.8 mmol), triphenylphosphine (1.0 g, 4.0 mmol) and 2-hydroxyethyl methacrylate (0.50 ml, 4.0 mmol) in THF (30 ml) was added dropwise a solution of diethyl azodicarboxylate (0.65 ml, 4.0 mmol) in THF (15 ml). After stirring for 1 day, the volatiles were removed by evaporation. The residue was purified by silica gel column chromatography, eluting with hexane / ethyl acetate (2: 1), to give the title compound (1.2 g, 86%) as a pale yellow liquid.

¹ H NMR (CDCl ₃ ) δ: 7.58-7.00 (m, 8H, m), 6.15 (dd, J = 4.4 and 3.7 Hz, 1H), 4.58-4, 45 (m, 2H), 4.32 (m, 2H), 4.08 (dd, J = 15.0 and 7.7 Hz, 1H), 3.85 (t, J = 4.8 Hz, 1H ), 1.94 (t, J = 3.3 Hz, 3H).

D. 2- [3- (4,5-Dihydro-5 (R) -phenyloxazol-2-yl) -2-fluorophenoxy] ethan-1-ol
To a solution of 2- [3- (4,5-dihydro-5 (R) -phenyloxazol-2-yl) -2-fluorophenoxy] ethyl methacrylate (1.2 g, 3.3 mmol) in THF (40 ml) and water (50 ml) add lithium hydroxide monohydrate (0.41 g, 9.8 mmol). After stirring for 2 hours, the mixture was extracted with ethyl acetate (3 x 50 ml) and the combined organic extracts were washed with saturated aqueous NaHCO ₃ (30 ml), brine (30 ml), dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with hexane / ethyl acetate (1: 2), to give the title compound (0.76 g, 78%) as a colorless liquid.

¹ H NMR (CDCl ₃ ) δ: 7.70 - 7.02 (m, 8H), 5.68 (dd, J = 10 and 8 Hz, 1H), 4.55 (dd, J = 10 and 15, 0 Hz, 1H), 4.19 (t, J = 4.4 Hz, 2H), 4.10 (dd, J = 8.1 Hz, 1H), 4.02 (t, J = 3.7 Hz , 2H); 2.54 (br s, 1H).

E. N, O-Di (tert-butoxycarbonyl) -2- [3- (4,5-dihydro-5 (R) - phenyloxazol-2-yl) -2-fluorophenoxy] ethylhydroxylamine
2- {3- (4,5-Dihydro-5 (R) -phenyloxazol-2-yl) -2-fluorophenoxy} ethan-1-ol is converted to the title compound according to the procedure for Example 10B.

¹ H NMR (CDCl ₃ ) δ: 7.70-7.04 (m, 8H), 5.69 (m, 1H), 4.54 (m, 1H), 4.40-4.22 (m, 2H), 4.20 - 3.90 (m, 3H), 1.58 (s, 18H).

J. (-) - N-1- [2- [3- (4,5-Dihydro-5 (R) -phenyloxazol-2-yl) -2-fluorophenoxy] ethyl] -N-hydroxyurea
N, O-Di (tert-butoxycarbonyl) -2- [3- (4,5-dihydro-5 (R) -phenyloxazol-2-yl) -2-fluorophenoxy] ethylhydroxylamine is converted to the title compound according to the procedure for Example 1G . The product was recrystallized from ethyl acetate to give a colorless solid.

Mp 107-108 ^o C.

IR (KBr) ν: 3400, 1740, 1650, 1360, 1050, 740 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.50 (s, 1H), 7.60-7.15 (m, 8H), 6.38 (s, 2H), 5.79 (t, J = 10 Hz, 1H), 4.45 (t, J = 10 Hz, 1H), 4.23 (m, 2H), 3.83 (dd, J = 15 and 8 Hz, 1H), 3.75 (t , J = 5.5 Hz, 18H).

[α] _D : = -71.4 ^° (c = 0.098, methanol).

Elemental analysis:
Calculated: C 60.16%; H 5.05%; N 11.69%
Found: C 59.67%; H 5.36%; N, 10.77%.

Example 38
(+) - N-1- [2- [3-6,5-Dihydro-5 (S) -phenyloxazol-2-yl) -2-fluorophenoxy] ethyl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 37 using (-) - 2-amino-1 (R) -phenylethanol (AI Meyers and J. Slade. J. Org. Chem. 1980, 45, 2785) instead of (+) - 2-amino-1 (S) -phenylethanol. The product can be recrystallized from ethyl acetate to give a white solid.

Mp: 106-107 ^o C
IR (KBr) ν: 3400, 1740, 1650, 1360, 1050, 720 cm ^-1 .

¹ H NMR (DMSO-d ₆ δ: 9.50 (s, 1H), 7.60-7.15 (m, 8H), 6.38 (s, 2H), 5.79 (t, J = 10 Hz, 1H), 4.45 (t, J = 10 Hz, 1H), 4.23 (m, 2H), 3.83 (dd, J = 15 and 8 Hz, 1H), 3.75 (t, J = 5.5 Hz, 18 H).

[α] _D : = +87.8 ^° (c = 0.11 methanol).

Elemental analysis:
Calculated: C 60.16%; H 5.05%; N 11.69%
Found: C 59.57%; H 5.35%; N 10.71%
Example 39
(+) - N-1- [2- [5-Chloro-3- [4,5-dihydro-4 (R) -phenyloxazol-2-yl] -2-fluorophenoxy] ethyl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 37 using (R) - (-) - 2-phenylglycinol instead of (-) - 2-amino-1 (R) -phenylethanol and 4-chloro-2-fluorophenol instead of 2-fluorophenol.

Mp: 71-73 ^o C
IR (KBr) ν: 3500, 1650, 1580, 1500, 1360, 1280, 1050, 700 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 7.51 (dd, J = 7.0, 2.6 Hz, 1H), 7.48-7.23 (m, 6H), 6.36 (s, 2H), 5.41 (t, J = 1.8 Hz, 1H), 4.81 (dd, J = 10.3 and 8.4 Hz, 1H), 4.25 (t, J = 5.5 Hz, 2H), 4.17 (t, J = 8.4 Hz, 1H), 3.70 (t, J = 5.5 Hz, 2H).

[α] _D : = +7.0 ^° (c = 0.17, methanol).

Elemental analysis:
Calculated: C 54.90%; H 4.35%; N 10.67%
Found: C 54.35%; H 4.41% 4 N 10.72%
Example 40
(+) - N-1- [2- [3- [4,5-Dihydro-4 (R) -phenyloxazol-2-yl] -2-fluoro-4-methylphenoxy] ethyl] -N-hydroxyurea
The title compound was prepared according to the procedure for Example 37 using (R) - (-) - 2-phenylglycinol instead of (-) - 2-amino-1- (R) -phenylethanol and 2-fluoro-4-methylphenol instead of 2-fluorophenol .

Mp: 53-55 ^o C
IR (KBr) ν: 3500, 1650, 1500, 1370, 1280, 1150, 1060, 980, 750, 700 cm ^-1 .

¹ H NMR (DMSO-d ₆ ) δ: 9.48 (s, 1H), 7.50-7.20 (m, 7H), 6.41 (s, 2H), 5.42 (m, 1H) 4.82 (m, 1H); 4.30-4.12 (m, 3H); 3.72 (t, J = 5.5 Hz, 2H); 2.31 (s, 3H).

Elemental analysis:
Calculated: C 61.12%; H 5.40%; N 11.25%
Found: C 59.85%; H 5.43%; N, 11.11%.

 An example of a pharmaceutical composition for parenteral administration.

Полученные данные представлены в таблице.Ingredients - Amount
The compound of Example 31 - 6 mg
Injection - Up to 100 ml
2. Data on biological activity
Test compounds

The data obtained are presented in the table.

 The data presented above show that the compound of the present invention is 1.6 times more active both in the HWB test and in the RPC test, which indicates that the compounds of this invention are more active lipoxygenase inhibitors than previously known.

Claims (10)

1. Derivatives of N-hydroxyurea of General formula I

or their pharmaceutically acceptable salts,
where A is C ₁ -C ₄ alkylene, CH (R), CH (R) CH ₂ or CH (R) CH ₂ CH ₂ , where R is methyl or ethyl;
m = 1 and n = 0 or 1;
R ¹ and R ² each represents hydrogen, C ₁ - C ₄ alkyl or C ₂ - C ₆ alkenyl;
X represents 0 or S;
Y represents 0 or C≡C;
Ar ¹ represents phenyl or phenyl monosubstituted with halogen;
Ar ² is phenylene, pyridylene or phenylene mono- or disubstituted with halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy. 2. The compound according to claim 1, where n = 0; R ¹ represents hydrogen; R ² represents hydrogen or methyl. 3. The compound according to claim 2, where R ² represents hydrogen, X represents 0; Ar ¹ is phenyl or 4-fluorophenyl and Ar ² is 1,3-phenylene or 1,3-phenylene having one substituent selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy. 4. The compound of claim 3, wherein A is CH ₂ , CH ₂ CH ₂ , CH (CH ₃ ) or CH (CH ₃ ) CH ₂ and Ar ² is 1,3-phenylene or 1,3-phenylene substituted with one fluorine; m = 1 and Y represents 0. 5. The compound according to claim 4, where Ar ^{1 is} attached at position 4 of the oxazoline ring and the carbon atom to which Ar ¹ is attached has a (R) configuration.  6. The compound according to claim 5, where the compound is selected from (-) - N-1- [2- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) -phenoxy] ethyl] - N-hydroxyurea; (+) - N-1- [2- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) -5-fluorophenoxy] ethyl] -N-hydroxyurea and N-1- [2 - [3- [4,5-dihydro-4 (R) -phenyloxazol-2-yl] -2-fluorophenoxy] ethyl] -N-hydroxyurea. 7. The compound according to claim 4, where A represents CH ₂ or CH (CH ₃ ); m = 1 and Y represents C≡C.
8. The compound according to claim 7, where the compound is selected from (+) - N- [3- [3- (4,5-dihydro-4 (R) -phenyloxazol-2-yl) -phenyl] -2-propin- 1-yl] -N-hydroxy-N'-methylurea; (+) - N- [3- [3- [4,5-dihydro-4 (R) - (4-fluorophenyl) oxazol-2-yl] phenyl] -2-propin-1-yl] -N- hydroxyurea; (-) - N- [3- [3- [4,5-dihydro-4 (R) -phenyloxazol-2-yl] -2-fluorophenyl] -2-pripin-1-yl] -N-hydroxyurea and N - [4- [3- [4,5-dihydro-5-phenyloxazol-2-yl] phenyl] -2-butyn-2-yl] -N-hydroxyurea.  9. A method of treating a disease that requires a 5-lipoxygenase inhibitor in a mammalian subject, which comprises administering to the subject a therapeutically effective amount of a compound according to claim 1.  10. The method according to claim 9, where the disease is an allergic or inflammatory condition.  11. A pharmaceutical composition having inhibitory activity against 5-lipoxygenase, which comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

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