MXPA97003485A

MXPA97003485A - Ariloxicicloalquenil- yariloxiiminocicloalquenilhidroxiur

Info

Publication number: MXPA97003485A
Application number: MXPA/A/1997/003485A
Authority: MX
Inventors: W Stevens Rodney; Kawai Akiyoshi
Original assignee: Pfizer Inc
Priority date: 1994-11-10
Filing date: 1995-05-26
Publication date: 1997-08-01

Abstract

The present invention relates to a compound of the formula (I) wherein Ar is (a) phenyl, naphthyl and biphenyl, each optionally substituted or (b) furyl, benzo [b] furyl, thienyl, benzo [b] thienyl, pyridyl or quinolyl, each optionally substituted, X is C1-C4 alkylene, C2-C4 alkenylene etc., p is the integer 1 or 2; Y is hydrogen, C1-4 alkyl, C1-4 haloalkyl etc., Z is hydrogen or C1-4 alkyl, and N is hydrogen, a pharmaceutically acceptable cation or a metabolically pharmaceutically acceptable cleavable group, furthermore, the invention provides a pharmaceutical composition for treating a medical disorder for which a 5-lipoxygenase inhibitor is necessary in a mammal, comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier, preferably, the medical disorder is an inflammatory disease, an allergy or cardiovascular disease

Description

09AHXK 1 ARILOXICICLOALOUENIL- AND ARILOXYIMINOCICLOALOUENILHIDROXIUREAS Technical Field This invention relates to novel aryloxycycloalkenyl- and aryloxyiminocycloalkenyl-hydroxyurea compounds. The compounds of the present invention inhibit the action of the enzyme 5-lipoxygenase and are useful in the prevention, treatment or alleviation of inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis, allergy and cardiovascular diseases in a mammal, by example, in the human being. This invention also relates to pharmaceutical compositions comprising these compounds. BACKGROUND ART It is known that arachidonic acid is the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclines, thromboxanes and leukotrienes. The first stage of the metabolism of arachidonic acid is the release of arachidonic acid and related unsaturated fatty acids, from the phospholipids of the membrane, by the action of phospholipase A2. Next, free fatty acids are metabolized by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids that can be further metabolized to leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemic 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 disorders. As a review article on 5-lipoxygenase inhibitors, see H. Masamune & L.S. Melvin, Sr., Annual Reports in Medicinal Chemistry, 24 (1989) p. 71-80 (Academic Press). More recently, other examples of 5-lipoxygenase inhibitors have been described in International Patent Publications Nos. WO 94/14762 and WO 92/9566. Brief Description of the Invention The invention provides a compound of formula (I): F wherein Ar is selected from the group consisting of: (a) phenyl, naphthyl and biphenyl, each optionally substituted with one to three substituents selected from alkyl Cl, haloalkyl ClA, hydroxyalkyl C, alkoxy C, haloalkoxy C, alkoxyalkoxy C2A, alkylthio C, hydroxy, halo, cyano, amino, alkylamino C, dialkyl (C2.8) amino, alkanoylaminoC2.6 carboxy, alkoxycarbonyl C2.6, phenyl optionally substituted with one to three substituents selected from alkyl ClJt, haloalkyl CM, alkoxy C , C 4 haloalkoxy, cyano and halo, phenoxy optionally substituted with one to three substituents selected from among C 1 -C 8 alkyl, C 1 alkoxy, C 1 -C haloalkoxy, cyano and halo, phenylthio optionally substituted with one to three substituents selected from C-alkyl, C 1 -Chaloalkyl / alkoxy CM, haloalkoxy CM, cyano and halo and phenylsulfinyl optionally substituted with one to three substituents selected from C-alkyl haloalkyl C, C-alkoxy, haloalkoxy CM cyano and Hello; and (b) furyl, benzo [b] furyl, thienyl, benzo [b] thienyl, pyridyl and quinolyl, optionally substituted with one to three substituents selected from C-alkyl, haloalkyl, halo, halo, alkoxy, hydroxy, phenyl optionally substituted with one to three substituents selected from C, .4 haloalkyl C, alkoxy C, haloalkoxy C, cyano and halo, phenoxy optionally substituted with one to three substituents selected from C-alkyl, C-haloalkyl, C-alkoxy, haloalkoxy C, cyano and halo; phenylthio optionally substituted with one to three substituents selected from among CM alkyl, CM haloalkyl, C 1, alkoxy, haloalkoxy, cyano, and halo; X is selected from C4-C4 alkylene, C2-C4 alkenylene, - (CHR '^ - Q'- CHR2), -, -O-fCHR'jj-Q2- and (CHR') - 0-N =, where the radical N = is attached to the cycloalkene ring; and where Q1 is 0, S, SO, S02 NR3, CH = N-0 or CO, Q2 is 0, S, SO, S02 or NR3 and R1, R2 and R3 are, each, hydrogen or Cj-C4 alkyl, myn are each an integer from 0 to 4 and j is an integer from 1 to 4; p is the integer 1 or 2; Y is hydrogen, C-alkyl, C-haloalkyl, CM-alkoxy, C2-alkoxyalkyl, C-alkylthio, hydroxy, halo, cyano or amino; Z is hydrogen or CM alkyl; and M is hydrogen, a pharmaceutically acceptable cation or a metabolically pharmaceutically acceptable cleavable group. The compounds of formula (I) can inhibit the action of 5-lipoxygenase. Therefore, the compounds are useful for the treatment of a medical disorder for which a 5-lipoxygenase inhibitor is necessary, in a mammal, for example, in a human. The compounds are especially useful for the treatment of inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis, allergy and cardiovascular diseases. Accordingly, the present invention also provides a pharmaceutical composition for treating a medical disorder for which a 5-lipoxygenase inhibitor is required, for example, inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis, allergy and diseases cardiovascular, in a mammal, for example, in a human being, comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

Detailed Description of the Invention As used herein, the term "pharmaceutically acceptable cation" refers to non-toxic cations, based on alkaline and alkaline earth metals such as sodium, lithium, potassium, calcium and magnesium, as well as those based on ammonia. non-toxic, quaternary ammoniums, including, but not limited to ammonium, ethylammonium, diethylammonium, triethylammonium, tetraethylammonium, tetramethylammonium and tetrabutylammonium; and the term "metabolically cleavable group" refers to a group that is cleaved in vivo to produce the parent molecule of structural formula (I) wherein M is hydrogen. Examples of the metabolically cleavable groups include the radicals -COW, C00W, -CONH, -CONWW ', -CH2OW, -CH (W') OW, -CH2OCOW, -CH2OC02W, -CH (W ') OC? 2W, in those W and W 'are each independently selected from alkyl (C, -C4), phenyl or substituted phenyl in which the substituents are selected from one or more of the following groups: C, -C4 alkyl, halogen, hydroxy or C ^ C ^ alkoxy. Specific examples of metabolically representative cleavable groups include, but are not limited to, acetyl, ethoxycarbonyl, benzoyl and methoxymethyl groups. Halo includes chlorine, bromine, iodine and fluorine, preferably fluorine. In formula (I) above, Ar is preferably (a), Y and Z are each hydrogen, p is 1 and M is hydrogen or a pharmaceutically acceptable cation. More preferably, Ar is phenyl, fluorophenyl, cyanophenyl, biphenyl or fluorophenoxyphenyl and X is O which is attached to the 4-position of the 2-cyclopentene ring; Ar is phenyl or fluorophenyl and X is -CH = N-0 which is attached to the 4-position of the 2-cyclopentene ring; or Ar is phenyl or fluorophenyl and X is -0-N = or -CH2-0-N = which is attached to the 4-position of the 2-cyclopentene ring. A more preferred group of individual compounds includes: N-. { (1R, 4R) -trans-4- (4-Fluorophenoxy) -2-cyclopenten-1-yl} -N-hydroxyurea; N-. { (IR, R) -trans-4- [3- (4-Fluorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hydroxyurea; N-. { (1S, 4R) -cis-4- [3- (4-Fluorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hydroxyurea; N-. { (IR) -4-Benzyloxyimino-2-cyclopenten-1-yl} -N-hydroxyurea; and N-. { (IR) -4- (4-Fluorobenzyloxyimino) -2-cyclopenten-1-yl} -N-hydroxyurea. The compounds of formula (I) can be prepared by numerous synthetic procedures well known in the art. Below, representative procedures are shown. In one embodiment, the compounds of the formula (I) (M = H) are prepared according to the reaction steps depicted in Scheme 1. Ar, X, Y, Z and p are as defined above. < GD (i) SCHEME 1 In Scheme 1, the hydroxylamine (II) is treated with a suitable trialkylsilyl isocyanate or a lower alkyl isocyanate of the formula ZNCO, in a reaction inert solvent, usually at a temperature between the ambient temperature and the reflux temperature. Preferably, the reaction temperature is between 20 and 100 ° C. Suitable solvents which do not react with the reactants and / or with the products are, for example, tetrahydrofuran, dioxane, methylene chloride or benzene. An alternative procedure employs the treatment of (II) with gaseous hydrogen chloride in a reaction-inert solvent such as benzene or toluene and then further treatment with phosgene. Normally, the reaction temperatures are in the range from room temperature to the boiling point of the solvent, preferably from 25 to 80 ° C. The intermediate carbamoyl chloride is not isolated, but is subjected (i.e., in situ) to a reaction with aqueous ammonia or amine ZNH2. As a modification of this process (Z = H), the acid addition salt of (II) can be reacted with an equimolar amount of an alkali metal cyanate, such as potassium cyanate, in water. The product of formula (I) thus obtained is isolated by conventional methods and the purification can be carried out by conventional means, such as recrystallization and chromatography. The hydroxylamine (II) mentioned above can be prepared by conventional synthesis methods from the corresponding carbonyl compound, ie, a ketone or an alcoholic compound. For example, a suitable carbonyl compound is converted to its oxime and then reduced to the desired hydroxylamine (II) with an appropriate reducing agent (for example, see RF Borch et al., J.A. Chem. Soc, 93_, 2897, 1971). The selected reducing agents are, but are not limited to, sodium cyanoborohydride and borane complexes, such as borane-pyridine, borane-triethylamine and borane-dimethylsulfide, however, triethylsilane in trifluoroacetic acid may also be employed. The suitable carbonyl compound, ie, cyclopentenones or cyclohexenones, can be prepared by numerous different methods (see WO 9209566) known to those skilled in the art. Alternatively, the aforementioned hydroxylamine (II) can be easily prepared by treating the corresponding alcohol with N, 0-bis (tert-butyloxycarbonyl) hydroxylamine under Mitsunobu type reaction conditions followed by acid catalyzed hydrolysis (e.g. trifluoroacetic acid) of the N, 0-protected intermediate (see JP 1045344). The desired alcohol is easily prepared by the reduction in positions 1 and 2 of the corresponding cycloalkenone using a suitable reducing agent such as sodium borohydride, sodium borohydride-cerium trichloride or the like. Alternatively, the desired alcohol can be prepared from a suitable cycloalkenediol, for example, commercially available (1S, 4R) -cis-4-acetoxy-2-cyclopentene-1-ol and the like, by conventional procedures. The hydroxylamine of formula (II) thus obtained by the representative procedures mentioned above is isolated by conventional procedures and the purification can be carried out by conventional means such as recrystallization and chromatography. In another embodiment, the compounds of formula (I) are prepared as illustrated in Scheme 2. R4 is phenyl and R5 is phenyl or lower alkyl: < ? D SCHEME 2 In this process, the compound of formula (III) is prepared from the corresponding alcohol and a bis-carboxyhydroxylamine, preferably N, 0-bis (phenoxycarbonyl) hydroxylamine, and subsequently converted to (I) by treatment with ammonia, hydroxide ammonium or an amine of structure ZNH2 (AO Ste art &DW Brooks., J. Org. Chem., 57, 5020, 1992). Reaction solvents suitable for the reaction are ammonia, ammonium hydroxide or the amine of formula ZNH2, for example, water, methanol, ethanol, tetrahydrofuran, benzene and the like, although the reaction can be carried out in the absence of cosolvent, that is, only with the desired amine. The reaction temperatures are typically in the range between room temperature and the boiling point of the solvent. The product of formula (I) thus obtained is isolated by conventional procedures and the purification can be carried out by conventional means, such as recrystallization and chromatography. The compounds of this invention can exist in stereoisomeric forms by the presence of one or more chiral centers. The present invention contemplates all of these stereoisomers, including enantiomers, diastereomers and mixtures. The individual isomers of the compounds of the formula can be prepared by numerous methods known to those skilled in the art. For example, they can be prepared by the chiral synthesis from the optically active starting materials. Alternatively, they can be prepared from a compound of formula (I) with a chiral auxiliary group followed by separation of the resulting diastereomeric mixture and removal of the auxiliary group to provide the desired isomer, or by separation using 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, in the case of a non-toxic cation, an appropriate amine, alkoxide or metal hydroxide, in aqueous solution or in a suitable organic solvent. In the case of a non-toxic acid salt, an appropriate mineral or organic acid may be used in aqueous solution or in a suitable organic solvent. The salt can then be obtained by purification or by evaporation of the solvent. The compounds of the formula I inhibit the activity of the enzyme 5-lipoxygenase. The ability of the compounds of the formula I to inhibit the 5-lipoxygenase enzyme makes them useful for controlling the symptoms induced by the endogenous metabolites that come from arachidonic acid in a mammal, especially in a human. Therefore, the compounds are valuable in the prevention and treatment of disorders in which the accumulation of arachidonic acid metabolites is the causative factor; for example, allergic bronchial asthma, skin disorders, rheumatoid arthritis, osteoarthritis and thrombosis. Thus, the compounds of the formula I and their pharmaceutically acceptable salts are of particular use in the treatment or alleviation of inflammatory diseases in a human being. The ability of the compounds of the formula I to inhibit the activity of the lipoxygenase enzyme can be demonstrated in vitro and in vivo by the following conventional procedures. 1) In vitro assay using whole human blood (HB) histaparinized In vitro inhibition has been demonstrated using heparinized complete human blood (British Journal of Pharmacology: (1990) 99, 113-118), which determines the inhibitory effect of said compounds on 5-lipoxygenase (LO) in the metabolism of arachidonic acid. Aliquots of heparinized human whole blood (1 ml) were preincubated from healthy donors, with drugs dissolved in dimethyl sulfoxide (final concentration, 0.1%) for 10 minutes at 37 ° C, then calcium ionophore A21387 was added ( 60 μM) and Heparapid (2, 5%, Sekisui Chemical Co. LTD., Japan) and the incubations were continued for an additional 30 minutes. The reactions were terminated by rapid cooling in an ice bath. Blood clots induced by Heparapid were removed by centrifugation. Acetonitrile (ACN, 1.5 ml) and PGB2 (200 ng, as internal standard) were added to the supernatants. The mixtures were mixed by a Voltex mixer and the precipitated proteins were removed by centrifugation. The supernatants were diluted in 15% ACN with water and poured into a washed cartridge C, g Sep-Pak (Waters Associates, Mildford, MS, USA) previously washed and the arachidonate metabolites were eluted with 4 ml of 70% methanol . The methanolic extract was evaporated and then the residue was reconstituted in 250 μl of 67% ACN. The reconstituents were injected in ACN (100 μl) onto a reversed phase C-8 column (Wakosil 5C18, 4.6x150 mm, Wako Puré Chemical Industries LTD, Japan). The temperature of the column was 40 ° C. The HPLC analysis was performed by a HPLC system of Hewlett Packard model 1090M. Chromatography was performed by gradient elution using two different mobile phases (mobile phase A consisted of 10% ACN, 0.1% trifluoroacetic acid and 0.05% triethylamine; and mobile phase B consisted of 80% ACN, 0.1% trifluoroacetic acid and 0.05% triethylamine). Each mobile phase was sprayed continuously with helium. The HPLC gradient was programmed as follows (where A + B = 100): from 0 to 9.7 minutes, a linear gradient from 35 to 100% of mobile phase A with a flow rate of 1 ml / min. The peaks of the elution products were quantified by UV absorbance (LTB4 and PGB2 at 275 nm, HHT and 5-HETE at 235 nm, respectively) and corrected by PGB2 recovery. Linear regression was used to estimate IC 50 values. The compounds of formula I described in the following examples were tested in the aforementioned assay and were shown to possess the ability to inhibit 5-lipoxygenase activity. 2J System for measuring in vivo the effects of orally administered test compounds against lethality induced by platelet activating factor (PAF) in mice The potency in vivo after oral administration of test compounds to ICR mice was determined (males) using the PAF lethality assay in a manner similar to that described in the following articles; J. M. Young, P. J. Maloney, S. N. Jubb, & J. S. Clark, Prostaglandins, 30, 545 (1985); M. Criscuoli & Subissi, Br. J. Pharmac, 90, 203 (1987); and H. Tsunoda, S. Abe, Y. Saku a, S. Kataya a and K. Katayama, Prostaglandins Leukotrienes and Essential Fatty Acids, 3_9, 291 (1990). PAF was dissolved at a concentration of 1.2 μg / ml in 0.05 g / ml of propranolol-saline containing 0.25% bovine serum albumin (BSA) and injected intravenously into a mouse. a dose of 12 μg / kg. Mortality was determined 1 hour after the injection of PAF. To investigate the effect of the 5-LO inhibitors, the compounds were dissolved in 5% Tween 80 and 5% EtOH -salt solution and orally administered (0.1 ml / 10 g) 45 minutes before injection of PAF. Linear regression was used to estimate the ED50 values. For the treatment of the various disorders described above, the compounds of Formula I of this invention can be administered to a human either alone or, preferably, together with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition in accordance with conventional pharmaceutical practice. The compounds can be administered by various conventional routes of administration, including orally, parenterally or by inhalation. When the compound is orally administered to treat an inflammatory disorder in a human, the dosage range will vary between about 0.1 and 10 mg / kg of body weight of the subject to be treated and per day, preferably between about 0.5 and 10. mg / kg of body weight and per day, in a single dose or in divided doses. If parenteral administration is desired, an effective dosage will be between about 0.1 and 1.0 mg / kg of body weight of the human being being treated and per day. In some cases, it may be necessary to use doses outside these limits, since the doses necessarily vary according to the age and response of the individual patient, as well as the type and severity of the patient's symptoms and the potency of the compound. particular that is 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, dragees, syrups, capsules, solution or aqueous suspension. In the case of tablets for oral use, vehicles that are commonly used include lactose and corn starch. Normally, additional lubricating agents such as magnesium stearate are added. In the case of capsules, the 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 may 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 adjusted and buffered conveniently. For intravenous use, the total concentration of solute must be controlled to make the preparation isotonic. In general, the therapeutically effective compounds of this invention are present in said dosage forms at concentration levels ranging from 5% to 70% by weight, preferably from 10% to 50% by weight.

EXAMPLES The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited by the specific details of these examples. The melting points were measured with a Büchi melting point apparatus (535) and were provided uncorrected. The optical rotations were obtained in a JASCO DIP-370 polarimeter. All NMR spectra were measured on CDC13 by a JEOL NMR spectrometer (JNM-GX270, 270 MHz) unless otherwise indicated, and the positions of the peaks are expressed in parts per million (ppm) downfield of tetramethylsilane. The shapes of the peaks are designated as indicated below; s, singlet; d, doublet; t, triplet; c, quadruplet; quint, quit; , ultiplete; a, wide. The following abbreviations are used; Boc for tert-butoxycarbonyl, DMF for dimethylformamide, DMSO for dimethyl sulfoxide, THF for tetrahydrofuran and TFA for trifluoroacetic acid. Example 1 U-. { fIR, 4R) -trans-4-f4-Fluorophenoxy) -2-cyclopenten-l-ill-N-hydroxyurea Acetate of (IR.4R) -trans-4-C4-fluorophenoxy) -2-cyclopenten-1-yl ( stage A); To a stirred solution of 4-fluorophenol (0.785 g, 7 mM), (1S, 4R) cis 4-acetoxy-2-cyclopentene-1-ol (1 g, 7.03 mM), and triphenylphosphine (2.02 g) 7.7 mM) in dry THF (20 mL) was added diisopropyl azodicarboxylate (DPAD, 1.56 g, 7.7 inM) at room temperature (ta). After stirring overnight, the volatiles were removed by evaporation. The resulting residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:20) to give 1.55 g (94%) of the sub-title compound.

? -RMN (CDCI3) í; 6.97 (t, J = 8.8 Hz, 2H), 6.82 (dd, J = 4.4 Hz, 8.8 Hz, 2H), 6.24 (d, J = 5.4 Hz, 1H), 6.16 (d, J = 5.4 HZ, 1H), 5.87-5.82 (m, 1H), 5.44-5.38 (m, 1H), 2.40-2 , 24 (m, 2H), 2.05 (s, 3H). (IR, 4R) -trans-4- (4-fluorophenoxy) -2-cyclopenten-l-ol (step Bl To a stirred solution of (1R, 4R) -4- (4-fluorophenoxy) -2-cyclopenten acetate -l-ilo (1.55 g, 6.56 mM) in methanol (10 mL) was added KOH (0.65 g, 9.84 mM) in water (8 mL) at rt After stirring for 15 minutes, the volatiles were removed by evaporation The residue was taken up in ethyl acetate (70 ml) and the whole was washed with water (50 ml), brine (50 ml), dried over MgSO 4 and concentrated in vacuo to give 1, 25 g (98%) of the subtitle compound: H-NMR (CDCl 3) S, 6.97 (t, J = 8.8 Hz, 2H), 6.82 (dd, J = 4.4 HZ, 8.8 HZ, 2H), 6.18-6.12 (m, 2H), 5.44-5.42 (m, 1H), 5.14-5.08 (S a, 1H), 2.33 (ddd, J = 2.9 Hz, 6.6 Hz, 14.3 Hz, 1H), 2.16 (ddd, J = 3, 3 Hz, 6.6 Hz, 14.3 Hz, 1H), 1.68 (s a, 1H). FlS.4R) -cis-4- (4-fluorophenoxy) -2-cyclopenten-1-yl benzoate (step C); To a stirred solution of (IR, 4R) -trans-4- (4-fluorophenoxy) -2-cyclopenten-1-ol (0.62 g; 3.2 mM) in THF (12 mL) was added triphenylphosphine (0.degree. , 92 g, 3.51 mM), benzoic acid (0.43 g, 3.51 mM) and DPAD (0.71 g, 3.51 mM) at room temperature. After stirring overnight, the volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1: 0) to give 0.82 g (86%) of the subtitle compound. 'H-NMR (CDC13) S; 8.04 (dd, J = 1.5 Hz, 8.5 Hz, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 6.98 (t, J = 8, 1 Hz, 2H), 6.90-6.84 (m, 2H), 6.29-6.23 (m, 2H), 5.88-5 , 82 (m, 1H), 5.19-5.15 (m, 1H), 3.08 (quinter, J = 7.3 Hz, 1H), 2.02 (dt, J = 4.4 Hz, 14.7 Hz, 1H). C1S.4R) -cis-4-f4-Fluorophenoxy) -2-cyclopenten-l-ol (stage DU.To a stirred solution of (1S, 4R) -cis-4- (4-fluorophenoxy) benzoate) -2- Cyclopenten-1-yl (0.82 g, 2.75 mM) in methanol (5 mL) was added with KOH (0.27 g, 4.13 mM) in water (4 mL), after stirring for 2 hours, The volatiles were removed by evaporation The residue was taken up in ethyl acetate (50 ml) and washed with water (50 ml) The aqueous layer was extracted with ethyl acetate (40 ml) and the combined organic layers were washed with water. water (50 ml), brine (50 ml), dried over MgSO 4 and evaporated in vacuo to give 0.6 g of the subtitle compound. H-NMR (CDC13), 6.98 (t, J = 8 , 8 Hz, 2H), 6.88-6.82 (m, 2H), 6.14 (dd, J = 6.2 Hz, 12.8 Hz, 2H), 5.07-5.03 (sa , 1H), 4.78-4.73 (sa, 1H), 2.85 (dt, J = 7, 3 Hz, 14.3 Hz, 2H), 1.78 (dt, J = 4.0 Hz , 14.3 HZ, 1H), 1.79 (sa, 1H).

N. Q-bis (tere-Buto icarboni 1) -Nf (IR.4R) -trans-4- (4-fluorophenoxy-2-cyclopenten-1-yl.}. Hydroxylamine (step E) To a stirred solution of ( 1S, 4R) -cis-4- (4-fluorophenoxy) -2-cyclopenten-1-ol (0.6 g, 2.75 mM) in THF (12 mL) was added triphenylphosphine (0.8 g, 3.025 mM) ), BocNH-OBoc (0.71 g, 3.025 mM) and DPAD (0.61 g, 3.025 mM) at RT After stirring for 2 hours, the volatiles were removed by evaporation, the residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:10) to give 0.689 (62%) of the subtitle compound. 'H-NMR (CDC13) d; 6.96 (t, J = 9.2 Hz, 2H), 6.82 (dd, J = 4.4 Hz, 9.2 Hz, 2H), 6.17-6.13 (sa, 1H), 6.06-6.03 (m, 1H), 5.55 -5.48 (sa, 1H), 5.42-5.35 (sa, 1H), 2.36 (ddd, J = 3.6 Hz, 6.6 Hz, 14.2 Hz, 1H), 2 , 28-2.15 (sa, 1H), 1.51 (S, 9H), 1.49 (S, 9H), N- f1R.4R] -trans-4- (4-Fluorophenoxy) -2-cyclopenten -l-ill-N-hydroxyurea (step F): A solution of N, 0-bis (tert-butoxycarbonyl) was stirred for 3 hours. -N-. {(IR, 4R) -trans-4- (4-fluorophenoxy) -2-cyclopenten-1-yl} hydroxylamine (0.688 g, 1.68 mM) and TFA (1.3 ml, 16.8 mM) in CH2C12 (5 ml). After removing the volatiles, the residue was taken up in ethyl acetate (80 ml) and the whole was washed with a saturated NaHCO3 solution (50 ml), water (50 ml) and brine (50 ml), dried over MgSO4. and concentrated in vacuo to give 0.35 g of the hydroxylamine. To a stirred solution of the hydroxylamine obtained above (0.35 g) in THF (7 ml) was added trimethylsilyl isocyanate (0.3 g).; 2.18 mM) at t.a. After stirring for 1 hour, ethanol (5 ml) was added and the volatiles were removed by evaporation. The residue was recrystallized from ethyl acetate-n-hexane (2: 1) to give 0.21 g (49%) of the title compound as colorless crystals. p.f. 157, 5-158, 5 ° C (dec). ? -RMN (DMS0-d6) 5; 9,03 (s, 1H), 7.10 (t, J = 8.4 Hz, 2H), 6.96-6.91 (m, 2H), 6.41 (S, 2H), 6.10 (d, J = 5.2 HZ, 1H), 5.96 (d, J = 5.2 Hz, 1H), .42-5.35 (s a, 2H), 2.32-2.25 (m, 1H), 1.94-1.86 (m, 1H).

Analysis calculated for C12H, 3N2? 3F: C. 57.14; H. 5.19; N. 11.11. Found: C. 56.99; H. 5.22; N. 11.05. Example 2 N-'f (lS, 4R? -cis-4- (4-Fluorophenoxy) -2-cyclopenten-l-ill-N-hydroxyurea The title compound was prepared according to the procedure described in Example 1 using (1R, 4R) -trans-4- (4-fluorophenoxy) -2-cyclopenten-l-ol instead of (1S, 4R) -cis-4- (4-fluorophenoxy) -2-cyclopenten-1-ol from step E. p.f. 142-143 ° C (dec). ? -NRM (DMSO-d6) 5; 9.03 (s, 1H), 7.11 (t, J = 8.4 Hz, 2H), 6.99-6.93 (m, 2H), 6.40 (s, 2H), 6.03 -6.01 (m, 1H), .92-5.88 (m, 1H), 5.20-5.15 (m, 2H), 2.66 (dt, J = 7.7 Hz, 14.6 Hz, 1H), 1.74. (dt, J = 6, 3 Hz, 14.6 Hz, 1H). Analysis calculated for C12H13N203F: C. 57.14; H. 5.19; N. 11.11. Found: C. 56.99; H. 5.22; N. 11.05. Example 3 N-f (IR.4S) -cis-4- (4-Fluorophenoxy) -2-cyclopenten-l-ill-N-hydroxyurea (1S, 4S) -trans-4- (4-Fluorophenoxy) -2 -cyclopenten-l-ol; To a stirred solution of (1S, 4R) -cis-4-acetoxy-2-cyclopentene-1-ol (1 g; 7.03 mM) in DMF (10 mL) was added imidazole (1.05 g; 48 mM) and tert-butyldimethylsilyl chloride (1.17 g, 7.47 mM) at RT. After stirring overnight, the mixture was poured into water (50 ml). The whole was extracted with ethyl acetate-n-hexane (1: 1, 70 ml x 2) and the organic layers were washed with water (50 ml), brine (50 ml), dried over MgSO 4 and concentrated in vacuo. to give 1.84 g (quant.) of (lR, 4S) -cis-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-yl lH-NMR acetate (CDC13) d; 5.97 (d, J = 5.5 Hz, 1H), 5.88 (d, J = 5.5 HZ, 1H), 5.46 (t, J = 4.0 Hz, 1H), 4, 72 (t, J = 4.0 Hz, 1H), 2.91 (d, J = 2.0 Hz, 1H), 2.80 (c, J = 7.0 Hz, 1H), 2.05 ( S, 3H), 0.90 (S, 9H), 0.09 (s, 6H). A stirred suspension of (IR, 4S) -cis-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-yl acetate (1.84 g, 7.03 mM) and potassium carbonate was stirred for 2 hours. (1.46 g, 10.55 mM) in methanol (30 ml). Water (50 ml) was added to the mixture, and the whole was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over MgSO 4 and concentrated in vacuo to give 1.65 g (quant.) Of (1R, 4S) -cis-4-tert. butyldimethylsilyloxy-2-cyclopenten-l-ol. To a stirred solution of (1R, 4S) -cis-4-tert-butyldiroethylsilyloxy-2-cyclopenten-1-ol (1.65 g, 7 mM), 4-fluorophenol (0.94 g, 8.4 mM) and triphenylphosphine (2.2 g, 8.4 mM) in THF (20 mL) was added DPAD (1.7 g, 8.4 mM) at RT. After stirring overnight, the volatiles were removed by evaporation. Chromatographic purification of the residue eluting with n-hexane yielded 1.53 g (71%) of (lS, 4S) -trans-4- (4-fluorophenoxy) -l- (tert-butyldimethylsilyloxy) -2-cyclopentane. 'H-NMR (CDC13) d; 7.00-6.93 (m, 2H), 6.83-6.78 (m, 2H), 6.07 (S, 2H), 5.42-5.35 (m, 1H), 5, 15-5.07 (m, 1H), 2.29 (ddd, J = 2.4 Hz, 6.9 Hz, 14.3 Hz, 1H), 2.09 (ddd, J = 3.6 Hz, 6.9 Hz, 14.3 Hz, 1H), 0.90 (s, 9H), 0.09 (s, 6H). To a stirred solution of (1S, 4S) -trans-4- (4-fluorophenoxy) -1- (tert-butyldimethylsilyloxy) -2-cyclopentane (1.52 g, 4.94 mM) in dry THF (15 mL) tetra-n-butylammonium fluoride (1M solution in THF, 7.4 ml, 7.4 mM) was added After stirring for 2 hours, the volatiles were removed by evaporation. The residue was taken up in ethyl acetate (100 ml), washed with water (50 ml), brine (50 ml), dried over MgSO 4 and concentrated in vacuo to give 1.34 g of the subtitle compound. 'H-NMR (CDCl 3) d; 6.97 (t, J = 8.8 Hz, 2H), 6.82 (dd, J = 4.4 HZ, 9.1 Hz, 2H), 6.16 (sa, 2H), 5.46- 5.40 (m, 1H), 5.15-5.09 (m, 1H), 2.34 (dq, J = 3.3 Hz, 14.3 Hz, 1H), 2.17 (dq, J = 3.3 HZ, 14.3 Hz, 1H), 1.64 (sa, 1H). N-'f (IR.4S) -cis-4- (4-Fluorophenoxy) -2-cyclopenten-l-ill-N-hydroxyurea; The title compound was prepared according to the procedure described in Example 1 using (1S, 4R) -trans-4- (4-fluorophenoxy) -2-cyclopenten-1-ol instead of the (1S, 4R) -cis-4- (4-fluorophenoxy) -2-cyclopenten-l-ol from step E. p.f. 137-139 ° C (dec.). 'H-NMR (DMS0-de) d,' 9.03 (s, 1H), 7.11 (t, J = 8.4 Hz, 2H), 6.99-6.93 (m, 2H), 6.40 (s, 2H), 6.03-6.01 (m, 1H), 5.92-5.88 (m, 1H), 5.20-5.15 (m, 2H), 2, 66 (dt, J = 7.7 Hz, 14.6 Hz, 1H), 1.74 (dt, J = 6.3 Hz, 14.6 Hz, 1H). Analysis calculated for C12H? 3N203F: C. 57.14; H. 5.19; N. 11.11. Found: C. 57.14; H. 5.21; N. 11.09. Example 4 N-f (lS.4S) -trans-4- (4-Fluorophenoxy) -2-cyclopenten-l-il > -N-hydroxyurea The title compound was prepared according to the procedure described in Example 1 using (1S, 4S) -trans-4- (4-fluorophenoxy) -2-cyclopenten-1-ol instead of (IR, 4R) -trans-4- (4-fluorophenoxy) -2-cyclopenten-l-ol from step C. p.f. 151-153 ° C (dec.). 'H-NMR (DMSO-d6) i; 9.03 (s, 1H), 7.10 (t, J = 8.4 HZ, 2H), 6.93 (dd, J = 3.6 Hz, 8.4 Hz, 2H), 6.42 ( s, 2H), 6.10 (d, J = 5.2 Hz, 1H), 5.96 (d, J = 5, 2 HZ, 1H), 5.42-5.35 (sa, 2H), 2.32-2.25 (m, 1H), 1.94-1.86 (m, 1H). Analysis calculated for C12H | 3N203F: C. 57.14; H. 5.19; N. 11.11. Found: C. 56.94; H. 5.21; N. 11.13. Example 5 N-f (1R.4R) -trans-4- (4-Cyanophenoxy) -2-cyclopenten-1-yl-N-hydroxyurea The title compound was prepared according to the procedure described in Example 1 using 4-cyanophenol in place of 4-fluorophenol from stage A. pf 162-163 ° C (dec.). ? -RMN (DMSO-d6) d; 9.04 (s, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.10 (d, J = 7.7 Hz, 2H), 6.41 (S, 2H), 6.12 (d, J = 5.5 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H), 6.57-6.53 (m, 1H), 6.41-6 , 36 (m, 1H), 2.37-2.27 (m, 1H), 1.99-1.87 (m, 1H). Analysis calculated for C, 3H, 3N3? 3: C. 60.23; H. 5.05; N. 16.21. Found: C. 60.35; H. 5.06; N. 15,91. Example 6 N-T (1S.4R) -cis-4- (4-Cyanophenoxy) -2-cyclopenten-1-yl-N-hydroxyurea The title compound was prepared according to the procedure described in Example 2 using (1R, 4R) -trans-4- (4-cyanophenoxy) -2-cyclopenten-1-ol instead of (IR, 4R) -trans-4- (4-fluorophenoxy) -2-cyclopenten-1-ol. p.f. 180-181 ° C (dec.). ? -RMN (DMSO-d6) d; 9.03 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.37 (S, 2H), 6.03 (d, J = 5.9 Hz, 1H), 5.94 (d, J = 5.9 Hz, 1H), 5.37-5.34 (m, 1H), 5.22-5 , 17 (m, 1H), 2.77-2.66 (m, 1H), 1.79-1.70 (m, 1H). Analysis calculated for C, 3Hi3N3? 3: C. 60.23; H. 5.05; N. 16.21. Found: C. 60.54; H. 5.03; N. 16.07. Example 7 N-((lRf4R) -trans-4-f3- (4-Fluorophenoxy) phenoxy-2-cyclopenten-1-yl-N-hydroxyurea The title compound was prepared according to the procedure described in Example 1 using 3- (4-f luorofenoxi) phenol in place of 4-f luorof enol from stage A. pf 127-128 ° C (dec.). [a] D = + 195.38 ° (ethanol, c = 0.127). ? -NMR (DMSO-d6) d, '9.08 (s, 1H), 7.35-7.02 (m, 5H), 6.68 (d, J = 8, 1 HZ, 1H), 6 , 48 (s, 2H), 6.39 (s, 2H), 6.15-5.88 (m, 2H), 5.39 (s, 2H), 2.35-2.16 (m, 1H) ), 2.00-1.80 (m, 1H). Analysis calculated for ClgH17N204F: C. 62.79; H. 4.98; N. 8.14. Found: C. 62.71; H. 4.93; N. 8.22. EXAMPLE 8 N- (1S. 4R) -cis-4- ^ 3- (4-Fluorofenoxi) f enoxy-2-cyclopenten-1-yl-N-hydroxyurea The title compound was prepared according to the procedure described in Example 2 using (1R, 4R) -trans-4-. { 3- (4-f luorofenoxi) f enoxi} -2-cyclopenten-l-ol instead of (IR, 4R) -trans-4- (4-f luorofenoxi) -2-cyclopenten-l-ol. p.f. 130-131 ° C (dec.). [α] D = -41.07 ° (ethanol, c = 0.112). ? -RMN (DMS0-d6) í; 9.05 (s, 1H), 7.40-7.05 (m, 5H), 6.80-6.45 (m, 3H), 6.34 (s, 2H), 6.10-5, 85 (m, 2H), 5.30-5.05 (m, 2H), 2.75-2.55 (m, 1H), 1.85-1.65 (m, 1H). Analysis calculated for C | gH, 7N204F: C. 62.79; H. 4.98; N. 8.14. Found: C. 62.67; H. 4.97; N. 8.25. Example 9 N-r (1S.4R) -cis-4- 2-tert-Butyl-5- (4-f luorofenoxi) f enoxi} -2-cyclopenten-1-yl-1-N-hydroxyurea The title compound was prepared as a side product of Example 8. p.p. 148-151 ° C (dec.). [α] D = -54.09 ° (c = 0.12, ethanol). ? -RMN (DMS0-d6) í; 8.99 (S, 1H), 7.23-7.13 (m, 3H), 7.08-7.02 (m, 2H), 6.67 (d, J = 2, 2 Hz, 1H) , 6.38 (d, J = 2.5 HZ, 1H), 6.36 (s, 2H), 6.02 (d, J = 5, 4 Hz, 1H), 5.90 (d, J = 5.4 HZ, 1H), 5.23-5.13 (m, 2H), 2.62-2.49 (m, 1H), 1.88-1.77 (m, 1H), 1.30 (s, 9H). IR (KBr) cm1: 3500, 3380, 2950, 1660, 1580, 1490, 1420, 1200, 1085, 1020, 830. Analysis calculated for C22H25N204F 1/5 H20: C. 65.40; H. 6.34; N. 6.93. Found: C. 65.34; H. 6.28; N. 7.22. Example 10 Nr (lR.4S) -cis-4-l3- (4-Fluorophenoxy) phenoxy-2-cyclopenten-1-yl-N-hydroxyurea The title compound was prepared according to the procedure described in Example 3 using 3- (4-fluorophenoxy) phenol instead of 4-f luorofenol. p.f. 133-135 ° C. [a] D = + 35.50 ° (c = 0.20, ethanol). ? -RMN (DMS0-d6) d; 9.01 (s, 1H), 7.29-7.20 (m, 3H), 7.13-7.05 (m, 2H), 6.72 (dd, J = 2.2 Hz and 8, 4 Hz, 1H), 6.54-6-48 (m, 2H), 6.38 (s, 2H), 6.00 (d, J = 5.8 Hz, 1H), 5.89 (d, J = 5.8 Hz, 1H), 5.21-5.12 (m, 2H), 2.63 (ddd, J = 7.7, 7.7 and 13.2 Hz, 1H), 1.75 (ddd, J = 5.8, 5.8 and 13.2 Hz, 1H). IR (KBr) cm "': 3300, 2900, 1635, 1610, 1500, 1200, 1140, 845, 785, 760. Analysis calculated for C, gH17N204F: C. 62.79, H. 4.98, N. 8 , 14. Found: C. 62.78, H. 5.02, N. 8.05, Example 11 Nr (lS.4S) -trans-4- 3- (4-Fluorophenoxy) phenoxy-2-cyclopenten-1. 1-N-hydroxyurea The title compound was prepared according to the procedure described in Example 1 using (1S, 4S) -trans-4-. {3- (4-f luorofenoxi) phenoxy}. -2-cyclopenten-l-ol instead of (IR, 4R) -trans-4- (4-f luorofenoxi) -2-cyclopenten-l-ol from step C. mp 163-164 ° C. ] D = -172.73 ° (c "0.10, ethanol).> H-NMR (DMSO-d6) d; 9.08 (s, 1H), 7.35-7.02 (m, 5H ), 6.68 (d, J = 8, 1 HZ, 1H), 6.48 (bs, 2H), 6.39 (s, 2H), 6.15-5.88 (m, 2H), 5 , 39 (bs, 2H) 2.35-2.16 (m, 1H), 2.00-1.80 (m, 1H) IR (KBr) Cltr1: 3450, 3320, 3200, 1620, 1583, 1505 , 1485, 1260, 1205, 1140, 1005, 830, 760, 690, 600. Analysis calculated for CIgH17N204F: C. 62.79, H. 4.98, N. 8.14, Found: C. 62.86; H. 4.99; N. 8.16. Example 12 N-Hydro iN-r (IR.4RS) -trans -4- (4-Phenylphenoxy) -2-cyclopenten-1-ylurea The title compound was prepared according to the procedure described in Example 1 using 4-phenylphenol in place of 4-f luorofol of stage A. pf 178-180 ° C (dec.). [a] D = -181.82 ° (ethanol, c = 0.145). ? -RMN (DMSO-d6) d; 9.14 (s, 1H), 7.64-7.58 (m, 5H), 7.44 (t, J = 7.5 HZ, 2H), 7.31 (t, J = 7, 3 Hz , 1H), 7.02 (d, J = 8.8 HZ, 2H), 6.43 (s, 2H), 6.19-6.14 (m, 1H), 6.00-5.97 (m, 1H), 5.50-5.38 (m, 2H), 2.36-1.90 (m, 2H). Analysis calculated for C18Hi9N2? 3: C. 69.44; H. 6.15; N. 9.00.

Found: C. 69.31; H. 5.74; N. 8.83. Example 13 N-T (1R.4R) -trans-4- (4-Fluorobenzaldoxime-Q-2-cyclopentyl ether) -l-il > -N-hydroxyurea 4-Fluorobenzaldoxime (O- (KR). 4 (R) -trans-4-hydroxy-2-cyclopenten-1-yl) ether: To a stirred solution of (1S, 4R) -cis-4- acetoxy-2-cyclopentene-1-ol (2.33 g; 16.4 mM), N-hydroxyphthalimide (2.68 g, 16.4 mM) and triphenylphosphine (4.73 g, 18 mM) in dry THF (50 ml), DPAD (3.8 ml, 18 mM) was added to the t.a.

After stirring for five hours, the volatiles were removed by evaporation. The resulting residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1: 4) to give 7.91 g (quant.) Of N- ((IR, 4R) -trans-4-acetoxy-2- cyclopent-1-oxy) phthalimide. ? -RMN (CDC13) d; 7.85 (dd, J = 3, 3 Hz, 5.5 Hz, 2H), 7.76 (dd, J = 3.3 HZ, 5.5 Hz, 2H), 6.24 (, 2H), 5.84 (m, 1H), 5.54 (m, 1H), 2.70 (dd, J = 3.0 Hz, 7.0 Hz, 1H), 2.19 (dd, J = 2.9 HZ, 7.0 HZ, 1H), 2.03 (s, 3H). To a stirred solution of N- ((1R, 4R) -trans-4-acetoxy-2-cyclopenten-1-oxy) phthalimide (9.95 g; 32.4 mM) in dry CH2C12 (95 ml) was added ethylhydrazine (1.8 ml, 32.4 mM) at -78 ° C under N2. After stirring for 30 minutes, the mixture was allowed to warm to t.a. and stirred for 1 hour more. The precipitates were separated by filtration and the filtrate was evaporated in vacuo to give 5.09 g (quant.) Of O- ((IR, 4R) -trans-4-acetoxy-2-cyclopent-1-yl) hydroxylamine. ? -RMN (CDCI3) d; 6.19-6.15 (m, 1H), 6.12-6.07 (m, 1H), 5.83-5.77 (, 1H), 5.60-4.70 (sa, 2H) , 5.03-4.96 (m, 1H), 2.04 (S, 3H), 2.30-1.97 (m, 2H). A mixture of 0- ((1R, 4R) -trans-4-acetoxy-2-cyclopenten-1-yl) hydroxylamine (5.09 g, 32.4 mM) and 4-fluorobenzaldehyde (3.5 ml; 32, 4 mM) in ethanol (90 ml) was stirred at for 2 days. After removing the volatiles, the resulting residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:20) to give 4.35 g (51%) of 4-f luorobenzaldoxime-O- (1 (R ), 4 (R) -trans-4-acetoxy-2-cyclopenten-1-yl) ether? -RMN (CDCl 3) d; 8.01 (s, 1H), 7.56 (dd, J = 5.5 Hz, 8.8 Hz, 2H), 7.05 (t, J = 8.8 Hz, 2H), 6.25-6.12 (m, 2H), 5.87- 5.48 (m, 1H), 5.50 -5.48 (m, 1H), 2.41 (ddd, J = 2.9 Hz, 7.3 HZ, 15 Hz, 1H), 2.17 (ddd, J = 3, 3 Hz, 7.3 Hz, 15 Hz, 1H), 2.05 (S, 3H). A mixture of 4-fluorobenzaldoxime-O- (1 (R), 4 (R) -trans-4-acetoxy-2-cyclopenten-1-yl) ether (4.35 g, 16.5 mM) and potassium carbonate ( 3.43 g; 24.8 M) in methanol (80 ml) was stirred at for 1 hour, and then the volatiles were removed by evaporation. Water (100 ml) was added and the whole was extracted with ethyl acetate (60 ml x 2), the combined organic layers were washed with water (50 ml), brine (50 ml), dried over MgSO 4 and concentrated at vacuum to give 3.59 g of the subtitle compound. "H-NMR (CDClj) 5; 8.01 (s, 1H), 7.55 (dd, J = 5.5Hz, 8.8 HZ, 2H), 7.06 (t, J = 8.6 Hz, 1H), 6.17-6.12 (m, 2H), 5.51- 5.48 (m, 1H), 5.10 -5.08 (m, 1H), 2.39 (ddd, J = 2.6 Hz, 6.6) HZ, 9.2 Hz, 1H), 2.06 (ddd, J = 3.7 Hz, 7. 0 Hz, 9.0 Hz, 1H).

N1 (1R.4R) -trans-4- (4-Fluorobenzaldoxime-0-2-cyclopentyl ether) -1-yl-N-hydroxyurea The title compound was prepared according to the procedure described in Example 1 using 4- fluorobenzaldoxime-O- (1 (R), 4 (R) -trans-4-hydroxy-2-cyclopenten-1-yl) ether instead of (1R, 4R) -trans-4- (4-fluorophenoxy) -2 -cyclopenten-l-ol of stage C. pf 150-151 ° C (dec.). [α] D = + 313.9 ° (ethanol, c = 0.1). 'H-NMR (DMSO-d6) 5; 9.00 (s, 1H), 8.22 (s, 1H), 7.70-7.65 (m, 2H), 7.30-7.22 (m, 2H), 6.37 (s, 2H), 6.05 (d, J = 5.5 HZ, 1H), 5.92 (d, J = 5, 9 Hz, 1H), 5.35 (m, 2H), 2.28-1, 90 (m, 2H). Analysis calculated for C 13 H 14 N 303 F: C. 55.91; H. 5.05; N. 15,05. Found: C. 56.16; H. 4.91; N. 15.27. Example 14 N-f (1S.4R) -cis-4- (4-Fluorobenzaldoxime-0-2-cyclopentyl ether) -l-il > -N-hydroxyurea The title compound was prepared according to the procedure described in Example 1 using 4-fluorobenzaldoxime-0- (l (R), 4 (R) -tr ans-4-h idrox i-2-cyclopenten -l-il) ether in place of (1S, 4R) -cis-4- (4-f luorofenoxi) -2-cyclopenten-l-ol from step E. pf 148-149 ° C (dec.). [a] D = + 49.5 ° (ethanol, c = 0.1). ? -RMN (DMS0-d6) í; 9.02 (d, J = 3, 3 Hz, 1H), 8.23 (S, 1H), 7.65 (dd, J = 2.2 Hz, 12.5 Hz, 2H), 7.25 (t, J = 9.0 HZ, 2H), 6.35 (sa, 2H) ), 6.02 (t, J = 1, 8 Hz, 1H), 5.87 (dt, J = 1, 46 Hz, 5.9 Hz, 1H), 5.30-5.10 (m, 2H) ), 2.53-2.46 (m, 1H), 1.83 (abbreviate, J = 6.6 Hz, 1H). Analysis calculated for C 13 H 14 N 303 F: C. 55.91; H. 5.05; N. 15,05. Found: C. 56.21; H. 4.89; N. 15.19. Example 15 N-T (IR) -4-benzyloxyimino-2-cyclopenten-1-yl-N-hydroxyurea (4R) - (E) -4-Hydroxy-2-cyclopentenone oxime-O-benzyl ether; (4R) -4-Acetoxy-2-cyclopentenone was prepared by the oxidation of (1S, 4R) -cis-4-acetoxy-2-cyclopentene-1-ol with pyridinium dichromate (PDC) (MP Schneider et al., J. Chem. Soc., Chem. Commun., 1298 (1986)). To a stirred solution of (4R) -4-acetoxy-2-cyclopentenone (1.56 g; 11.1 mM) in ethanol (22 ml) was added O-benzylhydroxylamine hydrochloride (1.77 g, 11.1 mM). ) and pyridine (1.1 ml, 11.1 mM) at the After stirring for 3 hours, the volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:10) to give 2.78 g (quant.) Of (4R) -4-acetoxy-2-cyclopentenone oxime-O-benzyl ether. ? -RMN (CDC13) d; 7.37-7.27 (m, 5H), 6.51 (dd, J = 2, 2 HZ, 5.9 Hz, 1H), 6.43 (dd, J-1.1 Hz, 5.9 Hz, 1H), 5.72 (ddd, J = 1, 1 HZ, 2.2 Hz, 4.8 Hz, 1H), 5.13 (s, 2H), 3.12 (dd, J = 7, 0 HZ, 9.1 HZ, 1H), 2.58 (dd, J = 2, 2 Hz, 9.4 Hz, 1H), 2.05 (S, 3H). A suspension of (4R) -4-acetoxy-2-cyclopentenone oxime-O-benzylether (2.64 g, 10.8 mM) and potassium carbonate (2.23 g, 16.1 M) in methanol (80 ml) it stirred for a night at the ta The volatiles were removed by evaporation, and the residue was extracted with ethyl acetate (40 ml x 2), the combined organic layers were washed with water (50 ml), brine (50 ml), dried over MgSO 4 and concentrated in vacuo. vacuum to give 2.33 g (quant.) of the subtitle compound. ? -RMN (CDC13) d; 7.40-7.26 (m, 5H), 6.52 (dd, J = 2, 2 HZ, 5.5 HZ, 1H), 6.34 (d, J = 5.5 Hz, 1H), 5.13 (s, 2H), 4.96 (sa, 1H), 3.09 (dd, J = 7.0 Hz, 18.7 Hz, 1H), 2.48 (dd, J = l, 8 Hz, 18.7 HZ, 1H). Nf (IR) -4-Benzyloxyimino-2-cyclopenten-1-yl-N-hydroxyurea: The title compound was prepared according to the procedure described in Example 1 using (4R) -4-hydroxy-2-cyclopentenone oxime -O-benzyl ether instead of (IR, 4R) -trans-4- (4-fluorophenoxy) -2-cyclopenten-l-ol from stage C. pf 166-170 ° C (dec.). [o] D = + 257.9 ° (ethanol, c = 0.15). ? -RMN (DMSO-d6) d; 9.18 (d, J = 1, 1Hz, 1H), 7.48-7.35 (m, 5H), 6.56 (sa, 2H), 6.51 (dd, J = 2, 2 Hz, 5.0 Hz, 1H), 6.41 (dd, J = 1, 8 Hz, 5.9 Hz, 1H), 5.41 (day, J = 7.0 Hz, 1H), 5.14 (S , 2H), 2.84 (dd, J = 7.7 Hz, 18.3 Hz, 1H), 2.67-2.53 (m, 1H). Analysis calculated for C? 3H15N3? 3: C, 59.76; H. 5.79; N. 16.08. Found: C. 60.01; H. 5.87; N. 16.08. Example 16 N-Í (1S) -4-Benzyloxyimino-2-cyclopenten-1-yl-N-hydroxyurea The title compound was prepared according to the procedure described in Example 1 using (4R) -4-hydroxyurea. 2-cyclopentenone oxime-O-benzylether in place of the (1S, 4R) -cis-4- (4-fluorophenoxy) -2-cyclopenten-l-ol of step E. pf 168-171 ° C (dec.). [a] D = -258.2 ° (ethanol, c = 0,136). ? -RMN (DMSO-d6) í; 9.18 (d, J-1.1 Hz, 1H), 7.48-7.35 (m, 5H), 6.56 (sa, 2H), 6.51 (dd, J = 2, 2 Hz , 5.0 Hz, 1H), 6.41 (dd, J = 1, 8 Hz, 5.9 Hz, 1H), 5.41 (da, J = 7.0 Hz, 1H), 5.14 (s, 2H), 2 , 84 (dd, J = 7, 7 Hz, 18.3 Hz, 1H), 2.67-2.53 (m, 1H). Analysis calculated for C 13 H 15 N 3 3 3: C. 59.76; H. 5.79; N. 16.08. Found: C. 59.83; H. 5.75; N. 16.01. Example 17 N-T (IR) -4- (4-fluorobenzyloxyimino) -2-cyclopenten-1-yl-N-hydroxyurea The title compound was prepared according to the procedure described in Example 15 using O-hydrochloride (4-fluorobenzyl) hydroxylamine in place of O-benzylhydroxylamine hydrochloride. p.f. 148-149 ° C (dec.). [o] D = + 243.75 ° (ethanol, c = 0.128). ? -RMN (DMSO-d6) d; 9.12 (s, 1H), 7.40 (dd, J = 5.9 HZ, 8.4 HZ, 2H), 7.17 (t, J = 8, 8 Hz, 2H), 6.48- 6.31 (m, 4H), 5.34-5.30 (m, 1H), 5.03 (s, 2H), 2.75 (dd, J = 7.7 Hz, 14.3 Hz, 1H ), 2.54-2.45 (m, 1H). Analysis calculated for C13H14N303F: C. 55.91; H. 5.05; N. 15,05. Found: C. 56.07; H. 5.06; N. 15,03. Example 18 N-Hydroxy-N (IR) -4-phenyloxyimino) -2-cyclopenten-1-illurea The title compound was prepared according to the procedure described in Example 15 using O-phenylhydroxylamine hydrochloride in place of the hydrochloride of O-benzylhydroxylamine. p.f. 156-157 ° C (dec.). [α] D «+ 258.0 ° (ethanol, c = 0.1). 'H-NMR (DMSO-d6) 5; 9.20 (s, 1H), 7.33 (t, J = 7, 6 Hz, 2H), 7.16-7.12 (m, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.63 (dd, J = 2.2 HZ, 5.9 Hz, 1H), 6.54-6.50 (m, 3H), 5.42 (d, J = 7.0 HZ, 1H), 3.00 (dd, J = 7.3 Hz, 18.3 Hz, 1H), 2.72 (d, J = 18.3 Hz, 1H). Analysis calculated for C12H13N303: C, 58.29; H. 5.30; N. 16.99. Found: C. 58.11; H. 5.45; N. 16.41.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. A compound of formula (I): (!) wherein Ar is selected from the group consisting of: (a) phenyl, naphthyl and biphenyl, each optionally substituted with one or three substituents selected from C 1 J alkyl} , haloalkyl C, hydroxyalkyl C, alkoxy C, haloalkoxy C, alkoxyalkoxy 2, alkylthio CM, hydroxy, halo, cyano, amino, alkylamino CM, dialkyl (C2.8) amino, alkanoylaminoC.6, carboxy, alkoxycarbonyl CM, phenyl optionally substituted with one to three substituents selected from C3J alkyl > , haloalkyl CM, Cw alkoxy, haloalkoxy C ,. 4, cyano and halo, phenoxy optionally substituted with one to three substituents selected from alkyl CM, haloalkyl CM, alkoxy CM, haloalkoxy CM, cyano and halo, phenylthio optionally substituted with one to three substituents selected from C-alkyl, C-haloalkyl, C-alkoxy, haloalkoxy C, cyano and halo, and phenylsulfinyl optionally substituted with one to three substituents selected from alkyl C, haloalkyl C, alkoxy C, haloalkoxy C, cyano and halo; and (b) furyl, benzo [b] furyl, thienyl, benzo [b] thienyl, pyridyl and quinolyl, optionally substituted with one to three substituents selected from alkyl ClA, haloalkyl C, halo, C-alkoxy, hydroxy, phenyl optionally substituted with one to three substituents selected from CM alkyl, Cu haloalkyl, CM alkoxy, CM haloalkoxy, cyano and halo, phenoxy optionally substituted with one to three substituents selected from C alkyl, CM haloalkyl, C alkoxy, haloalkoxy C, cyano and halo, and phenylthio optionally substituted with one to three substituents selected from C alkyl, haloalkyl CM, alkoxy Cl l haloalkoxy CM, cyano and halo; X is selected from C, -C4 alkylene, C2-C4 alkenylene, - (CHR ') ß-Q1- (CHR2) n-, -0- (CHR') j-Q2- and - (CHR ') - 0- N = where the radical N = is attached to the cycloalkene ring; and where Q1 is 0, S, SO, S02, NR3, CH = N-0 or CO, Q2 is O, S, SO, S? 2, or NR3 and R1, R2 and R3 are, each, hydrogen or alkyl C, -C4, m and n are each an integer from 0 to 4 and j is an integer of 4. p is the integer 1 or 2; Y is hydrogen, CM alkyl, CM haloalkyl, CM alkoxy, CM alkoxyalkyl, C-alkylthio, hydroxy, halo, cyano or amino; Z is hydrogen or CM alkyl; and M is hydrogen, a pharmaceutically acceptable cation or a metabolically pharmaceutically acceptable cleavable group.

2. A compound according to claim 1, wherein Ar is selected from the group (a), Y and Z are each hydrogen, p is 1 and M is hydrogen or a pharmaceutically acceptable cation.

3. A compound according to claim 2, wherein Ar is phenyl, fluorophenyl, cyanophenyl, biphenyl or fluorophenoxyphenyl and X is O which is attached to the 4-position of the cycloalkene ring.

4. A compound according to claim 2, wherein Ar is phenyl or fluorophenyl and X is -CH = N-0-, which is attached to the 4-position of the cycloalkene ring.

5. A compound according to claim 2, wherein Ar is phenyl or fluorophenyl and X is -0-N = or -CH2-0-N =, which is attached to the 4-position of the cycloalkene ring.

6. A compound according to claim 1 selected from the group consisting of N-. { (IR, 4R) -trans-4- (4-Fluorophenoxy) -2-cyclopenten-1-yl} -N-hydroxyurea; N-. { (1R, 4R) -trans-4- [3- (4-Fluorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hydroxyurea; N-. { (1S, 4R) -cis-4- [3- (4-Fluorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hydroxyurea; N-. { (IR) -4-Benzyloxyimino-2-cyclopenten-1-yl} -N-hydroxyurea; and N-. { (IR) -4- (4-Fluorobenzyloxyimino) -2-cyclopenten-1-yl} -N-hydroxyurea.

7. A pharmaceutical composition for treating a medical disorder for which a 5-lipoxygenase inhibitor is required in a mammal, comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition according to claim 7, wherein the medical disorder is an inflammatory disease, an allergy or a cardiovascular disease- ARILOXICICLOALOUENIL-AND ARILOXYIMINOCICLOALOUENILHIDROXIUREAS Summary of the Invention The present invention provides a compound of the formula (I): F wherein Ar is (a) phenyl, naphthyl and biphenyl, each optionally substituted with CM alkyl, CM haloalkyl, CM hydroxyalkyl, CM alkoxy, C1 haloalkoxy C1 alkoxyalkoxy C2, alkylthio C, hydroxy, halo, amino, alkylamino CM, dialkyl (C2.g) amino, C2-6 alkanoylamino, carboxy, Cw alkoxycarbonyl or phenyl, phenoxy, phenylthio or phenylsulphinyl, optionally substituted or (b) furyl, benzo [b] furyl, thienyl, benzo [b] thienyl, pyridyl or quinolyl , each optionally substituted by C, C, haloalkyl C, halo, alkoxy ClA, phenyl, phenoxy and phenylthio optionally substituted, X is C, -C4 alkylene, C2-C4 alkenylene, - (CHR1) m-Q '- ( CHR2) n, -0- (CHR ') j-Q2- and (CHR1) -0-N =, where the radical N = is attached to the cycloalkene ring; and wherein Q1 is O, S, SO, S02, NR3, CH = N-0 or CO, Q2 is O, S, SO, S02 or NR3 and R1, R2 and R3 are each hydrogen or C-alkyl [-C4, myn are, each, an integer from 0 to 4 and j is an integer from 1 to 4; p is the integer 1 or 2; Y is hydrogen, alkyl C, haloalkyl C, alkoxy C, alkoxyalkyl C2 l alkylthio C ,. 4, hydroxy, halo, cyano or amino; Z is hydrogen or C 4 -4 alkyl and M is hydrogen, a pharmaceutically acceptable cation or a metabolically pharmaceutically acceptable cleavable group. In addition, the invention provides a pharmaceutical composition for treating a medical disorder for which a 5-lipoxygenase inhibitor is required in a mammal, comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. Preferably, the medical disorder is an inflammatory disease, an allergy or cardiovascular diseases.