WO1994018158A1

WO1994018158A1 - Spiroalkylhydroxyureas for use as lipoxygenase inhibitors

Info

Publication number: WO1994018158A1
Application number: PCT/JP1994/000119
Authority: WO
Inventors: Akiyoshi Kawai; Kazunari Nakao
Original assignee: Pfizer Inc.; Pfizer Pharmaceuticals Inc.
Priority date: 1993-02-15
Filing date: 1994-01-28
Publication date: 1994-08-18

Abstract

The present invention provides novel N-hydroxyurea and hydroxamic acid derivatives of chemical formula (I), wherein R is C1-C4 alkyl or -NR?1R2; R1 and R2¿ are each, independently, hydrogen or C¿1?-C4 alkyl; M is hydrogen or pharmaceutically acceptable cation; p and q are independently integers of two or three, the substituent A is optionally substituted phenyl, furyl, or thienyl, wherein the substituents are each, independently, halogen, C1-C6 alkyl, C1-C6 alkoxy, phenoxy or mono-substituted phenoxy, wherein the substituent in the substituted phenoxy is halogen, C1-C4 alkyl, C1-C4 alkoxy or halosubstituted alkyl; and the substituent A may be attached at any available positions on the spiro-ring. These compounds are useful for treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals and as the active ingredient in pharmaceutical compositions for treating such conditions.

Description

SPIROALKYLHYDROXYUREAS FOR USE AS LIPOXYGENASE INHIBITORS

Technical Field

This invention relates to novel N-hydroxyurea and hydroxamic acid derivatives.

The compounds of the present invention inhibit the action of the lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals, especially human subjects. 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 biologically active endogenous metabolites. The first step in the metabolism of arachidonic acid is its release from membrane phospholipids, via the action of phospholipase A2. Arachidonic acid is then metabolized either by cyclooxygenase to produce prostaglandins including prostacyclin, and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. The leukotrienes are extremely potent substances which elicit a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The peptidoleukotrienes (LTC₄, LTD₄, LTE₄) are important bronchoconstrictors and vasoconstrictors, and also cause plasma extravasation by increasing capillary permeability. LTB₄ is a potent chemotactic agent, enhancing the influx of leukocytes and inducing their subsequent degranulation at the site of inflammation. A pathophysiological role for leukotrienes has been implicated in a number of human disease states including asthma, rheumatoid arthritis and gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel diseases (e.g. Crohn's disease), endotoxin shock, and ischemia-induced myocardial injury. Any agent that inhibits the action of Hpoxygenases is expected to be of considerable therapeutic value for the treatment of acute and chronic inflammatory conditions.

Among the prior art relating to compounds of similar structure to the object compounds of the present invention, there is WO 92/09566 and WO 92/09567.

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

wherein R is C,-C₄ alkyl or -NR'R²;

R¹ and R² are each, independently, hydrogen or C,-C₄ alkyl; M is hydrogen or pharmaceutically acceptable cation; p and q are independently integers of two or three; the substituent A is optionally substituted phenyl, furyl, or thienyl, wherein the substituent(s) are each, independently, halogen, C,-C₆ alkyl, C_ι-C₆ alkoxy, phenoxy or mono- substituted phenoxy, wherein the substituent in the substituted phenoxy is halogen, C_rC₄ alkyl, C,-C₄ alkoxy or halosubstituted alkyl; and the substituent A may be attached at any available positions on the spiro- ring.

A preferred group of compounds of this invention consists of the compounds of formula I, in which R is NH₂, p is 2 or 3, q is 2, A is optionally-substituted 3- phenoxyphenyl, A is at the 6-position and the N(OM)-CO-R group is at the 1-position or the 2-position.

Preferred individual compounds of the present invention are the following: N-Hydroxy-N-[6-(3-phenoxyphenyl)spiro[3,3]hept-2-yl]urea, N-Hydroxy-N-[6-(3-phenoxyphenyl)spiro[3,3]hept-l-yl]urea, N-[6-(4-Fluorophenyl)spiro[3 , 4] oct- 1-yl] -N-hydroxyurea and

N-Hydroxy-N-[6-(3-phenoxyphenyl)spiro[3,4]oct-2-yl]urea.

The compounds can inhibit the action of lipoxygenase. Therefore the compounds are useful for treating a medical condition for which a 5-lipoxygenase inhibitor is needed, in a mammalian subject, e.g., a human subject. The compounds are especially useful for treating inflammatory diseases, allergy and cardiovascular diseases. This invention also embraces pharmaceutical compositions which comprise a compound of the formula (I) and a pharmaceutically acceptable carrier. Detailed Description of the Invention

In this application, the term "halogen" is used herein to mean radicals derived from the elements fluorine, chlorine, bromine and iodine; the term "alkyl" is used herein to mean straight or branched hydrocarbon chain radicals including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like; the term "alkoxy" is used herein to mean -OR₃ (R₃ is alkyl) including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and the like; the term "halosubstituted alkyl" refers to an alkyl radical as described above substituted with one or more halogens including, but not limited to, chloromethyl, bromoethyl, trifluoromethyl and the like; and 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, and the like, as well as those based on non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethyl- ammonium, ethylammonium, diethylammonium, tetraethyl-ammonium, methylamine, dimethylamine, trimethylamine, ethylamine and the like.

The term "optionally-substituted phenyl, furyl or thienyl" means unsubstituted phenyl, furyl or thienyl, or phenyl, furyl or thienyl having up to three substituents. However, unsubstituted and mono-substituted groups are preferred.

The pharmaceutically acceptable salts of the compounds of the invention can be prepared from the compounds of formula I and non-toxic bases including inorganic bases and organic bases. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free acid form with a suitable base such as the above-mentioned pharmaceutically acceptable cation. When the compound of the present invention is basic, salts may be prepared from non-toxic acids including inorganic and organic acids. Such acids include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuricorbisulfuric, phosphoric or acid phosphoric, acetic, lactic, citric or acid citric, tartaric or bi-tartaric, succinic, maleic, fumaric, gluconic, saccharic, benzoic, methanesulfonic, benzenesulfonic, p- toluenesulfonic and pamoic acids and the like.

The pharmaceutical compositions of the present invention comprise a compound of formula I as an active ingredient, and a pharmaceutically acceptable carrier. Optionally, one or more NSAID (non-steroidal antiinflammatory drug) compounds can be added.

The compounds of formula I may be prepared by a number of synthetic methods.

The spiroalkylhydroxyurea compounds of formula I can be prepared from the corresponding ketone of formula IV by methods similar to those described in WO 92/9566.

Compounds of the formula HI are prepared as follows.

π m

In this step the hydroxylamine II is treated with trimethylsilyl isocyanate (TMS- NCO) in a reaction-inert solvent usually at ambient through to reflux temperature. Suitable solvents which do not react with reactants and/or products are, for example, tetrahydrofuran (THF), 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. The intermediate carbamoyl chloride is not isolated but subjected to (i.e. in situ) reaction with a compound of the formula NHR'R². When R¹ and R² are both hydrogen, aqueous ammonia can be conveniently used. The product of formula HI 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 readily prepared by standard synthetic procedures from corresponding carbon yl compound, i.e. ketone or aldehyde.

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, Journal of American Chemical Society, 93, 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 (TFA) may also be employed.

Alternately, hydroxylamine (II) can easily be prepared by treating the corresponding alcohol with N,O-bis(tert-butyloxycarbonyl)hydroxylamine under

Mitsunobu-type reaction conditions followed by acid catalyzed hydrolysis (for example, employing TFA) of the N,O-protected intermediate product (see JP(kokai)45344/ 1989).

The aforementioned hydroxylamine II may also be prepared from suitable halide compound by reaction with O-protected hydroxylamine and subsequent deprotection

(see W. P. Jackson et. al., Journal of Medicinal Chemistry, 31, 499, 1988). Preferred O-protected hydroxylamines are, but not limited to, O-tetrahydropyranyl-, O-trimethylsilyl- and O-benzylhydroxylamine.

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

Certain compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention contemplates all such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.

Ketones of formula IV ( e.g., spiro[3,3]hept-2-one and spiro[3,4]oct-2-one ) can be prepared from the corresponding cycloalkylidene of formula (V) by [2+2] cycloaddition reaction with a ketene equivalent.

For example, 6-(3-phenoxyphenyl)spiro[3,3]hept-2-one was prepared by the cycloaddition of 3-(3-phenoxyphenyl)cyclobutylidene with dichloroketene followed by the reductive dechlorination with zinc. Ketene and dichlorodifluoroethylene can be also useful as a ketene equivalent (S. L. Manatt, M. Vogel, D. Knutson, and D. Roberts,

J. Am. Chem. Soc., 86, 2645(1964)).

The cycloalkylidene can be prepared from the corresponding cycloalkanone by the methylenation reported by Wittig, Peterson, Tebbe, Mitsunobu and so on ( E. J.

Corey and J. Kang, J. Am. Chem. Soc, 104, 4724 (1982); D. J. Peterson, J. Org.

Chem., 33, 780(1968); S. H. Pine, G. S. Shen, H. Hoang, Synthesis, 165(1991); O.

Mitsunobu, Synthesis, 1(1981)).

The corresponding cycloalkanone can be prepared by the method described in International Publication No. WO 92/09566.

Spiro[3,3]hept-l-one and spiro[3,4]oct-l-one can be prepared by the method reported by Trost ( B. M. Trost and M. J. Bogdonowicz, J. Am. Chem. Soc., 95,

5321(1973)). For example, 6-(3-phenoxyphenyl)spiro[3,3]hept-l-onewas prepared by the oxaspiroannelation of 3-(3-phenoxyphenyl)-cyclobutanone with cyclopropyldi- -7- phenylsulfonium tetrafluoro-borate followed by acid treatment.

Spiro[3,4]oct-2-one and spiro[4,4]nona-2-one can be prepared by the intra¬ molecular Aldol condensation or the acid catalyzed intramolecular Aldol reaction (S. F. Martin and T.-s. Chou, J. Org. Chem., 43, 1027(1978)).

Spiro[4,4]nona-l-one can be also prepared by the intramolecular Aldol cychzation or the metal catalyzed intramolecular hydroacylation ( R. C. Larock, K. Oertie and G. F. Potter , J. Am. Chem. Soc, 102, 190(1980)). These methods are -8- applicable for all the "A" substituents in this patent.

The compounds of this invention inhibit the activity of lipoxygenase enzyme. This inhibition has been demonstrated by an assay using rat peritoneal cavity resident cells which determines the effect of said compounds on the metabolism of arachidonic acid.

The compounds of Examples 1 to 4 were tested according to the methods described in Japanese Journal of Inflammation 7: 145-150 (1987), "Synthesis of leukotrienes by peritoneal macrophages" and were shown to possess the efficacy of inhibiting lipoxygenase enzyme. In this test some preferred compounds indicated low

IC_JO values, in the range of about 0.1 to about 1 _/_M, with respect to lipoxygenase activity.

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

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 formula I can be administered to a human subject either alone, or preferably in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice.

The compounds can be administered to a human subject by various conventional routes of administration including oral, parenteral and by inhalation. When the compounds are administered orally, the dose range will be from about 0.1 to 20 mg/kg of body weight of the subject to be treated per day, preferably from about 0.1 to 5 mg/kg per day in single or divided doses, more preferably from about 0.1 to 1.0 mg/kg per day in single or divided doses. If parenteral administration is desired, then an effective dose will be from about 0.1 to 1.0 mg/kg of body weight of the 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 emulsifying and suspending agents. If desired, certain sweetening 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, q - quartet, quint - quintet, m - multiplet, br - broad. Synthesis of starting materials

3-(3-Phenoxyphenyl)cyclobutanone, 3-(4-fluorophenyl)cyclopentanone and 3-(3-phenoxyphenyl)cyclopentanone were prepared according to the procedure described in WO 92/9566.

Cyclopropyldiphenylsulphonium tetrafluoroborate was prepared according to the procedure reported in "Organic Synthesis", 54, p.27.

Example 1 N-Hvdroxy-N-r6-(3-phenoxyphenvI)spiro.3.3,hept-2-vπurea

(A) 3-.3-Phenoxyphenyl)cvclobutylidene

To a stirred solution of 3-(3-phenoxyphenyl)-cyclobutanone (4.76 g; 20 mM) in diethyl ether (30 ml) was added 3M solution of methylmagnesium bromide (8.4 ml;

25 mM) at 0-5 °C under nitrogen. After completion of addition, the mixture was refluxed for 30min. After cooling, the mixture was poured into saturated aqueous NH₄C1 (50 ml). The whole was extracted with ethyl acetate (100 ml x3), the combined organic layers washed with water (30 ml), brine (60 ml), dried over MgSO₄, and concentrated in vacuo to provide 5.7 g of crude alcohol.

To a stirred solution of the crude alcohol (5.7 g; 17.4 mM) in toluene (80 ml) was added triphenylphosphine (7.17 g; 27.3 mM) and diethyl azodicarboxylate (4.76 g; 27.3 mM) at room temperature. Then the mixture was heated at 70-90°C for 1 hr. After cooling, volatiles were removed. The residue was purified on silica gel column chromatography (eluted with n-hexane) to provide 3.45 g of the title compound as a colorless oil. (Yield is 73% from 3-(3-phenoxyphenyl)-cyclobutanone.)

Η-NMR CDCUδ: 7.36-6.80(m, 9H), 4.82(d of d, J= 2.5Hz, 4.4Hz, 2H), 3.56-3.43(m, 1H), 3.17-3.03(m, 2H), 2.90-2.77(m, 2H).

(B) 6-(3-Phenoχyphenyl)spiror3.31hept-2-one To a stirred suspension of exo methylene compound from Part (A),

3-(3-Phenoxyphenyl)cyclobutylidene (3.3 g; 14 M), and zinc-copper couple (1.01 g; -11- lS.4 mM) in dry diethyl ether (30 ml) was added a solution of trichloroacetyl chloride (CCl₃COCl, 1.72 ml; 15.4 mM) and phosphorus oxychloride (POCl₃, 1.44 ml; 15.4 mM) in diethyl ether (10 ml) dropwise under nitrogen at room temperature. After completion of addition, the mixture was refluxed two overnights. After cooling, the mixture was poured into water (60 ml).

The whole was extracted with diethyl ether (50 ml x2), the combined organic layers washed with water (50 ml), saturated aqueous NaHCO, (50 ml), water (50 ml), brine (100 ml), dried over MgSO₄, and evaporated in vacuo to provide 4.3 g of dichloroketone, which was used without further purification. To a stirred solution of crude dichloroketone (4.3 g) in acetic acid (AcOH, 30 ml) was added zinc (4 g;

61.8 mM) at room temperature. After stirring for 2 hrs, the mixture was filtered through a pad of Celite. The Celite cake was washed with ethyl acetate (25 ml x2). The filtrate was evaporated in vacuo, and water (100 ml) was added. The whole was extracted with ethyl acetate (70 ml x3), the combined organic layers was washed with water (50 ml x2), brine (50 ml), dried over MgSO₄, and evaporated in vacuo. The chromatographic purification of the residue (eluted with n-hexane-ethyl acetate (8:1)) provided 2.67 g (56%) of 6-(3-Phenoxyphenyl)spiro[3,3]hept- 2-one.

Η-NMR(CDCl,)δ: 7.37-7.23(m, 3H), 7.13-7.07(m, 1H), 7.02-6.81(m, 5H), 3.62-3.47(m, 1H), 3.25-3.22(m, 2H), 3.05-3.02(m, 2H), 2.62-2.53(m, 2H), 2.46-2.37(m, 2H).

(C) 6-(3-Phenoxyp_ιenyI)spiror3.3.hept-2-ol

To a cooled, stirred solution of lithium tri-tert-butoxyaluminum hydride (LiAl(OBu),H) (2.95 g; 11.6 mM) in THF (25 ml) was added dropwise a solution of the spiro[3,3]hept- 2-one from Part (B) (2.67 g; 9.67 mM) in THF (8 ml) at -70°C under nitrogen. After stirring for 3 hrs, saturated aqueous NH₄C1 (7 ml) was added and was stirred for 0.5 hr. Then MgSO₄ was added, filtered, and evaporated in vacuo to provide 2.36 g (87%) of the title alcohol compound.

'H-NMR CDC^δ: 7.36-7.20(m, 3H), 7.12(t, J= l. lHz, 1H), 7.09-6.77(m, 5H), 4.22(q, J=7.0Hz, 1H), 3.41(q, J=9.2Hz, 1H), 2.66-2.55(m, 1H), 2.42-2.26(m, 3H), 2.12(q, J= 10.2Hz, 2H), 2.05-1.82(m, 2H).

(D) 6-f3-Phenoxyphenyl)spiro[3,31heptyl-2-N.O-bis(tert-butoxycarbonyl)hvdroxyl- amine

To a stirred solution of the alcohol compound from Part (C) (2.36 g; 8.49 mM) in THF (20 ml) was added N,O-bis-tert-butoxycarbonylhydroxylamine (Boc-NH-OBoc, 2.28 g; 9.76 mM), triphenylphosphine (2.56 g; 9.76 mM) and a solution of diethylazo- dicarboxylate (1.7 g; 9.76 mM) in THF (4 ml) at room temperature under nitrogen.

After stirring for 1.5 hrs, volatiles were removed. n-Hexane (15 ml) was added, and the resulting precipitates were filtered off. The filtrate was evaporated in vacuo, and the residue was purified on silica gel column chromatography (eluted with n-hexane-ethyl acetate (50: 1)) to provide 2.9 g (69%) of the desired title product. Η-NMR(CDCl,)δ: 7.36-7.20(m, 3H), 7.12-6.77(m, 6H), 4.60-4.47(m, 1H),

3.45-3.33(m, 1H), 2.50-2.09(m, 8H), 1.54(s, 9H), 1.47(s, 9H). (E) N-Hvdroxy-N-{6-(3-phenoxy^phenyl⁾spiror3.3-he^pt-2-vUurea

To a stirred solution of N,O-bis-tert-butoxycarbonyl-hydroxylamine from Part (D) (2.8 g; 5.68 mM) in CH₂C1- (20 ml) was added trifluoroacetic acid (4.5 ml; 57 mM) at room temperature. After stirring for 3 hrs, volatiles were removed. Saturated aqueous NaHCO₃ (50 ml) was added, and the whole was extracted with ethyl acetate (50 ml x4), the combined organic layer was washed with water (50 ml), brine (70 ml), dried over MgSO₄, and was concentrated in vacuo. This provided 1.86 g of hydroxylamine as a colorless solid, which was used without further purification. To a stirred solution of crude hydroxylamine (1.86 g) obtained above in THF

(20 ml) was added trimethylsilyliso-cyanate (TMSNCO, purity 85%, 1.12 g; 8.25mM) at room temperature under nitrogen. After stirring for 2 hours, MeOH (10 ml) was added. Volatiles were removed, and the resulting solid was recystallized from ethyl acetate and n-hexane (1: 1). This provided 0.96 g (50%) of N-Hydroxy-N-{6-(3- phenoxyphenyl)spiro[3,3]hept-2-yl}urea as colorless crystals. m.p.: 130-132°C. IR(nujol)cm ': 3300, 1650, 1575, 1250, 1165, 770, 690. ¹H-ΝMR(DMSO-d6)δ: 9.05(s, 1H), 7.41-7.35(m, 2H), 7.29(t, J=7.7Hz, lH), 7.13(t, J=7.3Hz, 1H), 7.00-6.96(m, 3H), 6.83(s, 1H), 6.77(d of d, J=2.6Hz, 8.1Hz, 1H), 6.24(s, 2H), 4.60-4.49(m, 1H), 3.42-3.35(m, 1H), 2.47-1.85(m, 8H). Example 2

N-Hvdroxy-N-r6-(3-phenoxyphenvI)spiror3.31hept-l-vπurea (A) 6-(3-Phenoxyphenyl)spiror3.3-hept-l-one

To a cooled (-40 °C), stirred suspension of cyclopropyldiphenylsulphonium tetrafluoroborate (5.9 g; 18.8 mM) in dimethoxyethane (DME, 190ml) was added sodium dimsyl (22 ml of 1.02 M dimethyl sulfoxide solution; 22.6 mM) rapidly at -40°C. After stirring for 5 min, a solution of 3-(3-phenoxyphenyl)cyclobutanone

(4.47 g; 18.8 mM) in DME (20 ml) was added at same temperature., The mixture was stirred for 15 min at -40°C, and then stirred for 1 hour at room temperature. To the mixture was added 42% aqueous tetrafluoroboric acid (HBF₄, 38 ml), and the whole was extracted with diethyl ether (150 ml xl , 100 ml xl). The combined organic layers were washed with water (70 ml), brine (100 ml), dried over MgSO₄, and concentrated in vacuo. Chromatographic purification of the residue eluted with n-hexane-ethyl acetate (30:1)) provided 1 g (19%) of spiro[3,3]hept-l-one as diastereomeric mixture of 4: 1.

Η-NMR(CDCl,)δ: 7.37-6.80(m, 9H), 3.69-3.50(m, 1H), 3.01-2.94(m, 2H), 2.80-2.72(m, 1.62H), 2.67-2.56(m, 0.38H), 2.54-2.44(m, 0.38H), 2.32-2.19(m,

1.62H), 2.00(m, 2H).

(B) N-Hvdroxy-N-r6-(3-phenoxyphenγl)spiror3.3.hept-l-yl.urea

To a stirred solution of spiro[3,3]hept-l-one from Part (A) (1 g; 3.6 mM) in EtOH (8 ml) and pyridine (2 ml) was added hydroxylamine hydrochloride (0.3 g) at room temperature. After stirring for 1 hour, solvent was removed. 10% Aqueous citric acid (30 ml) was added, and the whole extracted with ethyl acetate (70 ml x3), the combined organic layers washed with water (40 ml), brine (70 ml), dried over MgSO₄, and concentrated in vacuo to provide 1.14 g of oxime, which was used without further purification. To a stirred solution of crude oxime (1.14 g) in AcOH (7 ml) was added sodium cyanoborohydride (NaBH₃CN, 0.367 g; 5.8 mM) at room temperature. After stirring for 30 min, the mixture was poured into ice and 15% aqueous NaOH (100 ml). The whole was extracted with diethyl ether (70 ml x3), the combined organic layers washed with water (50 ml), brine (70 ml), dried over MgSO₄, and concentrated in vacuo to provide 1.04 g of hydroxylamine, which was used without further purification. To a stirred solution of crude hydroxylamine (1.04 g) in THF (10 ml) was added TMSNCO (0.62 g; 4.58 mM) at room temperature. After stirring for 15 min, MeOH (10 ml) was added. Solvent was concentrated in vacuo, and the residue was purified on silica gel column chromatography (eluted with CH₂C1, and EtOH (40: 1)) to provide 0.616 g (52%) of the title hydroxyurea as a diastereomeric mixture of 4: 1. m.p.: 87-90°C.

IR(nujol)cm ': 1630, 1580, 1210, 1150, 980, 690. Η-NMR(DMSO-d6) δ: 9.19(s, 0.81H), 9.03(s, 0.19H), 7.42-6.75(m, 9H), 6.30(s, 1.62H), 6.27(s, 0.38H), 4.49-4.42(m, 0.81H), 4.33-4.25(m, 0.19H), 3.32-3.22(m, 1H), 2.88-2.79(m, 1H), 2.50-2.40(m, 1H), 2.25-1.54(m, 6H).

Example 3 N-r6-(4-Fluorophenyl)spiror3.41oct-l-yl1-N-hydroxyurea

(A) 6-(4-Fluorophenyl.spiror3.41octan-l-one

A suspension of cyclopropyldiphenylsulfonium fluoro-borate (1.8 g, 5.6 mM) in DME (50 ml) was cooled to -50°C. Sodium dimsyl (10 ml of 1.12 M dimethyl sulfoxide solution, 11.2 mmol) was added rapidly at -50°C. After being stirred for 5 min, 3-(4-fluorophenyl)cyclopentanone (1.0 g, 5.6 mM) was added and the mixture stirred for 30 min at -50°C. Then, the mixture was allowed to warm to room temperature and stirred for lhr. To the mixture was added 42% aqueous HBF₄ (10 ml) and the whole extracted with diethyl ether (200 ml). The organic extract was washed with water (100 ml), and dried over MgSO₄. Removal of solvent gave a yellow oil, which was purified on silica gel (300 g) column chromatography eluted with ethyl acetate-n-hexane (1:20-1:4) to afford 893 mg (73%) of 6-(4-fluorophenyl)spiro

[3,4]octan-l-one as a colorless oil. 'H-NMR(CDCl₃)δ: 7.24-7.14(m, 2H), 7.01-6.93(m, 2H), 3.22-2.99(m, 3H),

2.49-2.24(m, 1H), 2.19-1.66(m, 7H).

(B) N-[6-(4-FIuorophenyl)spiror3,41oct-l-vn-N-hvdroxyurea

To a stirred solution of 6-(4-fluorophenyl)spiro[3,4] -octan-1-one (556 mg, 2.5 mM) in pyridine (5 ml) was added hydroxyamine hydrochloride (265 mg, 3.8mM) at room temperature. After stirring for 19hr, the mixture was poured into water (50 ml) and the whole extracted with diethyl ether (50 ml). The organic extract was washed with 10% citric acid solution (50 ml), water (50 ml) and saturated aqueous NaHCO₃ solution (50 ml), dried over Na₂SO₄, and concentrated in vacuo.

The resulting oil was dissolved in AcOH (5ml) under nitrogen. To the solution was added NaBH₃CN (242 mg, 3.9 mM) at room temperature. After stirring for lhr, to the mixture was added water (5 ml). The mixture was poured into ice- ION NaOH

(100 ml) and the whole extracted with diethyl ether (100 ml). The organic extract was washed with water (100 ml), dried over MgSO₄ and concentrated in vacuo.

The residual oil was dissolved in THF (5 ml) and TMSNCO (0.42 ml, 2.7 mM) was added. After stirring for 1.5hr, to the mixture was added MeOH (5 ml) and the mixture concentrated in vacuo. The residual oil was purified on silica gel (50 g) column chromatography eluted with CH₂Cl₂-MeOH (40: 1) to afford 408 mg of white solid. The obtained solid was washed with diethyl ether-n-hexane (1:10) to give 348 mg (50%) of N-{6-(4-fluorophenyl)spiro[3,4]oct-l-yl}-N-hydroxyurea as a white powder. m.p.: 86-89°C.

IR(KBr)cm ¹: 3500, 1630, 1510, 1440, 1230.

•H-NMR(DMSO-d6)δ: 9.16(s, 0.27H), 9.11(s, 0.46H), 9.05(s, 0.27H), 7.27-7.01(m, 4H), 6.23(s, 1H), 6.21(s, 1H), 4.48-4.31(m, 1H), 3.10-2.49(m, 1H), 2.31-1.22(m, 10H). Example 4

N-Hvdroxy-N-r6-⁽3-phenoxyphenyl.spiror3_4.oct-2-vπurea (A) 3-(3-Phenoxyphenyl⁾cvclopentylidene

To a stirred solution of 3-(3-phenoxyphenyl)cyclo-pentanone (3.74 g, 15 mM) in THF (100 ml) was added Tebbe reagent (0.5 M soln. in toluene; 32.6 ml, 16 mM) at -50°C. The resulting red solution was stirred at -50 °C for 3hr. To the mixture was added 15% aqueous NaOH (6 ml) with vigorously stirring. The mixture was dried over MgSO₄ and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residual oil was purified on silica gel (300 g) column chromatography eluted with ethyl acetate-n-hexane (1:20) to afford 2.76 g (74%) of 3-(3- phenoxyphenyl)cyclopentylidene as a yellow oil.

Η-NMR(CDCl₃)δ: 7.38-6.88(m, 9H), 4.89(d, J=6.22Hz, 2H), 3.20-3.04(m, 1H), 2.86-2.67(m, 1H), 2.59-2.30(m, 3H), 2.20-2.07(m, 1H), 1.83-1.63(m, 1H). (B) 6-(3-Phenoxyphenyl)spiror3.41octan-2-one

To a stirred mixture of 3-(3-phenoxyphenyl)cyclo-pentylidene (2.64 g, 10.5 mM), Zn-Cu couple(1.80 g, 27.0 M) in dry diethyl ether (50 ml) was added a solution of Cl₃CCOCl (1.53 ml, 13.7 mM) and POCl₃ (1.28 ml, 13.7 mM) in diethyl ether (20 ml) with water-bath cooling. The resulting mixture was stirred at reflux temperature for 3hr and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residual oil was extracted with diethyl ether-n-hexane (1:5, 2x200 ml) by decantation. The organic extracts were washed with water (300 ml) and brine (300 ml). The organic layer was dried over MgSO₄ and concentrated in vacuo. The residual oil was dissolved in AcOH (50 ml). To the solution was added Zn powder (2.06 g, 32.0 mM) and the mixture was stirred at room temperature for 0.5hr. The resulting mixture was filtered through a pad of Celite. The filtrate was diluted with diethyl ether-n-hexane (1:2, 300 ml) and washed with water (3x200 ml), saturated aqueous NaHCO₃ (3x200 ml), brine (200 ml). The organic phase was dried over

MgSO₄ and concentrated in vacuo. The residual oil was purified on silica gel (300 g) column chromatography eluted with ethyl acetate-n-hexane (1:20) to afford 2.06 g (67%) of 6-(3-phenoxyphenyl)spiro[3,4]octan-2-one as a colorless oil.

'H-NMR(CDCl₃)δ: 7.40-6.80(m, 9H), 3.35-2.94(m, 4H), 2.31-1.47(m, 7H). (C) 6-(3-Phenoxyphenyl)spiror3.41octan-2-ol

To a stirred solution of LiA OΗu^H (2.6 g, 10.3 mM) in THF (30 ml) was added a solution of 6-(3-phenoxyphenyl)-spiro[3,4]octan-2-one(2.0 g, 6.8 mM) in THF (10 ml) at -70°C under nitrogen. After stirring for 17 hr the mixture was allowed to warm to room temperature and stirred for 0.5 hr. To the mixture was added saturated aqueous NH₄C1 (5 ml) and the mixture was stirred for a few minutes. The mixture was dried over MgSO₄ and concentrated in vacuo. The residual oil was purified on silica gel (500 g) column chromatography eluted with ethyl acetate-n-hexane (1:5) to afford 769 mg (38%) of 6-(3-phenoxyphenyl)spiro- [3,4]octan-2-ol as a colorless oil.

^>H-NMR(CDCl₃)δ: 7.39-6.76(m, 9H), 4.34-4.20(m, 1H), 3.10-2.95(m, 1H), 2.42-2.30(m, 2H), 2.15-1.51(m, 8H).

(D) N-H vdroxy-N-fθ- (3-phen oxyph en yl) spiro- .3.41 oct-2-yll u rea To a stirred solution of 6-(3-phenoxyphenyl)spiro[3,4]-octan-2-ol (759 mg, 2.6 mM), BocNHOBoc (793 mg, 3.4 mM) and triphenylphosphine (Ph₃P, 891 mg, 3.4mM) in THF (10 ml) was added diethyl azodicarboxylate (0.54 ml, 3.4 mM) at room temperature. After stirring for 23hr, the mixture was concentrated in vacuo. To the residual oil was added n-hexane-diethyl ether (10: 1 , 50 ml). The resulting precipitates were filtered off and washed with n-hexane (2x50 ml). The combined filtrates were concentrated in vacuo and the residue was purified on silica gel (100 g) column chromatography eluted with ethyl acetate-n-hexane (1: 10) to give 1.216 g of a yellow oil. The obtained oil was dissolved in CH₂C1₂ (5 ml). To the solution was added

CF₃COOH (5 ml) at room temperature. After stirring for 1 hr, the mixture was concentrated in vacuo. To the residue was added saturated aqueous NaHCO₃ (50 ml) and the whole extracted with CH₂C1₂ (2x30 ml). The organic extracts were dried over MgSO₄ and concentrated in vacuo. The residual oil was dissolved in THF (5 ml). To the solution was added

TMSNCO (0.33 ml, 1.9 mM) at room temperature. After stirring for lhr, to the mixture was added MeOH (2 ml). The resulting mixture was concentrated in vacuo and the residual solid was recrystallized from ethyl acetate-n-hexane to afford 253 mg (28%) of N-Hydroxy-N-[6-(3-phenoxyphenyl)-spiro[3,4]oct-2-yl]urea as a white powder. m.p.: 101-113°C.

IR KB^cπr¹: 3500, 1660, 1640, 1580, 1490. ¹H-NMR(DMSO-d6)δ: 9.08(s, 1H), 7.46-6.67(m, 9H), 6.23(s, 2H), 4.68-4.50(m, 1H), 3.12-2.90(m, 1H), 2.35-1.40(m, 10H).

Claims

-18- CLAIMS

1. A compound of the following chemical formula:

wherein R is C_rC₄ alkyl or -NR'R²; R¹ and R² are each, independently, hydrogen or C,-C₄ alkyl;

M is hydrogen or pharmaceutically acceptable cation; p and q are independently integers of two or three; the substituent A is optionally substituted phenyl, furyl, or thienyl, wherein the substituents are each, independently, halogen, C,-C₆ alkyl, C,-C₆ alkoxy, phenoxy or mono-substituted phenoxy, wherein the substituent in the substituted phenoxy is halogen, C_rC₄ alkyl, C C₄ alkoxy or halosubstituted alkyl; and the substituent A may be attached at any available position on the spiro-ring.

2. A compound according to claim 1, wherein R is -NH₂.

3. A compound according to claim 2 wherein both p and q are integer two, the N(OM)-CO-R group is at the 1-position or the 2-position and A is at the 6-position.

4. A compound according to claim 3 wherein A is 3-phenoxyphenyl which may be substituted.

5. A compound according to claim 2 wherein p is integer three and q is integer two, the N(OM)-CO-R group is at the 1-position or the 2-position and A is at the 6- position.

6. A compound according to claim 5 wherein A is optionally-substituted 3- phenoxyphenyl.

7. A compound according to claim 5 wherein A is halo- substituted phenyl.

8. A compound according to claim 1 , wherein the compound is selected from: N-Hydroxy-N-[6-(3-phenoxyphenyl)spiro[3,3]hept-2-yl]urea;

N-Hydroxy-N-[6-(3-phenoxyphenyl)spiro[3,3]hept-l-yl]urea; N-[6-(4-Fluorophenyl)spiro[3,4]oct-l-yl]-N-hydroxyurea; and

N-Hydroxy-N-[6-(3-phenoxyphenyl)spiro[3,4]oct-2-yl]urea.

9. A pharmaceutical composition for the treatment of inflammatory diseases, allergy and cardiovascular diseases in a mammalian subject which comprises a therapeutically effective amount of a compound of claim 1 and its pharmaceutically acceptable carrier.

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

11. A method according to claim 10, wherein the medical condition is an allergic or inflammatory condition.

12. A process for preparing a compound according to claim 1, which comprises reacting a hydroxylamine of the formula

with either (A) trimethylsilyl isocyanate in a reaction-inert solvent, or (B) gaseous hydrogen chloride and phosgene in a reaction-inert solvent, followed by a compound of the formula NHR'R².