CN1059669C - Aryloxycycloalkenyl and aryloxyiminocycloalkenylhydroxyureas - Google Patents

Abstract

The present invention provides a compound of formula (I), wherein the definition of groups refer to the description. Further the invention provides a pharmaceutical composition for treating a medical condition for which a 5-lipoxygenase inhibitor is needed in a mammalian subject which comprises a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. Preferably the medical condition is an inflammatory disease, allergy or cardiovascular diseases.

Description

Aryloxycycloalkenyl- and aryloxyiminocycloalkenyl hydroxyureas

The present invention relates to novel aryloxycycloalkenyl- and aryloxyiminocycloalkenyl hydroxyureas. The compounds of the present invention inhibit the action of 5-lipoxygenase and are suitable for preventing, treating or alleviating inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis, allergic diseases and cardiovascular diseases in mammals such as humans. The invention also relates to pharmaceutical compositions containing these compounds.

Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites: prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step in arachidonic acid metabolism is the release of arachidonic acid and associated unsaturated fatty acids from membrane phospholipids by the action of phospholipase _A2 . Free fatty acids are then metabolized either by cyclooxygenases to prostaglandins and thromboxanes, or by lipoxygenases to hydroperoxylated fatty acids, which can be further metabolized to leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases including rheumatoid arthritis, gout, asthma, ischemia-reperfusion injury, psoriasis, and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide an effective new treatment for acute and chronic inflammatory diseases.

For an article on 5-lipoxygenase inhibitors see H. Masamune and L.S. Melvin, Sr., Annual Reports in Modicinal Chemistry, 24 (1989) pp. 71-80 (Aca-demic Press). More recently, examples of another class of 5-lipoxygenase inhibitors are disclosed in International Patent Publications WO94/14762 and WO92/9566.

其中The invention provides a compound of formula (1):

in

Ar is selected from the following groups:

(a) phenyl, naphthyl and biphenyl, each of which can be optionally substituted or unsubstituted by 1-3 substituents selected from the following substituents: C _1-4 alkyl, C _1-4 haloalkyl, C _{1-4 4} hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkoxyalkoxy, C _1-4 alkylthio, hydroxyl, halogen, cyano, amino, C _1-4 alkylamino, di(C _2-8 ) alkylamino, C _2-6 alkanoylamino, carboxyl, C _2-6 alkoxycarbonyl, optionally replaced by 1-3 selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen substituent substituted or unsubstituted phenyl, optionally 1-3 selected from C _{1- 4} alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen substituent substituted or unsubstituted phenoxy, optionally substituted by 1-3 Substituents selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen substituted or unsubstituted phenylthio, and any substituted or unsubstituted by 1-3 substituents selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen phenylsulfinyl; and

(b) furyl, benzo[b]furyl, thienyl, benzo[b]thienyl, pyridyl and quinolinyl optionally substituted or unsubstituted by 1-3 substituents selected from the group consisting of: C _1-4 alkyl, C _1-4 haloalkyl, halogen, C _1-4 alkoxy, hydroxyl, optionally replaced by 1-3 selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen substituent substituted or unsubstituted phenyl, optionally 1-3 selected from C _1-4 alkyl, C _1-4 Haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen substituent substituted or unsubstituted phenoxy, and optionally 1-3 selected from C _1-4 alkane Base, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen substituent substituted or unsubstituted phenylthio;

X is selected from C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene, -(CHR ¹ ) _m -Q ¹ -(CHR ² ) _n -, -O-(CHR ¹ )jQ ² - and - (CHR ¹ )-ON=, wherein the N= moiety is attached to the cycloalkene ring; and wherein Q ¹ is O, S, SO, SO ₂ , NR ³ , CH=NO or CO, Q ² is O, S, SO, SO ₂ or NR ³ , and R ¹ , R ² and R ³ are each hydrogen or C ₁ -C ₄ alkyl, m and n are each an integer of 0-4, and j is an integer of 1-4;

p is an integer of 1 or 2;

Y is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-4 alkoxyalkyl, C _1-4 alkylthio, hydroxyl, halogen, cyano or amino;

Z is hydrogen or C _1-4 alkyl; and

M is hydrogen, a pharmaceutically acceptable cation, or a pharmaceutically acceptable metabolically cleavable group.

The compound of formula (I) can inhibit the action of 5-lipoxygenase. The compounds are therefore useful in the treatment of diseases in mammals (eg, humans) requiring 5-lipoxygenase inhibitors. The compounds are especially useful in the treatment of inflammatory diseases such as rheumatoid arthritis of inflammatory bowel disease, allergic diseases and cardiovascular diseases.

The present invention therefore also provides for use in the treatment of mammalian (e.g. human) diseases (e.g. inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis, allergic diseases and cardiovascular diseases) requiring 5-lipoxygenase inhibitors. disease), the composition contains a therapeutically effective amount of the compound of the present invention and a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable cation" as used herein refers to non-toxic cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium (including but not limited to ammonium , ethylammonium, diethylammonium, triethylammonium, tetraethylammonium, tetramethylammonium and tetrabutylammonium) those cations; and

The term "metabolically cleavable group" refers to a group that is cleaved in vivo to yield the parent molecule of formula (1) wherein M is hydrogen. Examples of metabolically cleavable groups include -COW, COOW, _-CONH2 , -CONWW', _-CH2OW , -CH(W')OW, _-CH2OCOW , _{-CH2OCO2W ,} -CH(W ') OCO ₂ W group, wherein W and W are each independently selected from (C ₁ -C ₄ ) alkyl, phenyl or substituted phenyl (wherein the substituent is selected from one or more C ₁ -C ₄ alkyl, halogen, hydroxy or C ₁ -C ₄ alkoxy). Specific examples of typical metabolically cleavable groups include, but are not limited to, acetyl, ethoxycarbonyl, benzoyl, and methoxymethyl.

Halogen includes chlorine, bromine, iodine and fluorine, preferably fluorine.

In the above formula (I), 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 attached to the 4-position of the 2-cyclopentene ring; Ar is phenyl or fluorophenyl, and X is -CH=NO- attached to the 4-position of the 2-cyclopentene ring; or Ar is phenyl or fluorophenyl, and X is attached to the 2-cyclopentene -ON= or -CH ₂ -ON= at the 4-position of the alkene ring.

The most preferred group of compounds includes: N-{(1R,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-{(1R)-4-benzyloxyimino -2-cyclopenten-1-yl}-N-hydroxyurea; and N-{(1R)-4-(4-fluorobenzyloxyimino)-2-cyclopenten-1-yl}-N - Hydroxyurea.

Compounds of formula (I) can be prepared by various synthetic methods known in the art. Typical methods are outlined below. In a specific embodiment, the compound of formula (I) (M=H) is prepared according to the reaction steps given in Reaction Scheme 1 . Ar, X, Y, Z and p are as defined above

Reaction scheme 1

In Reaction Scheme 1, hydroxylamine (II) is treated with the appropriate trialkylsilylisocyanate or lower alkyl isocyanate of formula ZNCO in a reaction-inert solvent, typically at room temperature to reflux temperature. The preferred reaction temperature is 20-100°C. Suitable solvents which do not react with the reactants and/or products are, for example, tetrahydrofuran, dioxane, dichloromethane or benzene.

Another approach is to treat (II) with hydrochloride followed by phosgene in a reaction-inert solvent such as benzene or toluene. The reaction temperature is generally within the range of room temperature to the boiling point of the solvent, preferably 25-80°C. Instead of isolating the intermediate carbamoyl chloride, it reacts directly (ie, in situ) with ammonia or the amine _ZNH2 .

As an improved method of this method (Z=H), the acid addition salt of formula (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 standard methods and can be purified using conventional methods such as recrystallization and chromatography.

The above hydroxylamines (II) can be prepared from the corresponding carbonyl compounds, ie ketone or alcohol compounds, by standard synthetic methods. For example, the appropriate carbonyl compound is converted to its oxime and then reduced to the desired hydroxylamine (II) with a suitable reducing agent (see, eg, R.F. Borch et al., J. Am, Chem. Soc. 93, 2897, 1971). The reducing agent is selected from, but not limited to: sodium cyanoborohydride and borane complexes such as borane-pyridine, borane-triethylamine and borane-dimethylsulfide, triethyl in trifluoroacetic acid can also be used methylsilane.

Suitable carbonyl compounds, i.e. cyclopentenones or cyclohexenones, can be prepared by various routes known to those skilled in the art (cf. WO 920 9566).

Alternatively, the above hydroxylamines (II) can be readily prepared by treatment of the corresponding alcohol with N,O-bis(tert-butoxycarbonyl)hydroxylamine under Mit-sunobu type reaction conditions, followed by acid-catalyzed hydrolysis (e.g. using trifluoroacetic acid) N, O-protected intermediate product (see JP 1045344). The desired alcohol can be readily prepared by reducing the corresponding cycloenone 1,2- using a suitable reducing agent such as sodium borohydride or sodium borohydride-cesium trichloride, etc. Alternatively, the desired alcohol can be prepared from the appropriate cycloalkenediol (eg, commercially available (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol, etc.) by standard methods.

The hydroxylamines of formula (II) obtained by each of the above methods are isolated by standard methods and can be purified by conventional methods such as recrystallization and chromatography.

In another embodiment, compounds of formula (I) are prepared as illustrated in Reaction Scheme 2. R ⁴ is phenyl, and R ⁵ is phenyl or lower alkyl:

Reaction Scheme 2

In this method, compounds of formula (III) are prepared from the corresponding alcohols and dicarboxylated hydroxylamines (preferably N _, O-bis(phenoxycarbonyl)hydroxylamines) and then converted to ( I) (AO Stewart and DW Brooks., J. Org. Chem. 57, 5020, 1992). Suitable reaction solvents for the reaction of ammonia, ammonium hydroxide or amine _ZNH2 are, for example, water, methanol, ethanol, tetrahydrofuran and benzene, etc., of course the reaction can be carried out without the presence of co-solvents, i.e. only amines are required. The reaction temperature is generally between room temperature and the boiling point of the solvent. The product of formula (I) thus obtained is isolated by standard methods and can be purified by conventional methods such as recrystallization and chromatography.

Due to the presence of one or more chiral centers, the compounds of the invention may exist in stereoisomeric forms. The present invention contemplates all such stereoisomers, including enantiomers, diastereomers and mixtures thereof. Individual isomers of compounds of this formula can be prepared by various methods known to those skilled in the art. For example, individual isomers may be prepared by chiral synthesis from optically active starting materials. Alternatively, it can be prepared by derivatizing the compound of formula (I) with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the auxiliary group to give the desired isomer, or by separation using a chiral stationary phase, single isomer.

Viable versions of the novel compounds of the invention are readily prepared by contacting stoichiometric amounts (for nontoxic cations) of the appropriate metal hydroxide or alkoxide or amine in aqueous or suitable organic solvent. Medicinal salt. For non-toxic acid addition salts, inorganic or organic acids can be employed in aqueous solution or in suitable organic solvents. The salt can then be obtained by purification or evaporation of the solvent.

Compounds of formula I inhibit the activity of 5-lipoxygenase. The ability of the compounds of formula I to inhibit the activity of 5-lipoxygenase makes them useful for the management of symptoms in mammals, especially humans, caused by endogenous metabolites produced by arachidonic acid. Therefore, the compound is valuable in the prevention and treatment of such diseases in which the accumulation of arachidonic acid metabolites is the cause; these diseases are, for example, allergic bronchial asthma, skin diseases, rheumatoid arthritis, osteoarthritis, Arthritis and Thrombosis. Therefore, the compounds of formula I and their pharmaceutically acceptable salts are particularly suitable for treating or alleviating inflammatory diseases in humans.

The ability of compounds of formula I to inhibit lipoxygenase activity can be demonstrated by in vivo and in vitro experiments using the following standard methods.

1) In vitro analysis using heparinized human whole blood (HWB)

Inhibitory effects were demonstrated by in vitro assays using heparinized human whole blood (British Journal of Pharmacology: (1990) 99, 113-118), which demonstrated that the compound inhibits arachidonic acid 5-lipoxygenase (LO ) metabolism inhibition. At 37°C, each aliquot of heparinized human whole blood (1ml) provided by a healthy donor was pre-incubated with the drug dissolved in dimethyl sulfoxide (final concentration 0.1%) for 10 minutes, and then calcium ionophore A21387 (60μM ) and heparin (2.5%, Sekisui Chemical Co. LTD., Japan), and continue to incubate for 30 minutes. Cool rapidly in an ice bath to terminate the reaction. Blood clots caused by heparin are removed by centrifugation. Acetonitrile (ACN, 1.5ml) and _PGB2 (200ng, as internal standard) were added to the supernatant. The samples were mixed with a Voltex mixer and the precipitated protein was removed by centrifugation. The supernatant was diluted to 15% ACN with water, loaded into a pre-washed Sep-Pak C ₁₈ column (Wa-ters Associates, Milford, MS, USA), and arachidonic acid metabolites were eluted with 4 ml of 70% methanol . The methanolic extract was evaporated and the residue was dissolved in 250 μl of 67% ACN.

ACN reconstitution (100 μl) was injected onto a reversed-phase C ₁₈ column (Wakosil 5C18, 4.6×150 mm, Wako Pure Chemical Industries LTD, Japan). The column temperature was 40°C. HPLC analysis was performed using a Hewlett Packard model 1090M HPLC system. Two different mobile phases were used (mobile phase A consisted of 10% ACN, 0.1% trifluoroacetic acid and 0.05% triethylamine; mobile phase B consisted of 80% ACN, 0.1% trifluoroacetic acid and 0.05% triethylamine) Gradient elution was performed for chromatography. Each mobile phase was continuously sparged with helium. The HPLC gradient was arranged as follows (condition A+B=100): from 0-9.7 minutes, a linear gradient of 35-100% mobile phase A at a flow rate of 1 ml/min. Eluted product peaks were quantified by UV absorption (LTB ₄ and PGB ₂ at 275 nm; HHT and 5-HETE at 235 nm) and calibrated by PGB ₂ recovery. Sexual regression was used to estimate _IC50 values.

The compounds of formula I described in the following examples were tested in the above assay and showed their ability to inhibit 5-lipoxygenase.

2) An in vivo system for measuring the effect of oral administration of experimental compounds on platelet-activating factor (PAF)-induced lethality in mice

The in vivo effects of oral test compounds on ICR mice (male) were determined using a PAF lethal assay similar to that described in: JM Young, PJ Maloney, SN Jubb, and JSClark, Prostaglandins, 30, 545 (1985); M and H. Tsunoda. S. Abc. Y. Sakuma, S. Katayama and K. Katayama, Prostaglandins Leukotrienes and Essential Fatty Acids, 39 , 291 (1990). At a concentration of 1.2 μg/ml, PAF was dissolved in 0.05 mg/ml naprodil-saline containing 0.25% bovine serum albumin (BSA), and administered intravenously to mice at a dose of 12 μg/kg. Mortality was determined 1 hour after PAF injection. To study the effect of 5-LO inhibitors, compounds were dissolved in 5% Tween 80, 5% EtOH-saline and administered orally (0.1 ml/10 g) 45 minutes before PAF injection. Linear regression was used to estimate _ED50 values.

In order to treat the above-mentioned various diseases, the compound of formula I of the present invention can be administered alone to humans, or preferably combined with a pharmaceutically acceptable carrier or diluent as in general pharmaceutical practice, and administered in the form of a pharmaceutical composition. The compounds can be administered by various conventional routes, including oral, parenteral and inhalational administration. When the compound is administered orally for the treatment of inflammatory diseases in humans, the dosage range is about 0.1-10 mg per kg body weight of the patient to be treated per day, preferably about 0.5-10 mg/kg body weight per day, in single or multiple doses. Dosing. If parenteral administration is desired, an effective dosage is about 0.1-1.0 mg per kg body weight of the patient being treated per day. In some cases it will be desirable to use dosages outside these limits as the dosage will necessarily vary according to the age and response of each patient, as well as the type and severity of the patient's symptoms and the efficacy of the particular compound being administered.

For oral administration, the compounds according to the invention and their pharmaceutically acceptable salts can be administered, for example, in the form of tablets, powders, lozenges, syrups, capsules, aqueous solutions or suspensions. 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 also typically added. For capsules, suitable diluents are lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening and/or flavoring agents may be added, if desired. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are generally prepared, and the pH of the solutions is adjusted and buffered appropriately. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. Generally, the therapeutically effective compound of the invention is contained in the dosage form at a concentration of 5% to 70% by weight, preferably 10% to 50% by weight.

Example

The invention is illustrated by the following examples. It should be understood, however, that the invention is not limited to the specific details described in these examples.

Melting points were determined with a Buchi melting point apparatus (535) and were uncalibrated. Optical rotation was measured on a JASCO DIP-370 polarimeter. Unless otherwise indicated, all NMR spectra were measured in _CDCl3 using a JEOL NMR spectrometer (JNM-GX270, 270 MHz) and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. Peak shape is represented by the following symbols: s, singlet; d, doublet; t, triplet; q, quadruplet; quint, quintet; m, multimodal; br, broad.

The following abbreviations are used: Boc is tert-butoxycarbonyl, DMF is dimethylformamide, DM-SO is dimethylsulfoxide, THF is tetrahydrofuran and TFA is trifluoroacetic acid.

Example 1N-{(1R, 4R)-trans-4-(4-fluorophenoxy)-2-cyclopenten-1-yl}-N-hydroxyureaacetic acid (1R, 4R)-trans-4- (4-Fluorophenoxy)-2-cyclopenten-1-yl ester (step A):

At room temperature (rt), to stirred 4-fluorophenol (0.785g; 7mM), (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol (1g; 7.03mM) To a solution of triphenylphosphine (2.02 g; 7.7 mM) in anhydrous THF (20 ml) was added diisopropyl azodicarboxylate (DPAD; 1.56 g; 7.7 mM). 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 afford 1.55 g (94%) of the subtitled compound.

¹ H-NMR (CDCl ₃ ) δ; 6.97 (t, J=8.8Hz, 2H), 6.82 (dd, J=4.4Hz, 8.8Hz, 2H), 6.24 (d, J=5.4Hz, 1H), 6.16 (d, J=5.4Hz, 1H), 5.87-5.82(m, 1H), 5.44-5.38(m, 1H), 2.40-2.24(m, 2H), 2.05(s, 3H).(1R, 4R) - trans-4-(4-fluorophenoxy)-2-cyclopenten-1-ol (step B):

To a stirred solution of (1R,4R)-4-(4-fluorophenoxy)-2-cyclopenten-1-yl acetate (1.55 g; 6.56 mM) in methanol (10 ml) at room temperature was added Solution of KOH (0.65 g; 9.85 mM) in water (8 ml). After stirring for 15 minutes, the volatiles were removed by evaporation. The residue was dissolved in ethyl acetate (70ml), which was washed with water (50ml), brine (50ml), dried over _MgSO4 , and concentrated to dryness in vacuo to afford 1.25g (98%) of the subtitled compound.

¹ H-NMR (CDCl ₃ ) δ; 6.97 (t, J=8.8Hz, 2H), 6.82 (dd, J=4.4Hz, 8.8Hz, 2H), 6.18-6.12 (m, 2H), 5.44-5.42( m, 1H), 5.14-5.08(br.s, 1H), 2.33(ddd, J=2.9Hz, 6.6Hz, 14.3Hz, 1H), 2.16(ddd, J=3.3Hz, 6.6Hz, 14.3Hz, 1H ), 1.68 (br.s, 1H). (1S, 4R)-cis-4-(4-fluorophenoxy)-2-cyclopenten-1-yl benzoate (step C):

To a stirred solution of (1R,4R)-trans-4-(4-fluorophenoxy)-2-cyclopenten-1-ol (0.62 g; 3.2 mM) in THF (12 ml) at room temperature was added Tris Phenylphosphine (0.92 g; 3.51 mM), benzoic acid (0.43 g; 3.51 mM) and DPAD (0.71 g; 3.51 mM). After stirring overnight, the volatiles were removed by evaporation. The resulting residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:10) to afford 0.82 g (86%) of the subtitled compound.

¹ H-NMR(CDCl ₃ )δ; 8.04(dd, J=1.5Hz, 8.5Hz, 2H), 7.56(t, J=7.7Hz, 1H), 7.43(t, J=7.7Hz, 2H), 6.98 (t, J=8.1Hz, 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 (quintet , J=7.3Hz, 1H), 2.02(dt, J=4.4Hz, 14.7Hz, 1H).(1S, 4R)-cis-4-(4-fluorophenoxy)-2-cyclopentene-1 - Alcohol (step D):

To a stirred solution of (1S,4R)-cis-4-(4-fluorophenoxy)-2-cyclopenten-1-yl benzoate (0.82g; 2.75mM) in methanol (5ml) was added Solution of 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 dissolved in ethyl acetate (50ml), which was washed with water (50ml). The aqueous layer was extracted with ethyl acetate (40ml) and the combined organic phases were washed with water (50ml), brine (50ml), dried over _MgSO4 and evaporated in vacuo to give 0.6g of the subtitled compound.

¹ H-NMR(CDCl ₃ )δ; 6.98(t, J=8.8Hz, 2H), 6.88-6.82(m, 2H), 6.14(dd, J=6.2Hz, 12.8Hz, 2H), 5.07-5.03( br.s, 1H), 4.78-4.73(br.s, 1H), 2.85(dt, J=7.3Hz, 14.3Hz, 2H), 1.78(dt, J=4.0Hz, 14.3Hz, 1H), 1.79( br.s, 1H).N, O-di(tert-butoxycarbonyl)-N-{(1R, 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) at room temperature was added Triphenylphosphine (0.8 g; 3.025 mM), BocNHOBoc (0.71 g; 3.025 mM) and DPAD (0.61 g; 3.025 mM). After stirring for 2 hours, the volatiles were removed by evaporation. The resulting residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:10) to afford 0.689 g (62%) of the subtitled compound.

¹ H-NMR (CDCl ₃ ) δ; 6.96 (t, J=9.2Hz, 2H), 6.82 (dd, J=4.4Hz, 9.2Hz, 2H), 6.17-6.13 (br.s, 1H), 6.06- 6.03 (m, 1H), 5.55-5.48 (br.s, 1H), 5.42-5.35 (br.s, 1H), 2.36 (ddd, J=3.6Hz, 6.6Hz, 14.2Hz, 1H), 2.28-2.15 (br.s, 1H), 1.51(s, 9H), 1.49(s, 9H).N-{(1R, 4R)-trans-4-(4-fluorophenoxy)-2-cyclopentene- 1-yl}-N-hydroxyurea (step F):

N, O-bis(tert-butoxycarbonyl)-N-{(1R,4R)-trans-4-(4-fluorophenoxy)-2-cyclopenten-1-yl}hydroxylamine (0.688g; 1.68mM) and TFA (1.3ml; 16.8mM) in dichloromethane (5ml) was stirred for 3 hours. After removal of volatiles, the residue was dissolved in ethyl acetate (80ml), washed with saturated sodium bicarbonate solution (50ml), water (50ml), brine (50ml), dried over _MgSO4 , and concentrated in vacuo to give 0.35 g hydroxylamine.

To a stirred solution of hydroxylamine (0.35 g) obtained above in THF (7 ml) was added trimethylsilyl isocyanate (0.3 g; 2.18 mM) at room temperature. After stirring for 1 hour, ethanol (5ml) was added and the volatiles were removed by evaporation. The residue was recrystallized from ethyl acetate-n-hexane (2:1) to obtain 0.21 g (49%) of the title compound as colorless crystals.

mp157.5-158.5°C (dec). ¹ H-NMR (DMSO-d ₆ ) δ; 9.03 (s, 1H), 7.10 (t, J=8.4Hz, 2H), 6.96-6.91 (m, 2H), 6.41(s, 2H), 6.10(d, J=5.2Hz, 1H), 5.96(d, J=5.2Hz, 1H), 5.42-5.35(br.s, 2H), 2.32-2.25(m, 1H) , 1.94-1.86 (m, 1H) elemental analysis, calculated for C ₁₂ H ₁₃ N ₂ O ₃ F: C, 57.14; H, 5.19; N, 11.11. Measured: C, 56.99; H, 5.22; N, 11.05.

Example 2N-{(1S,4R)-cis-4-(4-fluorophenoxy)-2-cyclopenten-1-yl}-N-hydroxyurea

According to the method described in Example 1, (1S, 4R)-cis -4-(4-Fluorophenoxy)-2-cyclopenten-1-ol, the title compound was prepared. Melting point 142-143°C (decomposition).

¹ H-NMR (DMSO-d ₆ ) δ; 9.03(s, 1H), 7.11(t, J=8.4Hz, 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=7.7Hz, 14.6Hz, 1H), 1.74(dt, J=6.3Hz, 14.6Hz , 1H). Elemental analysis, calculated for C ₁₂ H ₁₃ N ₂ O ₃ F: C, 57.14; H, 5.19; N, 11.11. Measured: C, 56.99; H, 5.22; N, 11.05.

Example 3N-{(1R, 4S)-cis-4-(4-fluorophenoxy)-2-cyclopenten-1-yl}-N-hydroxyurea (1S, 4S)-trans-4-( 4-fluorophenoxy)-2-cyclopenten-1-ol:

To a stirred solution of (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol (1 g; 7.03 mM) in DMF (10 ml) at room temperature was added imidazole (1.05 g; 15.48 mM) and tert-butyldimethylsilyl chloride (1.17 g; 7.47 mM). After stirring overnight, the mixture was poured into water (50ml). Extracted with ethyl acetate-n-hexane (1:1, 70ml×2), the combined organic layers were washed with water (50ml), brine (50ml), dried over _MgSO4 , and concentrated in vacuo to give 1.84g (quantitative) acetic acid ( 1R,4S)-cis-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-yl ester.

¹ H-NMR(CDCl ₃ )δ; 5.97(d, J=5.5Hz, 1H), 5.88(d, J=5.5Hz, 1H), 5.46(t, J=4.0Hz, 1H), 4.72(t, J=4.0Hz, 1H), 2.91(d, J=2.0Hz, 1H), 2.80(q, J=7.0Hz, 1H), 2.05(s, 3H), 0.90(s, 9H), 0.09(s, 6H).

Acetic acid (1R,4S)-cis-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-yl ester (1.84g; 7.03mM) and potassium carbonate (1.46g; 10.55mM) The suspension in methanol (30ml) was stirred for 2 hours. Water (50ml) was added to the mixture, followed by extraction with ethyl acetate (100ml). The organic layer was washed with water (50ml), brine (50ml), dried over _MgSO4 , and concentrated in vacuo to give 1.65g (quant.) of (1R,4S)-cis-4-tert-butyldimethylsilyloxy-2 - cyclopenten-1-ol.

To stirred (1R,4S)-cis-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-ol (1.65g; 7mM), 4-fluorophenol (0.94g; 8.4 mM) and triphenylphosphine (2.2 g; 8.4 mM) in THF (20 ml) was added DPAD (1.7 g; 8.4 mM). After stirring overnight, the volatiles were removed by evaporation. The resulting residue was purified by flash chromatography eluting with n-hexane to give 1.53 g (71%) of (1S,4S)-trans-4-(4-fluorophenoxy)-1-(tert-butyldimethyl silyloxy)-2-cyclopentene.

¹ H-NMR (CDCl ₃ ) δ; 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=2.4Hz, 6.9Hz, 14.3Hz, 1H), 2.09(ddd, J=3.6Hz, 6.9Hz, 14.3Hz, 1H), 0.90(s, 9H), 0.09(s, 6H).

At room temperature, to stirred (1S,4S)-trans-4-(4-fluorophenoxy)-1-(tert-butyldimethylsilyloxy)-2-cyclopentene (1.52g; 4.94mM) in dry THF (15ml) was added tetra-n-butylammonium fluoride (1M in THF; 7.4ml; 7.4mM). After stirring for 2 hours, the volatiles were removed by evaporation. The residue was dissolved in ethyl acetate (100ml), which was washed with water (50ml), brine (50ml), dried over _MgSO4 , and concentrated in vacuo to give 1.34g of the subtitled compound.

¹ H-NMR (CDCl ₃ )δ; 6.97(t, J=8.8Hz, 2H), 6.82(dd, J=4.4Hz, 9.1Hz, 2H), 6.16(br.s, 2H), 5.46-5.40( m, 1H), 5.15-5.09(m, 1H), 2.34(dq, J=3.3Hz, 14.3Hz, 1H), 2.17(dq, J=3.3Hz, 14.3Hz, 1H), 1.64(br.s, 1H).N-{(1R,4S)-cis-4-(4-fluorophenoxy)-2-cyclopenten-1-yl}-N-hydroxyurea:

According to the method described in Example 1, the (1S, 4R)-cis -4-(4-Fluorophenoxy)-2-cyclopenten-1-ol, the title compound was prepared.

mp137-139°C (dec). ¹ H-NMR (DMSO-d ₆ ) δ; 9.03 (s, 1H), 7.11 (t, J=8.4Hz, 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=7.7Hz, 14.6Hz, 1H), 1.74(dt , J=6.3Hz, 14.6Hz, 1H). Elemental analysis, calculated C ₁₂ H ₁₃ N ₂ O ₃ F: C, 57.14; H, 5.19; N, 11.11. Measured: C, 57.14; H, 5.21; N, 11.09.

Example 4N-{(1S, 4S)-trans-4-(4-fluorophenoxy)-2-cyclopenten-1-yl}-N-hydroxyurea

According to the method described in Example 1, replace (1R, 4R)-trans-4-(4-fluorophenoxy)-2-cyclopenten-1-ol in step C -4-(4-Fluorophenoxy)-2-cyclopenten-1-ol, the title compound was prepared.

mp151-153℃(dec). ¹ H-NMR(DMSO-d ₆ )δ; 9.03(s, 1H), 7.10(t, J=8.4Hz, 2H), 6.93(dd, J=3.6Hz, 8.4Hz , 2H), 6.42(s, 2H), 6.10(d, J=5.2Hz, 1H), 5.96(d, J=5.2Hz, 1H), 5.42-5.35(br.s, 2H), 2.32-2.25( m, 1H), 1.94-1.86 (m, 1H). Elemental analysis, calculated for C ₁₂ H ₁₃ N ₂ O ₃ F: C, 57.14; H, 5.19; N, 11.11. Measured: C, 56.94; H, 5.21; N, 11.13.

Example 5 N-{(1R, 4R)-trans-4-(4-cyanophenoxy)-2-cyclopenten-1-yl}-N-hydroxyurea

The title compound was prepared following the procedure described in Example 1, substituting 4-cyanophenol for 4-fluorophenol in Step A.

mp162-163℃(dec). ¹ H-NMR(DMSO-d ₆ )δ; 9.04(s, 1H), 7.75(d, J=7.7Hz, 2H), 7.10(d, J=7.7Hz, 2H) , 6.41(s, 2H), 6.12(d, J=5.5Hz, 1H), 6.00(d, J=5.5Hz, 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). Elemental analysis, calculated for C ₁₃ H ₁₃ N ₃ O ₃ : C, 60.23; H, 5.05; N, 16.21. Measured: C, 60.35; H , 5.06; N, 15.91.

Example 6N-{(1S,4R)-cis-4-(4-cyanophenoxy)-2-cyclopenten-1-yl}-N-hydroxyurea

According to the method described in Example 2, use (1R, 4R)-trans-4-(4-cyanophenoxy)-2-cyclopenten-1-ol instead of (1R, 4R)-trans-4- (4-Fluorophenoxy)-2-cyclopenten-1-ol, the title compound was prepared.

mp180-181℃(dec). ¹ H-NMR(DMSO-d ₆ )δ; 9.03(s, 1H), 7.75(d, J=8.0Hz, 2H), 7.13(d, J=8.0Hz, 2H) , 6.37(s, 2H), 6.03(d, J=5.9Hz, 1H), 5.94(d, J=5.9Hz, 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). Elemental analysis, calculated for C ₁₃ H ₁₃ N ₃ O ₃ : C, 60.23; H, 5.05; N, 16.21. Measured: C, 60.54; H , 5.03; N, 16.07.

Example 7 N-[(1R,4R)-trans-4-{3-(4-fluorophenoxy)phenoxy}-2-cyclopenten-1-yl]-N-hydroxyurea

The title compound was prepared by following the procedure described in Example 1, substituting 3-{4-fluorophenoxy)phenol for 4-fluorophenol in Step A.

mp127-128°C (dec).[α] _D = +195.38° (ethanol, c = 0.127). ¹ H-NMR (DMSO-d ₆ ) δ; 9.08 (s, 1H), 7.35-7.02 (m, 5H ), 6.68(d, J=8.1Hz, 1H), 6.48(s, 2H), 6.39(s, 2H), 6.15-5.88(m, 2H), 5.39(br.s, 2H), 2.35-2.16( m, 1H), 2.00-1.80 (m, 1H). Elemental analysis, calculated for C ₁₈ H ₁₇ N ₂ O ₄ F: C, 62.79; H, 4.98; N, 8.14. Measured: C, 62.71; H, 4.93; N, 8.22.

Example 8 N-[(1S,4R)-cis-4-{3-(4-fluorophenoxy)phenoxy}-2-cyclopenten-1-yl]-N-hydroxyurea

According to the method described in Example 2, replace (1R, 4R )-trans-4-

(4-Fluorophenoxy)-2-cyclopenten-1-ol, the title compound was prepared.

mp130-131°C (dec).[α] _D = -41.07° (ethanol, c = 0.112). ¹ H-NMR (DMSO-d ₆ ) δ; 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). Elemental analysis, calculated for C ₁₈ H ₁₇ N ₂ O ₄ F: C, 62.79; H, 4.98; N, 8.14. Measured: C, 62.67; H, 4.97; N, 8.25.

Example 9N-[(1S, 4R)-cis-4-{2-tert-butyl-5-(4-fluorophenoxy)phenoxy}-2-cyclopenten-1-yl]-N- Hydroxyurea

The title compound was prepared as a by-product of Example 8.

mp: 148-151°C. [α] _D = -54.09 (c = 0.12, ethanol). ¹ H-NMR (DMSO-d ₆ ) δ: 8.99 (s, 1H), 7.23-7.13 (m, 3H), 7.08-7.02(m, 2H), 6.67(d, J=2.2Hz, 1H), 6.38(d, J=2.5Hz, 1H), 6.36(s, 2H), 6.02(d, J=5.4Hz, 1H ), 5.90(d, J=5.4Hz, 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)cm ^-1 : 3500, 3380, 2950, 1660, 1580, 1490, 1420, 1200, 1085, 1020, 830. Elemental analysis, calculated C ₂₂ H ₂₅ N ₂ O ₄ F 1/5H ₂ O: C, 65.40 ; H, 6.34; N, 6.93. Measured: C, 65.34; H, 6.28; N, 7.22.

Example 10N-[(1R,4S)-cis-4-{3-(4-fluorophenoxy)phenoxy}-2-cyclopenten-1-yl]-N-hydroxyurea

The title compound was prepared following the procedure described in Example 3, substituting 3-{4-fluorophenoxy)phenol for 4-fluorophenol.

mp: 133-135°C. [α] _D = +35.50 (c = 0.20, ethanol). ¹ H-NMR (DMSO-d ₆ ) δ: 9.01 (s, 1H), 7.29-7.20 (m, 3H), 7.13-7.05(m, 2H), 6.72(dd, J=2.2 and 8.4Hz, 1H), 6.54-6.48(m, 2H), 6.38(s, 2H), 6.00(d, J=5.8Hz, 1H) , 5.89(d, J=5.8Hz, 1H), 5.21-5.12(m, 2H), 2.63(ddd, J=7.7, 7.7 and 13.2Hz, 1H), 1.75(ddd, J=5.8, 5.8 and 13.2Hz , 1H).IR(KBr)cm ^-1 : 3300, 2900, 1635, 1610, 1500, 1200, 1140, 845, 785, 760. Elemental analysis, calculated C ₁₈ H ₁₇ N ₂ O ₄ F: C, 62.79; H, 4.98; N, 8.14. Measured: C, 62.78; H, 5.02; N, 8.05.

Example 11N-[(1S,4S)-trans-4-{3-(4-fluorophenoxy)phenoxy}-2-cyclopenten-1-yl]-N-hydroxyurea

According to the method described in Example 1, use (1S,4S)-trans-4-{3-(4-fluorophenoxy)phenoxy}-2-cyclopenten-1-alcohol instead of (1R,4R)-trans-4-(4-fluorophenoxy)-2-cyclopenten-1-ol, the title compound was prepared.

mp: 163-164°C. [α] _D = -172.73 (c = 0.10, ethanol). ¹ H-NMR (DMSO-d ₆ ) δ: 9.08 (s, 1H), 7.35-7.02 (m, 5H), 6.68(d, J=8.1Hz, 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) cm ^-1 : 3450, 3320, 3200, 1620, 1583, 1505, 1485, 1260, 1205, 1140, 1005, 830, 760, 690, 600. Elemental analysis , calculated for C ₁₈ H ₁₇ N ₂ O ₄ F: C, 62.79; H, 4.98; N, 8.14. Found: C, 62.86; H, 4.99; N, 8.16.

Example 12 N-Hydroxy-N-{(1R, 4R)-trans-4-(4-phenylphenoxy)-2-cyclopenten-1-yl}urea

The title compound was prepared following the procedure described in Example 1, substituting 4-phenylphenol for 4-fluorophenol in Step A.

mp178-180°C (dec).[α] _D = +181.82° (ethanol, c = 0.145). ¹ H-NMR (DMSO-d ₆ ) δ; 9.14 (s, 1H), 7.64-7.58 (m, 5H ), 7.44(t, J=7.5Hz, 2H), 7.31(t, J=7.3Hz, 1H), 7.02(d, J=8.8Hz, 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). Elemental analysis, calculated C ₁₈ H ₁₉ N ₂ O ₃ : C, 69.44; H, 6.15; N, 9.00. Measured: C, 69.31; H, 5.74; N, 8.83.

Example 13 N-{(1R, 4R)-trans-4-(4-fluorobenzaldehyde oxime-O-2-cyclopentenyl ether)-1-yl}-N-hydroxyurea 4-fluorobenzaldehyde oxime O -(1(R),4(R)-trans-4-hydroxy-2-cyclopenten-1-yl)ether:

To stirred (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol (2.33 g; 16.4 mM), N-hydroxyphthalimide (2.68 g; 16.4mM) and triphenylphosphine (4.73g; 18mM) in anhydrous THF (50ml) was added DPAD (3.8ml; 18mM). After stirring for 5 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 (quantitative) of N-((1R,4R)-trans-4-acetoxy-2-cyclo pentene-1-oxy)phthalimide.

¹ H-NMR(CDCl ₃ )δ; 7.85(dd, J=3.3Hz, 5.5Hz, 2H), 7.76(dd, J=3.3Hz, 5.5Hz, 2H), 6.24(m, 2H), 5.84(m , 1H), 5.54(m, 1H), 2.70(dd, J=3.0Hz, 7.0Hz, 1H), 2.19(dd, J=2.9Hz, 7.0Hz, 1H), 2.03(s, 3H).

At -78°C under a nitrogen atmosphere, to stirred N-((1R,4R)-trans-4-acetoxy-2-cyclopentene-1-oxyl)phthalimide (9.95 g; 32.4mM) in anhydrous dichloromethane (95ml) was added methylhydrazine (1.8ml; 32.4mM). After stirring for 30 minutes, the mixture was allowed to warm to room temperature and stirred for an additional 1 hour. The precipitate was filtered off and the filtrate evaporated in vacuo, yielding 5.09 g (quantitative) of O-((1R,4R)-trans-4-acetoxy-2-cyclopenten-1-yl)hydroxylamine.

¹ H-NMR (CDCl ₃ )δ; 6.19-6.15 (m, 1H), 6.12-6.07 (m, 1H), 5.83-5.77 (m, 1H), 5.60-4.70 (br.s, 2H), 5.03- 4.96(m, 1H), 2.04(s, 3H), 2.30-1.97(m, 2H).

At room temperature, O-((1R,4R)-trans-4-acetoxy-2-cyclopenten-1-oxyl)hydroxylamine (5.09g; 32.4mM) and 4-fluorobenzaldehyde (3.5ml; 32.4mM) in ethanol (90ml) was stirred for 2 days. After removal of volatiles, the resulting residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:20) to yield 4.35 g (51%) of 4-fluorobenzaldehyde oxime O-(1(R) , 4(R)-trans-4-acetoxy-2-cyclopenten-1-yl) ether.

¹ H-NMR (CDCl ₃ )δ; 8.01(s, 1H), 7.56(dd, J=5.5Hz, 8.8Hz, 2H), 7.05(t, J=8.8Hz, 2H), 6.25-6.12(m, 2H), 5.87-5.48(m, 1H), 5.50-5.48(m, 1H), 2.41(ddd, J=2.9Hz, 7.3Hz, 15Hz, 1H), 2.17(ddd, J=3.3Hz, 7.3Hz, 15Hz, 1H), 2.05(s, 3H).

At room temperature, 4-fluorobenzaldoxime O-(1(R), 4(R)-trans-4-acetoxy-2-cyclopenten-1-yl) ether (4.35g; 16.5mM) and A mixture of potassium carbonate (3.43g; 24.8mM) in methanol (80ml) was stirred for 1 hour, then the volatiles were removed by evaporation. Water (100ml) was added, extracted with ethyl acetate (60ml x 2), the combined organic layers were washed with water (50ml), brine (50ml), dried over MgSO ₄ and concentrated in vacuo to give 3.95g of the subtitled compound.

¹ H-NMR (CDCl ₃ )δ; 8.01(s, 1H), 7.55(dd, J=5.5Hz, 8.8Hz, 2H), 7.06(t, J=8.6Hz, 1H), 6.17-6.12(m, 2H), 5.51-5.48(m, 1H), 5.10-5.08(m, 1H), 2.39(ddd, J=2.6Hz, 6.6Hz, 9.2Hz, 1H), 2.06(ddd, J=3.7Hz, 7.0Hz , 9.0Hz, 1H).N-{(1R,4R)-trans-4-(4-fluorobenzaldehyde oxime-O-2-cyclopentenyl ether)-1-yl}-N-hydroxyurea:

According to the method described in Example 1, use 4-fluorobenzaldehyde oxime O-(1(R), 4(R)-trans-4-hydroxyl-2-cyclopenten-1-yl) ether to replace step C (1R,4R)-trans-4-(4-fluorophenoxy)-2-cyclopenten-1-ol from (1R,4R) to prepare the title compound.

mp150-151°C (dec). [α] _D = +313.9° (ethanol, c = 0.1). ¹ H-NMR (DMSO-d ₆ ) δ; 9.00 (s, 1H), 8.22 (s, 1H), 7.70-7.65(m, 2H), 7.30-7.22(m, 2H), 6.37(br.s, 2H), 6.05(d, J=5.5Hz, 1H), 5.92(d, J=5.9Hz, 1H) , 5.35 (m, 2H), 2.28-1.90 (m, 2H). Elemental analysis, calculated for C ₁₃ H ₁₄ N ₃ O ₃ F: C, 55.91; H, 5.05; N, 15.05. Measured: C, 56.16; H , 4.91; N, 15.27.

Example 14N-{(1S,4R)-cis-4-(4-fluorobenzaldehyde oxime-O-2-cyclopentenyl ether)-1-yl}-N-hydroxyurea

According to the method described in Example 1, use 4-fluorobenzaldehyde oxime O-(1(R), 4(R)-trans-4-hydroxyl-2-cyclopenten-1-yl) ether instead of step E (1S,4R)-cis-4-(4-fluorophenoxy)-2-cyclopenten-1-ol from (1S,4R) to prepare the title compound.

mp148-149°C (dec). [α] _D = +49.5° (ethanol, c = 0.1). ¹ H-NMR (DMSO-d ₆ ) δ; 9.02 (d, J = 3.3Hz, 1H), 8.23 ( s, 1H), 7.65(dd, J=2.2Hz, 12.5Hz, 2H), 7.25(t, J=9.0Hz, 2H), 6.35(br.s, 2H), 6.02(t, J=1.8Hz, 1H), 5.87(dt, J=1.46Hz, 5.9Hz, 1H), 5.30-5.10(m, 2H), 2.53-2.46(m, 1H), 1.83(quint, J=6.6Hz, 1H). Elemental analysis , calculated for C ₁₃ H ₁₄ N ₃ O ₃ F: C, 55.91; H, 5.05; N, 15.05. Found: C, 56.21; H, 4.89; N, 15.19.

Example 15 N-{(1R)-4-benzyloxyimino-2-cyclopenten-1-yl}-N-hydroxyurea (4R)-(E)-4-hydroxyl-2-cyclopentenone Oxime-O-benzyl ether:

Preparation of (4R)-4-acetoxy-2-cyclopentene by oxidation of (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol with pyridinium dichromate (PDC) Enones (M.P. Schneider et al., J. Chem. Commun., 1298 (1986)). To a stirred solution of (4R)-4-acetoxy-2-cyclopentenone (1.56 g; 11.1 mM) in ethanol (22 ml) at room temperature was added O-benzylhydroxylamine hydrochloride (1.77 g; 11.1 mM) and pyridine (1.1 ml; 11.1 mM). 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 (quantitative) of (4R)-4-acetoxy-2-cyclopentenone oxime-O-benzyl base ether.

¹ H-NMR (CDCl ₃ ) δ; 7.37-7.27 (m, 5H), 6.51 (dd, J=2.2Hz, 5.9Hz, 1H), 6.43 (dd, J=1.1Hz, 5.9Hz, 1H), 5.72 (ddd, J=1.1Hz, 2.2Hz, 4.8Hz, 1H), 5.13(s, 2H), 3.12(dd, J=7.0Hz, 9.1Hz, 1H), 2.58(dd, J=2.2Hz, 9.4Hz , 1H), 2.05(s, 3H).

(4R)-4-Acetoxy-2-cyclopentenone oxime-O-benzyl ether (2.64g; 10.8mM) and potassium carbonate (2.23g; 16.1mM) were dissolved in methanol (80ml) at room temperature The suspension was stirred overnight. The volatiles were removed by evaporation, the residue was extracted with ethyl acetate (40ml x 2), the combined organic layers were washed with water (50ml), brine (50ml), dried over _MgSO4 , and concentrated in vacuo to give 2.33g (quantitative) of title compound.

¹ H-NMR(CDCl ₃ )δ; 7.40-7.26(m, 5H), 6.52(dd, J=2.2Hz, 5.5Hz, 1H), 6.34(d, J=5.5Hz, 1H), 5.13(s, 2H), 4.96(br.s, 1H), 3.09(dd, J=7.0Hz, 18.7Hz, 1H), 2.48(dd, J=1.8Hz, 18.7Hz, 1H).N-{(1R)-4 -Benzyloxyimino-2-cyclopenten-1-yl}-N-hydroxyurea:

Following the procedure described in Example 1, substituting (4R)-4-hydroxy-2-cyclopentenone oxime-O-benzyl ether for (1R,4R)-trans-4-(4-fluoro Phenoxy)-2-cyclopenten-1-ol, the title compound was prepared.

mp166-170°C (dec).[α] _D = +257.9° (ethanol, c = 0.15). ¹ H-NMR (DMSO-d ₆ ) δ; 9.18 (d, J = 1.1Hz, 1H), 7.48- 7.35(m, 5H), 6.56(br.s, 2H), 6.51(dd, J=2.2Hz, 5.0Hz, 1H), 6.41(dd, J=1.8Hz, 5.9Hz, 1H), 5.41(br. d, J=7.0Hz, 1H), 5.14(s, 2H), 2.84(dd, J=7.7Hz, 18.3Hz, 1H), 2.67-2.53(m, 1H). Elemental analysis, calculated C ₁₃ H ₁₅ N ₃ O ₃ : C, 59.76; H, 5.79; N, 16.08. Found: C, 60.01; H, 5.87; N, 16.08.

Example 16 N-{(1S)-4-benzyloxyimino-2-cyclopenten-1-yl}-N-hydroxyurea

Follow the procedure described in Example 1, substituting (4R)-4-hydroxy-2-cyclopentenone oxime-O-benzyl ether for (1S,4R)-cis-4-(4-fluoro Phenoxy)-2-cyclopenten-1-ol, the title compound was prepared.

mp168-171°C (dec).[α] _D = -258.2° (ethanol, c = 0.136). ¹ H-NMR (DMSO-d ₆ ) δ; 9.18 (d, J = 1.1Hz, 1H), 7.48- 7.35(m, 5H), 6.56(br.s, 2H), 6.51(dd, J=2.2Hz, 5.0Hz, 1H), 6.41(dd, J=1.8Hz, 5.9Hz, 1H), 5.41(br. d, J=7.0Hz, 1H), 5.14(s, 2H), 2.84(dd, J=7.7Hz, 18.3Hz, 1H), 2.67-2.53(m, 1H). Elemental analysis, calculated C ₁₃ H ₁₅ N ₃ O ₃ : C, 59.76; H, 5.79; N, 16.08. Found: C, 59.83; H, 5.75; N, 16.01.

Example 17

N-{(1R)-4-(4-fluorobenzyloxyimino)-2-cyclopenten-1-yl}-N-hydroxyurea

The title compound was prepared by following the procedure described in Example 15, substituting O-(4-fluorobenzyl)-hydroxylamine hydrochloride for O-benzylhydroxylamine hydrochloride.

mp148-149°C (dec).[α] _D = +243.75° (ethanol, c = 0.128). ¹ H-NMR (DMSO-d ₆ ) δ; 9.12 (s, 1H), 7.40 (dd, J = 5.9 Hz, 8.4Hz, 2H), 7.17(t, J=8.8Hz, 2H), 6.48-6.31(m, 4H), 5.34-5.30(m, 1H), 5.03(s, 2H), 2.75(dd, J =7.7Hz, 14.3Hz, 1H), 2.54-2.45 (m, 1H). Elemental analysis, calculated for C ₁₃ H ₁₄ N ₃ O ₃ F: C, 55.91; H, 5.05; N, 15.05. Measured: C, 56.07 ; H, 5.06; N, 15.03.

Example 18 N-Hydroxy-N-{(1R)-4-phenoxyimino-2-cyclopenten-1-yl}urea

The title compound was prepared following the procedure described in Example 15, substituting O-phenylhydroxylamine hydrochloride for O-benzylhydroxylamine hydrochloride.

mp156-157°C (dec). [α] _D = +258.0° (ethanol, c = 0.1). ¹ H-NMR (DMSO-d ₆ ) δ; 9.20 (s, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.16-7.12(m, 2H), 7.01(t, J=7.4Hz, 1H), 6.63(dd, J=2.2Hz, 5.9Hz, 1H), 6.54-6.50(m, 3H), 5.42(d, J=7.0Hz, 1H), 3.00(dd, J=7.3Hz, 18.3Hz, 1H), 2.72(d, J=18.3Hz, 1H). Elemental analysis, calculated C ₁₂ H ₁₃ N ₃ O ₃ : C, 58.29; H, 5.30; N, 16.99. Measured: C, 58.11; H, 5.45; N, 16.41.

Claims (8)

1. The compound of formula (I):

Wherein Ar is selected from the following groups: (a) phenyl, naphthyl and biphenyl, each of which may be substituted or unsubstituted by 1-3 substituents selected from the following C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 Haloalkoxy, C _2-4 alkoxyalkoxy, C _1-4 alkylthio, hydroxyl, halogen, Cyano, Amino, C _1-4 Alkylamino, Di(C _2-8 ) Alkylamino, C _2-6 Alkylamide Base, carboxyl, C _2-6 alkoxycarbonyl, selected from 1-3 C _1-4 alkyl, C _1-4 The substitution of haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen Substituent substituted or unsubstituted phenyl, by 1-3 selected from C _1-4 alkyl, C _1-4 The substitution of haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen Substituent substituted or unsubstituted phenoxy, with 1-3 selected from C _1-4 alkyl, C _1-4 Haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen Substituent substituted or unsubstituted phenylthio, and 1-3 selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen phenylsulfinyl substituted or unsubstituted by substituents; and (b) furanyl, benzo [b]furyl, thienyl, benzo[b]thienyl, pyridyl and quinolinyl: C _1-4 alkyl, C _1-4 haloalkyl, halogen, C _1-4 alkoxy, hydroxyl, by 1 -3 selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Halogenated alkoxy, cyano and halogen substituents substituted or unsubstituted phenyl, by 1-3 selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Halogenated alkoxy, cyano and halogen substituted or unsubstituted phenoxy, And by 1-3 selected from C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and halogen substituent substituted or unsubstituted phenylthio group; X is selected from C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene, -(CHR ¹ ) _m -Q ¹ -(CHR ² ) _n - , -O-(CHR ¹ ) _j -Q ² - and -(CHR ¹ )-ON=, which In N = part is connected with cycloalkene ring; And wherein Q ¹ is O, S, SO, SO ₂ , NR ³ , CH=NO or CO, Q ² is O, S, SO, SO ₂ or NR ³ , and R ¹ , R ² and R ³ are each hydrogen or C ₁ -C ₄ alkyl, m and n Each is an integer of 0-4, j is an integer of 1-4; p is an integer of 1 or 2; Y is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-4 alkoxyalkane C _1-4 alkylthio group, hydroxyl, halogen, cyano or amino; Z is hydrogen or C _1-4 alkyl; and M is hydrogen, a pharmaceutically acceptable cation or a pharmaceutically acceptable metabolically cleavable group. 2. The compound of claim 1, wherein Ar is selected from group (a), Y and Z are each hydrogen, p is 1 and M is hydrogen or a pharmaceutically acceptable cation. 3. The compound of claim 2, wherein Ar is phenyl, fluorophenyl, cyanophenyl, biphenyl or fluorophenoxyphenyl, and X is the oxygen attached to the 4-position of the cycloalkene ring . 4. The compound of claim 2, wherein Ar is phenyl or fluorophenyl, and X is -CH=N-O- attached to the 4-position of the cycloalkene ring. 5. The compound of claim 2, wherein Ar is phenyl or fluorophenyl, and X is _-CH2 -ON= attached at the 4-position of the cycloalkene ring. 6. The compound of claim 1, selected from the group consisting of N-{(1R, 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-{(1R)-4-benzyloxy Imino-2-cyclopenten-1-yl}-N-hydroxyurea; and N-{(1R)-4-(4-fluorobenzyloxyimino)-2-cyclopenten-1-yl} -N-hydroxyurea. 7. A pharmaceutical composition for the treatment of mammalian diseases requiring 5-lipoxygenase inhibitors, the composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 8. The pharmaceutical composition according to claim 7, wherein the disease is an inflammatory disease, an allergic disease or a cardiovascular disease.