MXPA96004429A - Heterociclic inhibitors of the biosynthesis de5-lipooxigen - Google Patents

Abstract

The present invention relates to a compound of the formula: wherein R 1 is C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl or (C 1 -C 6 alkyl) phenyl, wherein the alkyl portion is optionally substituted by methyl or ethyl and the phenyl portion is optionally substituted by C 1 -C 4 alkoxy, C 1 -C 4 alkyl, F, Cl, Br or CF 3, R 2 is hydrogen or fluoro; and R3 is hydrogen, methyl, ethyl, propyl, isopropyl, CF2H or C

Description

HETEROCICLIC INHIBITORS OF Lfl BI0SINTESI5 OF 5-LIPOOXIGENflSfl 'j BACKGROUND OF THE INVENTION The invention relates to a series of substituted compounds, which are inhibitors of 5-l-oooxy ensa (5 -LO) per se and as such, are useful in the Treatment or elevation of diseases or disorders, allergies, and diseases of mammals, in which the disease or disorder includes, but is not limited to, arthritis, bronchitis, chronic obstructive pulmonary disease. , psoriasis, allergic rhinitis, dermatitis, attack, dermat it is atop.ca, rheumatoid arthritis and osteoarf pt i s; and this invention also relates to the compositions (-a pn useful ce nts for ra t e s 1: The araqui doni co is known to be the biological precursor JQ of several groups of endotheliums, prostaglia, which include the prostacyclines, trornboxanes, and 1 eucotophenes. The first stage of the metabolism of the acid to rachidone is the release of the acidic acidic acid and the unsaturated fatty acids related to it. from the ,. > Phospholiphos of the membrane through the action of ln f-os rol i pasa. Then, free fatty acids are metabolized, either by cyclooxygenase, to produce the prostaglandmas and t-morboxanes or by 1-oxy-oxygenase to generate hydroperoxides, which can be converted into leukotrope. Leukotpenes have been linked to the pathophysiology of inflammatory diseases, including rheumatoid arthritis, got, asthma, ischemia, reperfusion damage, psoriasis, and inflammatory bowel disease. Any drug that inhibits 1 ipoox iqenase is expected to provide a novel therapy for inflammatory disorders, both acute and chronic. Recently, several articles of 'review on lipoox i gene inhibitors. See, for example, H. Masarnune and L.S. Melvín, i., In Pinnu l Reports m Medicinal Chemistry, 24, 71-80 (flcademic Press, 1989) and B.J. Fit ^ if mons and, 1"Rokaeh in Leu otr i enes and Lipox i genases, 427--502 (Elsevier, 1989). 15 SUMMARY OF INVENTION This invention is related to a serious one of substituted 1, 1-d? OxoCd] i ot? Ol-3-one compounds. Fstos new compounds inhibit the production of 5-1 ipoxygenase (5- LO) in a mammal and as such are useful in the treatment or alleviation of diseases or disorders mf larnat or io, alei gia and cardiovascular diseases in mammals, in which the Inflammatory disease or disorder includes, p ro ', "5 is limited to, as, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, dermatitis, attack, atopic dermatitis, reurnatoid arthritis or eoarf ptis" The compounds of the present invention are the formula (II) is that Ri is Ci-Ce alkyl, C3-Ce alkele cycloalkyl, C3-equinyl or Ci (C6 alkyl) phenol, Jn ol < The alkyl portion is optionally substituted by methyl or otyl and the fem portion is optionally substituted by Cj alkoxy. -C4, alkyl of Ci -r, F, Cl, 13 or CE3; > 2 (.-. <, hiRógeno or Huero: and R3 is hydrogen, methyl, ethyl, propyl, isopropyl, CE2H or (, T3.) A proffered group of compounds are those compounds of formula (1) or (ID in the that Ri is Ci-Ce alkyl, R 2 is hydrogen or fl-oro, and R 3 is hydrogen or methyl.

A particularly preferred group of the compounds of the present invention are those compounds of formula (I) or (ri) wherein R 1 is methyl or t-hutyl; R2 is fluoro; and R3 is in t L lo. A most preferred group of the compounds of the present invention are those compounds of formula (T) in which i is methyl or t-butyl; R2 is fluoro; and R3 or inet i lo. Another more particularly preferred group of compounds of the present invention are those compounds of formula (IT) in which P1 is methyl or t-butyl; R2 is fluoro, and R is inet i lo. In a further aspect, this invention provides pharmaceutical compositions comprising a compound of formula (I) or (TI) together with a pharmaceutically acceptable diluent or carrier, which are useful in the inhibition of 5- LO per se and in the treatment or relief of inflammatory diseases or disorders, allergy or cardiovascular diseases on mammals, in which the inflammatory disease or disorder includes, but is not limited to, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis , derma itis, attack, dermatitis atopiea, arthritis reu atoi eu osteoart ri 11 s on rnaini forums, especially human. This invention also provides an in-process procedure of -LO in a mammal in its need, said method comprising administering to said mammal an amount of a compound of formula (T) or (TI) that inhibits the 5-LO. This invention also provides a method of treating or alleviating a disease or disorder, inflammation, allergy or cardiovascular disease in a mammal, comprising administering to said mammal an effective amount of a compound of formula (1) or (TT). ). Still further, this invention provides a method for the treatment of asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, dermatitis, attack, atopLca dermatitis, rheumatoid arthritis or osteoarthritis LS in a mammal in need, which I understand the "tdrninist raci na said mammal of an effective amount of a compound of formula fl) or (IT). As used herein, and in the accompanying remarks, the term "dlquilo" includes both lo1- g? As a linear or branched chain alkyl, the term "alkoxy" includes both straight and branched chain groups and, The cycloalkyl expression includes only the monetaric groups Iqu 11 o.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention having formul (T) or (TI) are prepared easily and generally by the following reaction procedures.

A compound of formula (TIT) it is reacted with a (IV) composed of formula fTV) (V) or formula (V) in the presence of a weak base such as potassium carbonate and an organic inert reaction solvent, such as di eti-tormamide. The reaction is stirred for 6 to 4 hours, preferably approximately 18 hours at room temperature, however, elevated temperatures can be used. The mixture is treated according to conventional procedures well known to those skilled in the art. The desired compound is isolated and purified by conventional procedures well known to those skilled in the art, such as chromatography on a silica gel column or recrystallization using a solvent / non-solvent mixing system, such as ethylene chloride / ether. The preparation of the intermediate compounds is well known in the art and the preparation of certain intermediates is described hereinafter in the Preparations, the starting materials and reagents necessary for the thesis of the compounds of the present invention. invention are readily available, either commercially, according to the procedures of the bibliography or through the illustrator / later procedures in the Preparations. The ability of the compounds of formula fT) or (II) 0 to inhibit 5 -LO and, consequently, demo t ar < Effectiveness for the treatment of a disease or disorder and inflammation, allergy or cardiovascular disease in a mammal is shown by the following tests in vivo and in vivo.

BIOLOGICAL ESSAYS LIBERATION OF HUMAN BLOOD LEUKOTRENE (5-LO> INDUCED BY A23187 Venous blood was collected from healthy volunteers in hepap a (20 U / ml). The compounds were dissolved in DMSO. Each compound was tested at 4 concentrations. Zileuton was used (charges can be synthesized from zileuton, a 5-11 poox i gentane inhibitor available commercially from flbbot Laboratories, in the laboratory according to synthetic procedures well known in the art) and DMSO alone as positive and negative controls , respectively. 10 [μl of compound or DMSO was added to glass borosilicate tubes (12 x 75 nm) and heated to 37 ° C. One milliliter of whole blood was added to each tube. After an incubation period of 15 minutes, the whole blood was stimulated with calcium oloform A23J87 (commercially available from Sigma Chemical Co., St. Louis, MO 63178) 50uM for 1 hour. The tubes were immediately placed in a centrifuge at 4 ° C and rotated at 1500 x g to isolate the plasma. So I take a plasma volume of 50 μl for the measurement of the leucot peno- (I TB-4). Samples were diluted 1: 800 for the assay with the Leul-Otriene TI4 Enzyme T munoassay Kit (RET) (Cayman Ohernieal Co., flnn flrbor, MI) using the manufacturer's instructions. It was done < On each of the lacquers a normalized curve of LTB-4 from 750 to 7.0 μg / (50 μl of diluted sample per well was added.Then, 50 μl of LTB-4 acetylcholine naserase was added followed by 50 μl of LTB-4 antiserum The plates were covered with pLastica film and incubated for 18 hours at room temperature.The plates were drained and rinsed 5 times with washing buffer before developing with Elrnan's Reagent (available commercial of Cay an Chemical, Ann rbor, MI) in the dark for 1 hour at room temperature or, until the wells BO (total absorbance) showed a (1 absorbance between 0.3 and 0.8 AU) Plates were read at 405 n using A THERMO ax micropic reader (Molecular Devices, Menlo Pai, CH) .. The normalized curve of LTB-4 was adjusted to a sernilogarithmic equation, the heats of 5 Ja absorbance were averaged for the experimental wells and the concentration of LTB-4 in pg / l by interpolation of the average abscess in the normalized curve The percent inhibition was determined by the following equation: (-TLTB-4 experiment (? g /? nl) / l TT3- 4 0 with DMSO control (pg / mlH-1) x 100. The TC50 was determined by l A linear regression of the concentration of drug represented against the inhibition and interpolation of the value of xa-50. r? OBSTRUCTION OF RESPIRATORY ROUTES INDUCED BY PULVERIZED ANTIGEN This essay analyzes the ability of a compound to block the airway obstruction that is produced by a pulmonary anaphylaxis induced by a pulverized antigen. Passive male HartJey rabbits (300-350 g) were passively immunized by subcutaneous injection of 0.375 g / g of rabbit anti-rabbit ovoalbumin je. I purified days TgGJ, 48-72 hours after the antigen test. administered subcutaneously, 30 minutes before the test, pinlami (5 mg / kg) and propanol (2 mg / kg) (both are commercially available from Sigrna). The test compounds were administered in the stomach, either one or two hours before the test, as a suspension in water and Tween-00 ^ 2% (poloxide and sorbitan monovalate, commercially available from S? g? n.-t, St "Louis, Missouri) using an Argyle feeding tube (available energetics from Sherwood Medical, St. Louis, Missouri). The rabbits were then placed (5 test doses + 5 controls) in an infection device l "p R ttirbone (model 042, Rockwille Center, NY 11570.) The ovalbumm was dissolved (OA, 0.01-0, 03%) in 0.9% solution, placed in a glass venturi nebulizer unit and a sprayer generated dur-ante for 5 minutes (adjusted main flow meter 10). 8-minute cloud decrease (vacuum flow adjusted to 7.0). After removal, the animals were sacrificed by an i.p. of approximately 2 i of sodium pentobarbital. The pleural spaces of the animals were immediately opened by cutting in a xiphoid procedure that allowed the lungs to collapse. The lungs were then removed, the heart was separated and the trachea was obstructed. The volume of air trapped in the lungs was determined by measuring the upward force exerted on a 20 g anchor, when the lungs and anchor were submerged in saline. The volume of trapped gas was normalized to the body weight of the animals and expressed as volume of lung gas-eliminated (VGPE) in ml / kg.

INTERPRETATION: The efficacy of the test compounds was judged by their ability to reduce the mean VOPE of the t-group or with the f rmaco below the mean VGPF of the control group. A logarithmic linear regression was carried out VGPE - slope x llog (dose) * ordered at source with the average data grouped and an FD50 << < The dose is reduced to produce a 50% reduction below the VGPE of the control group. VGPF50% - ((VGPE de < or, trol - 2) / 2) + 7 The data in the control VGPE. % reduction - (VGPE control - VGPE test drug) / (VGPE control - 2) for a dose of test drug gives a. For the administration to humans to inhibit 5-LO and in the treatment of inflammatory or allergic diseases or disorders and cardiovascular diseases, oral dosages of the compounds of formula (T) of TT) are generally in the range of -e 0.1-500 rng daily for an average adult patient / 70 iy). Thus, for a typical adult patient, individual tablets or capsules contain 0.1 and 50 mg of active compound, in a suitable pharmaceutically acceptable carrier or diluent. Multiple tablets or capsules may be needed to cope with the dosage requirements. When needed, dosages for intravenous administration are normally within the range of 0.1 to 10 mg per single dose. Par-to the administration infranasal or in inhaler-, the dosage is usually formulated as a solution of 0.1 to t (w / v). In practice, the doctor will give you the actual dosage that < It was more < It is shared by an individual patient and will vary with the size, weight and response of the particular patient. The previous dosages are illustrative of the middle case, but there may, of course, be individual cases in which larger or smaller dosing intervals are needed and, such dosages are all within the scope of this invention. For human use, the compounds of formula (T) or (II) can be administered alone, but are generally administered in a mixture with a diluent or pharmaceutical carrier selected with respect to the intended administration route and practice usual pharmaceutical. For example, they can be administered orally in the form of tablets containing such excipients. 1 (1) as starch or lactose, or in capsules or valos, either alone or in a mixture with excipients, or in the form of elixirs or suspensions containing flavoring agents or colorants.These may be injected parenterally, for example, intravenous, int amuscular or subcutaneous form.

Ib parenteral administration, these are best used in the form of a sterile aqueous solution that can contain other substances; for example, enough salts or glucose to make the solution isotonic. For topical administration, these are best used- in the form of solutions, lotions, ointments, 70 ointments and the like. The present invention is illustrated by the following examples, but this is not limited to its details.

EXAMPLE 1 5- [3-Fluoro-5- (4-methoxy-tetrahydropyran-4-yl) - phenoxymethyl-l, 2-methyl-l, -dioxo-benzoyl "d] isothiazol-3-one A mixture of 2-methyl J-5-bromo-? Net 11 -1, 1 -d oxo-benzof d] was stirred at room temperature for approximately 18 hours. sot? azoJ-3-one (3.2 g), 4- (-f luoro ~ 3-h? dro-xifemJ) -4-rnetoxL-tet rahí drofuran (2.4 g) and potassium carbonate (4, 4 g) in 25 ml of dirnetii forrnamida. The mixture between ethyl acetate and water was added. The organic layer was separated, dried over sodium sulphate and evaporated. The residue was triturated with ether and filtered. The resulting solid was recrystallized in dichloromethane / ether to give 3 g of the title compound, m.p. 155-156 ° C, RMM (CDC13) or: (i, 95,? R ?, H), (3, 00, s, 3H), f 3, 33, s, 31-1), í3, 08, ¡n, 4H), (5, 25, s, "?), (0, 38-d, 55, m, 1H), (7,40, m, 2H) (8, 7 (), ' -,, IH), EXAMPLE 2 - [3- fiuoro-5- (-metox? -tetrahi ro-i an- -? L) - phenoxymethyl] -2-t-but? Ll, ld? Oxo-benzo [Id] isothiazole-3- ona Using an analogous procedure to that described in Example 1, 733 mg of the title-based peptide (mp 123-174 ° C) was obtained from 768 mg (3.4 mmol) of 4 - (- f 1 uoro-3-h? drox? fen? j) -4-? netox? - et rahidrofurano, 70 rng (3,4 nm) of 2- -but? -5-brorno? net 11-1, 1 -dioxobenzordlisot l ol -3-one and 1, 4 g (10.2 mrnol) of K2CO3. NMR (CDCl 3) 6: (1.75, S, 9H), (2, 00,, 4H), (3.04, S, 3H), (3.04,? N, 4H), (5.20, S, 2H), (6.60, d, lH), (6.73, d, lH), (6.83, S, 1H), (7.85, S, 2H), (8, 08, s, H).

EXAMPLE 3 6-C3-fluoro-5- (-ethoxy-tetrahydropyran-4-yl) -phenoxymethyl] -2-methyl-1, 1-dioxo-benzo Cd] isothiazol-3-one Using a procedure analogous to that described in example 1, starting from 2-met? L-d-brornomet 11-1, 1-ioxobenzoTdTisot (850 rng), 4- (5-f luoro-3- hi drox 1 fem 1) - ^ - met 0x1 -tet rahydrofur no (622 mg) and potassium carbonate (1.04 g), 231 mg of the title compound were obtained, mp 201-202 ° C. Mass spectrum: base ^ 18 - 454., PREPARATION 1 3 -benzyloxy-l-bromo-5-fluoro-enne .3 g of sodium hydroxide (00% dispersion / p in mineral oil) were added in vain portions to a solution of benzyl alcohol (28.8 rnl) in dirnet ilacet arn 1 da 00 rnl) and the mixture was stirred at room temperature for about 1 hour. 1-Bromo-, -difl-uorobenzene (50 g) was added dropwise. The mixture was stirred at the dur-ante ambient temperature for approximately 2 hours and the solvent was evaporated in vacuo. The residue was partitioned between liquid chloride and water and the organic phase was washed with water, dried over sodium sulfate and evaporated to give 90 g of crude product which was purified on silica gel eluting with sodium chloride. hexane / hexanes to give 47.7 g of the title compound or an oil. NMR (CDC13) 6: (5.00, s, 2H), (6.62, dd, 1H), (6.05, dd, 1H), (6.03, s, 1H), (4.50, width s, 5H).

PREPARATION 2 4- (3-benzyloxy-5-fluorophenyl) -4-hydroxytetrahydride Was a 3-benzyl solution cooled? -l-brorn? -5 -f luorobenzene (29.1 g) in 250 ml of tet rahydrofuran at approximately -75 ° C and added dropwise n-but 11-1 1 110 (1.6 M in hexane, 65 ml). The mixture was stirred at approximately -75 ° C for about 1 hour and a solution of tet rahydropyran-4-one (10 ml) was added dropwise., 4 g). The mixture was stirred at about -75 ° C for about 1 hour as and then allowed to warm to about 0 ° C. A saturated aqueous solution of ammonium chloride was added and the tetrahydrofuran was evaporated in vacuo. Was the waste distributed between? water and ethyl acetate. The organic phase was separated and dried over sodium sulfate, the residue was purified by gold, column chromatography on silica gel, eluting with nitric chloride / hexanes to give 9.7 g of the title compound as an extract. RM (CDCI3) 6: (I, 60, t, 2H), (2, 15, m, 2H), (3.90, rn, 4H) (5.05, s, 2H), (6.60, dd, lH), (6, 83, dd, 1 H), (6.93, S, 1H), (7, 40, ncho s, 5H ) Mass spectrum: base * 1 = 30 ?; base = 285 PREPARATION 3 4- (3-benzyloxy-5-fl? Gold phenyl) - * -methoxy te rahydro urane Sodium hydride (dispersion at 60% w / w in mineral oil, 1.3 g) was added to a solution of 4- (3-benzyloxy-5-f luor-ofenyl) -4-h? Drox? Tetrah Drofuran (9.1 g) in tetrahydrofuran (30 rnl). Was the mixture stirred at room temperature? for about 1 hour and then cooled to approximately 0 ° W with an ice bath. The iodide was added methyl 4 mL and the mixture was stirred at room temperature for approximately 20 hours. The mixture was quenched with 10% aqueous hydrochloric acid (1 mL) and evaporated with toluene. The residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate and evaporated to give 5.0 g of the title compound as an oil. NMR fCDCl3) 6: (1, 95,, 4H). (2.98, S, 3H), (3,00,10,41-1), (5.05, s, 2H), (ñ, 55, dd, 1H), (6, 7, dd, 1 H), (5.00, s, lH), < 7.4 (l, m, 5H) 10 PREPARATION 4 4- (5-fluoro-3-hydroxy enyl) - * - methoxytetrahydrofuran Hydrogenating in the presence of a 10% palladium on carbon catalyst (100 g) for about 3 hours a solution of 4-5 g. (3-benzyl lox? -5-f luorophenyl) -4-methox? Tetrah? Drofuran (1.1 g) in ethanol (20 rnl). The mixture was filtered and the filtrate was evaporated to give 840 in. Of the title compound, mp "-136-137 ° C. NMR (CDCl3) f: (1.95, m, 4H), (3.02, s, 3H), (3, 85,? n, 4H), (5, 70, width s, lH), (6.50, d, lH), (6,? l, m,? H).

PREPARATION 5 4-N-dimethylbenzene sulfone ida A solution of 4-methylene-benzene sulfonyl chloride was added at about 0 ° C in an ice bath, and was added dropwise to 11-ai. (40% solution in water, 18.6 g) The mixture was stirred at room temperature The organic layer was separated, dried over sodium sulfate and evaporated to give 14.5 g of the title compound. f.87 ~ 84 ° C.

PREPARATION 6 5-Methyl-2-methylsulfamoyl benzyl acid A solution of 4-H-d i and 11-benzenes l fonarnide (14.5 g) in 300 ml of tefachofuran was cooled to about 0 ° C in an ice bath. A solution of n-butyl lithium (1.6M in hexane, 98 ml) was added dropwise. The mixture was stirred and maintained at room temperature for about 2 hours. Gaseous carbon dioxide was then bubbled into the yellow mixture for about 10 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to a residue (14 g). The residue was triturated with dichloromethane and filtered to give 10 g of the title compound, m.p. 140-141 ° C. NMR (CDCI3): (?, 48, s, 3H), (2, l, s, 3H), (5.81, width S, 1H), (F, 45, d, lH), (7.76 , s, .lH), (8.00, d, lH), (8.30, width s, IH). F-specti or of masa'-: base «10-747.

PREPARATION 7 2, 5-d met? L-l, 1-d? Oxo-benzo L "d] isot? Azole-3-one Hydrogen chloride was bubbled in methane! (750 J) dui in about 5 minutes. It was added in an acid portion S-met 1 J -2-? Net 1 isul farnoi 1 benzoic (10 g). The mixture was heated in a steam bath for about 15 minutes and then concentrated to a volume of 50 ml.The mixture was filtered and filtered to give 6 g of the title compound, mp 11-1330 C. NMR (CDCl 3) 6: (2.55, s, 3H), (3.26, s, 3H), (7, 15, d, 111) (7, r 3, 10.211) PREPARATION 8 2-met? L-5-bromoethyl-l, 1-d? Oxo-benzoCd] isothiazol-3-one A solution of 2, S-dimet? Ll, 1-d? Oxo-benzoCdH? Sot-azole-3-one (5.0 g) in + carbon tetrachloride (100 ml) was refluxed for approximately 2 hours. ) containing 2-2 -azo-bi s (2-rnet 1 i-? ro? on? ti lo) (50 rng) and 4.8 g of sucrose N-brorno, the mixture was cooled to the room temperature and filter to eliminate succimrnide. The filtrate was evaporated and the residue triturated with methanol and filtered to give- 2.5 g of the title compound, m.p. 110-113 ° C. NMR (CDCl 3) or: (3.30, s, 3H), (4.55, s, 2H), (8, 10-7, 80, rn, 3H) PREPARATION 9 N-t-butyl benzenesulfone one way Using a procedure analogous to that described in Preparation 5, from 4-inet-1-l-benzene sulfonyl chloride (2.65 g) and t-haloalumin (3.9), 3.0 g of the compound was obtained deJitulo, pf 77-30 * 0.

PREPARATION 10 5-Methyl-2- (N-t-butylsulfamoylbenzoic acid Using a procedure analogous to that described in Preparation 6, starting with Nt-butylbenzene sulfonarnide (13.6 g) and n-butyl lithium (1.6M in hexanes, 75 ml) gave 16 g of the title compound. , pf 159-162 ° C.

PREPARATION 11 5-methyl-2-t-butyl-l, l-dioxo-benzo [d] isothiazol-3-one Using a procedure analogous to that described in Preparation 7, based on acid 5-? Net? 1 -2- (Nt-Butylsulfarnoyl benzole co (16 g) yielded 4 g of the title compound, mp 124-125 ° C. NMR (CDCl 3) d: (1, 30, s, 9H), (2, 54, s, 3H), (7, 60, d, 11- |) (7.64, (1, IH), (7.30, s, IH) PREPARATION 12 2-t-butyl-5-bromomethyl-l, l-dioxo-benzo [d] isothiazol-3-one Using a procedure analogous to that described in Preparation 8, to go from 1.2 g of 7-t-buf 11 -5-? Net? eleven , 1 - . 1-dioxo-benzoCdl? Sot? Aolol-3-one 0.4 g of the title compound was obtained as an oil. NMR DCICI3) d: (1.75, S, 9H), (4.55, S, 2H), (7, 0, d, 1 H), (, r3, d, lH), (7.80, s, 1H) ') "> PREPARATION 13 3 - . 3-N-dimethylbenzenesulfonamide 5 Using an f > roced? m? enf or analogous to that described in Preparation 5, from 3-rnet? l benzenesul foni lo chloride (15.2 g) and nephylarnine (40% solution in water, 18.6 g ) 13 g of the title compound were obtained. NMR (CDCl 3) d: (2.54, s, 3H), (2.55, d, 3H), (4.45, width s, ll-l) 10 (7.40,, 2H), (7 , 68, rn, 2H) PREPARATION 14 4-Methyl-2-methylsulfamoyl benzoic acid Using a procedure analogous to that described in Preparation 6, starting with 3-Nd? Met? L bencenosul fonarní da (10.7 g) and n-butyl li io (1,611 on hexane, 69 ml) 5 g of the title compound were obtained. NMR (CDCl 3) d: (2.40, s, 3H), (2.50, d, 3H), (7, 70-7, 45, rn, 311), (13.50, width s, 1H), Mass spectrum: base + 18 = 247.

PREPARATION 15 -)? 2, -5-d? Methyl-l, 1-dioxo-benzo L "d] isothiazol-3-one Using a procedure analogous to that described in Preparation 7, the addition of 4-meth? I-2-met i L to its 1-pyrnoylbenzoic acid (5 g) yielded 2 g of the title compound. NMR (CDC13) d: (2.50, s, 3H), (3.15, s, 3H), (8, 20 -7, 70, rn, 3H) Mass spectrum: base + 18 = 229.

PREPARATION 16 6-bromoet? L-2-methyl-l, l-dioxo-benzoL "d] isothiazol-3-one Using an analogous reaction analogous to that described in Preparation 8, from 2 6 -d? Met? L-1, 1-d? Oxo benzoCd] 1 sot yol -3-one (2 g), N-bromo succminide (1.7 9) and 2 • 2'-zo-b? S (7-? Net 11) -propionit rilo (10 rng), 650 g of the title compound were obtained. p.f. 153-154 ° C "NMR fCDCl3) 6: (3, 30, s, 3H), (4.08, S, 2H), (8, 10 -7, 75.111, 3H) Mass spectrum: base» -1 R - 309.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula (I) (II) wherein R 1 is C -Cß alkyl, C3-C10 cycloalkyl, C3-C-alkenyl, C3-C ekyl or C-Ci-phenyl alkyl, wherein the alkyl portion is substituted for optionally methyl or ethyl form and the femlo portion is optionally substituted by C1-O4 alkoxy, alkyl of O1 -O4, F, Cl, Br or CF3, R2 is hydrogen or fluoro- and R3 is hydrogen, methyl , ethyl, pr-oyl, isopr-opium, CE2H or CF3 .. 7. - A compound according to claim 1, wherein R1 is Ci-Ce alkyl. 3. A compound according to claim 2, wherein Ri is methyl or t-butyl; R2 is fluoro and R3 is methyl. 4. A compound of formula (I), according to claim 3. 5.- A compound of formula (II), according to claim 3. 6.- A pharmaceutical composition comprising an amount of a compound according to claim 1 and a pharmaceutically acceptable diluent or carrier. 7. Use of a compound according to claim 1, in which it inhibits 5-1 ipooxigenase, in the preparation of compositions for the inhibition of 5-l? Poox? Genase in a mammal in its necessity. - Use of a compound according to claim 1, - In the preparation of compositions for the treatment or alleviation of an inflammatory disease or disorder, allergy, or cardiovascular disease. in a mammal. 9.- Use of a compound according to the rei indication 8, characterized furthermore because the inflammatory disease or disorder which is treated with the composition obtained therefrom, asina, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, de matif? S, attack, atopic dermatitis, rheumatoid arthritis u osteoai t ri ti • _,.