BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel hydroxamic acid derivatives. The compounds of the present invention inhibit the enzyme lipoxygenase, and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treating inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention further relates to methods of making such compounds.

Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.

Description of the Related Art

Recently several review articles on lipoxygenase inhibitors have been reported (See H. Masamune et al., Ann. Rep. Med. Chem.. 24, 71-80 (1989) and B. J. Fitzsimmons et al., Leukotrienes and ϋpoxyαenases. 427-502 (1989).

Compounds of the same general class as the compounds of the present invention are disclosed in EP 279263 A2, EP 196184 A2, JP 63502179 and U.S. patent No. 4,822,809.

SUMMARY OF THE INVENTION The present invention provides novel hydroxamic acid derivatives of the formula

wherein R ^1" is hydrogen, C1 to 04 alkyl, 02 to 04 alkenyl, alkyl thioalkyl, alkoxyalkyl or NR ² R ³ ; R ² and R ³ are each independently hydrogen, 01 to 04 alkyl, hydroxy, aryl, or aryl substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, 01 to C12 alkyl, 01 to 012 alkoxy, 01 to 012 halosubstituted alkyl, 01 to 012 hydroxysubstituted alkyl, 01 to C12 aikoxycarbonyl, aminocarbonyl, 01 to 012 alkylaminocarbonyl, di ^" 01 to 012 alkylaminocarbonyl and 01 to 012 alkylsulfonyl, with the proviso that R ² and R ³ are not both hydroxy; M is hydrogen, a pharmaceutically acceptable cation, aroyf or 01 to 012 alkoyl; A is alkynylene or alkynylene substituted with one or more substituents selected from the group consisting of 01 to 04 alkyl, 02 to 04 alkenyl, cyano, halo, 01 to 04 alkoxy, 01 to 04 halosubstituted alkyl and 01 to 04 hydroxysubstituted alkyl; Ar is phenyl or naphthyl; B is hydrogen, 01 to C12 alkyl, 02 to 012 alkenyl, 01 to C12 halosubstituted alkyl, 01 to 012 hydroxysubstituted alkyl, OR*, NR ^* R ⁵ , aryl or aryl substituted with one or more substituents selected from the group

consisting of halo, nitro, cyano, 01 to 06 alkyl, 01 to 06 alkoxy, 01 to 06 halosubstituted alkyl, 01 to 06 hydroxysubstituted alkyl, 01 to 06 alkoxycarbonyl, aminocarbonyl, 01 to 06 alkylaminocarbonyl, di 01 to 06 alkylaminocarbonyl and 01 to 06 alkylsulfonyl; R and R ⁵ are each independently hydrogen, 01 to 012 alkyl, 03 to 012 alkenyl, 03 to 08 cycloalkyl, aryl or

n is 4 to 6; X is 0, NR ^β or S; and R* is hydrogen or 01 to 04 alkyl.

This invention also concerns pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound of the invention or a pharmaceutically acceptable salt thereof. This invention further concerns methods of treating inflammatory diseases, allergy and cardiovascular diseases in mammals comprising administration of such compounds or compositions.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the following definitions are used.

"Halo" means radicals derived from the elements fluorine, chlorine, bromine and iodine.

"Alkyl" means straight or branched saturated hydrocarbon radicals, for example, methyl, ethyl, n-propyl and isopropyl.

"Alkenyl" means straight or branched unsaturated (double bonded) hydrocarbon radicals, for example, ethenyl, 1- or 2-propenyl, 2-methyl-1- propenyl and 1- or 2-butenyl.

"Alkynylene" means straight or branched unsaturated (triple bonded) hydrocarbon radicals, for example, -C≡C-, C≡CCH ₂ -, -C≡CHCH ₂ CH ₂ - and -C≡CCH(CH ₃ )-.

"Cycloalkyl" means carbocyclic radicals, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

"Alkoxy" means -OR ⁷ wherein R ⁷ is an alkyl radical, for example, methoxy, ethoxy, propoxy, isopropoxy and butoxy.

"Alkoxyalkyl" means -R ⁸ OR ^β wherein R ⁸ and R ⁹ are independently alkyl radicals, for example, methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl.

"Alkylthioalkyl" means -R ¹⁰ SR ¹¹ wherein. R ¹⁰ and R ⁿ are independently alkyl radicals, for example, methylthiomethyl, ethylthioethyl and methythioethyl.

"Alkoyl" means -COR ¹² wherein R ¹² is an alkyl radical, for exampfe, formyl, acetyl, propioπyl, butyryl and isobutyryl.

"Aryl" means aromatic radicals, for example, phenyl and naphthyl.

"Aroyl" means -COR ¹³ wherein R ¹³ is an aryl radical, for example, benzoyl and naphthoyf.

"Aryloxy" means -OR ¹ * wherein R ¹ * is an aryl radical, for example, phenoxy and naphthoxy.

"Alkoxycarbonyl" means -C(=0)R ¹⁵ wherein R ¹⁵ is an alkoxy radical, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

"Alkylaminocarbonyl" means -C(=0)NHR ^1β wherein R ¹⁶ is an alkyl radical, for example, methylaminocarbonyl, ethylaminocarbonyl and propylaminocarbonyl.

"Dialkylaminocarbonyl" means -C(=0)N(R ¹⁷ )R ¹⁸ wherein R ¹⁷ and R ^1β are independently alkyl radicals, for example, dimethylaminocarbonyl, diethylaminocarbonyl and methylethylaminocarbonyl.

"Alkylsulfonyl" means -S0 ₂ R ^1β wherein R ^1β is an alkyl radical, for example, methanesulfonyl (mesyl) and ethanesulfonyl.

"Halosubstituted alkyl" means an alkyl radical as described above substituted with one or more halogens, for example, chloromethyl, trifluoromethyl and 2,2,2-trichloroethyl.

"Hydroxysubstituted alkyl" means an alkyl radical as described above substituted with one or more hydroxy radicals, for example, hydroxymethyl, dihydroxyethyl and trihydroxypropyl.

"Pharmaceutically acceptable cation" means non-toxic cations based on alkali and alkaline earth metals, for example, sodium, lithium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, for example, ammonium, tetramethyl- ammonium, methylamine, dimethyiamine, trimethylamine, ethylamine, diethylamine and triethylamine.

Methods of Preparation

The compounds of the invention may be prepared by a number of synthetic methods. As used in the following reaction schemes, A, B and Ar are as defined above. Although in Schemes 1 and 2 R ¹ is methyl and NH ₂ , respectively, compounds wherein R ¹ is otherwise, as defined above, may be prepared in a similar manner.

In one embodiment, compounds of the formula (III) are prepared according to the reaction steps outlined in Scheme 1.

B-

Reaction Scheme 1

In step 1 , the diacetyl compound (II) is prepared by standard methods known in the art. For example, the hydroxylamine (I) is reacted with acetyl chloride or acetic anhydride in a reaction-inert solvent in the presence of a suitable base. Preferred bases are sodium hydride, triethylamine and pyridine, with the latter two being particularly preferred. Suitable reaction- inert solvents include methylene chloride, chloroform, tetrahydrofuran, benzene and toluene. The reaction is usually carried out in the temperature range of about 0°C through to ambient temperature, with reaction times from ^* 30 minutes to a few hours being typical. The product can be isolated and purified by conventional procedures, such as recrystallization or chromatography.

Step 2 involves selective hydrolysis of the diacetyl (II) with an appropriate base. Typical bases include ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide preferably in methanol, ethanol, isopropyl alcohol or water, though binary solvent systems such as alcohol-water, tetrahydrofuran-water and the like may also be employed. Reaction temperatures are usually in the range of about -10°C through to ambient temperature, with the reaction usually complete within a few minutes to several hours. The product of formula (III) is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

ln another embodiment, compounds of the formula (IV) are prepared as illustrated in Scheme 2.

( I V )

Reaction Scheme 2

In this step the hydroxylamine (I) is treated with trimethylsilyl isocyanate in a reaction-inert solvent usually at ambient through to reflux temperature. Suitable solvents which do not react with reactants and/or products include, for example, tetrahydrofuran, dioxane, methylene chloride and benzene. An alternative procedure employs treatment of (I) with gaseous hydrogen chloride in a reaction-inert solvent such as benzene or toluene followed by treatment with phosgene. Reaction temperatures are usually in the range of ambient temperature through to boiling point of solvent. The intermediate carbamoyl chloride is not isolated but is subjected to (i.e. in situ) reaction with aqueous ammonia. The product of formula (IV) thus obtained is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The aforementioned hydroxylamine (I) is easily prepared by standard synthetic procedures from readily available aldehyde. For example, the aldehyde is converted to its acetylene alcohol (see E.J. Corey et al., Tetrahedron Lett.. 3769-3772 (1972)) and then the alcohol is treated with N,0-bis(fert-butoxycarbonyl)hydroxylamine under Mitsunobu-type reaction conditions followed by acid catalyzed hydrolysis of the N,0-pr otected intermediate product (see JP 1045344) to give the requisite hydroxylamine (I). N.O-diacetyl compound (II) can be prepared employing N.O-diacetyl

hydroxylamine in place of N,0-bis(te/t-bi_toxycarbonyl)hydroxylamine, thus providing a convenient route to the product of formula (III).

Alternatively, the hydroxylamine (I) can be prepared by direct coupling of the corresponding aryl bromide or aryl iodide and N,0-bis(ferf-butoxy- carbonyl)alkynylenehydroxylamine in the presence of (Ph ₃ P) ₂ PdCI ₂ in a reaction-Inert solvent such as diethylamine or triethylamine, followed by acid- catalyzed hydrolysis of the N.O-protected intermediate product to afford the desired hydroxylamine (I).

The hydroxylamine of formula (I) thus obtained by the aforementioned representative procedures is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The pharmaceutically acceptable salts of the novel compounds of the present invention are readily prepared by contacting said compounds with a stoichiometric amount of, in the case of a non-toxic cation, an appropriate metal hydroxide or alkoxide or amine in either aqueous solution or a suitable organic solvent. In the case of non-toxic acid salt, an appropriate mineral or organic acid in either aqueous solution or a suitable organic solvent can be used. T e salt may then be obtained by precipitation or by evaporation of the solvent.

Biological Activity

The compounds of this invention inhibit lipoxygenase. This inhibition has been demonstrated by an assay using rat peritoneal cavity resident cells which determines the effect of such compounds on the metabolism of arachidonic acid.

The compounds of the examples were tested according to the methods described in "Synthesis of leukotrienes by peritoneal

macrophages", Jap. J. Inflammation. 7, 145-150 (1987), and were shown to be lipoxygenase inhibitors. In this test some preferred compounds exhibit low IC _∞ values, in the range of about 0.01 to about 30μM, for lipoxygenase inhibition.

The ability of the compounds of the present invention to inhibit lipoxygenase makes them useful for controlling the symptoms induced by the endogenous metabolites arising from arachidonic acid in a mammalian subject. The compounds are therefore valuable in the prevention and treatment of such disease states in which the accumulation of arachidonic acid metabolites is the causative factor, e.g., allergic bronchial asthma, skin disorders, rheumatoid arthritis, osteoarthritis and thrombosis.

The compounds of the formula and their pharmaceutically acceptable salts are of particular use in the prevention and treatment of inflammatory diseases, allergy and cardiovascular diseases in a human subject.

Methods of Administration

For treatment of the various conditions described above, the compounds of the invention and their pharmaceutically acceptable salts can be administered to a human subject either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition, according to standard pharmaceutical practice. A compound can be administered via a variety of conventional routes of administration including orally, parenter ally and by inhalation. When the compounds are administered orally, the dose range will generally be from about 0.1 to about 20 mg/kg/day, based on the body weight of the subject to be treated, preferably from about 0.1 to about 1.0 mg/kg/day in single or divided doses. If parenteral administration is desired, then an effective dose will generally be from about 0.1 to about 1.0 mg/kg/day. In some instances it may be necessary to use dosages outside these limits, since the dosage will necessarily vary according to the age, weight and response of the

individual patient as well as the severity of the patient's symptoms and the potency of the particular compound being administered.

For oral administration, the- compounds of the 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 use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are commonly 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 emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, a sterile solution of the active ingredient is usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solute should be controlled to make the preparation isotonic.

Examples

The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to specific details of these examples. Proton nuclear magnetic resonance (NMR) spectra were measured at 270 MHz unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

Examole 1 N-Hvdroxy-N-r4-.3-phenoxyphenyl)-3-butvn-2-yl.acetamide

Step 1. 3-phenoxyphenylethylene-1.1 -dibromide

To a mixture of zinc (2.90 g, 0.044 mol), triphenylphosphine (Ph ₃ P, 11.6 g, 0.044 mol) in CH ₂ CI ₂ (100 ml) was added CBr ₄ (14.7 g, 0.044 mol) at 0°C. After stirring for 30 minutes, 3-ρhenoxybenzaldehyde (4.39 g, 0.022 mol) was added and stirred at room temperature overnight. The mixture was extracted with hexane/ethyl acetate (1:1), dried over magnesium sulfate and concentrated in vacuo to give a white precipitate which was suspended in ether/hexane (1 :1) and filtered. The filtrate was concentrated in vacuo to afford 7.67 g of the title compound as a pale yellow oil.

Η NMR (CDCg δ 7.43 (s, 1H), 7.28-7.38 (m, 3H), 7.18-7.25 (m, 2H), 7.12 (tt, J=7.0, 1.1 Hz, 1H), 6.97-7.05 (m, 3H).

Step 2. 4-.3-phenoχyphenyl,-3-butvn-2-ol

To a solution of the dibromide prepared in Step 1, above, (3.557 g, 10 mmol) in tetrahydrofuran (THF, 20 ml) was added n-butyllithium (n-BuLi, 13.4 ml, 21 mmol) at -78 to -45°C under nitrogen atmosphere. The reaction mixture was stirred at -78°C for 45 minutes and then at room temperature for 1 hour under nitrogen atmosphere. To the mixture was added dry acetaldehyde (about 2 ml) at 0°C and the mixture was stirred at room

temperature for 5 minutes. The mixture was combined with 2N HCI (11 ml, 22 mmol), extracted with ethyl acetate and washed with brine, NaHC0 ₃ solution and then brine again. The solution was dried over magnesium sulfate and concentrated (3.84 g). Chromatography on silica gel eluted with hexane/ethyl acetate (4:1) afforded 2.34 g (75.6% yield) of the title compound as a colorless oil.

Η NMR (CDCI ₃ ) δ 7.31-7.39 (m, 2H), 7.27 (t, J=7.9 Hz, 1H), 7.09-7.18 (m, 2H), 7.69-7.05 (m, 4H), 4.73 (qd, J=6.6, 5.5 Hz, 1H), 1.86 (d, J=5.5 Hz, 1H), 1.53 (d, J=6.6 Hz, 3H).

Step 3, N-acetoxy-N-[4-(3-phenoxyphenyl)-3-butyn-2-vπacetamide

To a solution of the alcohol prepared in Step 2, above, (2 g, 8.4 mmol), N ^' .O-diacetylhydroxylamine, Ph ₃ P (3.3 g, 12.6 mmol) in toluene (50 ml) and diethyl azodicarboxylate (DEΞAD, 2.19 g, 12.6 mmol) were added at -78°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, the resultant precipitate was filtered off and the filtrate was concentrated in vacuo. Chromatography on silica gel eluted with hexane/ethyl acetate (4:1) afforded 1.23 g (43% yield) of the title compound as a colorless oil.

Η NMR (CDCI ₃ ) δ 7.32-7.39 (m, 2H), 7.25 (t, J=7.7 Hz, 1H), 7.09-7.16 (m, 2H), 6.95-7.03 (m, 4H), 5.58 (q, J=6.6 Hz, 1H), 2.23 (s, 3H), 2.05 (s, 3H), 1.48 (d, J=6.6 Hz, 3H).

Step 4. N-hvdroxy-N-.4-(3-phenoxyphenv0-3-butvn-2-yl.acetamide

To a solution of the diacetate prepared in Step 3, above, (1.15 g, 3.41 mmol) in methanol (10 ml) was added NH ₄ OH (2 ml) at room temperature. The mixture was concentrated in vacuo and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solution was concentrated to give a colorless oil (1.09 g). Chromatography on silica gel eluted with hexane/ethyl acetate (2:1) afforded the title compound as a white powder. Recrystallization from ethyl acetate/hexane gave 787 mg (78% yield) of product as a white powder.

IR (film) v 3170, 2230, 1600 cm ¹ .

Η NMR (DMSO-d _β ) δ 7.35-7.46 (m, 3H), 7.15-7.22 (m, 2H), 7.02-7.07 (m, 3H), 6.94-6.97 (m, 1H), 5.47 (q, J=6.9 Hz, 1H), 2.01 (s, 3H), 1.37 (d, J=6.9 Hz, 3H).

Example 2 N-Hvdroxy-N-.4-(4-biphenylyl.-3-butvn-2-yl.acetamide

The title compound (m.p. 152.9-153.8°C) was prepared from 4- phenylbenzaldehyde using the same procedure as Example 1.

IR (KBr) V 3450, 1612 cm ¹ .

Η NMR (DMSO-d ₆ ) δ 9.90 (s, 1H), 7.66-7.72 (m, 4H), 7.33-7.54 (m, 5H), 5.53 (q, J=7 Hz, 1H), 2.04 (s, 3H), 1.42 (d, J=7 Hz, 3H).

Example 3 N-Hvdroxy-N-f4-(3-phenoxyphenyl)-3-butvn-2-yl,urea

Step 1. N.O-bis-Boc-(4-phenoxyphenyl-3-butyn-2-yl.hvdroxylamine

To a solution of 4-phenoxypheny!-3-butyn-2-ol (1.2 g, 5.04 mmol), Ph ₃ P (1.98 g, 7.56 mmol) and BocNH-OBoc (1.23 g, 5.29 mmol) in toluene (10 ml) was added DEΞAD (1.32 g, 7.56 mmol) in toluene (3 ml) at -78°C under nitrogen atmosphere. The mixture was concentrated in vacuo and a mixture of hexane/toluene (1:1, 30 ml) was added. The resulting precipitate was separated off by suction filtration and the filtrate was concentrated to give a yellow oil. Chromatography on silica gel eluted with hexane/ethyl acetate (8:1) afforded 1.77 g (77.5% yield) of the desired product as a pale yellow oil. A less pure fraction of the desired product was also obtained (579 mg, 25% yield).

Step 2. N-hvdroxy-N-,4-.3-phenoxyphenyl.-3-butvn-2-vπurea

To a solution of the hydroxylamine prepared in Step 1 in CH ₂ CI ₂ (10 ml) was added trifluoroacetic acid (TFA, 3 ml). The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere, then was washed with small amount of saturated NaH0O ₃ solution in brine. The solution was dried over magnesium sulfate and concentrated in vacuo to give a pale yellow oil. Without purification, the product was dissolved in THF

(10 ml), added to TMS-NCO (731 μl, 5.4 mmol), stirred for 1 hour and concentrated in vacuo. Chromatography on silica gel eluted with CHjCl _ϋ /acetone (10:1) afforded 610 mg of product as a white powder. This was recrystallized from ethyl acetate/hexane-IPE (1 :1 :1) to give 456 mg (42.7% yield) of the desired product as a white powder, m.p. 120.0-120.8°C.

IR (KBr) v 3150, 1670, 1580 cm ¹ .

Η NMR (CDCg δ 7.31-7.39 (m, 2H), 7.25 (t, J=7.7 Hz, 1H), 7.09-7.18 (m, 2H), 7.04-7.06 (m, 1H), 6.95-7.02 (m, 3H), 6.22 (s, 1H), 5.39 (br s, 2H), 5.34 (q, J=6.9 Hz, 1 H), 1.50 (d, J=6.9 Hz, 3H).

Example 4 N-Hvdroxy-N-r4-.4-biphenylvO-3-butvn-2-vHurea

The title compound (m.p. 170.3-171.2°C) was prepared from 4- phenylbenzaldehyde using the same procedure as Example 3.

IR (KBr) v 3460, 1610, 1575 cm ^"1 .

Η NMR (DMSO-d ₆ ) δ 9.36 (s, 1 H), 7.65-7.72 (m, 4H), 7.44-7.52 (m, 4H), 7.38 (tt, J=7.3, 1.5 Hz, 1H), 6.55 (s, 1H), 5.16 (q, J=7.3 Hz, 1H), 1.38 (d, J=6.9 Hz, 3H).

Example 5 N-Hydroxy-N-r4-(2-naphthyl)-3-butvn-2-yllurea

The title compound (m.p. 137.6-138.6°C) was prepared from 2- naphthaldehyde using the same procedure as Example 3.

IR (KBR) v 3450. 3250, 1630 cm ¹ .

Η NMR (CDC^-DMSO-dJ δ 9.24 (s. 1H). 7.96 (s, 1H), 7.67-7.87 (m, 3H), 7.38-7.55 (m, 3H), 5.78 (s, 2H). 5.38 (q. J=6.8 Hz, 1H), 1.54 (d. J=6.9 Hz, 3H).

Example 6 N-Hvdroχy-N-.4-(3-allyloxyphenyl)-3-butvn-2-vπurea

The title compound (m.p. 116.3-116.7°C) was prepared from 3- allyloxybenzaldehyde using the same procedure as EΞxample 3.

IR(KBr) v3450, 3330, 1630, 1595 cm ¹ .

Η NMR (DMSO-d _β ) δ 7.26 (t, J=8.4 Hz.1H), 6.90-6.99 (m, 2H), 6.52 (brs, 2H), 5.95-6.10 (m, 1H).5.38 (dq, J=16, 1 Hz, 1H), 5.26 (dq, J=9.5, 1 Hz, 1H), 4.54-4.60 (m, 2H), 1.35 (d, J=7Hz, 3H).

Example 7 N-Hvdroxy-N-r4-(3-cvclohexyloxyphenv0-3-butvn-2-yl.urea

Step 1. 3-cvclohexyloxy-1-iodobenzene A solution of cyclohexanol (6.0 g), 3-iodophenol (13.2 g) and triphenylphosphine (15.7 g) in THF (150 ml) was stirred at room temperature under nitrogen atmosphere. Diethyl azodicarboxylate (10.45 g) was added dropwise and the resulting solution was stirred for 7 days. The reaction mixture was evaporated to dryness under reduced pressure, hexane/ether (2:1) mixture (400 ml) was added to the precipitate, the undissolved precipitate was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (ether/hexane,

1 :4), and distillation (200°C, 0.4 mmHg, bath temp.) to provide 7.46 g (41% yield) of title product.

Step 2, N,0-bis-.ert-butoxycarbonyl-N-[4-(3-cyclohexyloxyphenyl)- 3-butyn-2-ylj hydroxylamine and N-fe- f-butoxycarbonyl]-N- -4-.3-cvclohexyloxyphenyl.-3-butvn-2-yl1hvdroxylamine

Diethylamine (25 ml), suspension of Cul (0.043 g) and (Ph ₃ P) ₂ PdCI ₂ (0.33 g) was stirred at room temperature under argon atmosphere. Diethylamjne solution of N,0-bis-fert-butoxycarbonyl-N-(3-butyn-2- yl) hydroxylamine (5.42 g) was added to the suspension, then the 3- cyclohexyloxy-1-iodobenzene (4.53 g) prepared in Step 1 was added. The resulting mixture was stirred for 17 hours. Solvent was removed under reduced pressure and ether (200 ml) and water (100 ml) were added. Undissoluble red grease was filtered off (celite). Ethereal layer of the filtrate was collected, dried (MgS0 ₄ ), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ether/hexane, 15:85), providing 4.0 g (59 % yield) of N.O-bis-terf- butoxycarbonyl-N-[4-(3-cyclohexyloxyphenyl)-3-butyn-2-yl]hyd roxylamine and 1.6 g (30% yield) of N-tert-butoxycarbonyl]-N-[4-(3-cyclohexyloxyphenyl)-3- buty n-2-yl] hydroxylamine.

Step 3, N-hvdroxy-N-[ ^, 4-(3-cvclohexyloxyphenv0-3-butvn-2-yl ^' )urea

The N-ferf-butoxycarbonyl (1.51 g) prepared in Step 2 was dissolved in CH ₂ CI ₂ (30 ml). CF ₃ C0 ₂ H (4 ml) was added to the solution at room temperature and the reaction mixture was stirred for 4 hours and concentrated under reduced pressure. NaHC0 ₃ solution was added and extracted with CH ₂ CI ₂ . The organic layer was dried (MgSOJ and concentrated in vacuo. The resulting crude product was dissolved in dry THF (10 ml). Trfmethylsilylisocyanate (1.09 g) was added to the solution, the mixture was stirred for 3 hours and the solvent was removed in vacuo. The resulting crude product was recrystallized with CHCLj hexane, affording 0.62 g (45% yield) of the title compound (m.p. 95-95.5°C).

IR. (KBr) v 3405, 1668 cm ¹ .

Η NMR (CDCI ₃ ) δ 7.17 (dd, J=7.7, 7.7 Hz, 1 H), 6.9-7.0 (m, 2H), 6.86 (ddd, J=8.4, 2.6, 1.1 Hz, 1H), 5.35 (q, J=7.0 Hz, 1H), 4.17-4.25 (m, 1H), 1.92-1.98 (m, 2H), 1.77-1.80 (m, 2H), 1.50 (d, J=7.0 Hz. 3H). 1.31-1.58 (m, 6H).

EΞxample 8 N-Hvdroxy-N-| ^" 4-(3-cvcloh&xyloxyphenyl)-3-butvn-2-yl1acetamide

Step 1 , N _r O-diacetyl-N-[4-(3-cyclohexyl- oxyphenyl)-3-butvn-2-vnhvdroxylamine N,0-Di-tert-butoxycarbonyl-N-[4-(3-cyclohexyloxyphenyl)-3-bu tyn-2- y[]hydroxylamine (2.0 g) was dissolved iri CH ₂ CI ₂ (15 ml). CF ₃ C0 ₂ H (4 ml) was added to the solution at room temperature and the reaction mixture was

stirred for 2 hours and concentrated under reduced pressure. The crude product was dissolved in CH ₂ CI ₂ (20 ml) and stirred, then pyridine (5 ml) and AcCI (2.5 ml) were added at 0°C and stirred for 2 hours. The solvent was removed under reduced pressure, the residue was combined with 10% citric acid and extracted with ether. The organic layer was washed with NaHC0 ₃ solution, dried (MgSOJ and concentrated in vacuo. The crude product was purified by silica gel column chromatography (hexane/EtOAc, 2:1), affording the title product as a colorless oil.

Step 2, N-hydroxy-N-[4-(3-cyclohexyl- oxyphenyl.-3-butvn-2-yllacetamide

To a stirred solution of the product of Step 1 , above (1.1 g), in MeOH

(15 ml) was added 25% NH ₃ solution (3 ml) at room temperature. The reaction mixture was stirred for 30 minutes and the solvent was evaporated off. To the resulting mixture water was added and the mixture was extracted with ether. The extract was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (hexane/EtOAc, 2:1), affording the title compound (0.412 g) as a colorless oil.

IR (neat) v 2940, 1617, 1605, 1422, 1282 cm ^"1 . Η NMR (DMSO) δ 9.9 (br, 1 H), 7.25 (dd, J=7.3, 8.8 Hz, 1 H), 6.93-

6.98 (m, 3H), 5.48 (q, J=7.0 Hz, 1H), 4.35 (m, 1 H), 2.03 (s, 3H). 1.24-1.87 (m, 10H). 1.36 (d, J=7.0 Hz, 3H).