BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel phenylsubstituted cycloalkyl N-hydroxyurea derivatives. The compounds of the present invention inhibit the action of the enzyme Iipoxygenase 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, prostagiandins 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 prostagiandins and thromboxanes or by Iipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysioiogy of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits Iipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.

Several review articles on Iipoxygenase inhibitors have been reported (See H.

Masamune et al., Ann. Rev. Med. Chem.. 24, 71-80 (1989) and B.J. Fitzsimmons et al., Leukotrienes and Lipoxygenases. 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 (Kohyo) 502179/88 and U.S. patent No. 4,822,809.

SUMMARY OF THE INVENTION The present invention provides novel phenylsubstituted cycloalkyl N- hydroxyurea derivatives of the following formula:

o

wherein A is C, to C ₄ alkylene or C ₂ to C ₆ alkenylene; each B is independently halogen, C, to C ₄ alkyl, C ₂ to C ₈ alkoxyalkyl or halosubstituted G, to C ₄ alkyl;

X is methylene or ethylene;

M is hydrogen or a pharmaceutically acceptable cation; Ar is phenyl or mono-, df- or tri-substituted phenyl wherein the substituents are independently selected from halogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy, halosubstituted C, to C ₄ alkyl, (G, to C ₄ alkyl)phenoxy, (C, to C ₄ a!koxy)phenoxy, halosubstituted phenoxy, halosubstituted (C ₁ to C ₄ alkyl)phenoxy, phenylthio, (C ₁ to C ₄ alkyl)phenyIthio, (C _t to C ₄ alkoxy)phenylthio, halosubstituted phenylthio or halosubstituted (C, to C ₄ alkyl)phenylthio;

A, B and Ar may be attached at any available position on the ring; m is 0 or 1 ; and n is 0, 1 or 2.

The preferred compounds of the invention are the compounds of formula I, in which the Ar group is a mono-, di- or tri-substituted phenyl group which bears at least one phenylthio group or substituted phenylthio group. Particularly preferred compounds of the invention are: N-hydroxy-N-(cte-3-[3-(phenylthio)phenyl]cyclobutyl)urea; N-hydroxy-N-(trans-3-[3-(phenylthio)phenyl]cycIobutyl)urea;

N-hydroxy-N-(cis-3-[3-(4-methoxyphenylthio)phenyl]cyclobu tyl)urea; . N-hydroxy-N-(trans-3-[3-(4-methoxyphenylthio)phenylJcyciobut yl)urea; and N-(trans-3-[3-(4-fluorophenylthio)phenyIIcyclobutyl)-N-hydro xyurea.

The compounds of formula I inhibit the enzyme 5-lipoxygenase. Therefore the compounds are useful for treating medical conditions for which a 5-lipoxygenase inhibitor is needed in a mammalian subject, e.g., a human subject. The compounds are especially useful for treating allergic and inflammatory conditions. This invention also embraces pharmaceutical compositions which comprise a compound of the formula I and a pharmaceutically acceptable carrier. This invention further relates to 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" and "halogen" mean a radical derived from the elements fluorine, chlorine, bromine and iodine.

"Alkyl" means a straight or branched saturated hydrocarbon chain radical of 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl and n-butyl.

"Alkylene" means a straight or branched hydrocarbon chain spacer radical, for example, -CH ₂ -, -CH(CH ₃ )-, -CH ₂ CH ₂ - and -CH _jj CHfCH _g )-.

"Alkenylene" means a straight or branched hydrocarbon chain spacer radical having one double bond, for example, -CH=CH-, -CH=CHCH ₂ - and -CH=CHCH(CH ₃ )-.

"Halosubstituted alkyl" refers to an alkyl radical as described above substituted with one or more halogen radicals, for example, chloromethyl, bromoethyl and trifluoromethyl.

"Alkoxy" means the group -OR wherein R is alkyl as defined above, for example, methoxy, ethoxy, propoxy, isopropoxy and n-butoxy.

"Alkoxyalkyl" means the group -ROR' wherein R is alkylene as defined above and R' is alkyl as defined above, for example, methoxymethyl, ethoxymethyl, n- propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl and t-butoxymethyl.

"Pharmaceutically acceptable cation" means a non-toxic cation, for example, a cation based on the alkali and alkaline earth metals such as sodium, lithium, potassium and magnesium, as well as non-toxic ammonium, quaternary ammonium and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, diethylamine, trimethylamine and triethylamine.

The novel compounds of this invention may be prepared as shown in the reaction scheme described below.

GENERAL SYNTHETIC SCHEME

o

c π O O

In the above scheme, Q is Ar

wherein Ar, B, X and n are as defined above.

The hydroxylamine (i) is treated with trimethylsilyl isocyanate (TMS-NCO) 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 (THF), 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 and then subsequent 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 subjected to (i.e. in situ) reaction with aqueous ammonia. The product of formula (ii) 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 carbonyl compounds (i.e. ketones or aldehydes), alcohols or halogen compounds. For example, a suitable carbonyl compound is converted to its oxime and then reduced to the requisite hydroxylamine (i) with a suitable reducing agent. See, for example, R.F. Borch et al, J. Am. Chem. Soc. 93, 2897 (1971). Reducing agents of choice include, but are not limited to, sodium cyanoborohydride and borane complexes such as boron-pyridine, boron-triethylamine and boron-dimethylsulfide, however triethylsilane in trifluoroacetic acid (TFA) may also be employed.

Alternatively, the hydroxylamine (i) can be prepared by treating the corresponding alcohol with N,0-bis(t-butoxycarbonyl)hydroxylamine under Mitsunobu-type reaction conditions followed by acid catalyzed hydrolysis of the N,O- protected intermediate product (see JP (Kokai) 45344/89).

The aforementioned hydroxylamine (i) may also be prepared from a suitable halide compound by the reaction with O-protected hydroxylamine and subsequent deprotection. See W.P. Jackson et al., J. Med. Chem.. 31, 499 (1988). Preferred O- protected hydroxyiamines include, but are not limited to, O-tetrahydropyranyl-, O-trimethylsilyl- and O-benzylhydroxylamine. The hydroxylamine (i) thus obtained can be isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The individual isomers of the compounds of the invention can be prepared by a process which comprises separation employing a chiral stationary phase or kinetic enzymatic resolution of an intermediate alcohol and transformation of the optically active alcohol to the final compound by procedures as described above.

The pharmaceutically acceptable salts of the novel compounds of the invention are readily prepared by contacting said compounds with a stoichiometric amount of an appropriate metal hydroxide, alkoxide or amine in either aqueous solution or a suitable organic solvent. The respective salts may then be obtained by precipitation or by evaporation of the solvent.

The compounds of this invention inhibit the activity of the enzyme Iipoxygenase. This inhibition has been demonstrated by an assay using rat peritoneal cavity-resident cells which determines the effect of said compounds on the metabolism of arachidonic acid, as described in "Synthesis of leukotrienes by peritoneal macrophages," Jap. J. Inflammation. 7, 145-150 (1987). In this test some preferred compounds exhibited IC _gg values in the range from 0.01 to about 30 μM, for Iipoxygenase inhibition.

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

The compounds of the invention and their pharmaceutically acceptable salts are of particular use in the treatment or alleviation of inflammatory 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. The compounds can be administered via a variety of conventional routes of administration including orally, parenterally 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 the specific details of these examples.

Proton nuclear magnetic resonance spectra (NMR) 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; m, multiplet; br, broad.

Example 1 (+)-(1 R,3S)-N-[3-(4-fluorophenyl)cyclopentyl]-N-hydroxyurea (5) and (-H1 S.3R)-N-f3-(4-fluorophenyl)cvcIopentvπ-N-hvdroxyurea (6)

Step 1. (1R,3S)-3-f4-fIuorophenyl)cvclθDentyl acetate (1) A mixture of powdered 4A Molecular Sieves (600 mg), cjs-3-(4-fluorophenyl)- cyclopentanol (1.06 g, 5.9 mmol) and vinyl acetate (40 ml) in hexane (40 ml) was stirred at room temperature for 10 minutes. To this mixture PPL (Sigma, Porcine Pancreas Lipase, 400 mg) was added and the whole stirred vigorously at room temperature for 4 hours. CHCI ₃ (200 ml) was then added to the reaction mixture, insoluble material was removed by filtration and the filtrate was concentrated jn vacuo. The resulting oil was separated by silica-gel column chromatography (SiO ₂ 100 g, hexane:ethyl acetate = 10:1 (1000 ml) and 3:1 (1500 ml)) to afford optically

pure title compound (1 , 379 mg, 31% yield) and alcohol (2, 650 mg, 65% yield) as colorless oils, respectively.

Step 2. (1 S.3R)-3-(4-fluorophenyl)cvclopentanol (2)

The recovered alcohol (650 mg) of step 1 , above, was subjected to the above-described reaction conditions for 24 hours. Standard work-up and purification by silica-gel column chromatography (SiO ₂ 100 g, hexane:ethyl acetate = 2:1 (1000 ml)) gave optically pure title compound (2, 438 mg, 44% yield from racemate) as a colorless oil.

Step 3. πS.3S)-3-(4-fluorophenyl)cvclopentanol (3) To a solution of compound 1 (379 mg, 1.7 mmol), from Step 1 , above, in methanol (50 ml) was added K _g CO _g (1.2 g, 8.5 mmol) and the mixture was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure and the residue was diluted with 100 ml of water. The aqueous mixture was extracted with ethyl acetate, washed with brine, dried over MgSO ₄ and concentrated In vacuo to afford crude title product. To a solution of this crude alcohol (299 mg, 1.7 mmol), benzoic acid (244 mg, 2.0 mmol) and triphenylphosphine (Ph ₃ P, 525 mg, 2.0 mmol) in dry THF (25 ml) was added dropwise diethyl azodicarboxylate (DEAD, 435 mg, 2.5 mmol) in dry THF (5 ml) at 0°C under an argon atmosphere. The mixture was stirred for 1 hour at room temperature and then the volatiles were removed under reduced pressure. The residue was suspended in dietylether and insoluble material removed by filtration. The ether layer was concentrated in vacuo to afford crude (1 S,3S)-3-(4-fluorophenyl)cyclopentyl benzoate. To a solution of this crude benzoate (1.2 g, 1.7 mmol) in methanol (30 ml) was added an aqueous solution of KOH (560 mg in 5 ml of water) and the mixture was heated under reflux for 12 hours. The volatiles were removed under reduced pressure and the residue was diluted with water. The aqueous mixture was extracted with ethyl acetate, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The resultant oil was purified by flash silica-gel chromatography (hexane:ethyl acetate = 2:1) to afford 245 mg (80% yield) of the title compound (3) as a colorless oil.

Step 4, (1 R,3S)-N,O-bis(t-butoxycarbonyl)-3- (4-fluorophenyl)cvclopentylhvdroxylamine, 4

To a stirred solution of compound 3 (245 mg, 1.4 mmol), from Step 3, above,

N,O-bιs(t-butoxycarbonyl)hydroxyiamine (400 mg, 1.7 mmol) and Ph ₃ P (450 mg, 1.7 mmol) in dry THF (25 ml) was added dropwise DEAD (350 mg, 2.0 mmol) in dry THF

(5 ml) at 0°C under an argon atmosphere. After completion of addition, the mixture was allowed to warm to room temperature, was stirred for 1 hour and the volatiles were removed under reduced pressure. Chromatographic purification (SiO ₂ 50 g, n- hexane:ethyl acetate = 15:1) of the residue gave the title compound (4, 489 mg, 88% yield) as a pale yellow oil.

Step 5. (+H1R.3S)-N-r3-(4-fluorophenvncvclopentvπ-N-hvdroxyurea (5) To a stirred solution of compound 4 (489 mg, 1.2 mmol), from Step 4, above, in CH ₂ CI ₂ (10 ml) was added TFA (4 ml). The mixture was stirred for 1 hour at room temperature and the volatiles were removed under reduced pressure and ethyl acetate was added. The organic layer was washed with water, saturated aqueous NaHCO ₃ solution and brine. The ethyl acetate solution was dried over MgSO ₄ and concentrated in vacuo to afford crude (1R,3S)-3-(4-fluorophenyl)cyclopentyIhydroxyl- amine as white solids. To a solution of this crude hydroxylamine (234 mg, 1.2 mmol) in THF (10 ml) was added trimethylsilyl isocyanate (TMS-NCO, 0.3 ml, 2.0 mmol) at room temperature and the mixture was stirred for 30 minutes. Volatiles were removed under reduced pressure and the residue purified by silica-gel column chromatography (SiO ₂ 30 g, CHCI ₃ :acetone = 3:2). Recrystallization from ethyl acetate gave the title compound (5, 142 mg, 50% yield) as a white powder, m.p. 139.2-140.2°C. The isomer was determined by HPLC analysis (eluting with 10% isopropanol/hexanes, chiralcel OJ column, 260 nm UV detector) to consist of >99% enantiomeric excess.

[α] _D = +22.2° (EtOH). IR (KBr) v : 3400, 3250, 1650, 1620, 1510, 1400, 1220, 840 cnrf ¹ .

¹ H NMR (DMSO-d ₆ )δ: 9.09 (s, 1H), 7.31-7.24 (m, 2H), 7.10 (t, J=9 Hz, 2H), 6.28 (s, 2H), 4.73-4.60 (m, 1H), 3.04-2.88 (m, 1H), 2.11-1.53 (m, 6H).

Step 6. (-H1S.3R)-N-r3-(4-fluorophenyl)cvclopentvn-N-hvdroxyurea (6) The title compound (6), m.p. 139.0-140.4°C, was prepared from the corresponding (1 S,3R)-alcohol (compound 2) in a manner similar to that described above for preparing compound 5 from compound 1. The isomer was determined by HPLC analysis (eluting with 10% isopropanol/hexanes, chiralcel OJ column, 260 nm UV detector) to consist of >99% enantiomeric excess.

[α] _D = -22.4° (EtOH).

IR (KBr)v: 3400, 3350, 1650, 1510, 1400, 1220, 950 cm- ¹ . ¹ H NMR (DMSO-d ₆ )δ: 9.09 (s, 1 H), 7.31-7.24 (m, 2H), 7.10 (t, J=9 Hz, 2H),

6.28 (br s, 2H), 4.73-4.60 (m, 1 H), 3.04-2.88 (m, 1 H), 2.11-1.53 (m, 6H).

Example 2 (+M1 R.3S)- and -(1S.3R)-N-hvdroxy-N-f3-phenylcvclopentv urea

The title compounds were prepared in a manner similar to that described in Example 1,

(+M1 R.3S)-N-Hvdroxy-N-(3-phenylcvclopentyl)urea

0

The isomer was determined by HPLC analysis (eluting with 10% isopropanol/ hexanes, chiralcel OJ column, 260 nm UV detector) to consist of >99% enantiomeric excess.

m.p.: 126.1-126.9°C. [α] _D = +26.2° (EtOH).

IR (KBr)v: 3480, 3350, 3300, 1610, 1580, 1450, 1150, 1070, 760, 700 cm ^-1 . ¹ H NMR (DMSO-d ₆ )δ: 9.10 (s, 1 H), 7.31-7.16 (m, 5H), 6.28 (s, 2H), 4.70-4.60

(m, 1 H), 2.95-2.90 (m, 1 H), 2.06-1.58 (m, 6H).

f-H1S,3R)-N-Hvdroxy-N-(3-phenylcvclopentyl)urea

0

The isomer was determined by HPLC analysis (eluting with 10% isopropanol/ hexanes, chiralcel OJ column, 260 nm UV detector) to consist of >99% enantiomeric excess.

m.p.: 125.8-126.8°C. [«] _D = -27.2° (EtOH).

IR (KBr)v: 3480, 3350, 3300, 1610, 1580, 1450, 1150, 1070, 760, 700 cm ^"1 . ¹ H NMR (DMSO-d^δ: 9.10 (s, 1H) _r 7.31-7.16 (m, 5H), 6.28 (s, 2H), 4,70-4.60 (m, 1H), 2.95-2.90 (m, 1H), 2.06-1.58 (m, 6H).

Example 3 N-(trans-3-[3-(4-chlorophenoxy)phenyl]cyclobutyl)-N-hydroxyu rea (11) and Bcample 4. N-(cis-3-r3-(4-chlorophenoxy)phenyπcvclobutvD-N-hvdroxyurea (13)

Step 1 , 3-(4-chlorophenoxy)styrene (7)

The title compound was prepared from commercially avilable 3-(4- chlorophenoxy)benzaldehyde by Wittig methylenation (see J. Am. Chem. Soc, 104, 4724 (1982) and J. Orα. Chem.. 52, 3595 (1987)).

Step 2, 3-f3-(4-chlorophenoxy)phenyl1cvclobutanone (9)

To a stirred solution of compound 7, from Step 1 , above, (14.3 g, 62 mmol) and zinc-copper couple (4.46 g) in anhydrous ether (100 ml) was added dropwise a solution of trichloroacetyl chloride (7.27 ml, 65 mmol) and phosphoryl chloride (6.06 ml, 65 mmol) in anhydrous ether (45 ml) over a 1.5 hour period under a nitrogen atmosphere. When addition of the solution was complete, the mixture was refluxed with stirring for 2 hours. The reaction mixture was then filtered through a pad of Celite and the unreacted zinc-copper couple was washed with ether (100 ml). The ethereal solution was concentrated in vacuo to about 50% of its original volume, an equal volume (100 ml) of pentane was added and the solution stirred for a.few minutes to precipitate the zinc salts. The solution was decanted from the residue, washed successively with ice water (100 ml), a cold saturated aqueous NaHCO ₃ solution (100 ml), water (100 ml) and brine (100 ml), then was dried over MgSO ₄ and the solvent was removed in vacuo to leave crude compound 8 (19 g) as a pale yellow oil which was used without further purification.

To a stirred solution of crude compound 8 (19 g) in acetic acid (60 ml) was added zinc powder (12 g) at about 10°C (exothermic). After stirring for 30 minutes at 50-70°C, the mixture was filtered through a pad of Celite and the unreacted zinc washed with acetic acid (20 ml) and ether (10 ml). The filtrate was concentrated in vacuo. Water (100 ml) was added to the mixture, and the whole was extracted with ether (2 x 100 ml, 50 ml). The organic layer was washed with saturated aqueous NaHCO ₃ solution (100 ml), water (100 ml), brine (100 ml), dried over MgSO ₄ , and evaporated in vacuo to afford the title compound (9, 15.8 g, 93.5% yield from compound 7).

Step 3. cis-3-r3-(4-chlorophenoxy)phenyllcvclobutanol (10) To a stirred solution of UAI[OC(CH ₃ ) ₃ ] ₃ H (17.7 g, 69.7 mmol) in THF (110 ml) cooled to -73°C was added compound 9, from Step 2, above, (58 mmol) in THF (30 ml) under a nitrogen atmosphere. The reaction mixture was stirred overnight at -70°C, and a cold saturated aqueous NH ₄ CI (25 ml) was added. MgSO ₄ (10 g) was added and the mixture filtered through Celite, washed with ethyl acetate (4 x 30 ml), and the filtrate was evaporated in vacuo to afford crude product. Ethyl acetate (100 ml) was added, the solution dried over MgSO ₄ and concentrated in vacuo to provide the title compound (10, 10 g, 63% yield) as a colorless oil.

¹ H NMR (CDCyδ: 7.31-7.23 (m, 3H), 7.00-6.78 (m, 5H), 4.29-4.23 (m, 1H), 2.97-2.90 (m, 1H), 2.80-2.70 (m, 2H), 2.04-1.92 (m, 2H), 1.83 (br s, 1H).

Step 4. N-(trans-3-[3-(4-chlorophenoxyl)phenyl]cvclobutyl)-N-hvdroxy urea (11) To a stirred solution of compound 10, from Step 3, above, (3.08 g, 1 .2 mmol), Ph ₃ P (2.61 g, 12.9 mmol) and N,O-bis(tert-butoxycarbonyl)hydroxyiamine (3.01 g, 12.9 mmol) in THF (20 ml) was added DEAD (2.25 g, 12.9 mmol) in THF (5 ml) at room temperature under a nitrogen atmosphere. After stirring for 5 hours, volatiles were removed under reduced pressure. Diethylether (20 ml)/n-hexane (80 ml) was added to the resultant oil, insolubles were filtered off and the filtrate was concentrated in vacuo. The resulting oil was purified by flash chromatography (Si0 ₂ 100 g, n-hexane:ethylacetate = 30:1) to afford N,O-bis(tert-butoxycarbonyI)-N-(trans- 3-[3-(4-chlorophenoxy)phenyl]cyclobutyl)hydroxylamine (3.28 g, 60% yield).

To a stirred solution of N,O-bis(tert-butoxycarbonyl)-N-(trans-3-[3-(4- chforophenoxy)phenyl]cyclobutyl)hydroxylamine (3.28 g, 6.7 mmol) in CH ₂ CI ₂ (30 ml) was added TFA (7 ml) dropwise at 5°C. After stirring for 3 hours, volatiles were removed in vacuo, saturated aqueous NaHCO ₃ (70 ml) was added and the whole extracted with ethyl acetate (2 x 150 ml). The organic layer was washed with water (100 ml), brine (100 ml), dried over MgSO ₄ and evaporated in vacuo to afford N- (trans-3-[3-(4-chIorophenoxy)phenyl]cyclobutyl)hydroxylamine (1.6 g).

To a stirred solution of N-(trans-3-[3-(4-chlorophenoxy)phenyI]cyclobutyI)- hydroxylamine (1.6 g, 5.53 mmol) in THF (10 ml) was added TMS-NCO (0.87 g, 7.56

mmol) at room temperature under a nitrogen atmosphere. After stirring for 2 hours, methanol (10 ml) was added to quench the reaction. Volatiles were removed in vacuo. and the resulting solid was recrystallized from ethyl acetate/n-hexane to afford the Example 3 title compound (11 , 0.94 g, 42.2% yield from protected hydroxylamine) as colorless needles, m.p. 133-134°C.

IR (nujol)v: 3200, 1660, 1640, 1575, 1250, 1210, 830 cm ^-1 . ¹ H NMR (DMSO-d ₆ )δ: 9.27 (s, 1 H), 7.45-7.33 (m, 3H), 7.13 (d, J=7.7 Hz, 1 H), 7.06-6.97 (m, 3H), 6.85-6.81 (m, 1 H), 6.33 (s, 2H), 4.81-4.75 (m, 1 H), 3.39-3.32 (m, 1 H), 2.73-2.62 (m, 2H), 2.20-2.10 (m, 2H).

Step 5. trans-3-[3-(4-chlorophenoxy)phenyl1cvclobutanol (12) To a stirred solution of compound 10, from Step 3, above, (6.86 g, 25 mmol) and Ph ₃ P (5.82 g, 27.85 mmol) in THF (25 ml) was added benzoic acid (3.51 g, 28.75 mmol) in one portion, and then DEAD (5.01 g, 28.75 mmol) in THF (8 ml) was added dropwise at 10°C (exothermic) under a nitrogen atmosphere. After stirring for 1.5 hours at room temperature, the volatiles were evaporated in vacuo. Diethylether/n-hexane (20 ml/50 ml) was added to the residue, insolubles were removed by filtration and the filtrate was concentrated in vacuo. This treatment was repeated twice to provide crude trans-3-f 3-(4-chlorophenoxv) phenvll cvclobutyl benzoate (12 g) as a yellow oil, which was used for without further purification.

To a stirred solution of the crude trans-3-[3-(4-chlorophenoxy)phenyl]cyclo- butyl benzoate (12 g) in THF/methanol (30 ml/30 ml) was added dropwise a KOH/water (2.7 g/45 ml) solution at room temperature. After stirring for 1.5 hours at room temperature, solvent was removed under reduced pressure and the whole was extracted with ethyl acetate (2 x 150 ml and 50 ml). The organic layer was washed with water (100 ml) and brine (200 ml), then was dried over MgSO ₄ and evaporated in vacuo to afford the title compound (12, 5.62 g, 82% yield from compound 4).

¹ H NMR (CDCI ₃ )δ: 7.31-7.24 (m, 3H), 7.01-6.78 (m, 5H), 4.57-4.47 (m, 1 H), 3.64- 3.57 (m,1H), 2.51-2.34 (m, 4H), 1.70 (br s, 1 H).

Step 6. N-fcis-3-| ^" 3-(4-chlorophenoxy)phenyllcvclobutyl)-N-hvdroxyurea (13)

The Example 4 title compound (13, m.p. 152-153.5°C) was prepared from the corresponding trans-alcohol (12) by the same method as described in Step 4 of Example 3, above.

IR (nujol)v: 3200, 1645, 1575, 1485, 1250, 1220, 945 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.17 (s, 1H), 7.43 (d, J=9.1 Hz, 2H), 7.33 (t, J=8 Hz, 1 H), 7.06-6.81 (m, 5H), 6.29 (s, 2H), 4.66-4.60 (m, 1 H), 3.11-3.04 (m, 1 H), 2.41-2.23 (m, 4H).

In the following examples, the title compounds were prepared from the corresponding aldehyde by methods similar to those described above in Examples 3 and 4.

Example 5 N-hvdroxy-N-(cis-3-f3-(4-methoxyphenoxy)phenyl1cvclobutyl)ur ea

₂ m.p.: 142-144°C. O H

IR (KBr)v: 3490, 1645, 1505, 1210 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.16 (s, 1H), 7.25 (dd, J=8.4, 7.7 Hz, 1H), 7.01-6.93 (m, 5H), 6.81 (br s, 1H), 6.69 (dd, J=8.1 , 2.6 Hz, 1H), 6.28 (s, 2H), 4.65-4.56 (m, 1 H), 3.75 (s, 3H), 3.07-3.00 (m, 1H), 2.39-2.21 (m, 4H).

Example 6. N-hvdroxy-N-(trans-3-f3-(4-methoxyphenoxy)phenvncvclobutyl)u rea

m.p.: 112-113°C. O H

IR (KBr)v: 3490, 1660, 1640, 1505, 1240, 1210 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.25 (s, 1 H), 7.28 (dd, J=8.1 , 7.7 Hz, 1 H), 7.03-6.93 (m, 5H), 6.86 (br S, 1 H), 6.69 (br d, J=8.1 Hz, 1 H), 6.31 (s, 2H), 4.79-4.73 (m, 1 H), 3.74 (s, 3H), 3.35-3.31 (m, 1 H), 2.72-2.66 (m, 2H), 2.16-2.12 (m, 2H).

Example 7. N-hvdroxy-N-(cis-3-f3-(3-trifluoromethylphenoxy)phenyl1cyclo butyl)urea

m.p.: 125.5-127.5°C.

IR (nujol)v: 3200, 1645, 1575, 1330, 1180, 1065, 900, 805, 700 cm ^"1 . ¹ H NMR (DMSO-d ₆ )δ: 9.17 (s, 1 H), 7.62 (t, J=8 Hz, 1 H), 7.50-7.46 (t, J=8 Hz, 1 H), 7.39-7.25 (m, 3H), 7.10 (d, J=7.7 Hz, 1 H), 6.97 (d, J=1.4 Hz, 1 H), 6.88 (dd, J=8, 2 Hz, 1 H), 6.29 (s, 2H), 4.67-4.61 (m, 1 H), 3.13-3.07 (m, 1 H), 2.40-2.25 (m, 4H).

Example 8. N-hvdroxy-N-(trans-3-r3-(3-trifluoromethylphenoxy)phenyljcvc lobutyl)urea

m.p.: 95-96°C.

IR (nujol)v: 3410, 3050, 1650, 1580, 1330, 1260, 1145, 1110, 1065, 945, 890, 880 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.27 (s, 1H), 7.62 (t, J=8 Hz, 1H), 7.49-7.26 (m, 4H), 7.18 (d, J=8 Hz, 1H), 7.04 (s, 1H), 6.89 (dd, J=8, 2 Hz, 1H), 6.33 (s, 2H), 4.81-4.76 (m, 1H), 3.43-3.30 (m, 1H), 2.75-2.63 (m, 2H), 2.21-2.12 (m, 2H).

Example 9. N-hvdroxy-N-rcis-3-(3-methoxyphenyl)cvclobutyl1urea

m.p.: 154.5-156.5°C.

IR (nujol) v : 3180, 1635, 1570, 1290, 1210, 1050, 980, 775 cm ^"1 . ¹ H NMR (DMSO-d ₆ )δ: 9.18 (s, 1H), 7.24-7.18 (m, 1 H), 6.81-6.72 (m, 3H), 6.29 (s, 2H), 4.67-4.60 (m, 1 H), 3.73 (s, 3H), 3.04-3.00 (m, 1 H), 2.35-2.27 (m, 4H).

Example 10, N-(ftrans-3-(4-fluorophenvl)-3-methyl]cyclobutvl)-N-hvdroxvu rea (18) and Example 11. N-(rcis-3-(4-fluorophenyl)-3-methyl1cvclobutyl)-N-hvdroxyure a (21)

.

.

Step 1. 3-(4-fluorophenyl)-3-methylcvclobutanone (14)

Sodium hydride (9.8 g, 0.24 mol as a 60% dispersion in mineral oil) in a 1000 ml three-necked flask was washed with several portions of n-hexane to remove the mineral oil. Dimethyl sulfoxide (500 ml) was introduced, and the mixture was heated at 60°C until the evolution of hydrogen ceased. To the resulting solution was added methyltriphenylphosphonium bromide (85.7 g, 0.24 mol) and the mixture was stirred

at 60°C for 0.5 hour. The resulting yellow solution of the ylide was cooled to ambient temperature and 4-fluoroacetophenone (25.0 g, 0.18 mol) in dimethyl sulfoxide (100 ml) was added. After being stirred for 5 minutes, ice water (500 ml) was added and the whole was extracted with n-hexane (1000 ml). The organic extract was washed with water (500 ml) and brine (500 ml), then was dried over Na^O^ Removal of solvent gave crude 4-fluoro-α-methylstyrene (19.6 g) as a colorless oil.

The crude 4-fluoro-α-methylstyrene (19.6 g) was dissolved in diethyl ether (300 ml), and zinc-copper (23.5 g, 0.36 mol) was added under nitrogen. To the resulting mixture was added dropwise a solution of phosphoryi chloride (16.8 ml, 0.18 mol) and trichloroacetylchloride (20.1 ml, 0.18 mol) in diethyl ether (100 ml) with ice cooling. The resulting mixture was heated at reflux temperature for 4 hours and cooled to ambient temperature. After being stirred for 14 hours, the mixture was filtered through Celite. The filtrate was concentrated jn vacuo and the residue was extracted with n-hexane (3 x 500 ml). The combined organic extracts were successively washed with water (500 ml), saturated aqueous NaHCO ₃ (500 ml) and brine (500 ml), then were dried over Na^O^ Removal of solvent gave crude 2,2-dichloro-3-(4-fluorophenyl)-3-methyicyclobutanone (19.3 g) as a yellow oil.

The crude 2,2-dichloro-3-(4-fluorophenyl)-3-methylcyclobutanone (19.3 g) was dissolved in acetic acid (150 ml). To the solution was added zinc powder (15.7 g, 0.24 mol) at ambient temperature and the resulting mixture was heated at 60°C for 1 hour. The resulting mixture was filtered through Celite, the filtrate was diluted with diethyl ether (500 ml) and successively washed with water (3 x 500 ml), saturated aqueous NaHCO ₃ (2 x 500 ml) and brine (500 ml), then was dried over Na _g SO^ Removal of solvent gave the title compound 14 (13.0 g, 41% yield) as a colorless oil.

¹ H NMR (CDCI ₃ )δ: 7.30-7.24 (m, 2H), 7.08-7.01 (m, 2H), 3.47-3.40 (m, 2H), 3.16-3.07 (m, 2H), 1.60 (s, 3H).

Step 2, cis-3-(4-fluorophenyl)-3-methylcyclobutyl-p-nitrobenzoate (16) and trans-3-(4-fluorophenyl)-3-methylcvclobutyl-p-nitrobenzoate (19)

To a stirred solution of LiAI[(OC(CH ₃ ) ₃ )] ₃ H (23.0 g, 0.11 mol) in THF (250 ml) was added dropwise compound 14 (12.9 g, 0.07 mol) in THF (100 ml) at -70°C

under nitrogen. After being stirred for 15 hours, water (20 ml) was added to the mixture. The mixture was warmed to room temperature and MgSO ₄ was added, the resulting mixture filtered, and the filtrate was dried over MgS0 ₄ . Removal of solvent gave diastereomeric 3-(4-fluorophenyl)-3-methyIcyclobutanol (15) as a yellow oil.

Compound 15 (5.63 g) was dissolved in THF (300 ml) and 4-nitrobenzoyl- chloride (8.9 g, 48 mmol), triethylamine (4.88 ml, 35 mmol) and dimethylaminopyri- dine (catalytic amount) were added successively at ambient temperature. After being stirred for 2 days, the mixture was poured into water (500 ml) and extracted with diethyl ether (500 ml). The organic extract was washed with water (500 ml) and brine (500 ml), then was dried over Na2SO ₄ and concentrated in vacuo. The residual oil was chromatographed over silica gel (ethyl acetate:n-hexane = 1 :20) to afford title compound 16 (2.04 g, rf=0.74) as yellow needles and title compound 19 (1.90 g, rf=0.78) as yellow plates.

¹ H NMR (CDCI ₃ )δ (16): 8.29-8.15 (m, 3H), 7.26-6.97 (m, 5H), 5.49-5.44 (m, 1H), 2.81-2.73 (m, 2H), 2.56-2.49 (m, 2H), 1.50 (s, 3H).

¹ H NMR (CDCI ₃ )δ (19): 8.32-8.21 (m, 2H), 7.30-7.25 (m, 5H), 7.07-7.00 (m, 1 H), 5.19-5.13 (m, 1H), 3.06-2.97 (m, 2H), 2.44-2.36 (m, 2H), 1.53 (s, 3H).

Step 3, cis-3-(4-fluorophenyl)-3-methylcvclobutanol (17)

To a stirred solution of compound 16 in THRmethanol (1 :1 , 20 ml) was added KOH (0.85 g, 12.8 mmol) in water (10 ml) at ambient temperature. After being stirred for 1 hour, the mixture was concentrated in vacuo. To the residue was added water (100 ml) and the whole was extracted with ethyl acetate:b ^* enzene (2:1 , 150 ml).

The organic extract was washed with brine (100 ml) and dried over MgSO ₄ .

Removal of solvent gave the title compound (17, 745 mg) as a colorless oil.

¹ H NMR (CDCIg)δ: 7.36-6.94 (m, 4H), 4.54-4.43 (m, 1 H), 2.63-2.54 (m, 2H), 2.22-2.04 (m, 2H), 1.62 (br s, 1 H), 1.37 (s, 3H).

Step 4. trans-3-(4-fluorophenyl)-3-methylcvclobutanol (20) Compound 20 was prepared from the corresponding trans-benzoate (compound 19) in a manner similar to that for compound 17 in Step 3, above.

¹ H NMR (CDCI ₃ )δ: 7.26-7.21 (m, 2H), 7.02-6.96 (m, 2H), 4.18-4.11 (m, 1 H), 2.85-2.78 (m, 2H), 2.12-2.05 (m, 2H), 1.78 (br s, 1H), 1.44 (s, 3H).

Step 5, N-(ftrans-3-(4-fluorophenyl)-3-methyllcvclobutyl)-N-hvdroxyu rea (18) The Example 10 title compound (18), m.p. 118-120°C, was prepared from compound 17 according to the method described in Example 1 , above.

IR (KBr)v: 3450, 1640, 1510, 840 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.19 (s, 1 H), 7.44-7.39 (m, 2H), 7.17-7.10 (m, 2H), 6.27 (S, 2H), 4.40-4.33 (m, 1H), 2.51-2.30 (m, 4H), 1.32 (s, 3H).

Step 6, N-(fcis-3-(4-fluorophenyl)-3-methyl]cyclobutyl)-N-hvdroxyure a (21 ) The Example 11 title compound (21), m.p. 132-133°C, was prepared from compound 20 according to the method described in Example 2.

IR (KBr) v : 3490, 1660, 1510, 1220, 830 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.06 (s, 1H), 7.22-7.07 (m, 4H), 6.28 (s, 2H), 4.89-4.77 (m, 1H), 2.51-2.41 (m, 2H), 2.17-2.10 (m, 2H), 1.38 (s, 3H).

Example 12 (1S*,2R*,3R*)-N-hydroxy-N-[(2-methyl-3-phenyl)cyclobutyl]ure a and (1 R*.2R*.3R*)-N-hvdroxy-N-r(2-methyl-3-phenyl)cvclobutyllurea, 1 :1 mixture (25)

24 25

Step 1, cis-1-phenyl-1-propene (22)

Compound 22 was prepared from 1-phenylpropyne according to the procedure reported in J. Chem. Soc Chem. Commun.. 553 (1973), then was converted to compound 23 via previously described methods.

Step 2, (2S*,3S*)-2-methyl-3-phenylcyclobutanone oxime (24)

To a solution of compound 23 (1.5 g, 10.67 mmol) in EtOH (20 ml)/pyridine (7 ml) was added hydroxylamine hydrochloride (0.99 g, 13.9 mmol). After being stirred for 4 hours, the solvent was removed. To the resulting residue was added 10% HCI (5 ml) and water (50 ml). The mixture was extracted with ethyl acetate (150 ml, 50 ml). The combined organic extracts were successively washed with water (50 ml), brine (50 ml) and dried over NagSO^ Removal of solvent gave crude oxime 24 (1.69 g) as a yellow oil.

¹ H NMR (CDCI _g )δ: 7.37-7.17 (m, 5H), 3.77-3.57 (m, 2H), 3.28-3.15 (m, 2H),

0.82 (d, J=7.0 Hz, 3H).

Step 3, (lS*,2R*,3R*)-N-hydroxy-N-[(2-methyl-3-phenyl)cyclobutyi]ure a and (1 R*.2R*.3R*)-N-hvdroxy-N-r(2-methyl-3-phenyl)cvclobutvnurea. 1 :1 mixture (25) To a solution of compound 24 in EtOH/THF (1 :2, 24 ml) was added boron- pyridine complex (1.44 ml, 14.4 mmol). After being stirred for 1 hour, 3N HCI (15 ml) was added dropwise and the reaction mixture was stirred through the night. Sodium carbonate was added to the resulting mixture, which was then extracted with chloroform (3 x 40 ml). The combined organic extracts were successively washed with water (50 ml) and brine (50 ml), then dried over MgSO ₄ . Removal of solvent gave crude hydroxylamine as a yellow oil. To the resulting hydroxylamine (0.83 g, 4.7 mmol) in THF was added TMS-NCO (0.74 g, 6.1 mmol). After being stirred for 1 hour, methanol (10 ml) was added to the mixture and the solvent was removed. Recrystallization from ethyl acetate/hexane and filtering off of insolubles gave the title compound (25, 0.52 g) as a colorless crystal, m.p. 133-136°C.

IR (nujol)v: 3100, 1650, 1590, 1170, 1080, 755 cm ^"1 .

¹ H NMR (DMSO-de)δ: 9.19 (s, 0.5H), 9.10 (s, 0.5H), 7.35-7.11 (m, 5H), 6.28 (s, 1H), 6.18 (s, 1H), 4.49-4.38 (m, 1H), 3.39-3.30 (m, 1 H), 3.00-2.71 (m, 2H), 2.27-2.18 (m, 1 H), 0.65 (d, J=7.7 Hz, 1.5H), 0.52 (d, J=6.9 Hz, 1.5H).

Example 13 N-hvdroxy-N-(cis-3-[3-(phenylthio)phenyllcvclobutyl)urea

The title compound was prepared from 3-phenylthiobenzaldehyde by methods similar to those used in Examples 3 and 4.

m.p.: 149-150°C.

IR (KBr)v: 3500, 1640, 1570, 1450 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.17 (s, 1 H), 7.40-7.09 (m, 9H), 6.29 (s, 2H), 4.70-4.57 (m, 1 H), 3.12-2.99 (m, 1 H), 2.41-2.21 (m, 4H).

Example 14 N-hvdroxy-N-(trans-3-[3-(phenylthio)phenyllcvclobutyl)urea

The title compound was prepared from 3-phenylthiobenzaldehyde by methods similar to those used in Examples 3 and 4.

m.p.: 118-119°C. IR (KBr) v : 3480, 1620, 1570, 1480, 1440 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.27 (s, 1 H), 7.45-7.26 (m, 8H), 7.12 (d, J=7.3 Hz, 1 H), 6.33 (s, 2H), 4.80-4.73 (m, 1 H), 3.45-3.34 (m, 1 H), 2.73-2.61 (m, 2H), 2.17-2.07 (m, 2H).

Example 15 N-hvdroxy-N-(cis-3-[3-(4-methoxyphenylthio)phenvπcvclobutyl )urea

The title compound was prepared from 3-(4-methoxyphenylthio)benzaidehyde by methods similar to those used in Examples 3 and 4.

m.p.: 153-154°C. IR (KBr) v : 3190, 1640, 1570, 1240 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.16 (s, 1 H), 7.41-7.37 (m, 2H), 7.26-7.19 (m, 1 H), 7.06- 6.98 (m, 4H), 6.89 (d, J=8.1 Hz, 1 H), 6.28 (s, 2H), 4.65-4.58 (m, 1 H), 3.78 (s, 3H), 3.04-2.97 (m, 1 H), 2.34-2.23 (m, 4H).

Example 16 N-hvdroxy-N-(trans-3-f3-(4-methoxyphenylthio)phenyl]cvclobut yl)urea

The title compound was prepared from 3-(4-methoxyphenylthio)benzaldehyde by methods similar to those used in Examples 3 and 4.

m.p.: 124-126°C.

IR (KBr)v: 3200, 1650, 1570, 1450, 1250 cm ^"1 .

¹ H NMR (DMSO-d ₆ )δ: 9.25 (s, 1 H), 7.44-7.38 (m, 2H), 7.25 (dd, J=7.7, 7.7 Hz, 1 H), 7.15-6.98 (m, 4H), 6.91 (d, J=8.1 Hz, 1 H), 6.32 (s, 2H), 4.77-4.71 (m, 1H), 3.78 (s, 3H), 3.40-3.22 (m, 1 H), 2.70-2.59 (m, 2H), 2.14-2.06 (m, 2H).

Example 17 N-(trans-3-[3-(4-fluorophenylthio)phenyl]cyclobutyl)-N-hvdro xyurea

The title compound was prepared from 3-(4-fluorophenylthio)benzaldehyde by methods similar to those used in Examples 3 and 4.

m.p.: 135-136°C.

IR (KBr)v: 3480, 1620, 1570, 1490 cm ^"1 .

¹ H NMR (DMSO-de)δ: 9.26 (s, 1H), 7.46-7.21 (m, 7H), 7.07 (br, J=7.69 Hz, 1 H), 6.33 (s, 2H), 4.79-4.73 (m, 1H), 3.37-3.32 (m, 1 H), 2.72-2.60 (m, 2H), 2.18-2.06 (m, 2H).