WO1995017379A1

WO1995017379A1 - Phenylthiophenyl cycloalkenyl hydroxyureas as lipoxygenase inhibitors

Info

Publication number: WO1995017379A1
Application number: PCT/JP1994/002032
Authority: WO
Inventors: Akiyoshi Kawai; Rodney W. Stevens
Original assignee: Pfizer Corp Belgium; Pfizer Pharmaceuticals KK; Pfizer Corp SRL
Current assignee: Pfizer Corp Belgium; Pfizer Japan Inc; Pfizer Corp SRL
Priority date: 1993-12-22
Filing date: 1994-12-02
Publication date: 1995-06-29
Anticipated expiration: 1996-06-22
Also published as: FI946007L; FI946007A7; IL111994A0; EP0736006A1; JP2756732B2; CA2178833A1; AU1120795A; FI946007A0; CO4230016A1; PE36395A1; JPH09503226A

Abstract

Certain novel phenylthiophenylcycloalkenyl hydroxyurea compounds having the ability to inhibit the 5-lipoxygenase enzyme and having formula (I) and the pharmaceutically acceptable salts thereof, wherein A and B, independently, are hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halo-substituted alkyl or C1-C4 halo-substituted alkoxy; R?1 and R2¿, independently, are hydrogen or C¿1?-C3 alkyl; X is S, SO or SO2; and Z is methylene or ethylene. These compounds are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals and as the active ingredient in pharmaceutical compositions for treating such conditions.

Description

PHENYLTHIOPHENYL CYCLOAKENYL HYDROXYUREAS fS LIPOXYGENASE INHIBITORS

Technical Field

This invention relates to novel N-hydroxyurea compounds. The compounds of the present invention inhibit the action of lipoxygenase enzyme 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.

Background Art

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 the arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase A2. 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 metabolized 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 diseases. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions. Recently several review articles on lipoxygenase inhibitors have been reported.

(See H.Masamune and L.S.Melvin, Sr. , Annual Reports in Medicinal Chemistry: 24

(1989) pp71-80 (Academic) and BJ.Fitzsimmons and J.Rokach, Leukotrienes and

Lipoxygenases (1989) pp427-502 (Elsevier)).

More particularly, International Patent Publication No. WO 92/9566 and U.S. Patent No. 5, 187, 192, disclose a wide variety of N-hydroxyurea and hydroxamic acid compounds as inhibitors of the lipoxygenase enzyme.

Brief Disclosure of the Invention The present invention provides novel N-hydroxyurea compounds of the following chemical formula I :

and the pharmaceutically acceptable salts thereof, wherein A and B, independently, are hydrogen, halogen, C,-C₄ alkyl, C_rC₄ alkoxy, C C₄ halo- substituted alkyl or C_j-C₄ halo-substituted alkoxy;

R¹ and R², independently, are hydrogen or C_{-C alkyl; X is S, SO or SO₂; and Z is methylene or ethylene.

The compounds of the formula I inhibit the 5-lipoxygenase enzyme. Therefore the compounds are useful for treating a medical condition 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. A preferred group of compounds of the invention consists of the compounds of the formula I , wherein R¹ and R² are each hydrogen and X is S. Within this preferred group, particularly preferred compounds are those wherein R¹ and R² are each hydrogen, X is S, A is 4-fluoro, B is hydrogen and Z is ethylene. Particularly preferred individual compounds of the invention are: N-[3-[3-(4-Fluorophenylthio)phenyl]-2-cyclopenten-l-yl]-N-hydroxyurea,

(+)-N-[3-[3-(4-Fluorophenylthio)phenyl]-2-cyclopenten-l-yl]-N-hydroxyureaand (-)-/V-[3-[3-(4-Fluorophenylthio)phenyl]-2-cyclopenten-l-yl]-N-hydroxyurea.

Detailed Description of the Invention

In this application, the term "halo" is used to mean radicals derived from the elements fluorine, chlorine and bromine.

The term "pharmaceutically acceptable salts" refers to salt incorporating non-toxic cations, including, but not limited to, cations based on the alkali and 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, methyl- ammonium, diethylammonium, trimethylammonium and triethylammonium.

The compounds of formula I may be prepared by a number of synthetic methods. In the following formulae, Q is

wherein A and B are as previously defined. In one embodiment, compounds of the formula I are prepared according to scheme 1:

Scheme 1

π

In Scheme 1 , the hydroxylamine II is treated with a suitable trialkylsilyl isocyanate or lower alkyl isocyanate of the formula R²NCO, in a reaction-inert solvent, usually at ambient through to reflux temperature. Preferably the reaction temperature is from 20 to 100 °C. Suitable solvents which do not react with reactants and/or products are, for example, tetrahydrofuran, dioxane, methylene chloride or benzene. An alternative procedure employs treatment of the hydroxylamine II with gaseous hydrogen chloride in 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, preferably 25 to 80 °C. The intermediate carbamoyl chloride is not isolated but subjected to (i.e. in situ) reaction with aqueous ammonia or amine R²NH₂. As a modification of this procedure the acid addition salt of the hydroxylamine II may be reacted with an equimolar amount of alkali metal cyanate, such as potassium cyanate, in water. The product of formula I thus obtained is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The aforementioned hydroxylamine II may be prepared by standard synthetic procedures from corresponding cycloalkenone of the formula III or cycloalkenol of the formula IV.

m IV

For example, suitable cycloalkenone is converted to its oxime and then reduced to the requisite hydroxylamine II with a suitable reducing agent (for example, see R.

F. Borch et al, J. Am. Chem. Soc, 93, 2897, 1971). Reducing agents of choice are, but not limited to, sodium cyanoborohydride and boron-complexes such as borane- pyridine, borane-triethylamine and borane-dimethylsulfide, however triethylsilane in trifluoroacetic acid may also be employed. The suitable carbonyl compound m, (i.e. cyclobutenones or cyclopentenones), - can be prepared by a number of different methods (see WO 92/9566). The cyclo- butenones may be prepared by the [2+2] cycloaddition of the corresponding ethylenes and dichloroketene followed by reductive dechlorination (for example, see R. L. Danheiser et al. , Tetrahedron Lett., 28, 3299, 1987). The cyclopentenones may be prepared by the intramolecular aldol cyclization of 1,4-diketones, readily accessible from the corresponding aldehydes and methyl vinyl ketone by the Stetter reaction (for example, see L. Novak et al. , Liebigs Annalen Chemie, 509, 1986). Alternatively, the cycloalkenones UI can be prepared by the cross coupling reaction of, for example, the corresponding aryl halides or triflates with the cycloalkenylstannanes or vice versa in the presence of suitable catalyst such as Pd(PPh₃)₄, PdCl₂(PPh₃)₂ and the like (for example, see J.K. Stille: Ange . Chem. Int. Ed. Engl., 25, 508, 1986).

Alternatively, the aforementioned hydroxylamine II can easily be prepared by treating the corresponding cycloalkenol IV with N, O-bis(tert-butyloxycarbonyl)- hydroxylamine under Mitsunobu-type reaction conditions followed by acid catalyzed hydrolysis (for example, employing trifluoroacetic acid) of the N, O-protected intermediate product. The requisite cycloalkenol IV is readily prepared by the 1,2- reduction of the corresponding cycloalkenone III using a suitable reducing agent such as sodium borohydride or sodium borohydride-cerium trichloride.

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

In another embodiment, compounds of the formula I are prepared as illustrated in Scheme 2. R³ is phenyl, and R⁴ is phenyl or lower alkyl:

Scheme 2

In this process, compound of formula V is prepared from the corresponding alcohol IV and a bis-carboxyhydroxylamine, preferably N, Obis(phenoxycarbonyl)- hydroxylamine, and subsequently converted to formula I by treatment with ammonia, ammonium hydroxide, or an amine of structure R²ΝH₂ (A. O. Stewart and D. W. Brooks. , J. Org. Chem., 57, 5020, 1992). Suitable reaction solvents for reaction with ammonia, ammonium hydroxide or the amine of formula R²NH₂ are, for example, water, methanol, ethanol, tetrahydrofuran, benzene and the like, though reaction may be run in the absence of co-solvent, that is, in requisite amine alone. Reaction temperatures are typically in the range of ambient temperature through to boiling point of solvent, preferably 25 to 80 °C. The product of formula I thus obtained is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The compounds of this invention can exist in stereoisomeric forms by virtue of the presence of one or more chiral centers. The present invention contemplate all such stereoisomers, including enantiomers, diastereomers, and mixtures. The individual isomers of compounds of the formula of this invention can be prepared by a number of methods known to those skilled in the art. For instance, they can be prepared by derivatization of a compound of formula I with a chiral auxiliary followed by separation of the resulting diastereomeric mixture and removal of the auxiliary group to provide the desired isomer, or by separation employing a chiral stationary phase.

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

The compounds of the present invention inhibit the activity of lipoxygenase enzyme. This inhibition can be demonstrated in vitro by an assay using heparinized Human Whole Blood (HWB) cells, according to the method described in British Journal of Pharmacology: 99, 1 13-118 (1990), which determines the effect of said compounds on the metabolism of arachidonic acid. The compounds of examples 1 to 7 were tested in the aforementioned assay and they were shown to possess the efficacy of inhibiting lipoxygenase activity. In this test, the compounds of Examples 1 to 7 show IC o values of 0.05 to 5 μM in HWB assay, with respect to lipoxygenase activity. The in vivo activity after oral administration of compounds of the invention to ICR mice (male) can be determined using PAF lethality assay in a similar manner as described by J. M. Young et al. ( J. M. Young, P. J. Maloney, S. N. Jubb, and J. S. Clark, Prostaglandins, 30, 545(1985). See also: M. Criscuoli and A. Subissi, Br. J. Pharmac , 90, 203(1987); H. Tsunoda, S. Abe, Y. Sa uma, S. Katayama, and K. Katayama, Prostaglandins Leukotrienes and Essential Fatty Acids, 39, 291(1990)). In this test, the compounds of Examples 1 to 7 indicate ED_J0 values in the range of 1 to

20 mg/kg.

The ability of the compounds of the present invention to inhibit lipoxygenase enzyme 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 are the causative factor; e.g. allergic bronchial asthma, skin disorders, rheumatoid arthritis and osteoarthritis. Thus, the compounds of the present invention and their pharmaceutically acceptable salts are of particular use in the treatment or alleviation of inflammatory diseases in a human subject.

For treatment of the various conditions described above, the compounds of the 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 a pharmaceutical composition according to standard pharmaceutical practice. This composition can consist of about 0. 1 to 90% , preferably about 10 to 60% , of the compound of formula I or the salt in liquid or solid form of the unit use.

The compounds can be administered to human subjects by various conventional routes of administration including oral or parenteral. When the compounds are administered orally, the dose range will be from about 0. 1 to 20 mg/kg of body weight of the subject to be treated per day, preferably from about 0.5 to 15 mg/kg of body weight per day, in single or divided doses. If parenteral administration is desired, then an effective dose will be from about 0.05 to 10 mg/kg of body weight of the human subject to be treated per day. In some instances it may be necessary to use dosages outside these limits, since the dosages 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. Further 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 emulsifing and suspending agents. If desired, certain sweetning and/or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are 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 and br - broad. Example 1 yv^"-r3-r3-(4-Fluorophenylthio phenyll-2-cvclobuten-l-yll- V-hydroxyurea [A] l-Bromo-3-(4-fluorophenylthio)benzene:

To a stirred solution of l-bromo-3-iodobenzene (143.5g; 0.507M) in EtOH (1.5L) was added 4-fluorothiophenol (65g; 0.507M), NaO'Bu (99.5g; 1.014M), and Pd(Ph₃P)₄ (40g; 0.032M) at room temperature under argon. The mixture was refluxed for 5 hr, and the mixture stirred over two days at room temperature. The mixture was filtered through a pad of celite, and the filtrate was evaporated in vacuo. Water (400ml) was added to the residue, and the whole was extracted with Et₂0 (400mlx2). The combined organic layers was washed with water (300ml), brine (200ml), dried over MgS0₄, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO₂) eluting with /z-hexane to give 113g (yield 79%) of subtitle compound as a pale yellow oil.

1H-NMR (CDC1₃) δ; 7.46-7.23 (m, 4H), 7.13-6.99 (m, 4H).

[B] 2-[3-(4-Fluorophenylthio)phenyl]-l-(trimethylsilyl)acetylene:

To a stirred solution of l-bromo-3-(4-fluorophenylthio)benzene (113g; 0.399M) in triethylamine (500ml) was added l-(trimethylsilyl)acetylene (62ml; 0.439M) and

Pd(Ph₃P)₂Cl₂ (28g; 0.0399M) at room temperature. The mixture was refluxed for 2 hr, and then stirred overnight at room temperature. Water (700ml) was added, and the whole was extracted with Et₂O (500ml). The organic layer was washed with saturated aqueous NH₄C1 (300ml), water (300mlx2), brine (300ml), dried over MgSO₄, and evaporated in vacuo. The residual oil was purified by flash column chromatography

(Si0₂) eluting with rc-hexane to give 130g (yield quant.) of subtitle compound as a pale yellow oil.

1H-NMR (CDCI₃) δ; 7.40-6.99 (m, 8H), 0.23 (s, 9H).

[C] 3-(4-Fluorophenylthio)phenyIacetyIene: To a stirred solution of 2-[3-(4-fluorophenylthio)phenyl]-l-(trimethylsilyl)- acetylene (130g; 0.433M) in THF (200ml) was added a 1M solution of π-Bu₄NF in THF (600ml; 0.649M) at room temperature under N₂. After stirring overnight, volatiles were removed by evaporation. Water (500ml) was added, and the whole was extracted with ethyl acetate-Et₂O-fl-hexane (100ml-100ml-200ml). The organic layer was washed with water (150ml), brine (150ml), dried over MgS0₄, and evaporated in vacuo. The residue was purified by flash column chromatography (SiCs) eluting with n-hexane to give 78g (yield 79%) of subtitle compound as a pale yellow oil.

^!H-NMR (CDCI₃) 0; 7.44-7.18 (m, 6H), 7.05 (t, J=8.5Hz, 2H), 3.06 (s, IH).

[D] 3-[3-(4-Fluorophenylthio)phenyl]-4,4-dichIoro-2-cyclobutenone: To a stirred suspension of 3-(4-fluorophenylthio)phenylacetylene (30g; 0.132M) and zinc-copper couple (34.4g; 0.526M) in Et₂0 (400ml) was added dropwise tri- chloroacetyl chloride (44ml; 0.395M) and phosphorus oxychloride (37ml; 0.395M) in Et O (300ml) at room temperature. After completion of addition, the mixture was refluxed for 48 hours. After cooling, zinc-copper couple was filtered off. The filtrate was concentrated in vacuo, and Et₂O-/z-hexane (400ml-600ml) was added. The whole was washed with water (500mlx3), saturated aqueous NaHCO₃ (350ml), water (350ml), brine (500ml), dried over MgSO₄, and filtered through a short column of silica gel to afford 21g (yield 47%) of crude subtitle compound as yellow solids, which was used without further purification. ^!H-NMR (CDC1₃) δ; 7.70 (d.t, J= 1.5Hz, 7.4Hz, IH), 7.65 (t, J= 1.5Hz, IH),

7.54-7.38 (m, 4H), 7.12 (t, J = 8.4Hz, 2H), 6.56 (s, IH).

[E] 3-[3-(4-Fluorophenylthio)phenyl]-2-cyclobutenone: To a stirred suspension of 3-[3-(4-fluorophenylthio)phenyl]-4,4-dichloro-2- cyclobutenone (21g; 0.062M) in acetic acid (100ml) was added zinc dust (20.3g; 0.31M) at room temperature. After stirring for 1.5 hours, insolubles were filtered off.

The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO₂) eluting with ethyl acetate-Λ-hexane (1: 10) to give 7.4g (yield 44%) of subtitle compound.

1H-NMR (CDCI₃) δ; 7.47-7.27 (m, 6H), 7.08 (t, J = 8.5Hz, 2H), 3.50 (s, 2H). [F] 3-[3-(4-Fluorophenylthio)phenyl]-2-cyclobutenone oxune:

To a stirred solution of cyclobutenone (7.4g; 27mM) in EtOH-pyridine(50ml- 17ml) was added hydroxylamine hydrochloride (2.48g; 35.6mM) at room temperature. The mixture was stirred for 2 hours at 50°C, and then stirred overnight at room temperature. The solvent was removed by evaporation, and the resulting oil dissolved in ethyl acetate (300ml). The organic phase was washed with diluted aqueous HC1

(100ml), and the aqueous layer extracted with ethyl acetate (150ml), the combined organic layers washed with water (100ml), brine (100ml), dried over MgS0₄, and filtered through a short column of silica gel to provide 8.3g (yield quant.) of subtitle compound. [G] N-[3-[3-(4-Fluorophenylthio)phenyI]-2-cyclobuten-l-yl]-N-hydroxyl- amine: To a stirred solution of 3-[3-(4-fluorophenylthio)phenyl]-2-cyclobutenoneoxime (8.31g; 29mM) in acetic acid (50ml) was added NaBH₃CN (2.75g; 43.7mM) at room temperature. After stirring for 1.5 hours, the reaction mixture was poured into 10% aqueous NaOH (500ml). The whole was extracted with ethyl acetate (200mlx2), and the combined organic layer washed with water (200ml), brine (200ml), dried over

MgS0₄, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO ) eluting with CH₂Cl₂-EtOH (40: 1) to give 1.55g (yield 19%) of subtitle compound.

1H-NMR (CDC1₃) δ; 7.40-6.98 (m, 8H), 6.32 (s, IH), 4.14 (d, J=4.0Hz, IH), 2.97 (d.d, J=4.4Hz, 13.6Hz, IH), 2.59 (d, J = 13.6Hz, IH).

[H]N-[3-[3-(4-Fluorophenylthio)phenyl]-2-cyclobuten-l-yl]-Λ'-hydroxyurea: To a stirred solution of N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclobuten-l-yl]- N-hydroxylamine (1.55g; 5.4mM) in THF (20ml) was added trimethylsilyl isocyanate (TMSΝCO) (0.95g; 7.02mM) at room temperature under Ν₂. The mixture was stirred overnight, and EtOH (10ml) was added. Solvent was removed in vacuo, and the residue was recrystallized from i-PrOH to provide 0.4g (yield 22%) of title compound as colorless flakes. m.p. 135-136°C. 1H-NMR (DMSO-d₆) δ; 9.07 (s, lH), 7.47-7.16 (m, 8H), 6.35 (s, 3H), 5.04 (br.s, IH), 2.92-2.75 (m, 2H).

Anal. Calcd. for C₁₇H₁₅FN₂O₂S: C, 61.80, H, 4.58, N, 8.48, F, 5.75, S, 9.70; found: C, 61.58, H, 4.55, N, 8.35, F, 5.68, S, 9.72.

Example 2 N-r3-f3-(4-Fluorophenylthio^')phenyll-2-methyl-2-cyclobuten-l-yn-N-hydroxyurea [A] l-[3-(4-Fluorophenylthio)phenyI]-l-propyne:

To a cooled, stirred solution of 1.5M solution of lithium diisopropylamide in cyclohexane (51.3ml; 77mM available from Aldrich) in THF (180ml) cooled to -78°C was added 3-(4-fluorophenylthio)phenylacetylene (I6g; 70mM) in THF (45ml) dropwise under No. After stirring for 1.5 hours, CH₃I (35g; 180mM) was added. The mixture was allowed to warm to room temperature, and stirred for a further 1 hour. Water (200ml) was added to the mixture and solvent was removed in vacuo. The whole was extracted with Et₂O (200mlxl , 150mlxl), the combined organic layer washed with water (150ml), brine (150ml), dried over MgSO₄, and concentrated in vacuo. Chromatographic purification (SiO₂) of the residue eluting with rc-hexane provided 12.08g (yield 71.3 %) of the subtitle compound as a colorless oil.

1H-NMR (CDC1₃) δ; 7.42-7.35 (m, 2H), 7.27-7.12 (m, 4H), 7.04 (t, J = 8.8Hz, 2H), 2.02 (s, 3H).

[B] N-[3-[3-(4-Fluorophenylthio)phenyl]-2-methyl-2-cyclobuten-l-yl]-Λ- hydroxyurea: The title compound was prepared according to the procedure of Example 1 using l-[3-(4-fluorophenylthio)phenyl]-l-propyne instead of 3-(4-fluorophenylthio)- phenylacetylene in step [D]. m.p. 149.5-150.5°C (dec). 1H-NMR (DMSO-d₆) δ; 8.98 (s, IH), 7.50-7.12 (m, 8H), 6.39 (s, 2H), 4.92 (br.s, IH), 2.70-2.60 (m, 2H), 1.80 (s, 3H).

Anal. Calcd. for C₁₈H₁₇FN₂O₂S: C, 62.77, H, 4.98, N, 8.13, F, 5.52, S, 9.31; found: C, 62.81 , H, 5.06, N, 8.12, F, 5.10, S, 9.55.

Example 3 N-r3-r3-(4-Fluorophenylthio)phenyn-2-methyl-2-cyclobuten-l-yI1-N-hydroxy-N'- methylurea

The title compound was prepared according to the procedure of Example 1 using l-[3-(4-fluorophenylthio)phenyl]-l-propyne instead of 3-(4-fluorophenylthio)- phenylacetylene in step [D], using methyl isocyanate instead of TMSΝCO in step [H]. m.p. 117.5-119.5°C. -ΝMR (DMSO-d₆) δ; 8.90 (s, IH), 7.50-7.12 (m, 8H), 6.95 (q, J=4.8Hz, IH),

4.90 (br. s, IH), 2.61 (d, J=4.8Hz, 3H), 2.72-2.55 (m, 2H), 1.79 (s, 3H). IR (nujol) cm^"1 : 3370, 1745, 1630, 1590, 1530, 1490, 1220, 835, 785. Anal. Calcd. for C₁₉H₁₉FΝ₂0₂S: C, 63.67, H, 5.34, N, 7.82, F, 5.30, S, 8.94; found: C, 63.83, H, 5.47, N, 7.50, F, 4.98, S, 9.31. Example 4 N-r3-[3-(4-Fluorophenylthio)phenyl1-2-cyclopenten-l-yll-N-hydroxyurea

[A] 3-(4-Fluorophenylthio)benzaldehyde:

To a stirred solution of l-bromo-3-(4-fluorophenylthio)benzene (28.3g; 0.1M) in THF (60ml) cooled to -75 °C was added dropwise a 1.6M solution of rz-BuLi (56ml; 0.09M) under N₂. After stirring for 0.5 hour at the same temperature, DMF (7.9g; 0.108M) was added to the mixture. The reaction mixture was stirred for 0.5 hour at -75 °C, and then allowed to warm to room temperature. After stirring for 0.5 hour at room temperature, diluted aqueous HC1 (80ml) was added to the mixture. The whole was extracted with Et₂O (150mlx2), the combined organic layer washed with water (80ml), brine (80ml), dried over MgSO₄, and evaporated in vacuo. The residue was purified by flash column chromatography (SiO₂) to give 18.03g (86%) of the subtitle compound as a pale yellow oil.

^!H-NMR (CDC1₃) δ; 10.30 (s, IH), 7.82 (d.d, J=2.6Hz, 6.6Hz, IH), 7.53 (d.d.d, J=2.6Hz, 5.1Hz, 8.8Hz, IH), 7.37-7.28 (m, 5H), 7.12 (d.d, J = 8.8Hz, 9.9Hz, IH).

[B] l-[3-(4-Fluorophenylthio)phenyl]-l,4-pentanedione:

To a stirred solution of 3-(4-fluorophenylthio)benzaldehyde (18.03g; 77.72mM) in EtOH (40ml) was added methyl vinyl ketone (5.2ml; 62.36mM), 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazolium chloride (3.63g; 13.47mM), and triethylamine (17.76ml; 127.42mM) at room temperature. After stirring for 48 hours, volatiles were removed by evaporation. To the residue was added water (150ml), and the whole was extracted with ethyl acetate (120mlx3). The combined organic layer washed with water (150ml), brine (200ml), dried over MgSO₄, and concentrated in vacuo. The residual oil was purified by flash column chromatography (Si0₂) eluting with ethyl acetate-π- hexane (1 :5) to give 19.3g (quant.) of the subtitle compound as a yellow oil.

^!H-NMR (CDCI₃) δ; 7.86 (d.d, J=2.6Hz, 7.0Hz, IH), 7.45 (d.d.d, J=2.6Hz, 4.8Hz, 8.8Hz, IH), 7.33-7.27 (m, 5H), 7.09 (d.d, J = 8.8Hz, 10.6Hz, IH), 3.26-3.20 (m, 2H), 2.85 (t, J = 6.2Hz, 2H), 2.24 (s, 3H).

[C] 3-[3-(4-Fluorophenylthio)phenyl]-2-cyclopentenone: Asolutionof l-[3-(4-fluorophenylthio)phenyl]-l ,4-petanedione(19.3g; 63.9mM) in 0.43M aqueous NaOH solution (300ml) was refluxed for 19 hours. After cooling, the whole extracted with ethyl acetate (150mlxl , 100mlx2). The combined extract was washed with water (150ml), brine (150ml), dried over MgSO₄, and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give 16.5g (yield 91 %) of the subtitle compound as a black oil.

1H-NMR (CDC1₃) δ; 7.54 (d.d, J=2.2Hz, 7.0Hz, IH), 7.43-7.27 (m, 6H), 7.12 (d.d, J=8.4Hz, 11.0Hz, IH), 6.69 (d, J=2.2Hz, IH), 3.00 (d.d, J=2.9Hz, 5.1Hz, 2H), 2.50 (d.t, J=2.2Hz, 5.1Hz, 2H).

[D] 3-[3-(4-Fluorophenylthio)phenyl]-2-cyclopentenone oxime: To a stirred solution of 3-[3-(4-fluorophenylthio)phenyl]-2-cyclopentenone

(16.5g; 58.1mM) in EtOH-pyridine (120ml-30ml) was added hydroxylamine hydro- chloride (5.25g; 75.5mM) at room temperature. After stirring overnight, solvent was removed by evaporation. To the residue was added diluted aqueous HC1 (120ml), and the whole was extracted with ethyl acetate (200mlx2). The combined organic layer was washed with water (150ml), brine (150ml), dried over MgSO₄, and concentrated in vacuo to give 19. g of crude subtitle compound as a brown oil, which was used without further purification.

[E] N-[3-[3-(4-Fluorophenylthio)phenyl]-2-cyclopenten-l-yI]-N-hydroxyl- amine: To a stirred solution of 3-[3-(4-fluorophenylthio)phenyl]-2-cyclopentenone oxime (19.5g; 65.2mM) in acetic acid (120ml) was added ΝaBH₃CΝ (6.15g; 97.8mM) at room temperature. After stirring for 3 hours, acetic acid (30ml) and NaBH₃CN (1.5g; 24.5mM) were added. The mixture was stirred for an additional 3 hours, and then volatiles were removed by evaporation. The residue was dissolved in ethyl acetate (200ml), and the whole was washed with saturated aqueous NaHC0₃ (80ml). The aqueous layer was extracted with ethyl acetate (100ml), and the combined organic layer washed with water (100ml), brine (100ml), dried over MgSO₄, and concentrated in vacuo. Chromatographic purification of the residue eluting with CH₂Cl₂-EtOH (50: 1) provided 8.7g (yield 44%) of the subtitle compound as a yellow oil. [F] Λ^?-[3-[3-(4-Fluorophenylthio)phenyl]-2-cyclopenten-l-yl]- V-hydroxy- urea:

To a stirred solution of N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-l-yl]- N-hydroxylamine (8.7g; 28.9mM) in THF (80ml) was added TMSNCO (5.88g; 43.4mM) at room temperature under N₂. After stirring for 1 hour, EtOH (50ml) was added. Volatiles were removed by evaporation, and the resulting residue was recrystallized from ethyl acetate (150ml) to provide 3.03g of the title compound as colorless solids. m.p. 159-160°C (dec). ^:H-NMR (DMSO-d₆) δ; 8.97 (s, IH), 7.43-7.23 (m, 8H), 6.34 (s, 2H), 6.17 (s, IH), 5.34 (br.s, IH), 2.79-2.67 (m, IH), 2.60-2.48 (m, IH), 2.12-2.00 (m, IH), 1.97-1.82 (m, IH).

Anal. Calcd. for C₁₈H₁₉FN₂O₂S: C, 62.77, H, 4.98, N, 8.13, F, 5.52; found: C, 62.76, H, 4.94, N, 8.17, F, 5.51.

Example 5 f+)-N-[3-r3-(4-Fluorophenylthio phenyπ-2-cyclopenten-l-yll-N-hydroxyurea

The title dextrorotatory enantiomer was obtained by separation on a chiral stationary phase of the racemate N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-l- yl]-N-hydroxyurea. The racemate (650mg) was resolved by HPLC (eluent; rc-hexane-i- PrOH (70:30)) using a chiral pak AS column (DAICEL CHEM IΝD) to give 276mg of the more polar enantiomer as colorless crystals after recrystallization from ethyl acetate-π-hexane. m.p. 156-156.5°C (dec); [a]_D = + 102° (c=0.08, EtOH).

Example 6 (- -/V-r3-r3-(4-Fluorophenylthio)phenyl1-2-cyclopenten-l-yl1-N-hydroxyurea The title levorotatory enantiomer was obtained by separation on a chiral stationary phase of the racemate N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-l- yl]-/V-hydroxyurea. The racemate (650mg) was resolved by HPLC (eluent; n-hexane-i- PrOH (70:30)) using a chiral pak AS column (DAICEL CHEM IΝD) to give 267mg of the less polar enantiomer as colorless crystals after recrystallization from ethyl acetate-π-hexane. m.p. 157-157.5°C (dec); [ ]_D= -106.82° (c=0.088, EtOH).

Example 7 N-r3-r2-(4-Fluorophenylthio)-4-fluorophenyll-2-cyclopenten-l-yl1-N-hydroxyurea

The title compound was prepared according to the procedure of Example 4 using 2-(4-fluorophenylthio)-4-fluorobenzaldehyde instead of 3-(4-fluorophenylthio)- benzaldehyde in step [B]. m.p. 138.2-139.6°C. 1H-NMR (DMSO-d₆) δ; 8.98 (s, IH), 7.52 (t, J=7.33Hz, 2H), 7.38-7.29 (m, 3H), 7.05 (t, J = 8.43Hz, IH), 6.56 (d, J=9.53Hz, IH), 6.33 (s, 2H), 5.81 (s, IH), 5.33 (br. s, IH), 2.76-2.64 (m, 2H), 2.11-1.95 (m, 2H).

IR (KBr) cm^"1: 3450, 3200, 1660, 1600, 1580, 1240, 1210, 900. Anal. Calcd. for C₁₈H₁₆F₂N₂O₂S: C, 59.66, H, 4.45, N, 7.73; found: C, 59.50, H, 4.39, N, 7.91.

Claims

CLAHMS

1. A compound of the following chemical formula:

and the pharmaceutically acceptable salts thereof, wherein A and B, independently, are hydrogen, halogen, C_rC₄ alkyl, C_rC₄ alkoxy, C_rC₄ halo- substituted alkyl or C_rC₄ halo-substituted alkoxy;

R¹ and R², independently, are hydrogen or C_j-C₄ alkyl; X is S, SO or SO₂; and Z is methylene or ethylene.

2. A compound according to claim 1 , wherein R¹ and R² are each hydrogen and X is S.

3. A compound according to claim 2, wherein A is 4-fluoro, B is hydrogen and Z is methylene.

4. A compound according to claim 3, wherein the compound is N-[3-[3-(4- fluorophenylthio)phenyl]-2-cyclobuten-l-yl]-N-hydroxyurea.

5. A compound according to claim 2, wherein A is 4-fluoro, B is hydrogen and Z is ethylene.

6. A compound according to claim 5 wherein the compound is selected from: N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-l-yl]-N-hydroxyurea;

(-l-)-N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten-l-yl]-N-hydroxyurea; and (-)-N-[3-[3-(4-fluorophenylthio)phenyl]-2-cyclopenten- l-yl]-N-hydroxyurea.

7. A pharmaceutical composition for the treatment of an allergic or inflammatory condition in a mammalian subject which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

8. A method for treatment of a medical condition for which a 5-lipoxygenase inhibitor is needed, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.

9. A method according to claim 8, wherein the medical condition is an allergic or inflammatory condition.