Antiinflammatory benzoxazolones

Abstract: This invention relates to certain benzoxazolinones which inhibit lipoxygenase and/or cyclooxygenase enzymes. Such compounds are useful in inhibiting such enzymes, per se, and are useful in treating allergic and inflam­ matory conditions in a mammal. This invention also relates to methods of inhibiting lipoxygenase and/or cyclooxygenase in a mammal with such benzoxazolinones; methods of treating an allergic condition in a mammal with such compounds; methods of treating an inflammatory condition in a mammal with such compounds; and pharma­ ceutical compositions comprising the benzoxazolinones hereof.

Description: This invention relates to benzoxazolinones. More specifically, this invention relates to certain benzoxazolinone compounds substituted not only at the 6-position with an amino side chain but also at the 4-, 5- or 7-position of the benzo-ring. Such compounds inhibit the action of lipoxygenase and/or cyclooxygenase enzymes and are useful as inhibitors of those enzymes, per se. The compounds of this invention are also useful in the treatment of a variety of allergic and inflammatory conditions in mammals. This invention also relates to pharmaceutical compositions comprising such benzoxazolinone compounds. European patent application, published December 16, 1987 under No. 249407, discloses benzoxalone compounds having an alkylamino group at the 6-position, which are lipoxygenase and/or cyclooxygenase inhibitors. This invention provides novel benzoxazolinone compounds of the formula: or a pharmaceutically-acceptable acid addition salt thereof, wherein Alk is a C n straight or branched chain divalent alkyl group; n is 0, 1, 2, 3, 4 or 5; R₁ is (C₁-C₃)alkyl or (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, hydrogen, halo, phenoxy, phenylthio or trifluoromethyl; and R is selected from the group consisting of: (a) wherein R₂ and R₃ are each, independently, H, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, or halo, X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen, sulfur, sulfoxide or sulfone, and the dotted line between the 2- and 4- positions represents an optional bond between positions 2 and 3 or positions 3 and 4; (b) wherein A and B are each, independently, O or S; (c) or (d) wherein R₄ and R₅ are each, independently, H or (C₁-C₄)alkyl, p is 0, 1 or 2 and t is 0, 1 or 2 provided that the sum of p plus t equals 1 or 2; and the wavy line indicates that the moiety containing such wavy line can be endo - or exo -7-oxabicyclo[2,2,1]heptan-1-yl; and (e) CH₃-(CH₂) m -Y- wherein m is an integer from 1 to 3 and Y is oxygen, sulfur, sulfoxide or sulfone. The term "halo" as used herein means fluoro, chloro, bromo or iodo. The term "nitrogen protecting group" as used herein means t-butoxycarbonyl, benzoyloxycarbonyl, acetyl or formyl. A preferred group of compounds are those wherein n is 0 or 1, R₁ is halo, R is a member selected from Group (a). Especially preferred are those wherein R₁ is 5-fluoro and X is oxygen. A second preferred group of compounds are those wherein n is 1, R₁ is halo and R is a member selected from Group (c). Especially preferred are those wherein R₁ is 5-fluoro. A third preferred group of compounds are those wherein n is 1, R₁ is (C₁-C₃)alkyl, and R is a member selected from Group (a). Especially preferred are those wherein R₁ is 5-ethyl and X is oxygen. A fourth preferred group of compounds are those wherein n is 1 and R is a member selected from Group (d). Especially preferred are those wherein R₁ is 5-fluoro. A fifth preferred group of compounds are those wherein R₁ is halo and R is a member selected from Group (e). Especially preferred are those wherein R₁ is 5-fluoro, m is 1 and Y is oxygen. A sixth preferred group of compounds are those wherein R₁ is (C₁-C₃)alkoxy and R is a member selected from Group (a). Especially preferred are those wherein R₁ is methoxy, n is 1 and X is oxygen. The compounds of formula (I) may contain an asymmetric center, and therefore may exist as a pair of enantiomers. This invention is to be considered as embracing each pure enantiomer thereof, the racemates thereof and a mixture of the enantiomers thereof, partially or completely optically resolved. The pharmaceutically-acceptable acid addition salts of the compounds of the formula (I) are those formed from acids which form non-toxic acid addition salts, for example, the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulfonate, benzene sulfonate, toluenesulfonate, and formate salts. This invention includes pharmaceutical compositions for treatment of allergic inflammatory conditions in a mammal which comprise a pharmaceutically-acceptable carrier or diluent and a compound of formula (I) or a pharmaceutically-acceptable acid addition salt thereof. This invention also includes pharmaceutical compositions for inhibiting the action of lipoxygenase enzyme and/or cyclooxygenase enzyme in a mammal which comprise a pharmaceutically-acceptable carrier and a compound of formula (I) or a pharmaceutically-acceptable acid addition salt thereof. The novel compounds of formula (I) may be prepared by the following reaction scheme: In the above formulae, Alk; R; and R₁ are as previously defined and n is 0, 1, 2, 3 or 4. In the first step, approximately equimolar amounts of the reactants, amine (II) and aldehyde (III) are combined in a suitable organic solvent. While the reaction is preferably conducted at ambient temperature, higher temperatures, for example, reflux, can be used without any significant disadvantages. Suitable organic solvents include (C₁-C₄)alkanol (e.g., methanol or ethanol), benzene, toluene and tetrahydrofuran. It may be advantageous to use a dehydrating agent. Molecular sieves are a preferred dehydrating agent. Optionally, a small amount of lower alkanoic acid such as acetic acid is added to catalyze the reaction. The reaction is essentially complete within 24 hours. The product of the formula (IV) can be isolated and purified by conventional procedures, e.g. recrystallization or chromatography, when the resulting imine is conjugated with an unsaturated group. It is, however, more convenient not to isolate this product but to subject it (i.e., in situ ) to reaction conditions of the second step. The second step of the reaction involves reduction of the C=N double bond by reaction with an appropriate hydrogen source. While the reduction may be carried out by employing a wide variety of reducing agents which are known to reduce a carbon-nitrogen double bond, the preferred method of this invention employs a metal hydride reagent or catalytic hydrogenation reaction. The hydride reagents suitably employed in this reaction include sodium borohydride, sodium cyanoborohydride and lithium cyanoborohydride. Typically, the reduction is carried out at ambient temperature, with an excess of the hydride reagent in (C₁-C₄)alkanol such as methanol or ethanol. A catalytic hydrogenation reaction employs a catalytic amount of a noble metal catalyst such as Pd/C or PtO₂ under hydrogen atmosphere. When the reduction is substantially complete, the desired product of formula (I) is isolated by standard methods. Purification can be achieved by conventional means, such as recrystallization or chromatography. Certain compounds of formula (I) wherein n is 0 and R is a member selected from Group (a) are also obtained substantially in a similar manner to the process described above. However, for this group of compounds the process requires a ketone instead of aldehyde (III). Preferably, the required ketone can be any one of the following: where X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen or sulfur and R₂ and R₃ are as defined above. For example, coupling of the compound (II) and the ketone (V) yields the imine of formula (VIII). The latter compound is readily reduced to the desired compound (I). Convenient conditions for the above two-step conversion are not significantly different from those employed with the synthesis of compounds (I) where n is other than 0. Compounds of formula (I) wherein R is a member of Group (a) wherein X is sulfoxide or sulfone; or R is a member of Group (e) wherein Y is sulfoxide or sulfone are prepared by oxidation of the corresponding compounds wherein X and Y are sulfur. The unoxidized compounds are prepared as described above. Suitable oxidation conditions include, but are not limited to, reaction of such compounds with alumina supported sodium metaperiodate in a suitable solvent such as (C₁-C₃)alkanol and/or tetrahydrofuran. The olefinic products of formula (I), i.e., those having an optional double bond between the 2- and 4-positions of the R radical are themselves active inhibitors of LO/CO enzymes and also serve as intermediates for preparation of the corresponding reduced compounds of the formula: A particularly preferred method for such reduction comprises hydrogenating a compound of formula (I) to be reduced under hydrogen in the presence of a noble metal catalyst in a suitable solvent. Suitable solvents for this hydrogenation are, for example, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate and (C₁-C₃)alkanol such as methanol or ethanol. The noble metal catalysts used are known in the art, for example, nickel, palladium, platinum and rhodium. Particularly preferred agents are platinum oxide and palladium on carbon. A platinum catalyst is sometimes more preferred because it is not readily poisoned by sulfur. This hydrogenation requires low hydrogen pressure (1 to 4 atm) and runs at ambient temperature. When the hydrogenation is complete (from about 2 hours to 24 hours), the catalyst is removed by filtration and the product of formula (IX) is then isolated and purified, if desired, by a conventional method. 6-Aminobenzoxazolin-2-ones (II) are prepared by a variety of methods known in the art and illustrated in the Preparations hereinbelow. The aldehydes or ketones required for the above syntheses are available commercially, or by preparation according to literature methods. The pharmaceutically-acceptable salts of the novel compounds of the present invention are readily prepared by contacting said compounds with a stoichiometric amount of an appropriate mineral or organic acid in either aqueous solution of in a suitable organic solvent. The salt may then be obtained by precipitation or by evaporation of the solvent. The compounds of this invention inhibit the activity of the lipoxygenase and/or cyclooxygenase enzymes. 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. In this test some preferred compounds indicate low IC50 values, in the range of 0.5µ to 30µM, with respect to both lipoxygenase/cyclooxygenase inhibitions. The ability of the compounds of the present invention to inhibit lipoxygenase and/or cyclooxygenase enzymes make 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. The activity of the compounds of this invention can also be demonstrated in the standard carrageenin-induced rat foot edema test (C. A. Winter et al., Proc. Soc. Exp. Biol. III, p 544, 1962). Thus, the compounds of formula (I) and their pharmaceutically-acceptable salts are of particular use in the treatment or alleviation of allergic or inflammatory conditions in a human subject as well in the inhibition of the cyclooxygenase and lipoxygenase enzymes. For treatment of the various conditions described above, the compounds of formula (I) and their pharmaceutically-acceptable salts 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. A compound can be administered by a variety of conventional routes of administration including orally, parenterally and by inhalation. When the compounds are administered orally, the dose range will be from about 0.1 to 20 mg/kg body weight of the subject to be treated per day, 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 0.1 to 1.0 mg/kg 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 dosage 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 formula (I) 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. 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 for solutions in perdeuterodimethyl sulfoxide (DMSO-d₆) 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; br, broad. EXAMPLE 1 5-Fluoro-6-[(5,6-Dihydro-2H-pyran-3-yl)methylamino]benzoxazolin-2-one To a solution of 6-amino-5-fluoro-benzoxazolin-2-one (0.97 g, 5.7 mmole) and 3-formyl-5,6-dihydro-2H-pyran (0.71 g, 6.3 mmole) in ethanol (40 ml) were added molecular sieves (4A, 1 g). The mixture was heated under reflux for 3 hours. Upon cooling, the reaction mixture was filtered and the filtrate was concentrated to yield a solid product, which was washed with ethanol. This product was dissolved in methanol (200 ml) and then sodium borohydride was added in portions at room temperature. Stirring was continued for hours. The reaction mixture was concentrated and water was added. The organic material was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was recrystallized from methanol to afford 420 mg of the title product (28%): m.p. 175-176°C. IR (KBr): 1790, 1520, 1100, 960 cm⁻¹ NMR : 2.03 (br, 2H), 3.61 (m, 4H), 3.97 (br, 2H), 5.53 (br, 1H), 5.74 (br, 1H), 6.68 (d, 1H), 6.90 (d, 1H), 11.23 (s, 1H) EXAMPLE 8 5-Fluoro-6-[(tetrahydro-4H-pyran-3-yl)propylamino]benzoxazolin-2-one To a solution of 6-amino-5-fluoro-benzoxazolin-2-one (2.1 g, 12.5 mmole) in methanol (80 ml) were added 3-(tetrahydro-2H-pyran-3-yl) propanal (1.95 g, 13.7 mmole) and acetic acid (1 ml) at room temperature, and then the mixture was stirred for 1 hour. Sodium cyanoborohydride (0.867 g, 13.7 mmole) was combined and stirring continued for 17 hours at room temperature. The reaction mixture was concentrated in vacuo , and residue was treated with aqueous ammonium chloride solution. The organic substance was extracted with ethyl acetate/tetrahydrofuran. The extracts were washed with brine, dried over magnesium sulfate, and concentrated to afford crude product. This crude product was recrystallized from methanol to give 1.40 g of the title compound: m.p. 144-145°C. IR (KBr): 1770, 1090 cm⁻¹ NMR : 1.00-1.30 (m, 3H), 1.38-1.63 (m, 5H), 1.75-1.85 (m, 1H), 2.91-3.03 (m, 3H), 3.20-3.28 (m, 1H), 3.73 (br.d, 2H), 5.13 (br, 1H), 6.73 (d, 1H), 6.89 (d, 1H), 11.21 (br, 1H) EXAMPLES 9-33 In like manner, employing the appropriate aldehydes (III) or ketones (V)-(VII) in the procedure of Example 8 afforded the corresponding compounds of formula (I). EXAMPLE 34 5-Fluoro-6-[(tetrahydro-4H-pyran-3-yl)methylamino]-2-benzoxazolone To a solution of 6-(5,6-dihydro-2H-pyran-3-yl)methylamino)-5-fluoro-2-benzoxazolone (1.0 g, 3.88 mmole) in 100 ml methanol was added 50 mg platinum oxide and the mixture was hydrogenated at 1 atm. and room temperature for 1 hour. The mixture was filtered, the filtrate concentrated in vacuo and the resulting solid was washed with ethanol. Recrystallization from ethanol gave 0.48 g of the title compound (47%): m.p. 177-178°C. IR (KBr): 1760, 1510, 1090, 950 cm⁻¹ NMR : 1.15-1.30 (m, 1H), 1.35-1.65 (m, 2H), 1.75-1.90 (m, 2H), 2.90-2.95 (m, 2H), 3.05-3.15 (m, 1H), 3.70-3.85 (m, 2H), 5.25 (br, 1H), 6.75 (d, 1H), 6.89 (d, 1H), 11.30 (br, 1H) EXAMPLE 35 5-Fluoro-6-[(tetrahydropyran-2-yl)methylamino]benzoxazolin-2-one In a like manner, employing 5-fluoro-6-[(3,4-dihydro-2H-pyran-2-yl)methylamino]benzoxazolin-2-one in the procedure of Example 34 afforded the title compound: m.p. 185-186°C. IR (CH₂Cl₂): 3500, 1790, 1780 cm⁻¹ NMR (CDCl₃): 1.36-1.67 (m), 1.89 (m, 1H), 3.04 (dd, 1H, J=8, 12 Hz), 3.16 (dd, 1H, J=3.5, 12 Hz), 3.42-3.61 (m, 2H), 4.03 (m, 1H), 4.27 (m, 1H), 6.62 (d, 1H, J=7.1 Hz), 6.78 (d, 1H, J=10.3 Hz), 8.52 (br.s, 1H) EXAMPLE 36 5-Fluoro-6-[(1,2,3,4-tetrahydro-2-naphthyl)methylamino]benzoxazolin-2-one In a manner similar to Example 3A starting with 5-fluoro-6-[(3,4-dihydro-2-naphthyl)methylamino]benzoxazolin-2-one but employing palladium carbon (5%) instead of platinum oxide, the title compound was prepared: m.p. 177-178°C. IR (KBr): 1770, 1660, 1520 cm⁻¹ NMR : 1.30-1.50 (m, 1H), 1.90-2.10 (m, 2H), 2.49 (dd, 1H), 2.65-2.95 (m, 3H), 3.06 (dd, 2H), 5.36 (m, 2H), 6.79 (d, 1H), 6.93 (d, 1H), 11.21 (s, 1H) EXAMPLE 37 5-Fluoro-6-[(chroman-3-yl)methylamino]benzoxazolin-2-one In a manner similar to Example 34, starting with 5-fluoro-6-[(4-chloro-2H-chromene-3-yl)methylamino]benzoxazolin-2-one and hydrogenating it in the presence of triethylamine, the title compound was prepared: m.p. 223-224°C. IR (KBr): 1750, 1510, 1490 cm⁻¹ NMR : 2.25-2.38 (m, 1H), 2.53-2.60 (m, 1H), 2.87 (dd, 1H), 3.06 (d, 1H), 3.09 (d, 1H), 3.87 (dd, 1H), 4.22-4.27 (m, 1H), 6.71-6.75 (m, 1H), 6.78-6.84 (m, 2H), 6.91 (d, 1H), 7.01-7.08 (m, 2H), 11.20 (br, 1H) EXAMPLE 38 5-Methoxy-6-[(tetrahydropyran-3-yl)methylamino]benzoxazolin-2-one Employing the procedure according to Example 34 with 5-methoxy-6-[(5,6-dihydro-2H-pyran-3-yl)methylamino]benzoxazolin-2-one afforded the title compound: m.p. 155°C (dec.). IR (Nujol): 3200, 1780, 1740, 1680, 1640 cm⁻¹ NMR : 1.20-1.25 (m, 1H), 1.42-1.60 (m, 2H), 1.72-1.91 (m, 2H), 2.87-2.94 (m, 2H), 3.08-3.15 (m, 1H), 3.69-3.81 (m, 6H), 6.58 (s, 1H), 6.62 (s, 1H), 11.09 (br.s, 1H) EXAMPLE 39 5-Ethyl-6-[(tetrahydropyran-3-yl)methylamino]benzoxazolin-2-one Employing the procedure according to Example 34 with 5-ethyl-6-[(5,6-dihydro-2H-pyran-3-yl)methylamino]benzoxazolin-2-one afforded the title compound: m.p. 148-150°C IR (Nujol): 3200, 2750, 1775, 1630 cm⁻¹ NMR : 1.25-1.30 (m, 1H), 1.86-2.00 (m, 4H), 2.04 (s, 3H), 2.91-2.95 (m, 2H), 3.13-3.17 (m, 2H), 3.72 (br.s, 1H), 3.84 (br.s, 1H), 5.01-5.03 (m, 1H), 6.40 (s, 1H), 6.43 (s, 1H) EXAMPLE 40 5-Fluoro-6-[(2,6-dimethyltetrahydropyran-3-yl)methylamino]benzoxazolin-2-one Employing the procedure according to Example 34 with 5-fluoro-6-[(2,6-dimethyldihydro-2H-pyran-3-yl)methylamino]benzoxazolin-2-one afforded the title compound: m.p. 123-139°C (methanol). IR (Nujol) : 1757, 1788 cm⁻¹ NMR (CDCl₃) : 1.22 (d, 3H, J=6.1 Hz), 1.27 (d, 3H, J=6.6 Hz), 1.44 (m, 2H), 1.77 (m, 2H), 1.90-2.06 (m, 1H), 3.17-3.39 (m, 2H), 3.55 (m, 1H), 3.77 (m, 1H), 4.03 (br.s, 1H), 6.61 (d, 1H, 7.1 Hz), 6.79 (d, 1H, J=10.3 Hz), 8.70 (br.s, 1H) EXAMPLE 41 5-Fluoro-6-[(tetrahydrothiopyran-3-yl)methylamino]benzoxazolin-2-one Employing the procedure according to Example 34 with 5-fluoro-6-[(dihydro-2H-thiopyran-3-yl)methylamino]benzoxazolin-2-one afforded the title compound. EXAMPLE 42 5-Fluoro-6-[(tetrahydrothiopyran-1-oxido-3-yl)methylamino]benzoxazolin-2-one Alumina-supported sodium metaperiodate [K. T. Liu and Y. C. Tong, J.O.C. 43 :2717 (1989)] (5.6 g) was added to a solution of 1.2 g (4.25 mmole) 5-fluoro-6-[(tetrahydrothiopyran-3-yl)methylamino]benzoxazolin-2-one in 200 ml ethanol and 50 ml THF. The mixture was stirred for 20 hours at room temperature. The alumina was filtered off and the solvent was removed in vacuo . The crude product was purified by silica gel column chromatography, eluting with ethyl acetate/THF/methanol (80:20:5), and recrystallized from methanol/diethyl ether to give the title compound (0.28 g, 22% yield). IR (KBr): 1765, 1520, 1020, 940 cm⁻¹ NMR : 1.1-1.25 (m, 1H), 1.4-1.55 (m, 1H of one isomer, E or Z at 1,3 position of tetrahydrothiopyran-1-oxide ring), 1.65-2.15 (m, 3H), 2.3-2.6 (m, 2H + 1H of one isomer), 2.75-2.85 (m, 1H of one isomer), 2.9-3.15 (m, 2H of one isomer), 5.4-5.55 (m, 1H), 6.77-6.85 (m, 1H), 6.91 (d, 1H, J=10.6 Hz), 11.2 (br, 1H) EXAMPLE 43 5-Fluoro-6-[3-(butylsulfinyl)propylamino]benzoxazolin-2-one Employing the procedure according to Example 42 with 5-fluoro-6-[3-(butylthio)propylamino]benzoxazolin-2-one afforded the title compound: m.p. 116-117°C (methanol). IR (CH₂Cl₂): 3480, 1780, 1660 cm⁻¹ NMR : 0.90 (t, 3H, J=7.3 Hz), 1.40 (m, 2H), 1.60 (m, 2H), 1.91 (m, 2H), 2.57-2.88 (m, 4H), 3.18 (m, 2H), 5.38 (m, 1H), 6.79 (d, 1H, J=7.3 Hz), 6.90 (d, 1H, J=11.0 Hz), 11.23 (br.s, 1H) PREPARATION A 6-Amino-5-fluorobenzoxazolin-2-one A.1 4-Fluoro-2-nitrophenol To a mechanically stirred solution of 400 ml concentrated nitric acid, at 0°C, was added dropwise a solution of 4-fluorophenol (204 g, 1.8 mole) in acetic acid (200 ml) over 2 hours. Stirring was continued for another 2 hours at 5°C. The reaction mixture was poured onto ice, and the resulting yellow solids were collected and washed with water. The solids were recrystallized from methanol-water (5:1) to afford 198 g of the title compound. The NMR spectrum showed absorption at 7.17 (dd, 1H, J=9, 5 Hz), 7.44-7.52 (m, 1H) and 7.80 (dd, 1H, J=8, 3 Hz). A.2 2-Amino-4-fluorophenol To a solution of 4-fluoro-2-nitrophenol (48.3 g, 0.30 mole) in 300 ml ethanol was added 0.24 g platinum oxide under nitrogen atmosphere. The mixture was hydrogenated with a Parr shaker for 8 hours at 45 psi. The catalyst was filtered off and the filtrate was concentrated to leave 40.5 g of the title compound as a brown powder. The NMR spectrum showed absorption at 4.79 (br.s, 2H), 6.11 (m, 1H), 6.36 (dd, 1H, J=11, 3 Hz), 6.53 (dd, 1H, J=5, 9 Hz) and 8.89 (s, 1H). A.3 5-Fluorobenzoxazolin-2-one To a solution of 2-amino-4-fluorophenol (40.5 g, 0.32 mole) in 400 ml tetrahydrofuran, at 0°C, was added dropwise trichloromethyl chloroformate (44.8 ml, 0.32 mole). The reaction mixture was allowed to warm up to room temperature. Stirring was continued for 2 hours. Then, the reaction mixture was poured onto ice and the organic substance was extracted with ethyl acetate (500 ml x 3). The combined extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated to yield 44.3 g of the title compound as brown solids. The NMR spectrum showed absorption at 6.86-6.90 (m, 1H), 7.01 (dd, 1H, J=8 3 Hz), 7.30 (dd, 1H, J=9, 5 Hz) and 11.82 (br.s, 1H). A.4 5-Fluoro-6-nitrobenzoxazolin-2-one To a stirred solution of 300 ml concentrated nitric acid, at room temperature, was added portionwise 73.2 g (0.48 mole) of 5-fluorobenzoxazolin-2-one. The reaction mixture was warmed to 50°C, and was stirred for 4 hours. After cooling, the reaction mixture was poured onto ice. The precipitate which formed was collected, washed with water, and dried to give 72.8 g of the title compound as a brown powder: m.p. 207-209°C. IR (Nujol): 3300, 1810, 1780, 1630 cm⁻¹ NMR : 7.35 (d, 1H, J=11.0 Hz), 8.16 (d, 1H, J=6.6 Hz), 12.6 (br.s, 1H) A.5 6-Amino-5-fluorobenzoxalin-2-one To a solution of 5-fluoro-6-nitro-benzoxazolin-2-one (20 g, 0.1 mole) in 300 ml tetrahydrofuran was added 2 g palladium carbon (5%) under nitrogen atmosphere. The mixture was hydrogenated with a Parr shaker for 10 hours at 45 psi. The precipitate which resulted from hydrogenation was redissolved by adding tetrahydrofuran. The catalyst was removed by filtration and the filtrate was concentrated to give 18.1 g of the title compound as a brown solid: m.p. 180-182°C (dec.). IR (Nujol): 3400, 3280, 1750, 1630 cm⁻¹ NMR : 4.93 (br.s, 2H), 6.71 (d, 1H, J=7.3 Hz), 6.84 (d, 1H, J=10 Hz), 11.2 (br.s, 1H) PREPARATION B 6-Amino-5-ethylbenzoxazolin-2-one 5-Ethyl-2-benzoxazolone was prepared via the condensation of 2-amino-4-ethylphenol with urea according to the procedure of W. J. Closs et al., J. Am. Chem. Soc., 71 , 1265 (1949). In a manner similar to Preparation A, starting with 5-ethylbenzoxazolin-2-one, 6-amino-5-ethylbenzoxazol was prepared: m.p. 146-147°C. IR (Nujol): 3430, 3340, 3130, 1710, 1640 cm⁻¹ NMR : 1.10 (t, 3H, J=7.3 Hz), 2.43 (q, 2H, J=7.3 Hz), 4.73 (br.s, 2H), 6.56 (s, 1H), 6.64 (s, 1H), 10.99 (br.s, 1H). PREPARATION C The procedure of Preparation A is employed to prepare 6-amino-4-methylbenzoxazolin-2-one, 6-amino-5-methylbenzoxazolin-2-one, 6-amino-5-trifluoromethylbenzoxazolin-2-one, 6-amino-5-methoxybenzoxazolin-2-one, 6-amino-5-methylthiobenzoxazolin-2-one, 6-amino-5-phenoxybenzoxazolin-2-one, 6-amino-5-phenylthiobenzoxazolin-2-one, 6-amino-7-chlorobenzoxazolin-2-one and 6-amino-7-fluorobenzoxazolin-2-one. PREPARATION D 3-(Tetrahydropyran-3-yl)propionaldehyde D.1 Ethyl-3-(5,6-dihydro-2H-pyran-3-yl)acrylate To a stirred suspension of sodium hydride (60% in mineral oil; 1.43 g, 35.7 mmoles) in 50 ml tetrahydrofuran, at room temperature, was added dropwise triethyl phosphonoacetate (8.35 g, 37.2 mmoles) under a nitrogen atmosphere. The reaction mixture was stirred for 15 minutes. To this was added dropwise a solution of 3.34 g (29.8 mmoles) of 3-formyl-5,6-dihydro-2H-pyrane (Japan Kokai 59-167,584 to BASF) in 20 ml tetrahydrofuran. The resulting mixture was stirred for 1 hour. The reaction was quenched by adding acetic acid. Then, the reaction mixture was concentrated and an aqueous sodium bicarbonate solution was added. The organic substance was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified by column chromatography on silica gel eluted with 25% ethyl acetate-hexane to yield 3.1 g of the title compound. The NMR spectrum showed absorption at 1.26-1.38 (m, 3H), 2.34 (br., 2H), 3.8 (t, 2H, J=5 Hz), 4.15-4.30 (m, 4H), 5.63 (d, 1H, J=17 Hz), 6.28 (br., 1H) and 7.21 (d, 1H, J=17 Hz). D.2 Ethyl-3-(tetrahydro-2H-pyran-3-yl)propionate A solution of ethyl-3-(5,6-dihydro-2H-pyran-3-yl) acrylate (3.1 g) in 50 ml methanol was hydrogenated over 0.15 g of palladium carbon (5%) at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated to yield a crude oil. The crude product was purified by column chromatography on silica gel eluted with 50% ethyl acetate-hexane to give 3.0 g of the title compound. The NMR spectrum showed absorption at 1.10-1.20 (m, 1H), 1.26 (t, 3H, J=7 Hz), 1.45-1.63 (m, 5H), 1.82-1.91 (m, 1H), 2.27-2.34 (m, 2H), 3.06 (dd, 1H, J=9.5, 11 Hz), 3.30-3.40 (m, 1H), 3.83-3.89 (m, 2H) and 4.13 (q, 2H, J=7 Hz). D.3 3-(Tetrahydro-2H-pyran-3-yl)propionaldehyde To a solution of ethyl-3-(tetrahydro-2H-pyran-3-yl)propionate (3.0 g) was, at -78°C, added dropwise DIBAL (16 ml of 1.5 mole toluene solution) under a nitrogen atmosphere. Stirring was continued for one hour. The reaction was quenched by adding a methanol-water mixture. The resulting solution was allowed to warm up to room temperature. The solids which formed were removed. The filtrate was dried over magnesium sulfate and concentrated to yield a crude oil. The crude product was purified by distillation to yield 2.0 g of the title compound. The NMR spectrum showed absorption at 1.09-1.28 (m, 1H), 1.42-1.65 (m, 5H), 1.80-1.91 (m, 1H), 2.42-2.49 (m, 2H), 3.07 (dd, 1H, J=9, 11 Hz), 3.31-3.40 (m, 1H), 3.84-3.89 (m, 2H) and 9.78 (s, 1H). PREPARATION E 3-Methylcyclohexanecarboxaldehyde E.1 3-Methylcyclohexanecarboxylic acid To a solution of m-toluic acid (13.6 g, 0.1 mole) in acetic acid was added platinum oxide (0.1 g) under nitrogen. The mixture was hydrogenated in a Parr shaker at 35 psi. Upon completion, the catalyst was removed by filtration and the filtrate was concentrated to dryness to give 12 g of the title compound. The NMR spectrum showed absorption at 0.84 (d, 3H), 0.90 (d, 3H), 0.99-1.13 (m, 1H), 2.21-1.46 (m, 3H), 1.54-1.65 (m, 3H), 1.70-1.98 (m, 2H) and 1.23-2.41 (m, 1H). E.2 1-Hydroxymethyl-3-methylcyclohexane To a boran-methyl sulfide complex (1.7 ml, 0.028 mole) in 7 ml tetrahydrofuran, at 0°C, was added dropwise 2 g of 3-methylcyclohexanecarboxylic acid (0.014 mole) in 7 ml tetrahydrofuran. Stirring was continued for one hour. The reaction mixture was diluted with ether and washed with 1N aqueous sodium hydroxide and then with brine. Concentration and distillation gave 1.34 g of the title compound. The NMR spectrum showed absorption at 0.54-0.74 (m, 1H), 0.90, 0.93 (s, 3H), 1.17-1.53 (m, 3H), 1.65-1.77 (m, 3H) and 3.39-3.52 (m, 2H). E.3 3-Methylcyclohexanecarboxaldehyde To a solution of 1-hydroxymethylcyclohexane (6.8 g, 0.053 mole) in 150 ml dichloromethane was added pcc (22.9 g, 0.106 mole) under nitrogen. Stirring continued for 1 hour at room temperature. The solids were removed by filtration through Florisil and the filtrate was concentrated to give 8 g of the title compound. The NMR spectrum showed 0.90, 0.95 (d, 3H, J=8 Hz), 0.86-2.32 (m, 10H), and 9.68, 9.70 (d, 1H, J=2 Hz). PREPARATION F Endo -7-Oxabicyclo(2,2,1)heptane-2-carboxaldehyde Using the procedure of Preparation D3 endo -2-carbomethoxy-7-oxabicyclo(2,2,1)heptane (M. P. Kunstmann et al., J. Am. Chem. Soc., 84 , 4115 (1962); 2.13 g, (12.5 mmoles) was reduced to the title compound (1.51 g). The NMR spectrum showed absorption at 1.46-1.95 (m, 6H), 3.07 (m, 1H), 4.68 (m, 1H), 4.86 (dd, 1H, J=5.6, 5.6 Hz) and 9.73 (d, 1H, J=1.5 Hz). In like manner exo -2-carbomethoxy-7-oxabicyclo(2,2,1)heptane was reduced to the corresponding exo -7-oxabicyclo(2,2,1)heptane-2-carboxaldehyde. PREPARATION G 5-Fluoro-6-[(4-chloro-2H-chromen-3-yl)methylamino]benzoxazolin-2-one G.1 4-Chloro-3-formyl-2H-chromene The title compound was prepared according to the procedure of J. A. Vigilio et al., Organic Preparations and Procedures Inc., 14 , 9 (1982). G.2 5-Fluoro-6-[(4-chloro-2H-chromen-3-yl)methylamino]benzoxazolin-2-one To a solution of 6-amino-5-fluorobenzoxazolin-2-one (2.02 g, 12 mmole) in ethanol (100 ml) was combined the product of G.1 (2.53 g, 13 mmole). The mixture was stirred at room temperature for 6 hours. The reaction mixture was then concentrated in vacuo to yield a solid. The solid product was washed with ethanol. This product was dissolved in methanol (150 ml) and sodium borohydride was added in portions at room temperature. Stirring was continued for hours. The reaction mixture was concentrated and aqueous ammonium chloride was added. The organic material was extracted with ethyl acetate/THF. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluted with ethyl acetate/hexane (1:3) to afford the crude product, which was recrystallized from ethanol to give 0.90 g of the title compound (22%): m.p. 197°C (dec.). PREPARATION H 6-Oxabicyclo[3.2.1]oct-1'-ylmethanol H.1 6-Oxabicyclo[3.2.1]oct-1'-ylmethanol A mixture of 3-cyclohexene-1,1-dimethanol (10.0 g, 70 mmol; Aldrich Chemical Company, Inc.) and NBS (13.7 g, 77 mmol) in 200 ml dichloromethane was stirred for 13 hours at room temperature. Then, the reaction mixture was washed with water (2 x 100 ml) and brine and dried over Na₂SO₄. The solvent was removed by evaporation to give a pale yellow oil (17.0 g). To a mixture of this oil and 20 ml toluene were added ALBN (0.2 g) and then n-tributyltinhydride (21.5 g, 84 mmol) with stirring. The mixture was heated to 110°C and stirred for 1.5 hours. Silica gel chromatography of the product (150 g, 50% ethyl acetate/hexane, twice) gave the title compound (7.75 g, 77% yield). The NMR spectrum (CDCl₃) showed absorption at 1.28-1.52 (m, 3H), 1.66-1.84 (m, 6H), 3.57 (dd, 2H, J=1.84 Hz, 5.50 Hz), 3.65 (dd, 1H, J=1.84 Hz, 7.69 Hz), 3.84 (d, 1H, J=7.69 Hz), 4.40 (t, 1H, J=5.31 Hz). H.2 6-Oxabicyclo[3.2.1]oct-1'-ylcarboxaldehyde A mixture of 6-oxabicyclo[3.2.1]oct-1'-ylmethanol (3.55 g, 25 mmol), pcc (8.08 g, 37.5 moles) and 100 ml dichloromethane was stirred at room temperature for one hour. The resulting mixture was diluted with 100 ml diethylether and filtered through silica gel. The silica gel was washed with diethylether (7 x 100 ml). The filtrate and washings were combined, the solvent was removed by evaporation to give the title compound (3.00 g, 86% yield). The NMR spectrum (CDCl₃) showed absorption at 1.29-1.40 (m, 1H), 1.57-1.90 (m, 6H), 2.19-2.26 (m, 1H), 3.89 (d, 1H, J=8.4 Hz), 4.03 (dd, 1H, J=1.8 Hz, 8.4 Hz), 4.53 (dd, 1H, J=4.8 Hz, 5.9 Hz), 9.56 (s, 1H). PREPARATION I (1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-carboxaldehyde I.1 (4S)-3-[(1S,2R,4R)-7-oxabicyclo[2.2.1]hept-2-yl-carbonyl]-4-isopropyloxazolidin-2-one and (4S)-3-[(1R,2S,4S)-7-oxabicyclo[2.2.1]hept-2-ylcarbonyl]-4-isopropyloxazolidin-2-one A stirred, cooled (-78°C) solution of 7.75 g (60 mmol) of (4S)-4-isopropyloxazolidin-2-one in 200 ml of THF was metalated with 44 ml of n-butyllithium (1.49 M in hexane, 65 mmol). To the reaction was then added racemic exo-oxabicyclo[2.2.1]heptan-2-carboxyl chloride prepared from 8.95 g (63 mmol) of racemic acid and oxalyl chloride. The reaction mixture was warmed to 0°C and stirred for one hour. Excess acid chloride was hydrolyzed by the addition of 50 ml of 1M aqueous potassium carbonate followed by stirring of the mixture for one hour at room temperature. Organic solvent was removed under reduced pressure. The resulting product was diluted with 200 ml of water and extracted with dichloromethane (4 x 200 ml). The combined organic extracts were successively washed with water (200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 18.0 g of a pale yellow oil. Separation of the diastereomeric imides was accomplished on a Waters Prep LC/System 500A using two Prep-PAK-500/silica cartridges (57 mm x 30 cm, ether/n-hexane (1:5), flow rate 250 ml/min.) in three runs. The retention times of the less polar imide and the more polar imide were 16 and 22 minutes, respectively. The less polar imide (6.47 g), which contained an unknown impurity, was purified by recrystallization from ether-hexane to give 4.47 g (29% yield) of the pure, less polar imide, (4S)-3-[(1S,2R,4R)-7-oxabicyclo[2.2.1]hept-2-ylcarbonyl]-4-isopropyloxazolidin-2-one, ( > 99% de). The structure of the less polar imide was determined by X-ray analysis using crystal obtained by another slow recrystallization from ether-hexane. The more polar imide (4S)-3-[(1R,2S,4S)-7-oxabicyclo[2.2.1]hept-2-ylcarbonyl]-4-isopropyloxazolidin-2-one, (6.36 g, 42% yield, 98.5% de) was used without further purification. I.2 Methyl(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-carboxylate To a cooled (0°C) solution of (4S)-3-[(1S,2R,4R)-7-oxabicyclo[2.2.1]hept-2-ylcarbonyl]-4-isopropyloxazolidin-2-one (4.35 g, 17 mmol) in 350 ml of THF was added slowly and dropwise, with stirring, an aqueous lithium hydrogen peroxide solution (prepared from 15 ml of 30% aqueous hydrogen peroxide, 1.28 g (30 mmol) of lithium hydroxide and 120 ml of water). After stirring for one hour at 0°C, the reaction was quenched by dropwise addition of 300 ml of 2N sodium sulfite. After stirring the resulting slurry for 15 minutes at 0°C, the mixture was basified with saturated sodium bisulfite and the organic solvent was removed in vacuo . The remaining aqueous mixture was washed with 200 ml of dichloromethane. After acidification with concentrated HCl, the chiral acid was extracted ten times with 300 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give the unpurified acid as a pale-yellow oil. The unpurified acid was diluted with 100 ml of ether and treated with excess diazomethane in ether. After 15 minutes, the excess diazomethane was removed by bubbling nitrogen through the solution. The resulting solution was concentrated under reduced pressure and purified by flash chromatography [100 g of silica gel, ether/hexane (1:1)] to give 2.03 g (76% yield) of the title compound as a clear volatile oil. An analytical sample was purified by Kugelrohr distillation: b.p. 106-109°C/0.9 mm Hg. IR (Nujol): 3000, 2970, 2880, 1736, 1064, 1002, 938 cm⁻¹ NMR (CDCl₃): 1.42-1.55 (m, 2H), 1.67-1.80 (m, 3H), 2.09-2.17 (m, 1H), 2.61 (dd, 1H, J=4.9 Hz, 9.1 Hz), 3.70 (s, 3H), 4.66 (dd, 1H, J=4.9 Hz, 5.1 Hz), 4.84 (d, 1H, J=4.9 Hz). [α] 20 / D: +31.3° (c1.00, methanol) I.3 (1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-carboxaldehyde Using the procedure of Preparation D.3, methyl (1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-carboxylate was converted to the title compound. The NMR spectrum (CDCl₃) showed absorption at 1.46-1.95 (m, 6H), 3.07 (m, 1H), 4.68 (m, 1H), 4.86 (dd, 1H, J=5.6 Hz, 5.6 Hz), 9.73 (d, 1H, J=1.5 Hz). PREPARATION J (1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-carboxaldehyde J.1 Methyl(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-carboxylate Employing the procedure according to Preparation I.2 with (4S)-3-[(1R,2S,4S)-7-oxabicyclo[2.2.1]hept-2-ylcarbonyl]-4-isopropyloxazolidin-2-one afforded the title compound (96% yield): b.p. 94-98°C/0.5 mm Hg. IR (Nujol): 3000, 2970, 2880, 1736, 1064, 1002, 938 cm⁻¹ NMR (CDCl₃): 1.42-1.55 (m, 2H), 1.67-1.80 (m, 3H), 2.09-2.17 (m, 1H), 2.61 (dd, 1H, J=4.9 Hz, 9.1 Hz), 3.70 (s, 3H), 4.66 (dd, 1H, J=4.9 Hz, 5.1 Hz), 4.84 (d, 1H, J=4.9 Hz). [α] 20 / D: -29.8° (c1.00, methanol) J.2 (1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-carboxaldehyde Using the procedure of Preparation D.3, methyl (1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-carboxylate was converted to the title compound. The NMR spectrum (CDCl₃) showed absorption at 1.46-1.95 (m, 6H), 3.07 (m, 1H), 4.68 (m, 1H), 4.86 (dd, 1H, J=5.6 Hz, 5.6 Hz), 9.73 (d, 1H, J=1.5 Hz). PREPARATION K 2-Oxabicyclo[2.2.1]hept-4-ylmethanol To a mixture of 3-cyclopenten-1,1-dimethanol, prepared according to J-P. Deprés, et al., J. Org. Chem. 49 :928 (1984) and H. Paulsen, et al., Chem. Ber. 144 :346 (1981), (3.74 g, 29 mmol), 100 ml of dichloromethane and 100 ml THF was added NBC (5.71 g, 32 mmol) with stirring at 0°C. After addition of NBS was completed, the ice-bath was removed and the reaction mixture was stirred at room temperature. After 2.5 hours, another portion of NBS (5.71 g, 32 mmol) was added and the reaction mixture was stirred for an additional one hour at room temperature. The reaction mixture was then partitioned between 200 ml of CHCl₃ and 200 ml of water. The aqueous phase was extracted with 100 ml CHCl₃. The combined organic phases were washed with 0.5N Na₂S₂O₃ and then with brine, dried over MgSO₄ and evaporated. The residual oil was applied to a silica gel column (150 g) and eluted with 33% ethyl acetate/hexane to about 50% ethyl acetate/hexane. Fractions containing the desired product as a main component were combined. Evaporation of the solvent gave 3.47 g of a pale yellow oil. A mixture of the oil, tri-n-butyltinhydride (5.44 g, 18.7 mmol), ALBN (0.05 g) and 4 ml toluene was refluxed for 80 minutes. Silica gel column chromatography (150 g, 50% ethyl acetate/hexane to about 67% ethyl acetate/hexane) gave the title compound (1.10 g). The NMR spectrum (CDCl₃) showed absorption at 1.41 (d, 1H, J=9.5 Hz), 1.54-1.79 (m, 5H), 3.67 (dd, 1H, J=2.8 Hz, 6.8 Hz), 3.83 (s, 2H), 4.36 (s, 1H).

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE A compound of the formula: or a pharmaceutically-acceptable acid addition salt thereof, wherein Alk is a C n straight or branched chain divalent alkyl group; n is 0, 1, 2, 3, 4, or 5; R₁ is (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, hydrogen, halo, phenoxy, phenylthio or trifluoromethyl; and R is selected from the group consisting of: (a) wherein R₂ and R₃ are each, independently, H, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio or halo, X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen, sulfur, sulfoxide or sulfone, and the dotted line between the 2- and 4- positions represents an optional bond between positions 2 and 3 or positions 3 and 4; (b) wherein A and B are each, independently, O or S; (c) or (d) wherein R₄ and R₅ are each, independently, H or (C₁-C₄)alkyl, p is 0, 1 or 2 and t is 0, 1 or 2 provided that the sum of p plus t equals 1 or 2; and the wavy line indicates that the moiety containing such wavy line can be endo - or exo -7-oxabicyclo[2,2,1]heptan-1-yl; and (e) CH₃-(CH₂) m -Y- wherein m is an integer from 1 to 3 and Y is oxygen, sulfur, sulfoxide or sulfone. A compound according to claim 1 or a pharmaceutically-acceptable acid addition salt thereof wherein R is n is 0 or 1 and R₁ is 5-halo or n is 1 and R₁ is 5-(C₁-C₃)alkyl or (C₁-C₃)alkoxy. A compound according to claim 2 or a pharmaceutically-acceptable acid addition salt thereof wherein X is oxygen and R₁ is 5-fluoro, ethyl or methoxy. A compound according to claim 1 or a pharmaceutically-acceptable acid addition salt thereof wherein n is 1, 2, 3, 4 or 5, R₁ is halo and R is a member selected from Group (b). A compound according to claim 1 or a pharmaceutically-acceptable acid addition salt thereof wherein n is 1, R₁ is 5-fluoro and R is a member selected from Group (c). A compound according to claim 1 or a pharmaceutically-acceptable acid addition salt thereof wherein n is 1, R₁ is 5-fluoro and R is a member selected from Group (d). A compound according to claim 1 or a pharmaceutically-acceptable acid addition salt thereof wherein n is 1, 2, 3, 4 or 5, R₁ is 5-halo and R is a member selected from Group (e). A compound according to claim 7 or a pharmaceutically-acceptable acid addition salt thereof wherein R₁ is 5-fluoro, m is 1 and Y is oxygen or sulfur. A compound according to claim 1 or a pharmaceutically-acceptable acid addition salt thereof wherein R₁ is (C₁-C₃)alkoxy and R is a member selected from Group (a). A pharmaceutical composition which comprises an effective amount of a compound according to any one of the preceding claims or a pharmaceutically-acceptable acid addition salt thereof and a pharmaceutically-acceptable carrier or diluent. A compound of the formula (I) as claimed in any one of claims 1 to 9, or a pharmaceutically-acceptable acid addition salt thereof, for use as a medicament. The use of a compound of the formula (I) as claimed in any one of claims 1 to 9, or of a pharmaceutically-acceptable acid addition salt thereof, for the manufacture of a medicament for treating allergic or inflammatory conditions. A compound of the formula: or a pharmaceutically-acceptable acid addition salt thereof, wherein Alk is a C n straight or branched chain divalent alkyl group; n is 0, 1, 2, 3, 4, or 5; R₁ is (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, hydrogen, halo, phenoxy, phenylthio or trifluoromethyl; and R is wherein R₂ and R₃ are each, independently, H, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio or halo, X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen, sulfur, sulfoxide or sulfone, and the dotted line between the 2- and 4- positions represents a bond between positions 2 and 3 or positions 3 and 4. Claims for the following Contracting State : GR A process for the preparation of a compound of the formula: or a pharmaceutically-acceptable acid addition salt thereof, wherein Alk is a C n straight or branched chain divalent alkyl group; n is 0, 1, 2, 3, 4, or 5; R₁ is (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, hydrogen, halo, phenoxy, phenylthio or trifluoromethyl; and R is selected from the group consisting of: (a) wherein R₂ and R₃ are each, independently, H, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio or halo, X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen, sulfur, sulfoxide or sulfone, and the dotted line between the 2- and 4- positions represents an optional bond between positions 2 and 3 or positions 3 and 4; (b) wherein A and B are each, independently, O or S; (c) or (d) wherein R₄ and R₅ are each, independently, H or (C₁-C₄)alkyl, p is 0, 1 or 2 and t is 0, 1 or 2 provided that the sum of p plus t equals 1 or 2; and the wavy line indicates that the moiety containing such wavy line can be endo - or exo -7-oxabicyclo[2,2,1]heptan-1-yl; and (e) CH₃-(CH₂) m -Y- wherein m is an integer from 1 to 3 and Y is oxygen, sulfur, sufoxide or sulfone characterized in that (a) a compound of the formula wherein R₁ is as defined above, is reacted in a suitable organic solvent with an approximately equimolar amount of a compound of the formula R-(Alk)-CHO (III) wherein R is as defined above and Alk is as defined above but wherein n is 0, 1, 2, 3 or 4, to produce a compound of the formula wherein R, R₁ and Alk are as defined above and n is 0, 1, 2, 3 or 4, and the compound of formula (IV) is reduced according to known methods to yield a compound of formula I; or (b) for compounds of formula I wherein n is 0 and R is selected from certain members of Group (a), a compound of the formula wherein X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen or sulfur and R₂ and R₃ are as defined above, is coupled with a compound of the formula wherein R₁ is as defined above, to yield a compound of the formula or wherein X, R₁, R₂ and R₃ are as defined above, and the compound of formula (VIII), (VIII') or (VIII'') is reduced according to known methods to yield compounds of formula (I) wherein n is 0, R is X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen or sulfur and R₂ and R₃ are as defined above; or (c) for compounds of formula (I) wherein R is selected from Groups (a) or (e) wherein X or Y is sulfoxide or sulfone are desired, the corresponding compound wherein X or Y is sulfur, prepared as described in (a) or (b), above, is oxidized; or (d) for compounds of formula (I) wherein R is wherein X, R₂ and R₃ are as defined above, a compound of formula (I) wherein R is wherein X, R₂ and R₃ and the dotted line are as defined above which have been prepared as described in (a) or (b), above, is reduced and, optionally the compound of formula (I) is converted to its pharmaceutically-acceptable acid addition salt by methods known per se. The process according to claim 1 wherein, in part (a) or (b) the suitable organic solvent is (C₁-C₄)alkanol, benzene, toluene or tetrahydrofuran, additionally, a dehydrating agent is present and the reducing reaction employs a metal hydride reagent or a catalytic hydrogenation reaction; in part (c), oxidation is characterized by reaction of the compounds with alumina supported sodium metaperiodate in (C₁-C₃)alkanol or tetrahydrofuran; and, in part (d), the reducing reaction is characterized by dehydrogenation of the compound under hydrogen in the presence of a noble metal catalyst and a suitable solvent. A process according to claims 1 or 2 wherein R is n is 0 or 1 and R₁ is 5-halo or n is 1 and R₁ is 5-(C₁-C₃)alkyl or (C₁-C₃)alkoxy. A process according to claim 3 wherein X is oxygen and R₁ is fluoro, methyl or methoxy. A process according to claim 1 or 2 wherein n is 1, 2, 3, 4 or 5, R₁ is halo and R is a member selected from Group (b). A process according to claim 1 or 2 wherein n is 1, R₁ is 5-fluoro and R is a member selected from Group (c). A process according to claim 1 or 2 wherein n is 1, R₁ is 5-fluoro and R is a member selected from Group (d). A process according to claim 1 or 2 wherein n is 1, 2, 3, 4 or 5, R₁ is 5-halo and R is a member selected from Group (e). A process according to claim 8 wherein R₁ is 5-fluoro, m is 1 and Y is oxygen or sulfur. A compound of the formula: or a pharmaceutically-acceptable acid addition salt thereof, wherein Alk is a C n straight or branched chain divalent alkyl group; n is 0, 1, 2, 3, 4, or 5; R₁ is (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, hydrogen, halo, phenoxy, phenylthio or trifluoromethyl; and R is wherein R₂ and R₃ are each, independently, H, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio or halo, X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen, sulfur, sulfoxide or sulfone, and the dotted line between the 2- and 4- positions represents a bond between positions 2 and 3 or positions 3 and 4. Claims for the following Contracting State : ES A process for the preparation of a compound of the formula: or a pharmaceutically-acceptable acid addition salt thereof, wherein Alk is a C n straight or branched chain divalent alkyl group; n is 0, 1, 2, 3, 4, or 5; R₁ is (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (C₁-C₃)alkylthio, hydrogen, halo, phenoxy, phenylthio or trifluoromethyl; and R is selected from the group consisting of: (a) wherein R₂ and R₃ are each, independently, H, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio or halo, X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen, sulfur, sulfoxide or sulfone, and the dotted line between the 2- and 4- positions represents an optional bond between positions 2 and 3 or positions 3 and 4; (b) wherein A and B are each, independently, O or S; (c) or (d) wherein R₄ and R₅ are each, independently, H or (C₁-C₄)alkyl, p is 0, 1 or 2 and t is 0, 1 or 2 provided that the sum of p plus t equals 1 or 2; and the wavy line indicates that the moiety containing such wavy line can be endo - or exo -7-oxabicyclo[2,2,1]heptan-1-yl; and (e) CH₃-(CH₂) m -Y- wherein m is an integer from 1 to 3 and Y is oxygen, sulfur, sufoxide or sulfone characterized in that (a) a compound of the formula wherein R₁ is as defined above, is reacted in a suitable organic solvent with an approximately equimolar amount of a compound of the formula R-(Alk)-CHO (III) wherein R is as defined above and Alk is as defined above but wherein n is 0, 1, 2, 3 or 4, to produce a compound of the formula wherein R, R₁ and Alk are as defined above and n is 0, 1, 2, 3 or 4, and the compound of formula (IV) is reduced according to known methods to yield a compound of formula I; or (b) for compounds of formula I wherein n is 0 and R is selected from certain members of Group (a), a compound of the formula wherein X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen or sulfur and R₂ and R₃ are as defined above, is coupled with a compound of the formula wherein R₁ is as defined above, to yield a compound of the formula or wherein X, R₁, R₂ and R₃ are as defined above, and the compound of formula (VIII), (VIII') or (VIII'') is reduced according to known methods to yield compounds of formula (I) wherein n is 0, R is X is methylene which is unsubstituted or substituted with one methyl group, nitrogen which is unsubstituted or substituted with a protecting group, oxygen or sulfur and R₂ and R₃ are as defined above; or (c) for compounds of formula (I) wherein R is selected from Groups (a) or (e) wherein X or Y is sulfoxide or sulfone are desired, the corresponding compound wherein X or Y is sulfur, prepared as described in (a) or (b), above, is oxidized; or (d) for compounds of formula (I) wherein R is wherein X, R₂ and R₃ are as defined above, a compound of formula (I) wherein R is wherein X, R₂ and R₃ and the dotted line are as defined above which have been prepared as described in (a) or (b), above, is reduced and, optionally the compound of formula (I) is converted to its pharmaceutically-acceptable acid addition salt by methods known per se. The process according to claim 1 wherein, in part (a) or (b) the suitable organic solvent is (C₁-C₄)alkanol, benzene, toluene or tetrahydrofuran, additionally, a dehydrating agent is present and the reducing reaction employs a metal hydride reagent or a catalytic hydrogenation reaction; in part (c), oxidation is characterized by reaction of the compounds with alumina supported sodium metaperiodate in (C₁-C₃)alkanol or tetrahydrofuran; and, in part (d), the reducing reaction is characterized by dehydrogenation of the compound under hydrogen in the presence of a noble metal catalyst and a suitable solvent. A process according to claims 1 or 2 wherein R is n is 0 or 1 and R₁ is 5-halo or n is 1 and R₁ is 5-(C₁-C₃)alkyl or (C₁-C₃)alkoxy. A process according to claim 3 wherein X is oxygen and R₁ is fluoro, methyl or methoxy. A process according to claim 1 or 2 wherein n is 1, 2, 3, 4 or 5, R₁ is halo and R is a member selected from Group (b). A process according to claim 1 or 2 wherein n is 1, R₁ is 5-fluoro and R is a member selected from Group (c). A process according to claim 1 or 2 wherein n is 1, R₁ is 5-fluoro and R is a member selected from Group (d). A process according to claim 1 or 2 wherein n is 1, 2, 3, 4 or 5, R₁ is 5-halo and R is a member selected from Group (e). A process according to claim 8 wherein R₁ is 5-fluoro, m is 1 and Y is oxygen or sulfur.

Inventors: ANDO KAZUO TAITO PFIZER APARTM, ASAI NOBUKO TAITO PFIZER APART, ITO FUMITAKA - - SAKURAGAOKA-, MANO TAKASHI, NAKANE MASAMI, SATAKE KUNIO, SHIMADA KAORU, ANDO, KAZUO, TAITO PFIZER APARTMENT 1, ASAI, NOBUKO, TAITO PFIZER APARTMENT 1-2, ITO, FUMITAKA, 1-2-206, SAKURAGAOKA-1, MANO, TAKASHI, NAKANE, MASAMI, SATAKE, KUNIO, SHIMADA, KAORU
Applicants: PFIZER, PFIZER INC.
Application year: 1990
Main classification: C07D263
IPC codes: A61K31, C07D407, C07D409, A61P43, A61P29, C12N9, C07D413, A61P37, C07D263, C07D493