DIHYDROBENZOFURAN COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS

Abstract: A compound having structure (I) wherein (a) n is from 1 to about 3; (b) X is selected from the group consisting of O, S, SO, or SO2; (c) Y is independently hydrogen or straight, branched or cyclic alkyl having from about 1 to about 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to about 7 atoms; (d) Z is hydrogen or straight, branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen; (e) W is hydrogen or straight, branched or cyclic alkyl, aryl, hydroxy or alkoxy; and (f) R1 and R2 are independently hydrogen or straight, branched or cyclic alkyl having from one to 10 carbons, aryl, heterocyclyl, heteroaryl, hydroxy, or alkoxy; or R1 and R2 are bonded together to form a ring having from 3 to about 7 atoms wherein one to three atoms may be heteroatoms. Pharmaceutical compositions comprising such compounds, and methods of treating inflammation or pain using such compounds.

Description: DΓHYDROBENZOFURAN COMPOUNDS USEFUL AS ANTI-ΓNFLAMMATORY AGENTS TECHNICAL FIELD The subject invention relates to nonsteroidal anti-inflammatory drugs, particularly to substituted dihydrobenzofuran and related compounds BACKGROUND OF THE INVENTION Certain dihydrobenzofuran compounds and other compounds structurally related thereto have been found to have significant disease altering activities Such compounds, processes for making them, and uses for them are disclosed in the following references U.S Patent No 4,670,457 issued to Dona, Romeo & Corno on June 2, 1987, U.S Patent No 4,849,428 issued to Dobson, Loomans, Matthews & Miller on July 18, 1989, Japanese Patent Publication No 53-005178 of Yoshitomi Pharm Ind KK published January 1 , 1978, Hammond, M L I E Kopka, R A. Zambias, C G Caldwell, J Boger, F Baker, T Bach, S Luell & D E Maclntyre, "2,3-Dιhydro-5-benzofuranols as Antioxidant-Based Inhibitors of Leukotπene Biosynthesis", J Med Chem . Vol. 32 (1989), pp 1006-1020, Ortiz de Montellano, P R & M A Correia, "Suicidal Destruction of Cytochrome P-450 dunng Oxidative Drug Metabolism", Ann Rev Pharmacol Toxicol . Vol 23 (1983), pp 481-503 Chakrabarti, J K , R J Eggleton, P T Gallagher, J Harvey T A Hicks, E A Kitchen, and C W Smith, "5-Acyl-3-substιtuted-benzofuran-2(3H)-ones as Potential Anti-inflammatory Agents", J Med Chem , Vol 30 (1987), pp 1663- 1668 It is an object of the subject invention to provide compounds which have effective anti-inflammatory, analgesic and/or anti-oxidant activity It is a further object of the subject invention to provide such compounds which cause few adverse side effects It is also an object of the subject invention to provide methods for treating inflammation and/or pain using the subject compounds SUMMARY OF THE INVENTION The subject invention compounds having the structure wherein (a) n is from 1 to about 3, (b) X is selected from the group consisting of O, S, SO, or SO , (c) Y is independently hydrogen or straight, branched or cyclic alkyl or having from 1 to about 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to about 7 atoms, (d) Z is hydrogen or straight, branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen, (e) W is hydrogen or straight, branched or cyclic alkyl, aryl, hydroxy or alkoxy, and (f) Ri and R2 are independently hydrogen or straight, branched or cyclic alkyl having from one to 10 carbon atoms, aryl, heterocyclyl, heteroaryl, hydroxy, or alkoxy, or R-| and R2 are bonded together to form a ring having from 3 to about 7 atoms wherein one to three atoms may be heteroatoms DETAILED DESCRIPTION OF THE INVENTION As used herein, unless otherwise indicated, "alkyl" or "alkanyl" means a straight, branched or cyclic hydrocarbon chain, saturated or unsaturated, unsubstituted or substituted Preferred alkyl are Cη-Cin. more preferred are C< | - CQ, especially C1-C4 Preferred alkyl are straight chain Preferred branched alkyl have one or two branches, preferably one branch Preferred cyclic alkyl are monocyclic or are a straight chain with a monocyclic terminus Preferred alkyl are saturated Unsaturated alkyl have one or more double bonds or/and one or more triple bonds Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond Preferred alkyl are unsubstituted Preferred substituted alkyl are mono-, di-, or tπsubstituted, more preferably monosubstituted Preferred alkyl substituents include halo, hydroxy, oxo, alkoxy (e.g , methoxy, ethoxy, propoxy, butoxy, pentoxy), aryloxy (e.g , phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxyphenoxy, alkyloxycarbonylphenoxy, acyloxyphenoxy), acyloxy (e g , propionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio, acylthio, arylthio (e g , phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, alkyloxycarbonylphenylthio), aryl (e g , phenyl tolyl alkyloxphenyl, alkyloxycarbonylphenyl, halophenyl), heterocyclyl, heteroaryl, ammo (e g , ammo mono- and di- C-1-C3 alkanylamino, methylphenylammo, methylbenzylamino), C- - C3 alkanylamido, ureido, N'-alkylureido, N'N'-dialkylureidao, N'N'N-tnalkylureido, guanidino, N'-alylguaπidino, N',N",-dιalkylguanιdιnιono or alkoxy carbonyl As used herein, "alkoxy" means -O-alkyl As used herein, "aryl" means a moiety having an unsubstituted or substituted aromatic ring having 6 to about 10 carbon atoms Preferred aryl are phenyl and naphthyl, most preferred aryl is phenyl Preferred aryl are unsubstituted Preferred substituted aryl are mono-, di-, or trisubstituted, more preferably monosubstituted Preferred aryl substituents include hydroxy, mercapto, halo, methyl, ethyl and propyl As used herein, "heterocyclyl" means a moiety having a saturated or unsaturated non-aromatic ring having from 3 to about 8 ring atoms, including from 2 to about 6 carbon atoms and from 1 to about 4 heteroatoms selected from O, S, and N Preferred heterocycles are saturated Preferred heterocycles have 5 or 6 atoms in the ring including 1 or 2 heteroatoms in the ring, also preferably 1 heteroatom in the ring Specific preferred heterocycles include piperidinyl, tetrahydrothienyl pyrro dinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrof uranyl, imidazohdinyl, pyrazolidinyl, oxazohdinyl, isoxazolidinyl, thiazohdinyl, isothiazolidinyl, azepmyl, oxepinyl, thiepinyl, tπazolidinyl, tetrazohdinyl Heterocycles are unsubstituted or substituted, preferably unsubstituted Preferred substituted heterocycles are mono-, di-, or trisubstituted, more preferably monosubstituted Preferred heterocycle substituents include alkyl, halo, hydroxy, alkoxy, acyloxy, carboxy, carbamyloxy, thio, ammo, amido, ureido, guanidino, thiocarbamamido, thioureido As used herein, "heteroaryl" means a moiety having an aromatic ring of 5 or 6 atoms including from 1 to 5 carbon atoms and from 1 to 4 heteroatoms selected from O, S, and N Preferred heteroaryl groups include 1 to 3 heteroatoms in the ππg, also preferably 1 or 2 heteroatom in the ring Specific preferred heteroaryls include furyl thienyl, pyrrolyl either unsubstituted or alkyl substituted on nitrogen, thiazolyl, oxazolyl, 5-ιmιdazolyl either unsubstituted or alkyl-substituted on nitrogen, isoxazolyl, isothiazolyl, pyrazolyl unsubstituted or alkyl-substituted on nitrogen, oxdiazolyl, thiadiazolyl, tπazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl Fused heteroaryls include imidazothiazoltnyl, imidazopyπdinyl, imidazoimidazolinyl indolyl, quinolyl, isoquinolyl Heteroaryl groups are unsubstituted or substituted, preferably unsubstituted Preferred substituted heteroaryls are mono-, dt-, or trisubstituted, more preferably monosubstituted Preferred heteroaryl substituents include alkyl, halo, hydroxy, alkoxy, thio, nitro, ammo, nitro, amido, ureido , guanidino, thiocarbamamido, thioureido As used herein, "halo" means fluoro, chloro, bromo or iodo Preferred halo are fluoro, ' chloro and bromo; more preferred are chloro and bromo, especially chloro Compounds The subject invention involves compounds having the following structure wherein (a) n is from 1 to about 3; (b) X is selected from the group consisting of O, S, SO, or SO2, (c) Y is independently hydrogen or straight, branched or cyclic alkyl having from 1 to about 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from about 3 to about 7 atoms; (d) Z is hydrogen or straight, branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen; (e) W is hydrogen or straight, branched or cyclic alkyl, aryl, hydroxy or alkoxy; and (f) Ri and R2 are independently hydrogen or straight, branched or cyclic alkyl having from one to 10 carbon atoms, aryl, heterocyclyl, heteroaryl, hydroxy, or alkoxy; or R-| and R2 are bonded together to form a ring having from from 3 to about 7 atoms wherein one to three atoms may be heteroatoms. In the above structure, each Y is independently selected from hydrogen, straight or branched alkanyl having from 1 to about 4 carbon atoms, and cyclic alkyl having about 3 carbon atoms, cyclopropyl, or the Y's are bonded together to form an unsubstituted cyclic alkanyl ring having from 3 to about 7 carbon atoms in the ring Each Y is preferably hydrogen, methyl, ethyl or cyclopropyl, more preferably hydrogen or methyl, most preferably methyl Preferably both Y's are the same When the Y's are bonded together to form a cyclic ring, the ring is preferably cyclopropyl, cyclobutyl or cyclopentyl, more preferably cyclopropyl In the above structure Z is selected from branched or cyclic alkyl and unsubstituted or alkanyl-substituted phenyl or benzyl, Z having from 3 to about 10 atoms other than hydrogen Z is preferably saturated Z is preferably branched alkanyl having from about 3 to about 8 carbon atoms more preferably from about 4 to about 6 carbon atoms Z is preferably branched alkanyl having 2 or more branches, more preferably 2 branches Preferred branched alkanyl Z include t- butyl neopentyl, isopropyl, most preferred is t-butyl Preferred cyclic alkanyl Z include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl In the above structure, Ri and R2 are independently hydrogen, straight, branched or cyclic alkyl having from one to 10 carbon atoms Ri and R2 may be bonded together to form a cyclic alkanyl ring having from about 3 to about 7 atoms in the ring wherein 1 to about 3 atoms may be heteroatoms Preferred heteroatoms are O, N, or S Other preferred R groups include aryl, heterocyclyl, heteroaryl hydroxy, or alkoxy Preferred compounds of the subject invention are included in the following table Compound No W R1 R2 1 OH H H 2 H H butyl 3 H methyl methyl 4 H -(CH 2 ) 4 - In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art The anti-inflammatory activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to antagonize the local edema which is characteristic of the inflammatory response Examples of such known tests include the rat carrageenan edema test, the oxazolone-induced inflamed mouse ear test, and the mouse arachadonic acid-induced inflamed ear test Analgesic activity may be tested in art-known models such as the phenylbenzoquinone-induced writhing test in mice and the Randall & Selitto test in rats Another useful art-known test is the rat adjuvant arthritis test which is a useful model for assessing anti-inflammatory activity, anti-arthritic and anti-resorptive activity in a chronic, rather than an acute model These and other appropriate tests for pharmacological activity are disclosed and/or referred to in U S Patent No 4,130,666 issued to Moore on December 19, 1978, U S Patent No 4,431 ,656 issued February 14, 1984 to Katsumi, et al , U S Patent No 4 440,784 issued to Katsumi, et al on April 3, 1984, Japanese Patent Application 85/54315 of Katsumi, et al , published March 28, 1985, European Patent Application No 0,059,090 of Yamanuchi Pharmaceutical Company Ltd , published September 1 , 1982, Opas, E V , R J Bonney & J L Humes, "Prostaglandin and Leukotπene Synthesis in Mouse Ears Inflamed by Arachadonic Acid", The Journal of Investigative Dermatology. Vol 84, No 4 (1985), pp 253- 256, Swingle, K F , R L Bell & G G I Moore, "Anti-inflammatory Activity of Antioxidants" Antt-inflammatorv and Antirheumatic Drugs, Vol III, Chapter 4 K D Ramsford, ed , CRC Press, Inc , (1985), pp 105-126, Adamkiewicz, V W , W B Rice & J D McColl, "Antiphlogistic Effect of Trypsin in Normal and in Adrenalectomized Rats", Canadian Journal of Biochemistry & Physiology. Vol 33 (1955), pp 332-339, Sellye, H , "Further Studies Concerning the Participation of the Adrenal Cortex in the Pathogenesis of Arthritis", British Medical Journal. Vol 2 (1949), pp 1129-1135, and Winter, C A , E A Risley & G W Nuss, "Carrageenan-lnduced Edema in Hind Paw of the Rats as an Assay for Antiinflammatory Drugs" Proceedings of Society of Experimental Biology and Medicine. Vol 11 1 (1962), pp 544-547, Otterness, I , & M L Bliven, "Laboratory Methods for Testing Nonsteroidal Antiinflammatory Drugs" Nonsteroidal Antiinflammatory Drugs. Chapter 3, J G Lombardmo, ed , John Wiley & Sons, Inc (1985), pp 111-252 Hitchens, J T , S Goldstein, L Shemano & J M Beiler, "Analgesic Effects of Irritants in Three Models of Experimentally-Induced Pain", Arch Int Pharmacodvn . Vol 169, No 2 (1967) pp 384-393, Milne, G M & T M Twomey "The Analgetic Properties of Ptroxicam in Animals and Correlation with Experimentally Determined Plasma Levels", Agents and Actions, Vol 10, No 1/2 (1980), pp 31-37, Randall, L O & J J Selitto, "A Method for Measurement of Analgesic Activity on Inflamed Tissue", Arch Int Pharmacodvn , Vol 11 1 , No 4 (1957) pp 409-419, Winter, C A & L Faltaker, "Nociceptive Thresholds as Affected by Parenteral Administration of Irritants and of Various Antinociceptive Drugs" J Pharmacol Exo Ther . Vol 148, No 3 (1965), pp 373-379, the disclosure of all these references are incorporated herein by reference Many anti-inflammatory drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs) cause undesirable gastrointestinal side effects, especially when dosed perorally, such side effects may include ulcers and erosions These side effects, which are often asymptomatic, can become serious enough to require hospitalization and can even be lethal Compounds of the subject invention generally cause fewer such gastrointestinal side effects compared to other NSAIDs Some compounds of the subject invention are even gastroprotective, protecting the stomach and intestines from ulcers and erosions, particularly those caused by ethanol or other NSAIDs Certain NSAIDs, when dosed systematically, cause an undesirable increase in systemic levels of certain liver enzymes Compounds of the subject invention generally cause little or no liver enzyme side effects Compounds useful in the subject invention can be made using the following general reaction schemes The amidines can be prepared by two different routes The first route involves conversion of the substituted benzene starting material to the corresponding nitrile with chlorosulfonylisocyanate and dimethylformamide Reaction with acidic ethanol gives the imidate which is then reacted with the amine of choice to provide the amidine The nitrile intermediate can be reacted with a hydroxylamine or an alkoxylamine to provide the N-hydroxyamidine or N-alkoxyamidine product The second route involves conversion of the brominated benzene starting material to the aryl lithium by lithium halogen exchange with f-butyllithium followed by reaction with the appropriate N,N-dιsubstιtuted cyanamide HjNO Synthesis Examples The following non-limiting examples provide further information regarding synthesis of the subject compounds. Example 1 N-Butyl-7-t'erf-butyl-2.3-dιhvdro-3,3-dιmethylbenzofuran-5-carboxιmιdamιde hydrochloride 7-ter7-Butyl-5-cvano-2.3-dιhvdro-3,3-dιmethylbenzofuranA solution of 7-tert-butyl- 2,3-dιhydrobenzofuran (16 75 g, 82 mmol) in CH2CI2 (175 mL) is heated to reflux, and chlorosulfonylisocyanate (3.5 eq, 287 mmol, 25 4 mL) is added in a single portion The reaction is judged complete by TLC (5% EtOAc / hexanes) after 2 h. The reaction mixture is then cooled to 0°C and DMF (10 eq, 0 82 mol, 65 mL) is added The solution is allowed to stir at ambient temperature for 1.5 h The solvents are evaporated and the resulting oil partitioned between hexanes (200 mL) and H2O (3 x 100 mL) The aqueous phase is discarded, and the hexanes are dried (MgSO4) and evaporated to a yellow oil which solidifies upon sitting (18 2 g) This solid is purified by medium pressure chromatography (5% EtOAc / hexanes) to give the desired compound (8.58 g, 46%) as a yellow oil of sufficient purity (approx 85% by 1 H-NMR) for the next reaction Ethyl 7-terf-Butyl-2.3-dιhvdro-3.3-dιmethylbenzofuran-5-carboxιmιdιc acιd hydrochloride Into a solution of 7-tert-butyl-5-cyano-2 3-dιhydro-3 3-dιmethylbenzofuran (4 90 g, 18 6 mmol) in Et2θ (30 mL) and EtOH (3 eq, 55 8 mmol, 3 2 mL) is bubbled HCl gas for 10 mm The resulting red solution is stirred at 23 °C for 4 days The solvents are evaporated, the red oil triturated with hexanes (30 L), and the resulting red solid collected by filtration to give the title compound as a red powder (3 55 g, 62%) of sufficient purity for the next reaction Step 3 N-Butyl-7-ter} t -butyl-2.3-dιhvdro-3 3-dιmethylbenzofuran-5- carboximidamide hydrochloride To a solution of ethyl 7-ι , e/τ-butyl-2,3-dιhydro-3,3-dιmethylbenzofuran-5- carboximidic acid hydrochloride (400 mg, 1 29 mmol) in dioxane (10 mL) is added excess butylamine (0 5 mL) A color change from red to yellow is observed during the addition, and a precipitate forms The reaction is also monitored by TLC (10% MeOH / CHCI3) After 3 h, the white solid is collected by filtration and washed with MeOH to give the title compound as a white powder (243 mg, 55 7%), mp = 236 - 237 0 C Example 2 7-ι t ef -Butyl-2.3-dιhvdro-3.3-dιmethyl-5-(ιmιno-1-pyrrolιdιnylmethyl)-benzofuran hydrochloride To a solution of ethyl 7-terf-butyl-2,3-dιhydro-3,3-dιmethylbenzofuran-5- carboximidic acid hydrochloride (400 mg, 1 29 mmol) in dioxane (10 mL) is added excess pyrrolidine (0 6 mL) A color change from red to yellow is observed during the addition, and a precipitate forms The reaction is also monitored by TLC (10% MeOH / CHCI3) After 3 h, the yellow precipitate is collected by filtration and purified by preparative TLC (10% MeOH / CHCI3) to give the desired product as a white powder (210mg, 54 2%), mp = 255 - 256 °C Example 3 7-fe -Butyl-2,3-dιhvdro-N,N-dιmethyl-3.3-dιmethylbenzofuran-5-carboxιmιdamιde hydrochloride To a solution of 5-bromo-7-tert-butyl-2,3-dιhydro-3,3-dιmethyibenzofuran (500 mg, 1 8 mmol) in Et2θ (0 6 mL), and hexanes (5 5 mL) at -78°C is added t-BuLi (1 5 M in hexanes, 2 9 eq, 5 3 mmol, 3 3 mL) at such a rate that the reaction temperature does not exceed -60°C This solution is stirred for 1 h and then slowly cannulated into a -78°C solution of dimethylcyanamide (1 0 eq, 1 8 mmol, 0 15 mL) in Et2θ (5 mL) The reaction is kept at -78°C for 0 5 h and then is allowed to warm to 0°C After 1 5 h, TLC (10% MeOH in CHCI3) indicates the reaction to be complete The reaction is quenched with H2O (10 mL) and 1 N HCl (10 mL) and then extracted with Et2θ (2 x 10 mL) The aqueous layer is brought to pH 9 with 1 N NaOH and extracted with Et2θ (3 x 15 mL), which is dried (MgSO4) and evaporated to a yellow oil (410 mg) This oil is purified by preparative TLC (15% MeOH in CHCI3) to give a yellow oil, which is stirred in EtOH (5 mL) and 1 N HCl (10 mL) for 5 m The EtOH is evaporated and the resulting solution extracted with CH2CI2 (3 x 10 mL) The dried organic layers are evaporated to a yellow oil, which is triturated with Et2θ to give the title compound as a white powder (110 mg, 19 7%), mp >160 °C (dec) Example 4 7-te/t-Butyl-2,3-dιhvdro-3.3-dιmethyl-5-benzorblfurancarboxamιde Oxime A mixture of 7-tert-butyl-5-cyano-2,3-dιhydro-3,3-dιmethylbenzo[b]furan (6.39 g, 27 9 mmol), potassium carbonate (15.80 g, 114.0 mmol), hydroxylamine hydrochloride (7.93 g, 114 0 mmol), and 135 mL of ethanol is heated at reflux for 20 h The reaction mixture is cooled to room temperature, filtered, and concentrated in vacuo to give a solid residue Purification by flash column chromatography on silica gel (20% ethyl acetate-hexane -> 5% methanol- ichloromethane) furnishes 3 13 g (43%) of the title compound as a colorless foamy solid mp 109-110 °C Example 5 N-Butyl-7-rert-butyl-2,3-dιhvdro-3,3-dιmethylbenzothιenyl-5-carboxιmιdamιde hydrochloride Step 1 . 2-Bromo-6-te/t-butylthιophenol To a solution of tetramethylethylenediamme (198 4 mmol, 30 mL) in cyclohexane (140 mL) is slowly added n-BuLi (198 4 mmol, 99 2 mL, 2 M solution in cyclohexane) at 23 °C The resulting solution is cooled to 0 °C A solution of 2-tert-butylthιophenol (15 0 g, 90 2 mmol) in cyclohexane (40 mL) is then added at a rate such that the temperature stays below 10°C The reaction is then stirred at 0 °C for 5 h and is then allowed to warm to 23 °C overnight To the resulting yellow solution at 23 °C is added sec-BuLi (90 2 mmol, 69 4 L of 1 3 M solution in cyclohexane) over 0 5 h The resulting solution gradually turns orange After 1 5 h, the orange, cloudy reaction mixture is cannulated into a stirring solution of 1 ,2- dibromotetrafluoroethane (180 4 mmol, 21 5 mL) in THF (50 mL) over 1 h After addition is complete, the resulting reaction mixture is quenched with 1 N HCl (80 mL), and extracted with hexanes (3 x 100 mL) The hexanes are dried (MgSO4) and evaporated to a dark oil (2948 g) This oil is taken up in 1 N NaOH (100 mL), and extracted with CH2CI2 (3 x 50 mL) The organic phase is discarded, and the aqueous phase is acidified with 12 N HCl, and extracted with CH2CI2 (3 x 100 mL) The organic phase is dried (MgSO4) and evaporated to provide the title compound as a yellow oil Step 2 2-Bromo-6-fe/τ-butylphenyl 2-methallyl thioether A solution of 2-bromo-6- tert-butylthiophenol (12 4 g, 50 6 mmol), K2CO3 (8 44 g, 61 1 mmol), Nal (766 mg, 50 6 mmol), and CJ-methallylchloπde (5 17 mL, 50 6 mmol) in acetone (250 mL) is heated at reflux for 2 h The reaction is monitored by TLC (hexanes) The reaction mixture is allowed to cool to 23 β C, and the precipitated solids are filtered off The filtrate is evaporated to a dark yellow oil, which is taken up in hexanes (100 L) and stirred with silica gel (10 g) for 20 mm The silica gel is filtered off and discarded, and the filtrate is evaporated to yield the title compound as a light yellow Step 3 7-tert-Butyl-2.3-dιhvdro-3,3-dιmethylbenzothιophene A solution of (2- bromo-6-tert-butylphenyl)-(2-methallyl)-thιoether (9 00 g, 30 0 mmol), dι-/so- propylethylamine (160 mL, 0 90 mol) and 80% aqueous hypophosphorous acid (58 g, 0 90 mol) in dioxane (450 mL) is deoxygenated by bubbling with N2 for 0 5 h The solution is heated to reflux, and a similarly deoxygenated solution of azo-bis- /so-butyrylnιtrιle (1 7 g, 8 8 mmol) in dioxane (5 mL) is added via syringe in 0 5 mL portions in 0 5 h intervals The reaction is monitored by TLC (hexanes) After 24 h, the reaction mixture is allowed to cool to 23 °C, and partitioned with 1 N HCl (300 mL), brine (100 mL), and Et2θ (3 x 150 mL) The combined ethereal extracts are back extracted with 1 N NaOH (3 x 50 mL) and H2O (2 x 50 mL), and then are dried (MgSO4) and evaporated to yield the crude product as a yellow oil Short path vacuum distillation (85 °C, 40 mm Hg) of this material provides the title compound as a faint yellow oil Step 4 7-tert-Butyl-5-cvano-2,3-dιhvdro-3,3-dιmethylbenzothιopheneA solution of 7-tert-butyl-2,3-dιhydrobenzothιophene (5 0 g, 23 mmol) in CH2CI2 (50 mL) is heated to reflux, and chlorosulfonylisocyanate (3 5 eq, 80 mmol, 7 0 mL) is added in a single portion The reaction is monitored by TLC (5% EtOAc / hexanes) The reaction mixture is then cooled to 0 °C and DMF (10 eq, 0.23 mol, 18 mL) is added The solution is allowed to stir at ambient temperature The solvents are evaporated and the resulting oil partitioned between hexanes (100 mL) and H2O (3 x 50 mL) The aqueous phase is discarded, and the hexanes are dried (MgSO4) and evaporated to a yellow oil which solidifies gradually This solid is purified by medium pressure chromatography (5% EtOAc / hexanes) to give the desired compound Step 5 Ethyl 7-fen t -butyl-2.3-dιhvdro-3,3-dιmethylbenzothιenyl-5-carboxιmιdιc acid hydrochloride Into a solution of 7-ferf-butyl-5-cyano-2,3-dιhydro-3,3-dιmethylbenzothιophene (2 0 g, 8 2 mmol) in Et2θ (18 mL) and EtOH (3 eq, 24 6 mmol, 1 4 mL) is bubbled HCl gas for 10 m The resulting red solution is stirred at 23 β C for 4 days The solvents are evaporated, the red oil triturated with hexanes (15 mL), and the resulting red solid collected by filtration to give the title compound as a red powder of sufficient purity for the next reaction 13 Step 6 N-Butyl-7-te/t-butyl-2.3-dιhvdro-3,3-dιmethylbenzothιenyl-5- carboximidamide hydrochloride To a solution of ethyl 7-fer -butyl-2,3-dihydro-3,3-dimethylbenzothienyl-5- carboximidic acid hydrochloπde (400 mg) in dioxane (10 mL) is added excess butylam e (0 5 mL) A color change from red to yellow is observed during the addition, and a precipitate forms The reaction is also monitored by TLC (10% MeOH / CHCI3) After 3 h, the white solid is collected by filtration and washed with MeOH to give the title compound as a white powder, mp > 240 °C Compositions Compositions of the subject invention comprise a safe and effective amount of the subject compounds, and a pharmaceutically-acceptable carrier As used herein, "safe and effective amount" means an amount of a compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/πsk ratio), within the scope of sound medical judgment A safe and effective amount of a compound will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically- acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician Compositions of the subject invention preferably comprise from about 0 1% to about 99.9% by weight of a compound, more preferably from about 20% to about 80%, and most preferably from about 40% to about 70% In addition to the compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier The term "pharmaceutically- acceptable earner", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated Some examples of substances which can serve as pharmaceutically- acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose, starches, such as cornstarch and potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, powdered tragacanth, malt, gelatin, talc, solid lubricants, such as stearic acid, magnesium stearate, calcium sulfate, vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma, polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol, algmic acid, emulsifiers, such as the Tweens®, wetting agents such as sodium lauryl sulfate, coloring agents, flavoring agents, excipients, tabletmg agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline, and phosphate buffer solutions The choice of a pharmaceutically-acceptable carrier to be used in conjunction with a subject compound is basically determined by the way the compound is to be administered If the subject compound is to be injected, it is preferably injected non- intravenously, the preferred pharmaceutically-acceptable earner is sterile, physiological saline, with blood compatible suspending agent, the pH of which has been adjusted to about 7.4 Such injectable compositions preferably comprise from about 1% to about 50% of the subject compound, more preferably from about 5% to about 25%, also preferably from about 10 mg to about 600 mg of the subject compound per dose Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in lotions, creams, gels and the like Topical compositions preferably contain from about 1% to about 50% of an emollient, more preferably from about 5% to about 25% of an emollient Such topical compositions preferably comprise from about 0.1% to about 50%, of the subject compound, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 3500 mg per dose. The preferred mode of administering the subject compound is perorally The preferred unit dosage form is therefore tablets, capsules and the like, compnsing a safe and effective amount of the compound, which is preferably from about 5 mg to about 3500 mg, more preferably from about 10 mg to about 1000 mg, and most preferably from about 25 mg to about 600 mg The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well-known in the art Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by a person skilled in the art Many of the subject compounds are hydrophobic If it is desired to provide an aqueous-based composition or a composition soluble in or miscible with aqueous media, a solubilizing agent may be included in the composition Non- limiting examples of such solubilizing agents include polyethylene glycol, propylene glycol, ethanol, and polyoxyethylene (35) castor oil Particularly preferred oral composition earners suitable for compositions of the subject invention are disclosed in U S Patent Nos 5,189,066 of Kelm & Bruns, issued February 23, 1993, entitled "Pharmaceutical Compositions of Tebufelone", and 5,281 ,420 of Kelm & Dobrozsi, issued January 25, 1994, entitled "Solid Dispersion Compositions of Tebufelone", hereby incorporated herein by reference Methods Another aspect of the subject invention is methods for treating or preventing diseases characterized by inflammation by administenng a safe and effective amount of a subject compound to a human or lower animal in need of such treatment The term "diseases characterized by inflammation", as used herein, means conditions which are known to involve inflammation, and may include conditions such as arthritis (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthπtis, juvenile arthritis, Reiter's syndrome, infectious arthritis, and ankylosmg spondylitis, systemic lupus, erythematosus and gout), as well as the presence of inflammation whether or not it is associated with an identifiable disease Diseases characterized by inflammation further may include inflammation in the oral cavity (e g , inflammation associated with gingivitis or peπodontal disease), inflammation in the gastrointestinal tract, (e g , inflammation associated with ulcers and irritable bowel disease), inflammation associated with dermatological diseases (e g , psoriasis, acne, and other skin inflammation), inflammation associated with the respiratory tract (e g , asthma, bronchitis, and allergies), and inflammation in the central nervous system (e g , Alzheimer's disease) Another aspect of the subject invention is methods for treating or preventing pain by administenng a safe and effective amount of a subject compound to a human or lower animal in need of such treatment Pain which can be treated or prevented by administering the subject compounds may include peπpheral pain, menstrual pain, dental pain, and lower back pain Another aspect of the subject invention is methods for preventing oxidative damage at inflammatory sites by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment While not limited to a particular mechanism, it is believed that the subject compounds inhibit leukotπene synthesis, thereby decreasing neutrophil accumulation at an inflammatory site Another aspect of the subject invention is methods for treating or preventing gastric or duodenal ulcers or erosions by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment In particular, such ulcers or erosions caused by ethanol or non-steroidal antiinflammatory drugs (NSAIDs) can be treated and/or prevented by administration of preferred subject compounds Appropriate tests for determining the gastrointestinal safety or gastroprotective or gastric healing properties of the subject compounds are known Methods for determining acute gastrointestinal safety are disclosed and/or referred to in the following references Unangst, P C , G P Shrum, D T Connor, R D Dyer, and D J Schπer, "Novel 1 ,2,4-Oxadιazoles and 1 ,2,4-Thιadιazoles as Dual 5-Lιpoxygenase and Cyclooxygenase Inhibitors", J Med Chem . Vol 35 (1992), pp 3691-3698, and Segawa.Y, O Ohya, T Abe, T Omata, et al , "Anti- inflammatory, Analgesic, and Antipyretic Effects and Gastrointestinal Toxicity of the New Anti-inflammatory Drug N-{3-[3-(pιpeπdιnylmethyl)phenoxy] propyl}- carbamoylmethylthιo]ethyl 1 -(p-chlorobenzoyl) 5-Methoxy-2methyl-3- indolylacetate", Arzneim -Forsch /Drug Res , Vol 42 (1992), pp 954-992 In the methods disclosed therein, stomachs of the animals are typically examined two hours after dosing a compound Methods for determining subchronic gastrointestinal safety are disclosed and/or referred to in the following references Melarange, R , C Gentry, et al , "Anti-inflammatory and Gastrointestinal Effects of Nabumetone or Its Active Metabolite, 6-Methoxy-2-naphthylacetιc Acid (6MNA)" Dig Pis Sci , Vol 37 (1992), pp 1847-1852, and Wong, S , S J Lee, et al , "Antiarthπtic Profile of BF-389 - A Novel Anti-inflammatory Agent With Low Ulcerogenic Liability", Aoents Actions. Vol 37 (1992), pp 90-91 Methods for determining acute gastroprotection are disclosed and/or referred to in the following reference Playford, R J , D A Versey, S Haldane, M R Alison, and J Calan, "Dose-dependent Effects of Fentanyl on Indomethacm- induced Gastric Damage", Digestion. Vol 49 (1991), pp 198-203 In the method disclosed therein, female Lewis rats (130-175 g) are dosed perorally with the subject compound (40 mg/kg b i d ) or vehicle at 2 hours and immediately before administration of a gastric damaging dose of mdomethacin The rats are sacrificed 4 hours later by CO2 asphyxiation Gastric corpus damage (millimeters of hemorrhagic lesions) is measured by digitized imaging The preferred mode of administration of the subject compounds is peroral but other known methods of administration are contemplated as well, e g , dermatomucosally (for example, dermally, rectally and the iike), and parenterally (for example, by subcutaneous injection, intramuscular injection, intraarticular injection, intravenous injection and the like) Ocular administration and inhalation are also included Thus specific modes of administration include, without limitation, peroral, transdermal, mucosal, sublingual, intranasal, intramuscular, intravenous, intrapeπtoneal, subcutaneous, and topical administration Preferred doses of the subject compounds range from about 0 2 mg/kg to about 70 mg/kg, more preferably from about 0 5 mg/kg to about 12 mg/kg Preferred injectable doses comprise from about 0 1 mg/kg to about 10 mg/kg of the subject compound Preferred topical doses comprise from about 1 mg/cm 2 to about 200 mg/cm 2 of the subject compound applied to the skin surface Preferred peroral doses comprise from about 0 5 mg/kg to about 50 mg/kg, more preferably from about 1 mg/kg to about 20 mg/kg, more preferably still from about 2 mg/kg to about 10 mg/kg, of the subject compound Such doses are preferably administered from about once to about six times daily, more preferably from about twice to about four times daily Such daily doses are preferably administered for at least one week, also preferably for at least two weeks, also preferably at least one month, also preferably for at least 2 months, also preferably for at least 6 months, 1 year, 2 years, or more Compositions and Method Examples The following non-limiting examples illustrate the subject invention Example A Pharmaceutical compositions in the form of tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows Ingredient Quantity (mg per tablet) Compound 1 200 Microcrystalline Cellulose 100 Sodium Starch Glycollate 30 Magnesium Stearate 3 When administered orally two times daily, the above composition significantly reduces the inflammation in a patient suffering from rheumatoid arthritis A significant benefit is also achieved by twice daily administration of this composition to a patient suffeπng from osteoarthritis Example B A pharmaceutical composition in capsule form is prepared by conventional methods, formulated as follows Ingredient Quantity (mg per capsule) Compound 2 200 Lactose To fill to volume of capsule The above capsule administered orally once a day substantially reduces the symptomology of a patient afflicted with rheumatoid arthritis or osteoarthritis Example C A pharmaceutical composition in liquid form is prepared by conventional methods, formulated as follows Ingredient Quantity Compound 3 200 mg EtOH 4 ml Methyl cellulose 0 4 mg Distilled water 76 ml Tween 80 1 6 ml 50 ml of the above composition administered perorally once a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthntis Example D A pharmaceutical composition in liquid form is prepared by conventional methods, formulated as follows Ingredient Quantity Microcrystalline (micronoized) 200 mg Compound 4 Avicel (microcrystalline cellulose) 50 mg Tween 80 1 6 ml Methyl cellulose 0 4 mg Deionized water 80 ml 50 ml of the above composition administered perorally twice a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthritis While particular embodiments of the subject invention have been described, it would be obvious to those skilled in the art that various changes and modifications to the compositions disclosed herein can be made without departing from the spirit and scope of the invention It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention

Claims: I A compound having the structure: wherein (a) n is from 1 to about 3; (b) X is selected from the group consisting of O, S, SO, or SO2; (c) Y is independently hydrogen or straight, branched or cyclic alkyl having from 1 to about carbon atoms, or the Y's are bonded together to form an alkanyl nng having from 3 to about 7 atoms; (d) Z is hydrogen or unsubstituted straight, branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen; (e) W is hydrogen or straight, branched or cyclic alkyl, aryl, hydroxy or alkoxy; and (f) Ri and R2 are independently hydrogen, straight, branched or cyclic alkyl having from one to 10 carbon atoms, aryl, alkyl, heterocyclyl, heteroaryl, hydroxy, or alkoxy; or R-| and R2 are bonded together to form a ππg having from from 3 to about 7 atoms wherein one to three atoms may be heteroatoms. -> The compound of Claim 1 wherein X is oxygen or sulphur; and W is hydrogen or hyroxyl. The compound of Claim 1 wherein each Y is independently selected from the group consisting of hydrogen, methyl and ethyl: and Z is selected from the group consisting of C4-C5 branched alkanyl having 2 branches, C3-C6 cyctoalkanyl The compound of Claim 3 wherein R-| is hydrogen or methyl, and R2 is nydrogen, C-μCs straight or single-Dranched alkyl or straight alkyl with a terminal cyclic alkyl. saturated or unsaturated with one double oond Detween non-terminal carbon atoms, or C3-C5 cycloalkanyl or R^ and R2 are oonded togetner to form a ring navng from 3 to aoout 7 atoms RECTIFIED SHEET (RULE 91) ISA/EP 20 The compound of Claim 4 wherein X is oxygen, R-| and R2 are hydrogen, methyl or butyl The compound of Claim 5 wherein both Y are methyl, and Z is t-butyl The compound of Claim 6 wherein W is OH or hydrogen and n is one The compound of Claim 3 wherein R<ι and R2 are bonded to form a ring selected from the group selected from the group consisting of -(CH2)4-, - (CH 2 )5-. or -(CH 2 ) 6 - The compound of Claim 8 wherein both Y are methyl, and Z is t-butyl The compound of Claim 9 wherein X is oxygen, and R-| and R 2 are - (CH 2 ) 4 - The compound of Claim 11 wherein W is hydrogen and n is one A composition compnsing a compound of Claim 1 and a pharmaceutically- acceptable earner A method of treating inflammation or pain comprising admmistation, to a human or lower animal in need of such treatment, of a safe and effective amount of a compound of Claim 1 A method of treating arthπtis compnsing daily peroral administration, to a human in need of such treatment, of from about 1 mg/kg to about 20 mg/kg of a compound of Claim 1 A composition compnsing a compound of Claim 7 and a pharmaceutically- acceptable carrier A method of treating inflammation or pain comprising admmistation, to a human or lower animal in need of such treatment, of a safe and effective amount of a compound of Claim 7 RECTIFIED SHEET (RULE 91) ISA/EP 17 A method of treating arthritis comprising daily peroral administration, to a human in need of such treatment, of from about 1 mg/kg to about 20 mg/kg of a compound of Claim 7. 18 A composition comprising a compound of Claim 11 and a pharmaceutically- acceptable carrier. 19. A method of treating inflammation or pain comprising admmistation, to a human or lower animal in need of such treatment, of a safe and effective amount of a compound of Claim 11. 20. A method of treating arthritis comprising daily peroral administration, to a human in need of such treatment, of from about 1 mg/kg to about 20 mg/kg of a compound of Claim 11. RECTIFIED SHCE (RULE 91) ISA / EP

Inventors: SCHERZ MICHAEL WIARD, WU LAURENCE ICHIH, SCHERZ, MICHAEL, WIARD, WU, LAURENCE, ICHIH
Applicants: PROCTER & GAMBLE, THE PROCTER & GAMBLE COMPANY
Application year: 1997
Main classification: C07D307
IPC codes: A61K31, A61P19, A61P29, A61P43, C07D307, C07D333, C07D335, C07D337, C07D405