Technical Field

This invention relates to novel N-hydroxyurea compounds. The compounds of the present invention inhibit the action of Hpoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds.

Background Art Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of the arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase A2. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by Hpoxygenase to generate hydroperoxy fatty acids which may be further metabolized to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel diseases. Any drug that inhibits Hpoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions. For a review article on Hpoxygenase inhibitors, see H. Masamune and

L.S.Melvin, Sr. , Annual Reports in Medicinal Chemistry: 24 (1989) pp71-80 (Academic). More recently, International Patent Publication No. WO 92/09566 discloses a wide variety of N-hydroxyurea and hydroxamic acid compounds as inhibitors of the Hpoxygenase enzyme. Brief Disclosure of the Invention

The present invention provides novel N-hydroxyurea compounds of the following chemical formula (I) :

(I)

and the pharmaceutically acceptable salts thereof, wherein A is selected from the group consisting of (a) phenyl, naphthyl, biphenylyl and fluorenyl; optionally substituted with

C _w alkyl,

C _w haloalkyl,

C,^ hydroxyalkyl,

C alkoxy, C _1-0 alkoxyalkoxy,

C, _-6 alkylthio, hydroxy, halo, cyano, amino,

C _1-0 alkylamino,

C _w dialkylamino,

C _2-g alkanoylamino,

N-alkanoyl-N-alkylamino in which the alkanoyl contains from two to eight carbon atoms and the alkyl contains from one to six carbon atoms,

C ₂ . _g alkylaminocarbonyl,

C _3-7 dialkylaminocarbonyl, carboxy,

C ₂ . _g alkoxycarbonyl, phenyl optionally substituted with C alkyl, C,^ haloalkyl, C _1-6 alkoxy, C, _{. 0} haloalkoxy, cyano or halo, phenoxy optionally substituted with C alkyl, C^ haloalkyl, C alkoxy, C _1-6 haloalkoxy, cyano or halo, phenylthio optionally substituted with C alkyl, C,^ haloalkyl, C^ alkoxy, C _w haloalkoxy, cyano or halo, pyridyl optionally substituted with C^ alkyl, C haloalkyl, C,^ alkoxy, C,^ haloalkoxy, cyano or halo, or pyridyloxy optionally substituted with C,^ alkyl, C _1-6 haloalkyl, C, _.6 alkoxy,

C| _-6 haloalkoxy, cyano or halo;

(b) furyl optionally substituted with C.. ₆ alkyl, C,^ haloalkyl, halo, phenyl optionally substituted with C,^ alkyl, C _w haloalkyl, C,^ alkoxy, C, _{. 6} haloalkoxy, cyano or halo, phenoxy optionally substituted with C _1-0 alkyl, C _w haloalkyl, C,^ alkoxy, C _1-6 haloalkoxy, cyano or halo, phenylthio optionally substituted with C _w alkyl, C _w haloalkyl, C alkoxy,

C _1-6 haloalkoxy, cyano or halo, pyridyl optionally substituted with C^ alkyl, C _I-0 haloalkyl, C _1-<s alkoxy, C _I-0 haloalkoxy, cyano or halo, or pyridyloxy optionally substituted with C _1-0 alkyl, C,^ haloalkyl, C _1-0 alkoxy, C _1-0 haloalkoxy, cyano or halo;

(c) benzo[b]furyl optionally substituted with C _1-0 alkyl, C _I-6 haloalkyl, C,^ alkoxy, hydroxy, or halo;

(d) thienyl optionally substituted with

C alkyl, C _1-0 haloalkyl, C _1-0 alkoxy, hydroxy, or halo, phenyl optionally substituted with C _1-6 alkyl, C _w haloalkyl, C _I-6 alkoxy, C, _{. 6} haloalkoxy, cyano or halo, phenoxy optionally substituted with C _1-6 alkyl, C _M haloalkyl, C _1-0 alkoxy,

C _1-6 haloalkoxy, cyano or halo, phenylthio optionally substituted with C alkyl, C _I-6 haloalkyl, C _1-6 alkoxy, C haloalkoxy, cyano or halo, pyridyl optionally substituted with C _1-6 alkyl, C _1-6 haloalkyl, C,^ alkoxy, C _w haloalkoxy, cyano or halo, or pyridyloxy optionally substituted with C _I-6 alkyl, C _w haloalkyl, C,^ alkoxy, C _w haloalkoxy, cyano or halo;

(e) benzo[b] thienyl, optionally substituted with

C _1-0 alkyl, C,. ₆ haloalkyl,

C _1-0 alkoxy, hydroxy, or halo; (0 pyridyl optionally substituted with C _{l 5} alkyl,

C,. _o haloalkyl,

C _M alkoxy, hydroxy, or halo; (g) quinolyl optionally substituted with

C alkyl,

C _1-0 haloalkyl,

C _1-0 alkoxy, hydroxy or halo; and

(h) indolyl optionally substituted with

C _M alkyl, Cι. ₀ haloalkyl, C,^ alkoxy, hydroxy or halo;

B is selected from the group consisting of

(a) phenylene optionally substituted with C^ alkyl, C _1-6 haloalkyl, C _M haloalkoxy, cyano or halo;

(b) furylene optionally substituted with C alkyl or C,^ haloalkyl; (c) thienylene optionally substituted with C,^ alkyl or C,^ haloalkyl;

(d) pyridylene optionally substituted with C,^ alkyl or C _1-6 haloalkyl;

(e) thiazolylene optionally substituted with C,^ alkyl or C haloalkyl; (0 oxazolylene optionally substituted with C,^ alkyl or C,^ haloalkyl;

(g) benzoxazolylene optionally substituted with C,^ alkyl or C^ haloalkyl; and (h) benzothienylene optionally substituted with C _1-0 alkyl or C _M haloalkyl; p is selected from zero, one and two; X is selected from the group consisting of

(a) C,. ₀ alkylene;

(b) C ₂ . ₆ alkenylene; (c) C _2-0 alkynylene;

(d) CF ₂ ;

(e) CC1 ₂ ;

(f) -(CHRVZ'- CHRV; (g) -O-(CHR') _r Z ² -; and (h) groups of the formula

wherein Z ¹ is O, S, SO ₂ , NR ³ , CO, C(=N-OR') or CH=N-O; Z ² is O, S, SO, or

NR ² ; Z ³ is O, S or NR ¹ ; R\ R ² and R ³ are each H or C _M alkyl; m and n are each zero to six; j and q are each one to six; and the dotted line in group (h) represents an optional additional bond; with the proviso that when Z ¹ is O or S, m and n are not zero simultaneously; Y is selected from hydrogen, C _1-6 alkyl, C,_«- haloalkyl, C _I-6 alkoxy, C _w alkoxyalkyl,

C ₂ . ₀ alkoxyalkoxy, C alkylthio, hydroxy, halo, cyano and amino; and

Z is selected from hydrogen and C,_ ₃ alkyl.

The compounds of the formula (I) inhibit the 5-Hpoxygenase enzyme.

Therefore the compounds are useful for treating a medical condition for which a 5- Hpoxygenase inhibitor is needed, in a mammalian subject, e.g., a human subject. The compounds are especially useful for treating allergic and inflammatory conditions, and cardiovascular diseases. This invention also embraces pharmaceutical compositions which comprise a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, and a pharmaceutically acceptable carrier. A preferred group of compounds of the invention consists of the compounds of the formula (I), wherein A is phenyl or fluorophenyl; B is phenylene or thienylene; p is one; X is C alkylene; Y is hydrogen; and Z is hydrogen.

Another preferred group of compounds of the invention consists of the compounds of the formula (I), wherein A is phenyl or fluorophenyl; B is phenylene or thienylene; p is one; Y and Z are each hydrogen; and X is -(CHR'^-Z'-^HR ² ),,- wherein Z ¹ is O, and either R ¹ is H, m is one and n is zero, or R ² is H, m is zero and n is one.

Particularly preferred individual compounds of the invention are:

N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten-l -yl]-N-hydroxyurea; (+)-N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopenten- l-yl]-N-hydroxyurea;

(-)-N-[3-[5-(4-Fluorophenylmethyl)-2-thienyl]-2-cyclopent en-l-yl]-N-hydroxyurea;

N-Hydroxy-N-[[3-[3-(2-phenoxy)ethoxy]phenyl]-2-cyclopente n-l-yl]urea;

N-[[3-(3-Benzyloxy)phenyl]-2-cyclopenten-l-yl]-N-hydroxyu rea; N-[3-[3-(4-Fluorophenoxymethyl)phenyl]-2-cyclopenten-l-yl]-N -hydroxyurea; and N-[3-[5-(4-Fluorophenylcarbonyl)-2-thienyl]-2-cyclopenten-l- yl]-N-hydroxyurea.

Detailed Description of the Invention

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

The term "pharmaceutically acceptable salts" refers to salt incorporating non- toxic cations, including, but not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, magnesium, and the like, as well as non-toxic ammonium, substituted ammonium and quaternary ammonium cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methyl-ammonium, diethylammonium, trimethylammonium and triethylammonium. The compounds of formula (I) may be prepared by a number of synthetic methods. In one embodiment, compounds of the formula (I) are prepared according to the reaction steps outlined in scheme 1 :

Scheme 1

(π) (D

In Scheme 1, the hydroxylamine (II) is treated with a suitable trialkylsilyl isocyanate or lower alkyl isocyanate of the formula ZNCO, in a reaction-inert solvent usually at ambient through to reflux temperature. Preferably the reaction temperature is from 20 to 100 °C. Suitable solvents which do not react with reactants and/or products are, for example, tetrahydrofuran, dioxane, methylene chloride or benzene. An alternative procedure employs treatment of (II) with gaseous hydrogen chloride in a reaction-inert solvent such as benzene or toluene and then subsequent treatment with phosgene. Reaction temperatures are usually in the range of ambient temperature through to boiling point of solvent, preferably 25 to 80 °C. The intermediate

carbamoyl chloride is not isolated but subjected to (i.e. in situ) reaction with aqueous ammonia or amine ZNH ₂ . As a modification of this procedure (Z=H) the acid addition salt of (II) may 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 purification can be achieved by conventional means, such as recrystallization and chromatography.

Alternatively, the compounds of formula (I) can be directly prepared by the cross coupling reaction of the corresponding aryl halides or triflates with the stannylcycloalkenylhydroxyureas or vice versa in the presence of suitable catalyst such as Pd(PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ or the like (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986). The product of formula (I) thus obtained is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The aforementioned hydroxylamine (II) may be prepared by standard synthetic procedures from corresponding carbonyl compound, i.e. ketone or alcohol compound. For example, suitable carbonyl compound is converted to its oxime and then reduced to the requisite hydroxylamine (II) with a suitable reducing agent (for example, see R. F. Borch et al, J. Am. Chem. Soc, 21, 2897, 1971). Reducing agents of choice are, but 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, i.e. cyclobutenones, cyclopentenones, or cyclohexenones, can be prepared by a number of different approaches (see WO 92/09566). The cyclobutenones may be prepared by the [2+2] cycloaddition of the corresponding ethylenes and dichloroketene followed by reductive dechlorination (for example, see R. L. Danheiser et al., Tetrahedron Lett., 28, 3299, 1987). The cyclopentenones may be prepared by the intramolecular aldol cyclization of 1,4- diketones, readily accessible for the corresponding aldehydes and methyl vinyl ketone by the Stetter reaction (for example, see L. Novak et al., Liebigs Ann. Chem., 509, 1986). The cyclopentenones and the cyclohexenones can be prepared by the addition of the corresponding aryl lithium or aryl magnesium to 3-alkoxy-2-cyclopentenone and

3-alkoxy-2-cyclohexenone, respectively. Alternatively, the cycloalkenones can be prepared by the cross coupling reaction of the corresponding aryl halides or triflates with the cycloalkenylstannanes or vice versa in the presence of suitable catalyst such as Pd(PPh ₃ ) ₄ or PdCl ₂ (PPh ₃ ) ₂ (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986).

Alternatively, the aforementioned hydroxylamine (II) can easily be prepared by treating the corresponding alcohol with N,*0-bis(te/τ-butyloxycarbonyl)hydroxylamine under Mitsunobu-type reaction conditions followed by acid catalyzed hydrolysis (for example, employing trifluoroacetic acid) of the N,0-protected intermediate product (see Japanese Patent No. 1045344). The requisite alcohol is readily prepared by the 1,2- reduction of the corresponding cycloalkenone using a suitable reducing agent such as sodium borohydride, or sodium borohydride-cerium trichloride.

Alternatively, the NOprotected intermediate can be prepared by the cross coupling reaction of the corresponding aryl halides or triflates with the N,0-protected stannylcycloalkenyl-hydroxylamines or vice versa in the presence of suitable catalyst such as Pd(PPh ₃ ) ₄ or PdCl ₂ (PPh ₃ ) ₂ (for example, J. K. Stille, Angew. Chem. Int. Ed.

Eng., 25, 806 1986).

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

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

Scheme 2

(TV)

In this process, compound of formula (IV) 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, ammonium hydroxide, or an amine of structure ZΝH ₂ (A. O. Stewart and D. W. Brooks., J. Org. Chem., 57, 5020, 1992). Suitable reaction solvents for reaction with ammonia, ammonium hydroxide or the amine of formula ZNH ₂ are, for example, water, methanol, ethanol, tetrahydrofuran, benzene and the like, though reaction may be run in the absence of co-solvent, that is, in requisite amine alone. Reaction temperatures are typically in the range of ambient temperature through to boiling point of solvent. The compounds of formula (IV) can be prepared by the cross coupling reaction of the corresponding aryl halides or triflates with the N,O-protected stannylcycloalkenylhydroxylamines or vice versa in the presence of suitable catalyst such as Pd(PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ or the like (for example, J. K. Stille, Angew. Chem. Int. Ed. Eng., 25, 806 1986). The product of formula (I) thus obtained is isolated by standard methods and purification can be achieved by conventional means, such as recrystallization and chromatography.

The compounds of this invention can exist in stereoisomeric forms by virtue of the presence of one or more chiral centers. The present invention contemplate all such stereoisomers, including enantiomers, diastereomers, and mixtures. The individual isomers of compounds of the formula can be prepared by a number of methods known to those skilled in the art. For instance, they can be prepared by derivatization of a compound of formula (I) with a chiral auxiliary followed by separation of the resulting diastereomeric mixture and removal of the auxiliary group to provide the desired isomer, or by separation employing a chiral stationary phase. The pharmaceutically acceptable salts of the novel compounds of the present invention are readily prepared by contacting said compounds with a stoichiometric amount of, in the case of a non-toxic cation, an appropriate metal hydroxide or alkoxide or amine in either aqueous solution or a suitable organic solvent. In the case of non-toxic acid salt, an appropriate mineral or organic acid in either aqueous solution or a suitable organic solvent can be used. The salt may then be obtained by purification or by evaporation of the solvent.

The compounds of the present invention inhibit the activity of Hpoxygenase enzyme. This inhibition can be demonstrated in vitro by an assay using heparinized Human Whole Blood (HWB) cells, according to the method described in British Journal of Pharmacology: 99, 113-118 (1990), which determines the effect of said compounds on the metabolism of arachidonic acid. Some of the compounds additionally possess the ability to inhibit the CO enzyme.

The ability of the compounds of the present invention to inhibit Hpoxygenase enzyme makes them useful for controlling the symptoms induced by the endogenous metabolites arising from arachidonic acid in a mammalian subject. The compounds are therefore valuable in the prevention and treatment of such disease states in which the accumulation of arachidonic acid metabolites are the causative factor; e.g. allergic bronchial asthma, skin disorders, rheumatoid arthritis and osteoarthritis. Thus, the compounds of the present invention and their pharmaceutically acceptable salts are of particular use in the treatment or alleviation of inflammatory diseases in a human subject.

For treatment of the various conditions described above, the compounds of the formula (I) of this invention can be administered to a human subject either alone, or preferably in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice. This composition can consist of about 0.1 to 90%, preferably about 10 to 60%, of the compound of formula (I) or the salt in liquid or solid form of the unit use.

The compounds can be administered to human subjects by various conventional routes of administration including oral or parenteral. When the compounds are administered orally, the dose range will be from about 0.1 to 20 g/kg of body weight of the subject to be treated per day, preferably from about 0.5 to 15 mg/kg of body weight per day, in single or divided doses. If parenteral administration is desired, then an effective dose will be from about 0.05 to 10 mg/kg of body weight of the human subject to be treated per day. In some instances it may be necessary to use dosages outside these limits, since the dosages will necessarily vary according to the age, weight and response of the individual patient as well as the severity of the patient's symptoms and the potency of the particular compound being administered.

For oral administration, the compounds of the invention and their pharmaceutically acceptable salts can be administered, for example, in the form of tablets, powders, lozenges, syrups or capsules or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Further lubricating agents such as magnesium stearate are commonly added. In the case of capsules, useful diluents are lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifing and suspending agents. If desired, certain sweetning and/or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solute should be controlled to make the preparation isotonic.

Examples The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance spectra (NMR) were measured at 270 MHz unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak shapes are denoted as follows: s - singlet, d - doublet, t - triplet, m -multiplet and br - broad. Example 1

N-r3-r5-(4-FluorophenylmethvI)-2-thienvn-2-cvclopenten-l- vn-N-hvdroxyurea a. 3- ^r 5-(4-Fluoropheny1methyD-2-thienyπ-2-cyclopentenone

To a stirred solution of 2-bromo-5-(4-fluorophenylmethyl)thiophene (12.15g; 44.83mM) in dry THF (120ml) was added 1.6M solution of n-BuLi in hexane (28ml; 44.83mM) dropwise at -76 °C under Ν ₂ . After stirring for lhr, 3-ethoxy-2- cyclopentenone (5.65g; 44.83mM) in THF (30ml) was added dropwise at -76 °C. The mixture was stirred for lhr at -76 °C, and the mixture was poured into water. The whole was extracted with ethyl acetate (150ml x2), and the combined organic layers washed with water (70ml), brine (100ml), dried over MgSO ₄ , and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate- hexane (1: 1) to give 3.75g (31 %) of the subtitle compound.

'H-NMR (CDC1 ₃ ); 7.27 (d, J=4.7Hz, IH), 7.21 (dd, J=5.5Hz, 8.4Hz, 2H),

7.02 (t, J=8.4Hz, 2H), 6.82 (d, J=3.6Hz, IH), 6.24 (s, IH), 4.14 (s, 2H), 3.00-2.95

(m, 2H), 2.55-2.51 (m, 2H). b. 3-r5-(4-Fluorophenylmethyl)-2-thienyl1-2-cyclopentenone oxi e To a stirred solution of 3-[5-(4-fluorophenylmethyl)-2-thienyl]-2-cyclopentenone

(3.75g; 13.79mM) in ethanol (28ml)-pyridine (7ml) was added NH ₂ OH HC1 (1.25g;

17.92mM) at room temperature. After stirring overnight, volatiles were removed by evaporation. The residue was dissolved in ethyl acetate (150ml), and the whole washed with diluted aqueous HC1 (70ml), water (100ml), brine (100ml), dried over MgSO ₄ , and concentrated in vacuo to give 3.7g (quant.) of the subtitle compound as brown solids.

'H-NMR (CDC1 ₃ ); 7.20 (dd, J=5.5Hz, 8.4Hz, 2H), 7.00 (t, J=8.4Hz, 2H),

6.97 (d, J=3.6Hz, IH), 6.71 (d, J=3.6Hz, IH), 6.33 (s, IH), 4.10 (s, 2H), 2.89-2.80

(m, 4H). c. N-f3-r5-C4-Fluorophenylmethy1)-2-thienyn-2-cyclopenten-l-yπ -N-hydroxylamine To a stirred solution of 3-[5-(4-fluorophenylmethyl)-2-thienyl]-2-cyclopentenone oxime (3.9g; 13.59mM) in acetic acid (30ml) was added ΝaBH ₃ CΝ (1.28g; 20.38mM) at room temperature. After stirring for 3hr, water (50ml) was added. Volatiles were removed by evaporation, and the residue was poured into aqueous 5% NaOH (300ml). The whole was extracted with ethyl acetate (150ml x2), and the combined organic layers washed with water (70ml x2), brine (70ml), dried over MgSO ₄ , and concentrated in vacuo. The residue was purified by flash chromatography eluting with CH ₂ C1 ₂ - ethanol (30: 1) to give 1.17g (30%) of the subtitle compound.

^■ H-NMR (CDC1 ₃ ); 7.19 (dd, J=5.5Hz, 8.0Hz, 2H), 7.02-6.93 (m, 4H), 6.83 (d, J=3.7Hz, IH), 6.67 (dd, J = l . lHz, 3.7Hz, IH), 5.84 (s, IH), 4.31-4.23 (m, IH),

4.07 (s, 2H), 2.89-2.77 (m, IH), 2.71-2.61 (m, IH), 2.33-2.19 (m, IH), 2.10-1.95

(m, IH). d. N-r3-r5-(4-Fluorophenylmethyl -2-thienyπ-2-cyclopenten-l-yl1-N-hydroxyurea

Toastirred solution of N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-2-cyclopenten- l-yl]-N-hydroxylamine (1.17g; 4mM) in THF (10ml) was added trimethylsilyl

isocyanate (0.71g; 5.26mM) at room temperature. After stirring overnight, ethanol (10ml) was added, and volatiles were removed by evaporation. The resulting residue was recrystallized from ethanol to give 0.64g of the title compound, m.p. 196-197 °C (decompose) 'H-NMR (DMSO-d ₆ ); 8.92 (s, IH), 7.32-7.26 (m, 2H), 7.14 (dd, J=2.2Hz,

8.8Hz, 2H), 6.89 (d, J=3.2Hz, IH), 6.81 (d, J=3.2Hz, IH), 6.33 (s, 2H), 5.68 (s, IH), 5.28 (s, IH), 4.10 (s, 2H), 2.70-2.64 (m, IH), 2.53-2.46 (m, IH), 2.15-2.08 (s, IH), 1.94-1.88 (m, IH).

Anal. Calcd. for C ₁₇ H ₁₆ FN ₂ O ₂ S C; 61.62, H; 4.87, N; 8.45, Found C; 61.69, H; 5.08, N; 8.48. e. f + -N-r3- 5-(4-Fluorophenylmethyl ^' )-2-thienyl1-2-cyclopenten-l-yn-N-hvdroxyurea and f. -N-r3-r5-f4-Fluorophenylmethyπ-2-thienyn-2-cyclopenten-l-yn -N-hydroxyurea

The title respective enantiomers were obtained by separation on a chiral stationary phase (DAICEL chiral pak AS) of the racemate N-[3-[5-(4-fluorophenyl- methyl)-2-thienyl]-2-cyclopenten-l-yl]-N-hydroxyurea. HPLC condition; eluent n- hexane/EtOH =70/30, Flow rate 11.0 ml/min.

The less polar enantiomer; retention time 15.9 min, [α] _D = + 16.5 (c=0.2, EtOH). The more polar enantiomer; retention time 19.3 min, [α] _D =-19.0 (c=0.2, EtOH).

Example 2 N-Hvdroxy-N-rr3-r3-(2-phenoxy)ethoxy1phenvn-2-cvclopenten-l- vnurea a. 3-|Y2-Phenoxykthoxy1benza1dehyde

A mixture of m-hydroxybenzaldehyde (6.1g; 50mM), 0-bromophenetole (11.06g; 55mM) and K ₂ CO ₃ (13.82g; lOOmM) in DMF (150ml) was stirred overnight. Insolubles were filtered off, and the filtrate was diluted with water (300ml), and extracted with ethyl acetate-hexane (2:1, 150ml x2), the combined organic layers washed with water (100ml x2), brine (100ml), dried over MgSO ₄ , and evaporated in vacuo. The resulting residue was recrystallized from ethyl acetate-hexane to give 7.01g (58%) of the subtitle compound.

'H-NMR (CDC1 ₃ ); 9.97 (s, IH), 7.50-7.42 (m, 3H), 7.33-7.21 (m, 3H), 7.01- 6.93 (m, 3H), 4.41-4.32 (m, 4H). b. l-r3-|T2-Phenoxy)ethoxy1phenyπ-1.4-pentanedione

To a stirred solution of 3-[(2-phenoxy)ethoxy]benzaldehyde (7g; 28.93mM) in ethanol (15ml) was added methyl vinyl ketone (2.4ml; 28.93mM), 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazolium chloride (1.72g; 6.36mM) and triethylamine (8.06ml; 57.9mM) at room temperature. After stirring overnight, volatiles were removed by evaporation. The residue was dissolved in water (250ml), and extracted with ethyl acetate (160ml x2). The combined organic layers were washed with water (100ml), brine (80ml), dried over MgSO ₄ , and evaporated in vacuo. This provided lOg of crude subtitle compound, which was used without further purification.

'H-NMR (CDC1 ₃ ); 7.61-6.94 (m, 9H), 4.36 (t, J=3.7Hz, 4H), 3.26 (t, J=6.6Hz, 2H), 2.88 (t, J=6.6Hz, 2H), 2.26 (s, 3H). c. 3-r3-|Y2-Phenoxytethoxy1phenyπ-2-cyclopentenone A solution of l-[3-[(2-phenoxy)ethoxy]phenyl]-l,4-pentanedione (lOg;

28.93mM) in 2.5% NaOH solution (120ml) was heated at reflux temperature overnight. After cooling, the solution was extracted with ethyl acetate (150ml x2), the combined organic layers washed with water (70ml), brine (70ml), dried over MgSO ₄ , and evaporated in vacuo. The resulting residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:3) to give 1.3g of the subtitle compound.

'H-NMR (CDC1 ₃ ); 7.41-6.94 (m, 9H), 6.56 (s, IH), 4.37 (br. s, 4H), 3.03 (dd, J=3.0Hz, 4.8Hz, 2H), 2.59 (t, J=4.8Hz, 2H). d. N-Hvdroxy-N-rr3-p-r2-phenoxy)ethoxylDhenvn-2-cyclopenten-l-y l1urea

The title compound was prepared according to the procedure of Example 1 using 3-[3-[(2-phenoxy)ethoxy]phenyl]-2-cyclopentenone instead of 3-[5-(4- fluorophenylmethyl)-2-thienyl]-2-cyclopentenone. m.p. 170-173 °C (decompose)

'H-ΝMR (DMSO-d ₀ ); 8.92 (s, IH), 7.29 (q, J=8.4Hz, 3H), 7.12-7.07 (m, 2H), 7.03-6.87 (m, 4H), 6.32 (s, 2H), 6.12 (s, IH), 5.37-5.33 (m, IH), 4.33 (br.s, 4H), 2.81-2.69 (m, IH), 2.62-2.50 (m, IH), 2.20-2.17 (m, IH), 2.00-1.90 ( , IH). Anal. Calcd. for C ₂₀ H ₂₂ Ν ₂ O ₄ C; 67.78, H; 6.26, N; 7.90,

Found C; 67.86, H; 6.29, N; 7.96.

Example 3 N-rf3-f3-BenzvIoxy)phenvn-2-cvclopenten-l-vn-N-hvdroxyurea

The title compound was prepared according to the procedure of Example 1 using 3-(benzyloxy)benzaldehyde instead of 3-[(2-phenoxy)ethoxy]benzaldehyde. m.p. 158-160 °C (decompose)

'H-ΝMR (DMSO-d ₆ ); 8.91 (s, IH), 7.46-7.21 (m, 6H), 7.08-7.04 (m, 2H), 6.93-6.89 (m, IH), 6.30 (s, 2H), 6.08 (d, J= 1.8Hz, IH), 5.33 (br.s, IH), 5.11 (s, 2H), 2.80-2.67 (m, IH), 2.58-2.48 (m, IH), 2.17-2.05 (m, IH), 1.96-1.88 (m, IH). Anal. Calcd. for C _I9 H ₂ 0Ν ₂ O ₃ C;70.35, H; 6.21, N; 8.64,

Found C; 70.26, H; 6.22, N; 8.52.

Example 4 N-rr3-(4-Benzyloxy)phenvπ-2-cvclopenten-l-vπ-N-hvdroxyurea

The title compound was prepared according to the procedure of Example 1 using 4-(benzyloxy)benzaldehyde instead of 3-[(2-phenoxy)ethoxy]benzaldehyde. m.p. 175-177 °C (decompose)

'H-ΝMR (DMSO-d ₆ ); 8.90 (s, IH), 7.46-7.32 (m, 7H), 6.99 (d, J=8.8Hz, 2H), 6.28 (s, 2H), 5.94 (s, IH), 5.32 (br.s, IH), 5.12 (s, 2H), 2.79-2.68 (m, IH), 2.57-2.47 (m, IH), 2.15-2.06 ( , IH), 1.96-1.88 (m, IH). Anal. Calcd. for C ₁₉ H ₂ 0Ν ₂ O ₃ C;70.35, H; 6.21, N; 8.64,

Found C; 70.08, H; 6.18, N; 8.68.

Example 5

N.O-Bis(rg f-butoxycarbθnvπ-N- ⁽ 3-tributylstannvI-2-cvcloa1ken-l-vπhvdroxylamine

3-Tributylstannyl-2-cyclopenten-l-ol was prepared from 3-ethoxy-2-cyclo- pentenone according to the literature (E. Laborde et al, Tetrahedron Letters, 31, 1837

(1990)). To a stirred solution of 3-tributylstannyl-2-cyclopenten-l-ol (9.1g; 24.4mM) in THF (70ml) was added triphenylphosphine (7.36g; 28mM), Boc-ΝH-O-Boc (6.52g;

28mM), and diisopropyl azodicarboxylate (5.66g; 28mM) at room temperature. After stirring for 2 hrs, volatiles were removed by evaporation. The resulting residue was purified by flash chromatography eluting with n-hexane-ethyl acetate (50: 1) to give 6g

of the title compound.

'H-NMR (CDC1 ₃ ); 5.76 (s, IH), 5.33 (br.s, IH), 2.65-2.52 (m, IH), 2.45-2.35 (m, IH), 2.19-2.06 (m, IH), 1.87-1.75 (m, IH), 1.49 (s, 18H), 1.65-1.23 (m, 18H), 0.89 (t, J=7.0Hz, 9H). The title compound is useful to synthesize the compounds of the following

Examples 6, 7, 8 and 9 as the starting compound.

Example 6 N-r3-r5-(4-Fluorophenylcarbonyl)-2-thienvn-2-cvclopenten-l-y ll-N-hvdroxyurea g. N.O-Bis-tt ^, rr-butoxycarbonyl-N-r3-r5-(4-fluorophenylcarbonyl ^' )-2-thienyn-2- cyclopenten- 1 -yll-h ydroxylamine

To a suspension of 2-bromo-5-(4-fluorobenzoyl)thiophene (0.71g; 2.5mM) in dry dioxane (20ml) previously purged with nitrogen, were added N,0-Bis(tert- butoxycarbonyl)-N-(3-tributylstannyl-2-cycloalken-l-yl)hydro xylamine(1.47g;25mM), tetrakis(triphenylphosphine)palladium(0) (58mg; 0.05mM), and 2,6-di-tert-butyl-4- methylphenol (3 crystals). The mixture was heated at gentle reflux for 40hrs and it was then concentrated to dryness. The residue was purified by flash chromatography eluting with n-hexane to give 0.33g (26%) of the subtitle compound.

'H-ΝMR (CDC1 ₃ ); 7.88 (dd, J=5.5Hz, 8.8Hz, 2H), 7.51 (d, J=4.0Hz, IH), 7.18 (t, J = 8.8Hz, 2H), 7.08 (d, J=4.0Hz, IH), 6.17 (d, J=2.2Hz, IH), 5.49 (br.s, IH), 2.95-2.85 (m, IH), 2.75-2.64 ( , IH), 2.47-2.35 (m, IH), 2.17-2.05 (m, IH), 1.50 (s, 18H). b. N-r3-r5-(4-Fluorophenylcarbonyl)-2-thienyn-2-cyclopenten-l-y l1-N-hydroxyurea

To a stirred solution of N,0-bis-t -butoxycarbonyl-N-[3-[5-(4-fluorophenyl- carbonyl)-2-thienyl]-2-cyclopenten-l-yl]-hydroxylamine (0.33g; 0.656mM) in dry CH ₂ C1 ₂ (4ml) was added 2,6-lutidine (0.17ml; 1.44mM) and trimethylsilyl trifluoro- methanesulfonate (0.28ml; 1.44mM) at room tempreture. After stirring for 1 hr, volatiles were removed by evaporation. The residue was dissolved in ethyl acetate (80ml), and the whole was washed with saturated ΝH ₄ C1 solution (50ml x3), water (50ml), brine (100ml), dried over MgSO ₄ , and concentrated in vacuo to give 0.237g of the crude hydroxylamine.

To a stirred solution of the crude hydroxylamine (0.237g; 0.656mM) in dry

THF (7ml) was added TMSNCO (0.13g; 0.984mM) at room temperature. After stirring for 1 hr, ethanol (10ml) was added and the solvent was evaporated in vacuo.

The residue was recrystallized from ethyl acetate to give 0.15g of the title compound. m.p. 206-207 °C (decompose)

'H-NMR (DMSO-d ₆ ); 9.04 (s, IH), 7.92 (dd, J=5.8Hz, 8.0Hz, 2H), 7.66 (d, J=4.1Hz, IH), 7.41 (t, J=8.0Hz, 2H), 7.29 (d, J=4.1Hz, IH), 6.38 (s, 2H), 6.19 (s, IH), 5.37 (br.s, IH), 2.84-2.72 (m, IH), 2.67-2.55 ( , IH), 2.25-2.12 (m, IH), 2.05-1.93 (m, IH). Anal. Calcd. for C ₁₇ H ₁₅ N ₂ O ₃ S C;58.95, H; 4.36, N; 8.09,

Found C; 59.15, H; 4.41, N; 7.79.

Example 7 N-Hvdroxy-N-r3-r3-(O-benzyloxycarboxaldoxime ⁾ phenvn-2-cvclθDenten-l-vnurea The title compound was prepared according to the procedures described in Example 6 using 3-(O-benzyloxycarboxaldoxime)phenyliodide instead of 2-bromo-5-(4- fluorobenzoyl)thiophene. m.p. 166.5-167.5 °C (decompose)

'H-ΝMR (DMSO-d ₆ ); 8.94 (s,lH), 8.32 (s, IH), 7.71 (s, IH), 7.55-7.32 (m, 9H), 6.32 (s, 2H), 6.12 (s, IH), 5.35 (br.s, IH), 5.18 (s, 2H), 2.82-2.71 (m, IH), 2.63-2.56 ( , IH), 2.19-2.12 (m, IH), 2.02-1.93 (m, IH).

Anal. Calcd. for C ₂₀ H ₂₁ Ν ₃ O ₃ : C, 68.36; H, 6.02; N, 11.96. Found: C, 68.07; H, 5.95; N, 11.80.

Example 8 N-Hvdroxy-N-f3-f 5-phenylethenyl)thien-2-vn-2-cvclopenten-l-yllurea The title compound was prepared according to the procedures described in

Example 6 using 2-bromo-5-(phenylethenyl)thiophene instead of 2-bromo-5-(4- fluorobenzoyl)thiophene. m.p. 179-180 °C (decompose)

Η-ΝMR (DMSO-d ₆ ); 8.99 (s,lH), 7.57 (d, J=7.7Hz, 2H), 7.45-7.33 (m, 3H), 7.27 (d, J=7.3Hz, IH), 7.12 (d, J=3.7Hz, IH), 7.03 (d, J=3.7Hz, IH), 6.91 (d,

J= 16.1Hz, IH), 6.35 (s, 2H), 5.84 (s, IH), 5.33 (br.s, IH), 2.82-2.73 (m, IH), 2.62-

2.54 (m, IH), 2.21-2.10 (m, IH), 1.99-1.90 (m, IH).

Anal. Calcd. for C, _g H ₁₈ N ₂ O ₂ S: C, 66.23; H, 5.56; N, 8.58. Found: C, 66.29; H, 5.60; N, 8.44.

Example 9 N-r3-r3-(4-Fluorophenoxymethyl ⁾ phenvn-2-cvclopenten-l-vn-N-Hvdroxyurea

The title compound was prepared according to the procedures described in Example 6 using 3-(4-fluorophenoxymethyl)phenyliodide instead of 2-bromo-5-(4- fluorobenzoyl)thiophene. m.p. 155-157 °C (decompose) 'H-ΝMR (DMSO-d ₆ ); 8.93 (s, lH), 7.56 (S, IH), 7.45-7.34 (m, 3H), 7.12 (t,

J=8.4Hz, 2H), 7.05-6.98 (m, 2H), 6.32 (s, 2H), 6.10 (s, IH), 5.34 (br.s, IH), 5.08 (s, 2H), 2.82-2.71 (m, IH), 2.62-2.50 (m, IH), 2.18-2.08 (m, IH), 2.00-1.92 (m, IH).

Anal. Calcd. for C ₁₉ H ₁₉ FΝ ₂ O ₃ : C, 66.66; H, 5.59; N, 8.18. Found: C, 66.31; H, 5.60; N, 8.16.