AU717412B2 - Dihydrobenzofuran and related compounds useful as anti-inflammatory agents - Google Patents

Description

f t'/UU/Ul 28/5/91 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT

S

*SS.

Application Number: Lodged: Invention Title: DIHYDROBENZOFURAN AND RELATED COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS The following statement is a full description of this invention, including the best method of performing it known to us 1 DIHYDROBENZOFURAN AND RELATED COMPOUNDS USEFUL AS ANTI-INFLAMMATORY 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 Doria, Romeo Como on June 2, 1987; U.S. Patent 15 No. 4,849,428 issued to Dobson, Loomans, Mathews Miller on July 18, 1989; Japanese Patent Publication No. 53-005178 of Yoshitomi Pharm. Ind. KK published January 1, 1978; Hammond, M. I. E. Kopka, R.

A. Zambias, C. G. Caldwell, J. Boger, F. Baker, T. Bach, S. Luell D. E.

Maclntyre, "2,3-Dihydro-5-benzofuranols as Antioxidant-Based Inhibitors of 20 Leukotriene Biosynthesis", J. Med. Chem., Vol. 32 (1989), pp. 1006-1020; Ortiz de Montellano, P. R M. A Correia, "Suicidal Destruction of Cytochrome P-450 during Oxidative Drug Metabolism", Ann. Rev.

Pharmacol. Toxicol., Vol. 23 (1983), pp. 481-503; Chakrabarti, R.J.

Eggleton, P.T. Gallagher, J. Harvey, T.A. Hicks, E.A. Kitchen, and C.W.

25 Smith, "5-Acyl-3-substituted-benzofuran-2(3H)-ones as Potential Antiinflammatory 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 and/or analgesic 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: x 'W

Z

wherein X is sulfur; each Y is independently hydrogen or unsubstituted straight, or branched alkyl or cycloalkyl having from 1 to 3 carbon atoms, or the two Y's are bonded to form a cycloalkyl ring having from 3 to 7 carbon atoms; Z is hydrogen or unsubstituted branched or cyclic alkyl, or unsubstituted o. or alkanyl-substituted phenyl, Z having from 3 to 10 atoms other than 10 hydrogen; and W is straight, or branched alkyl or cycloalkyl or alkenyl or alkadienyl unsubstituted or substituted, cycloalkenyl, cycloalkadienyl; where no terminal carbon atom of W is part of a double bond, or aryl, W having from 1 to 15 atoms other than hydrogen, wherein when both Ys are hydrogen, Z is not hydrogen; wherein when both Ys are methyl and Z is hydrogen, W is not methyl and when one Y is methyl and the other is hydrogen, W is not 2-(piperidine-1-yl)ethyl.

The invention also relates to: o A method of treating inflammation or pain, method including p administration, to a human or lower animal in need of such treatment, of a safe and effective amount of a compound having the general formula: Y Y O I

[Y

Z

wherein X is sulfur; each Y is independently hydrogen or unsubstituted straight, or branched alkyl or cycloalkyl having from 1 to 3 carbon atoms, or the two Y's are bonded to form a cycloalkyl ring having from 3 to 7 carbon atoms; Z is hydrogen or unsubstituted branched or cyclic alkyl, or unsubstituted or alkanyl-substituted phenyl, Z having from 3 to 10 atoms other than hydrogen; and W is straight, or branched alkyl or cycloalkyl, or alkenyl or alkadienyl unsubstituted or substituted, cycloalkenyl, cycloalkadienyl; where no terminal carbon atom of W is part of a double bond or aryl, W having from 1 to 15 atoms other than hydrogen, where when both Y are hydrogen, Z is not hydrogen.

DETAILED DESCRIPTION OF THE INVENTION As used herein, unless otherwise indicated, "alkyl" means a straight, 15 branched or cyclic hydrocarbon carbon-containing chain, saturated or unsaturated, unsubstituted or substituted. Preferred alkyl are straight chain.

Preferred branched alkyl have one or two branches, preferably one branch.

Preferred cyclic alkyl are monocyclic or are straight chain and monocyclic :o combination, especially a straight chain with a monocyclic terminus. Preferred 20 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 trisubstituted, more preferably monosubstituted. Preferred alkyl substituents include halo, hydroxy, oxo, alkoxy methoxy, ethoxy, propoxy, butoxy, pentoxy), aryloxy phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, acyloxyphenoxy), acyloxy proprionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio, acylthio, arylthio phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, alkyloxycarbonylphenylthio), 4u 3 aryl phenyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl, halophenyl), heterocyclyl, heteroaryl, amino amino, mono- and di- C1-C3 alkanylamino, methylphenylamino, methylbenzylamino, C1-C3 alkanylamido, carbamamido, ureido, guanidino). Preferred alkyls also include alkyls having heteroatoms within the chain said heteroatoms selected from the group consisting of oxygen, sulfur, nitrogen and combinatibns thereof.

As used herein, "alkanyl" means a saturated alkyl.

As used herein, "alkoxy" means -O-alkyl.

As used herein, "terminal carbon atom" means a carbon atom in an alkyl chain which is bonded to only one non-hydrogen atom; "non-terminal carbon atom" means a carbon atom in an alkyl chain bonded to two or more non-hydrogen atoms.

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 alkyl, alkoxy, hydroxy, thiol, amino, halo. Preferred alkyl substituents are 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 25 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, pyrrolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, oxathiazolidinyl, isothiazolidinyl, azepinyl, oxepinyl, triazolidinyl. Heterocycles are unsubstituted or substituted, preferably unsubstituted. Preferred substituted heterocycles are mono-, di-, or trisubstitued, more preferably monosubstituted. Preferred heterocycle substitutents include alkyl, halo, hydroxy, alkoxy, thio, amino, amido, ureido, guanidino, thiocarbamamido, thioureido.

As used herein, "heteroaryl" means a moiety having an aromatic ring having 5 or 6 ring atoms including from 2 to 5 carbon atoms and from 1 to 3 heteroatoms selected from O, S and N. Preferred heteroaryls have 1 or 2 heteroatoms in the ring, also preferably 1 heteroatom in the ring. Specific preferred heteroaryls include pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, pyranyl, thienyl, tetrazolyl, thiazolyl, isothiazolyl, furyl, oxathiazolyl. Heteroaryls are unsubstituted or substituted, preferably unsubstituted. Preferred substituted heterocycles are mono-, di-, or trisubstituted, more preferably monosubstituted. Preferred heteroaryl substituetts include alkyl, halo, hydroxy, alkoxy, thio, amino, amido, ureido, guanidino, thiocarbamamido, thiouredio.

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.

The subject invention involves compounds having the following structure:

O

Y Y x 15 In the above structure, X is 0 or S. Preferred X is O.

In the above structure, each Y is independently selected from hydrogen, or unsubstituted straight, branched or cyclic alkanyl having from 1 to about 3 carbon atoms, or the Y's are bonded together to form a cyclic alkanyl ring having from 3 to about 7 carbon atoms in the ring. Each Y is 20 preferably hydrogen, methyl, ethyl or cyclopropyl; more preferably hydrogen or methyl; most preferably methyl. When the Ys 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 the group consisting of hydrogen, unsubstituted branched or cyclic alkyl, and unsubstituted or alkanyl-substituted phenyl, having from 3 to about 10 atoms other than hydrogen. Z is preferably branched alkanyl having from about 4 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, isopropyl, neopentyl; most preferred is t-butyl. Preferred cyclic alkanyl Z include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; most preferred is cyclopentyl. Also preferred Z is unsubstituted phenyl or phenyl substituted with methyl.

In the above structure, W is straight, branched or cyclic alkyl or aryl, unsubstituted or substituted, saturated or mono- or di-unsaturated with double bonds except that no terminal carbon atom of W is part of a double bond; W having from 1 to about 15 atoms other than hydrogen. Preferred W have from about 2 to about 9 atoms other than hydrogen; more preferred W have from about 3 to about 7 atoms other than hydrogen. Preferred substitutents for alkyl W include hydroxy, thiol, amino, halo, phenyl, heterocycle and heteroaryl; more preferred include hydroxy, thiol, halo, and saturated heterocycle; more preferred still are hydroxy and chloro.

Preferred straight chain alkyl W are alkanyl, including methyl, ethyl, n-propyl and n-butyl. Preferred straight chain alkanyl W are unsubstituted or substituted; if substituted, they are preferably monosubstituted with S: 15 hydroxy or halo, especially chloro.

Preferred branched chain alkyl W are alkanyl, preferably having a single alkanyl branch, more preferably a single methyl branch. Preferred branched chain alkanyl W are unsubstituted or substituted; if substituted, they are preferably monosubstituted with hydroxy or halo, especially chloro.

Preferred cyclic alkyl W are alkanyl, preferably cyclopropyl, cyclobutyl or cyclopentyl, or C 1 to about C 4 straight chain alkanyl with a terminal cyclopropyl, cyclobutyl or cyclopentyl, preferably cyclopropyl.

Preferred cyclic alkanyl W are unsubstituted.

Preferred unsaturated alkyl W have one double bond between non- 25 terminal carbon atoms, the double bond preferably being between the carbon atom bonded to the carbonyl carbon atom and an adjacent nonterminal carbon atom. Preferred unsaturated alkyl W are unsubstituted.

Preferred unsaturated alkyl W are straight chain or branched chain with a single branch, preferably a single methyl branch.

Preferred cyclic aryl W are phenyl or naphthyl, preferably phenyl.

Preferred cyclic aryl W are unsubstituted.

Preferred compounds of the subject invention include those having the above structure with the X, W, the two Ys, and Z as indicated in the following table: Compound No. X W Y Z 1 O methyl methyl, methyl t-butyl a. a.

a a a *aa.

a.

a.

a. a 2 0 ethyl 3 0 n-propyl 4 0 n-butyl 0 i-propyl 6 0 cyclopropyl 7 0 cyclopentyl 8 0 3-cyclopropylpropyl 9 0 2-chloro-2-rnethylpropyl 0 2-hydroxy-2 -methyl propyl 11 0 2-methyl-2-propenyl 12 0 2-methylcyclopropyl 13 0 2-thio-2-methylpropyl 14 0 methyl-1 -hydroxycyclopentyl 15 0 3-cyclopropylpropyl 16 0 2-methyl-2-propenyl 17 0 methylthiomethyl 18 0 n-butyl 19 0 3-cyclopropylpropyl 0 n-pentyl 21 0 n-butyl 22 0 1 -methylethyl 23 0 ethyl 24 0 methyl 0 2-hydroxy-2methylpropyl 26 S n-propyl 27 S n-butyl 28 0 phenyl 29 0 3-cyclopropylpropyl 0 2-hydroxy-2-methyl propyl 31 0 methylsulfinylmethyl 32 0 acetylthiomethyl methyl, methyl, methyl, methyl, methyl, methyl, methyl, methyl, methyl, methyl methyl, methyl methyl, methyl methyl, methyl methyl, methyl methyl, methyl H, H methyl, methyl H, H H, H methyl, methyl methyl, methyl H, H H, H H, H H, H methyl, methyl methyl, methyl methyl, methyl methyl, methyl methyl, methyl methyl, methyl methyl, methyl methyl methyl methyl methyl methyl methyl methyl methyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl cyclopentyl t-butyl t-butyl t-butyl t-butyl t-buty cyclopentyl t-butyl t-butyl t-buty t-butyl t-butyl t-butyl t-butyl

H

H

t-butyl t-butyl 7 33' O ethylthiomethyl methyl, methyl t-butyl 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 oxazoloneinduced 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 00 adjuvant arthritis test which is a useful model for assessing antiinflammatory activity, anti-arthritic and anti-resorptive activity in a chronic, 15 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, R.J. Bonney J. L. Humes, "Prostaglandin and Leukotriene Synthesis in Mouse Ears Inflamed by Arachadonic Acid", The Journal of 25 Investigative Dermatology, Vol. 84, No. 4 (1985), pp. 253-256; Swingle, K.

R. L. Bell G. G. I. Moore, "Anti-inflammatory Activity of Antioxidants", Anti-inflammatory and Antirheumatic Drugs, Vol. III, Chapter 4, K D.

Rainsford, 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 Physioloqy, Vol. 33 (1955), pp. 332-339; Sellye, "Further Studies Conceming the Participation of the Adrenal Cortex in the Pathogenesis of Arthritis", British Medical Journal, Vol. 2 (1949), pp. 1129-1135; and Winter, 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. 111 (1962), pp. 544-547; Otteress, M. L. Bliven, "Laboratory Methods for Testing Nonsteroidal Antiinflammatory Drugs", Nonsteroidal Antiinflammatory Drugs, Chapter 3, J. G. Lombardino, ed., John Wiley Sons, Inc. (1985), pp. 111-252.

Hitchens, J. S. Goldstein, L. Shemano J. M. Beiler, "Analgesic Effects of Irritants in Three Models of Experimentally-Induced Pain", Arch. Int.

Pharmacodyn. Vol. 169, No. 2 (1967) pp. 384-393; Milne, G. M. T. M.

Twomey, "The Analgetic Properties of Piroxicam 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.

Pharmacodyn., Vol. 111, 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. Exp. Ther., Vol. 148, No. 3 (1965), pp. 373-379; the disclosure of all these references are incorporated herein by reference.

15 Many anti-inflammatory drugs, particularly non-steroidal antiinflammatory 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.

:25 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 scheme: Scheme 1

FIX'

(I)

x=o rMeOH Bu 1, TMED A, x=s CBrF2CBrF 2 00 000 00 0 0* 0 *00000 0 *0 00 0 *000 0* 00 0 0 00 0* 00 00 0 0e (Mf) Y, CL

Y

Na I (catalyst)

(IV)

Br

B

Y z

Y'

Y

Pd(OAc)2, P(C6H 1 3) 3 piperidine forinate, DMFf

(VI)

y Y z

(VMI

WC02H, TFAA or WCOC1, SnC14~

(VIII)

0 Y Y w x In Scheme 1, X, Y. Z and W are as defined above. The substituted phenols or thiophenols depicted as starting materials in Scheme 1 are known, commercially available, or readily prepared by methods known to one of ordinary skill in the art. Bromination of such phenol or thiophenol starting materials can be carried out as depicted in steps and (II) in Scheme 1. For example, 2,4-dibromo-6-t-butylphenol is obtained by reaction of 2-t-butylphenol with bromine in MeOH. 2-Bromo-6-tbutylthiophenol is obtained by treatment of 2-t-butylthiophenol with excess alkyl lithium reagent in a strongly coordinating solvent such as tetramethylethylenediamine (TMEDA) or hexamethylphosporamide followed by reaction with 1,2-dibromo-tetrafluoroethane in an ethereal solvent at low temperature.

Allylation of such brominated substituted phenol or thiophenol with an allylic halide is depicted in steps (III) and (IV) of Scheme 1. Allylic halides such as 3-chloro-2-methylpropene, 1-chloro-2-methyl-2-butene, 1chloromethylcylcopentene, or 1-chloromethylcyclobutene are reacted with :.appropriate brominated substituted phenols and thiophenols using reaction conditions readily apparent to a skilled organic chemist. For example, 3chloro-2-methylpropene in the presence of catalytic sodium iodide in 15 refluxing acetone reacts with substituted phenols or thiophenols to provide the corresponding allylated compounds.

Such allylated compounds are cyclized as depicted in steps and (VI) of Scheme 1. Reaction conditions useful for achieving this cyclization are known to those skilled in the art, and can, for example, involve either the intermediacy of free radical species, or Pd or Ni coordination complexes.

SOne method of achieving the ring closure is in hot dimethyfformamide solvent with Pd 2 or Ni 2 salts in the presence of trivalent alkyl or aryl phosphorous compounds, such as tricyclohexylphosphine (P(C 6

H

1 3)3), triphenylphosphine or analogous materials. An altemative method when Z :25 has no hydrogen bonded to its alpha-carbon atom (the carbon bonded to the phenyl ring), involves treatment of the allylated compound with a reductant such as tri-n-butyltinhydride, tetra-kis-trimethylsilylsilane, or hypophosphorus acid in hot dioxane, in the presence of a base (such as triethylamine, diisopropyethylamine, or the like) and a radical chain initiator such as azo-bis-isobutyrylnitrile.

Compounds of the subject invention are prepared from the fused-ring compounds provided by steps and (VI) of Scheme 1 by one of several methods. Acylation of such fused-ring compounds with an appropriate carboxylic acid as depicted in Step (VII) of Scheme 1 can be achieved under reaction conditions readily apparent to one skilled in the art. For example, this reaction can be performed in an inert halogenated solvent, such as CH 2 C12 using an activating agent such as trifluoroacetic acid 11 anhydride at the appropriate temperature. Alternatively, the same transformation can be accomplished as depicted in Step (VIII) of Scheme 1 using an acid chloride, derived from the appropriate organic carboxylic acid by well known methods, and a Lewis acid catalyst such as tin tetrachloride.

In general, the appropriate organic carboxylic acids needed for this reaction are known, commercially available, or readily prepared by those of ordinary skill in the art.

In the processes described herein for the preparation of compounds of the subject invention, requirements for protective groups on reactive moieties are well recognized by one skilled in the art of organic chemistry; accordingly, the use of appropriate protecting groups is included in the processes disclosed herein, even if not expressly depicted in all schemes and examples. Introduction and removal of such suitable protecting groups, for N, S and O, are disclosed, for example, in the following references: McOmie, "Protective Groups in Organic Chemistry", Advances in Organic Chemistry, Vol. 3 (1963), pp. 159-190; and Greene, P.G.M.

S• Wuts, Protecting Groups in Organic Synthesis, Wiley (New York), 1991.

The following non-limiting examples provide further information regarding synthesis of the subject compounds.

Example 1 1-(7-tert-Butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-4- S" cyclopropylbutan-1-one .9Do 0 •0 2.4-dibromo-6-tert-butvlphenol. In a 2 L 3-neck flask, equipped with Ar inlet, reflux condenser, addition funnel, and efficient magnetic stir bar, is placed 2-tert-butylphenol (150.2 g, 1.00 mol) and MeOH (300 mL). The stirred solution is cooled in an ice bath as neat Br2 (321.6 g, 2.01 mol, 2.01 eq) is added dropwise over 0.5 h (Caution: this reaction is exothermic.

Control with rate of addition.) The reaction is monitored by TLC (2% EtOAc/hexane), and is complete after 2 hrs. The reaction mixture is transfered to a 1 L beaker, along with a 20-mL rinse of the reaction flask.

The red solution solidifies rapidly to a bright orange crystalline mass. The crystalline mass is redissolved by heating over a steam bath, and then a solution of Na 2 S205 (1.45 g, 5.4 mmol) in 40 mL H 2 0 is added, followed immediately by fresh MeOH (60 mL). The resulting suspension is reheated on the steam bath for 10 min (the mixture does not redissolve), and then is vigorously stirred while allowing to cool to room temperature. After 0.5 h, practically all yellow color has vanished, and faint orange-white crystals are deposited. These are filtered and air dried to yield 2,4-dibromo-6-tertbutylphenol as faint orange-white platelets.

2,4-dibromo-6-tert-butylphenyl isobutenyl ether. In a 3000 mL 3-neck flask, equipped with Ar inlet and magnetic stirrer, is placed 2,4-dibromo-6tert-butylphenol (70.0 g, 226 mmol), K 2 C0 3 (37.6 g, 276 mmol, 1.2 eq), Nal (3.38 g, 22.6 mmol, 0.1 eq), p-methallyl chloride (33.9 mL, 339 mmol, eq), and acetone (1500 mL). The reaction mixture is vigorously stirred at 23°C for 56 hrs, and monitored by TLC analysis (pet. ether). The solids are removed by filtration, washed with acetone, and the filtrates rotoevaporated (bath temperature kept below 35"C) to give an oil. The oil is dissolved in hexane (100 mL), and stirred with silica gel (80 The slurry is filtered through a pad of Celite, and eluted with additional hexane (6 x 100 mL).

SThe filtrate is evaporated to give 2,4-dibromo-6-tert-butylphenyl isobutenyl ether as a yellow oil. The material is stored in the freezer and is used as soon as possible.

7-tert-butvl-3.3-dimethyl-2.3-dihydrobenzofbfuran. Anhydrous hypophosphorus acid (275 g, 4.16 mol) is prepared by azeotropically removing water from commercial 50% aqueous solution (550 g) using toluene (5 x 500 mL). Caution: perform behind a shatter-proof shield, since a sudden pressure increase occasionally occurs. In a 5000 mL 3-neck flask, equipped with Ar bubbler and submersed Ar inlet, reflux condenser, addition funnel, and magnetic stirrer is placed dioxane (3000 mL), 2,4dibromo-6-tert-butylphenyl isobutenyl ether (50.3 g, 0.14 mol), the anhydrous hypophosphorus acid (275 g, 4.16 mol) prepared above, and triethylamine (585 mL, 4.16 mol). An exotherm to 50C is apparent. The mixture is degassed by bubbling with Ar for 30 min, and then is maintained under an atmosphere of Ar A solution of azo-bis-isobutyrylnitrile (AIBN) mL of a 0.7 M solution in de-gassed dioxane) is added via the addition funnel. The stirred solution is brought to reflux. Every 0.5 h, an additional mL of the AIBN solution is added. The reaction is monitored by TLC for disappearance of starting material. After 3 h, further addition of AIBN is discontinued, the reaction is allowed to reflux an additional 14 h, and then is allowed to cool to 24 The reaction is twice extracted with a mixture of 13 brine (250 mL) and 1 N HCI (100 mL). The organic layer is dried over MgSO4, filtered, and evaporated to give a yellow oil admixed with a white solid. This is triturated with hexane (300 mL), and the insolubles are filtered off, rinsed with fresh hexane (50 mL), and discarded. The hexanes are evaporated to give a clear yellow oil. Distillation, followed by hydrogenation using 20% by weight of 10% Pd/C and 50 psi H 2 atmosphere in EtOH solution (0.6 g/mL) for 14 h results in complete dehalogenation to yield 7tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan.

4-cyclopropanebutan-1-ol. In a 500 mL 3-neck flask, equipped with Ar inlet, magnetic stirrer, reflux condensor, and septum, is placed 1-ol (25 g, 0.25 mol), diiodomethane, (25.2 mL, 83.8 g, 0.31 mol, 1.25 eq), and CH 2

CI

2 (150 mL). The solution is cooled in an ice bath, and neat AIMe 3 (Caution: extremely pyrophoric) (52 mL, 39.6 g, 0.55 mol, 2.2 eq) is added (Caution: strong exotherm and gas evolution) via canula over 20 min.

After 1 h at 0°C, the reaction mixture is warmed at 35*C for 14 h. The solution is cooled in an ice bath, and 1.5 N NaOH (1000 mL) is added gradually (Caution: violent exotherm), followed by H 2 0 (1000 mL). The mixture is extracted with CH 2

CI

2 (3x250 mL). The organic layers are dried (MgSO 4 filtered, and evaporated to a yellow oil. This 4cyclopropanebutan-1-ol is used in the next reaction without further purification.

4-cyclopropylbutanoic acid. Jones reagent is prepared by carefully adding H 2 S0 4 (321 mL) to a cold solution of Cr0 3 (366 g) in H 2 0 (600 mL) over a period of 0.5 h. In a 5-L 3-neck flask, equipped with mechanical 25 stirrer, interal thermometer, and 1-L addition funnel is placed a solution of 4-cyclopropylbutan-l-ol (127.0 g) in acetone (300 mL). Stirring is commenced, and the solution is cooled below -10*C with an ice/MeOH bath. The Jones reagent is added at a rate such that the temperature of the reaction mixture never exceeds 10'C. The reaction mixture becomes dark green and heterogenous. 300 mL of Jones reagent is added over 3.5 h and the reaction appears to be complete by TLC (hexane:EtOAc:HOAc, 3:1:0.05). An additional 50 mL Jones reagent is added, and the red color of the reagent persists. The reaction is quenched by the addition of isopropanol (80 mL), and the mixture is allowed to warm to 23*C. A small amount of green precipitate is filtered off, rinsed with acetone (3 x 200 mL), and discarded. The filtrate is evaporated to a biphasic mixture, poured onto 1.8 kg ice/water, and made alkaline to indicator paper with 50 wt% NaOH 14 (133 g) added in portions. The resulting green solution is filtered to remove a small amount of solids which are discarded. The filtrate is extracted with (2 x 40 mL), and the Et20 layers are dried and evaporated to yield 4cyclopropylbutyl 4-cyclopropylbutanoate. The aqueous layer is cooled in ice while it is acidified with 12 N HCI (139 The resulting solution is extracted with EtOAc (3 x 1 The aqueous layer is discarded. The organic phases are combined, dried over MgSO 4 filtered through paper and evaporated to yield 4-cyclopropylbutanoic acid as a faint green oil.

This can be further purified by filtration through Celite and distillation at reduced pressure (0.2 0.4 mbar, 60 1-( 7 -tert-butvl-3,3-dimethyl-2,3-dihydrobenzofblfuran-5yl)-4cvclopropylbutan-1-one. In a 50 mL 3-neck flask equipped with magnetic stir bar, Ar inlet, and septum inlet, is placed 3,3-dimethyl-2,3dihydrobenzo[b]furan (5.39 g, 26.4 mmol), 4-cyclopropylbutanoic acid (3.33 15 g, 26.4 mmol), and CH 2 Cl 2 (10 mL). The solution is cooled to -200C, and then trifluoroacetic anhydride (4.10 mL, 29.0 mmol) (freshly distilled) is added. After 7 h at this temperature, the reaction is allowed to warm to 25°C and quenched with H 2 0 (20 mL). The aqueous layer is extracted with fresh CH 2

CI

2 (3 x 20 mL) and discarded. The combined organic layers are dried (MgSO 4 filtered, and evaporated to a dark oil (9.05 g) which is purified by column chromatography over SiO 2 (200 g) using hexane and then 2% EtOAc in hexane as eluent, to provide 1-(7-tert-butyl-3,3-dimethyl- 2,3-dihydrobenzo[b]furan-5-yl)-4-cyclopropylbutan-1-one as a faint yellow oil.

25 Utilizing substantially the method of Example 1 (and making suitable substitutions for the appropriate carboxylic acid) the following subject compounds of Examples 2-12 are obtained.

Example 2 1-(7-tert-Butyl-3,3-dimethyl-2,3-dihydrobenzo(b]furan-5-yl)-ethan-1one ExaMDle 3 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-d ihydrobenzo(byfuran-5-yi cyclopropylmethanone Example 4 1 -(7-tert-B utyl 3-d imethylI-2, 3-d ihyd robenrzo~byfura n-5-yl methylpropan-1 -one Example 1 -(7-tert-Butyl-3,3-dimethyI-2, 3-dihydrobenzobyfuran-5-yI)-propan-1 one Example 6 1 (-etBtl33dm ty-,-ihdoeiobua i-ua 15 one Example 7 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-d ihydrobenizo[blfuran-5-yI )-pentan-1 0 one Examole 8 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-di hydrobertzo(b]furan-5-yI )-hexan-1 one Example 9 1 -(7-tert-Butyl-3, 3-dimethyl-2, cyciohexylmethanone 4 4. 4 .4 9 0*S a. a.

9 a 49 a a a.

*0494* 0 44..

44 .4 9 49 *9 9 9* *9 .4 *499 9 4* 4 49 .4 9 44 .4 Example 1 -(7-tert-Butyl-3, 3-dimethyl-2, cyclopentylmethanone Example 11 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzo~byfuran-5-yl methylcyclopropyimethanone 17 ExaMDle 12 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzo~b~furan-5-yl )-3-methyl- 2-buten-1 -one 0 0 Example 13 I -(7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzo~b~furan-5-yl )-3-chloro- 3-methyl-butan-1 -one 0 C1 0 A solution of 1 -(7-tert-butyl-3,3-dimethyl-2, yI)-3-methyl-2-buten-1 -one (Example 12) (2.0 g, 6.2 mmol) in HCI-saturated Et2O (30 mL) is stirred at 25*C overnight. The solution is treated with (20 mL), and partitioned against CH2CI2 (3 x 20 rnL). The combined organic layers are dried (MgSO4), filtered, and evaporated to a cream-colored solid which is crystallized from hexane to give 1-(7-tert-butyl-3,3-dimethyl-2,3dihydrobenzo[byfuran-5-yl)-3-chloro-3-methylbutan-l -one.

Example 14 *1 -(7-tert-Butyl-3, 3-d imethyl-2, 3-d ihyd robenrzo[b~fura n-5-y I)-3-hyd roxy- 3-methylbutan-1 -one 0 OH 0 A solution of 1 -(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b~furan-5 yl)-ethan-1-one (Example 2) (1.07 g, 4.3 mmol) in 0H2C12 (65 mL) is cooled to -78*C, and diisopropylethylamine (0.97 mL, 5.6 mmol) and trimethylsilyltriflate (1.08 mL, 5.6 mmol) are added sequentially via syringe.

The reaction is stirred at -78*C for 10 min and then is allowed to warm to 240C and is stirred at that temperature for 45 min. The solution is once again cooled to -78 0 C, and acetone (0.54 mL, 4.3 mmol) is added, followed by TiCI4 (1 M solution in CH2CI2, 4.3 mL, 4.3 mmol). After 1 h at -78"C, the 18 reaction mixture is allowed to warm to 24*C and evaporated. The residue is partioned between MeOH/1 N HCI and 0H2C12. The CH2CI2 layer is dried (MgSO4), filtered, evaporated, and chromatographed over SiO2 using EtOAc/hexane to yield 1 -(7-tert-butyl-3,3-dimethyl-2,3d ihydrobenzof byuran-5-yI )-3-hydroxy-3-methyf butan-1 -one.

Utilizing substantially the method of Example 14 (and making suitable substitution for the appropriate ketone) the subject compound of Example is obtained.

Example 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzo[b~furan-5-yl)-2-( 1hydroxycyclopentyl)-ethan-1 -one Example 16 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzo[b~furan-5-yl)-3-( N,Ndimethylamino)propen-1 -one 00 A solution of 1 -(7-tert-butyl-3, 3-dimethyl-2, yl)-ethan-1-one (Example 2) (1.54 g, 6.25 mmol) in dimethylformamide dimethylacetal (15 ml) is heated at reflux for 17 h. The reaction mixture is evaporated, and the yellow residue is crystallized from hexanes to give 1-(7tert-butyl-3, 3-dimethyl-2, 3-dihydrobenzo~byfuran-5-yl)-3-( N, Ndimethylamino)propen-1 -one.

19 Examole 17 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzof b]furan-5-yl mercapto-3-methylbutan-1 -one 0 SH 0 1 -(7-tert-butvl-3. 3-d imethy 1-2.,3-d ihyd robe nzof bfura n-5-vl)-3- (thiomethvl(4'-methoxvphenvl))-3-methvlbutan-1 -one. To a solution of 1 OV, ~~tert-butyl 3-d imethyl 3-d ihyd robe nzo (b]fu ran-5-yI)-3-methyl1-2-buten- 1 one (Example 12) (2.19 g, 7.6 mmol) in bernzene (70 ml-) is added piperidine (0.08 mL, 0.76 mmol), and 4-methoxybenzylthiol. The resulting yellow solution is allowed to stir for 56 hours, and then additional piperidine (0.08 mL, 0.76 mmol) is added; and stirring is continued an additional 17 h.

The solvent is evaporated, and the resulting oil is chromatographed over *SiO2 using hexane to yield 1-(7-tert-butyl-3,3-dimethyl-2,3- *15 dihydrobenzo~bjfuran-5-yl )-3-(thiomethyl- (4'-methoxyphenyl))-3-methylbutan-1 -one as a white solid.

1 -f 7-tert-butvl-3. 3-dimethvl-2. 3-d ihvdrobenzo~blfuran-5-vl mercapto-3-methylbutan-1 -one. In a Teflon hydrogen fluoride handling apparatus, equipped with stir bar and external cold bath, a solution of 1 *.20 tert-butyl-3,3-.dimethyl-2,3-dihydrobenzo(byfuran-5-yl)-3-(thiomethyl(4'methoxyphenyl))-3-methylbutan-1 -one (1.12 g, 2.5 mmol) in para-cresol ml) and para-thiocresol (2.5 ml-) is cooled to 0*C, and treated with neat hydrogen fluoride (approximately 50 ml) for 1 hour. The hydrogen fluoride is removed under vacuum. The resulting dark oil is applied to a column of SiO2 and eluted with hexane to remove dark-colored impurities. The resulting oil (972 mg) is chromatographed repeatedly on neutral alumina, and finally crystallized from EtOH to provide 1-(7-tert-butyl-3,3-dimethyl-2,3dihydrobenzo[byfuran-5-yl)-3-mercapto-3-methylbutan-1 -one as a white solid.

Example 18 1-(7-Cyclopentyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-4cyclopropylbutan-1 -one 0 0 2,4-dibromo-6-cyclopentylphenol. A solution of 2-cyclopentyl phenol (24 g, 149 mmol) in MeOH (50 mL) is cooled to 0OC, and Br2 (22.9 mL, 446 mmol) is added dropwise over 1 h. The reaction is allowed to warm to 24°C and stir for 72 h. Then H20 (50 mL) is added, and the MeOH is rotovaped off. The resulting mixture is extracted with CH2CI2 (3 x 50 mL). The organic layers are combined, dried (MgSO4), and evaporated to yield dark red oil, which is mixed with SiO2 (5 g) and hexane (30 mL), filtered, and once again evaporated to provide 2,4-dibromo-6-cyclopentylphenol suitably pure for the 15 next step.

2,4-dibromo-6-cyclooentyl isobutenyl ether. Substantially the method described in Example 1 is employed for the reaction between 2,4-dibromo- 6-cyclopentylphenol and 3-chloro-2-methylpropene, to provide 2,4-dibromo- 6-cyclopentyl isobutenyl ether as a colorless oil.

S.i 20 7-cyclopentvl-3,3-dimethvl-2.3-dihvdrobenzoblfuran. To a solution of 2,4-dibromo-6-cyclopentyl isobutenyl ether (37.9 g, 102 mmol) in dimethylformamide (1200 mL) is added palladium acetate (1.14 g, 5.1 mmol), and triphenylphosphine (1.34 g, 5.1 mmol) The mixture is deoxygenated by bubbling with N2 for 15 minutes, and is heated to 70"C. A deoxygenated solution of piperidine (0.34 M) and formic acid (0.26 M) in dimethylformamide is injected via syringe pump at a rate of 0.9 mL/min.

After 250 mL had been injected, the reaction is complete by GC analysis.

The reaction is allowed to stir under N2 at 70"C for 14 h. After cooling to 240C, the reaction is poured onto H20 (1500 mL) and extracted extensively with hexane (6 x 2000 mL). The aqueous dimethyfformamide layer is discarded, and the hexanes are concentrated and partitioned against 1 N NaOH (3 x 150 mL). The hexane layer is washed with H20 (150 mL), dried (MgSO4), filtered and evaporated to yield 7-cyclopentyl-3,3-dimethyl-2,3dihvdrobenzofblfuran as an oil.

21 1 -(7-cyclopentyl-3. 3-d imethyl-2.3-dihvdrobenzof blfuran-5-vl)-4cyclopropylbutan-1 -one. Substantially the method described in Example 1 is employed for the reaction between 7-cyclopentyl-3, 3-dimethyl-2, 3dihydrobenzo(b~furan and 4-cyclopropylbutanoic acid to provide 7cyclopentyl-3,3-dimethyl-2,3-dihydrobenzo[byfuran as a colorless oil.

Example 19 1 '-(7-tert- Butyl-2,3-d ihyd robe nzo (bjfu ran-5-yl)-pentan- 1 -one 0 1,.5-d ibromo-(2-bromoethoxy)-3-tert-butvl benzene. To a solution of 2,4-dibromo-6-tert-butylphenol (5.00 g, 16.2 mmol) in acetone (70 ml) is added 1,2-dibromoethane (2.80 mL, 32.5 mmol) and K2C03 (6.70 g, 48.7 mmol). The mixture is heated at reflux: for 14 h, and then is filtered and evaporated. The residue is purified by chromatography over SiO2 eluting with hexanes. The resulting oil is distilled to give 1,5-dibromo-(2bromoethoxy)-3-tert-butyl bernzene as a pale yellow 0oil.

:7-tert-butvl-2,3-dihvdrobenzofblfuran. A cold solution of 1 2-{2-bromoethoxy)-3-tert-butylbenzene (5.00 g, 12.05 mmol) in tetrahydrofuran/hexane (100 mLI2O mL) is cooled to -950C (MeOH/Et2O, :20 liquid N2). A solution of n-butyl lithium in hexane (12 mL, 30.1 mmol) is :added dropwise, and the reaction is allowed to stir for 0.5 h between and -800C. After 4 h, the reaction is poured onto saturated NH4CI, and extracted with ethylacetate. The organic layer is washed twice with and once with brine. The combined organic layers are dried (MgSO4), filtered, and evaporated. The resulting oil is purified by chromatography over SiO2 using hexanes. The resulting oil is distilled at reduced pressure to give 7-tert-butyl-2,3-dihydrobenzo[b~furan as a low melting white solid.

1 (-etbtl23-iyrbnobfua l-ua- -one.

Substantially the method described in Example 1 is employed for the reaction between 7-tert-butyl-2,3-dihydrobenzo(bfuran and pentanoic acid, to provide 1 -(7-tert-butyl-2, 3-dihydrobenzo~b~furan-5-yl)-butan-1 -one as a colorless oil.

Using substantially the method of Example 19, the compounds of Examples 20 through 23 are prepared by reaction of 7-tert-butyl-2,3dihydrobenzo(b]furan and the appropriate carboxylic acid.

Examole 1 -(7-tert-Butyl-2, 3-dihydrobenzo(b~furan-5-yi)-3-methyl-2-buten- 1-one Example 21 1 -(7-tert-Butyl-2, 3-dihydrobenzo[byfuran-5-yl)-4-cyclop ropylbutan-1 one Example 22 1 -(7-tert-Butyl-2, 3-dihydrobenzo~b]furan-5-yl)-2-methyipropan-1 -one 0 Example 23 1 -(7-tert-Butyl-2, 3-dihydrobenzof b]furan-5-y I)-propan-1 -one 23 Examole 24 1-(7-tert-Butyl-3, 3-dimethyl-2,3-dihydrobenzo(b]thiophen-5-yl )-butan- 1-one 0 2-bromo-6-tert-butylthiophenol. To a solution of freshly distilled tetramethylethylenediamine (7.5 mL, 50 mmol) in dry cyclohexane (35 mL) is added dropwise at 24*C a solution of n-butyl lithium in hexanes (31 mL, mmol). After addition is complete, the reaction mixture is cooled to 0*C.

A solution of 2-tert-butylthiophenol (3.77 g, 22.7 mmol) in dry cyclohexane mL) is added at a rate such that the reaction temperature stays below The reaction is allowed to stir at 240C for 14 h. A solution of sec-butyl lithium in hexanes (17.5 mL, 22.7 mmol) is added at this temperature, and the color of the reaction changes from yellow to orange. After 1 h, the reaction mixture is added at -78*C to a solution of 1,2dibromotetrafluoroethane (5.4 mL, 45.4 mmol) in dry tetrahydrofuran (100 mL). The mixture is allowed to warm to 24C, and is partitioned against 0.1 N HCI (100 mL). The organic phase is dried (MgSO4), filtered and evaporated to give 2-bromo-6-tert-butylthiophenol as a yellow oil.

20 2-bromo-6-tert-butlphenyl isobutenyl thioether. A mixture of 2bromo-6-tert-butylthiophenol (6.04 g, 22.7 mmol), K2C03 (3.76 g, 27.2 mmol), Nal (0.34 g, 2.27 mmol), and 3-chloro-2-methylpropene (2.3 mL, 22.7 mmol) in acetone (125 mL) is heated at reflux for 3 h. The reaction is allowed to cool to 24'C. The solids are filtered and discarded, and the filtrate is evaporated to a biphasic oil. The upper light colored layer is separated, taken up in hexane (50 mL), and treated with SiO2 (5 g).

Filtration and evaporation provides 2-bromo-6-tert-butylphenyl isobutenyl thioether as a yellow oil.

3,3-dimethyl-7-tert-butvl-2.,3-dihydrobenzorblthiophene. A solution of 2-bromo-6-tert-butylphenyl isobutenyl thioether (600 mg, 2.07 mmol), hypophosphorous acid (4.4 g, 60 mmol), and triethylamine (8.4 mL, mmol) in dioxane (30 mL) is deoxygenated by bubbling with N2 for 20 min.

The solution is then heated under N2 to reflux, and a solution of azo-bisisobutyrylnitrile (205 mg, 1.04 mmol) in deoxygenated dioxane (2 mL) is added in 0.2-mL portions over 3 h. The reaction is allowed to cool to 24-C, and 1 N HOI (40 mL) and brine (30 mnL) are added. The mixture is extracted with Et2O (3 x 50 mL), and the ethereal layers are back extracted with 1 N NaOH (40 mL). The organic phase is dried (MgSO4), filtered and evaporated to a yellow oil. Kugelrohr distillation provides 3,3-dimethyl-7tert-butyl-2, 3-dihydrobenzo[b]thiophene as a colorless oil.

1 47-tert-butvl-3, 3-dimethyl-2, 3-dihvdrobenzofblthiophen-5-vl)-buta8n- 1 -one. Substantially the method described in Example 1 is employed for the reaction between 7-tert-butyl-3, 3-dimethyl-2, 3-dihydrobenzo(b]thiophene and butanoic acid, to provide 1 -(7-tert-butyl-3,3-dimethyl-2,3dihydrobenzo(b]thiophen-5-yl)-butan-1 -one as a colorless oil.

Using substantially the method of Example 24, the compounds of Examples 25 and 26 are prepared by reaction of 7-tert-butyl-3,3-dimethyl- 2, 3-dihydrobenzofb]thiophene and the appropriate carboxylic acid.

Example 1 -(7-tert-Butyl-3, 3-dimethyl-2, pentan-1 -one

S

:20 Example 26 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzo~b]thiophen-5-yl)-4cyrlopropylbutan-1 -one Example 27 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzo[bfuran-5-y phenylmethanone Utilizing substantially the method of Example 1.

Examcole 28 1 3-Dimethyl-2, 3-dihydrobenzo[b]furan-5-y)-4-cyclopropylbutan-1 -one 0 0 Utilizing substantially the method of Example 1.

Example 29 1 3-Dimethyl-2, 3-dihydrobenzo~bjfuran-5-y)-3-hydroxy-3-methylbutan- 1one

H

0* Utliin susatal6h ehdo xml 4 06 0 A6 mitr6f1(-etbt133dmty-,-iyrbnobfrn 26 0 (020,19mo)i 0m fahdosaeoei etda elxfr2h betweenUtiliin suanwtall the methora ae sdid oe anampleo14 mansu sfaead ocnrte nvcu.Prfcainb lahclm choaogah onslc6e 1%ehlaett-ea ie .1go te ttle ompundinitallEasamyowis 30 hchuo toaei rergrtr6eaealih elw oi 6 6-3O) Examole 31 1 -(7-tert-Butyl-3, 3-dimethyl-2, 3-d ihydrobenzo b~furan-5-yl ethylthioethan-1 -one 0 N. SEt 0 1 -(7-tert-Butvl-3, 3-dimethyl-2. 3-dihvdrobenzofblfuran-5-vl)-2chloroethan-1 -one. A mixture of benzyltrimethylammonium dichloroiodate (18.18 g, 52.2 mmol), 1 -(7-tert-butyl-3, 3-dimethyl-2, 3-dihydrobenzofb~furan- 5-yl)-ethan-1-one (6.65 g, 27.0 mmol), 325 mL of 1,2-dichloroethane, and 130 mL of methanol is heated at reflux for 1.5 h. The reaction mixture is cooled to room temperature and concentrated in vacuo; 5% aqueous sodium bisulfite solution (126 ml-) is added to the residue obtained. .This mixture is extracted with ether and the extract is dried over anhydrous magnesium sulfate and concentrated to afford 8.38 g of the title compound as a reddish.solid.

1 -(7-tert-Butyl-3, 3-dimethyl-2. 3-dihvdrobenzofblfuran-5-vl)-2- .:ethylthioethan-1 -one. Sodium thicethoxide (0.54 g, 6.4 mmcl) is added in portions to a solution of 1 -(7-tert-butyl-3,3-dimethyl-2,3dihydrobenzo[b~furan-5-yl)-2-chloroethan-1 -one (1.12 g, 4.0 mmol) in 30 mL of methanol at room temperature. The reaction is stirred for 2.5 h, and concentrated in vacuo. The residue is dissolved in ether, washed with water and with brine, dried over anhydrous magnesium sulfate, and concentrated to give 1.12 g of the crude product Purification by flash column chromatography on silica gel ethyl acetate-hexane) afforded 0.72 g of the title compound as a light yellow oil.

Example 32 1 -7-tert-Butyl-3, 3-dimethyl-2, 3-dihydrobenzo[b~furan-5-yl)-3-thia-butan-1 one Utilizing substantially the method of Example 1.

Example 33 1-(7-tert-Butyl-3,3-diemthyl-2,3-dimethyl-23-dihydrobenzo[b}furan-5-yl)-3sulfinylbutan-1 -one 0 0 thiabutan-1-one (Example 32, 1.08g, 3.70 mmol) in 7.5 mL of CH2CI2 is cooled to 0 OC and m-chloroperbenzoic acid (826 mg, 4.07 mmol) is added.

SAfter stirring for 45 min, the reaction is poured into 15 mL of saturated *5 bicarbonate diluted with 15 mL of water and was extracted with CH2Cl2.

The combined extracts are dried with molecular sieves and evaporated.

The crude product is purified by column chromatography on silica with >50% EtOAc in hexane followed by 100% acetone. The resulting white solid was recrystallized from EtOAc/hexanes to provide 1-(7-tert-butyl-3,3- 10 dimethyl-2,3-dihydrobenzo(bofuran-5-yl)-3-sulfinylbutan-1-one .i 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/risk 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 to about 80%, and most preferably from about 40% to about In addition to the compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", 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 pharmaceuticallyacceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as comstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl 20 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; alginic acid; emulsifiers, such as the Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents, excipients; tableting 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 nonintravenously; the preferred pharmaceutically-acceptable carrier 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 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 of the subject compound, more preferably from about 0.5% to about also preferably from about 5 mg to about 1000 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, comprising a safe and effective amount of the compound, which is preferably from about 5 mg to about 3500 mg, more preferably from about 0. 10 mg to about 1000 mg, and most preferably from about 25 mg to about 600 mg.

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 20 polyethylene glycol, propylene glycol, ethanol, and polyoxyethylene castor oil.

Particularly preferred oral composition carriers 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.

Another aspect of the subject invention is methods for treating or preventing diseases characterized by inflammation by administering 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 rheumatoid arthritis, osteoarthritis, psoriatic arthritis, juvenile arthritis, Reiter's syndrome, infectious arthritis, and ankylosing 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 inflammation associated with gingivitis or periodontal disease); inflammation in the gastrointestinal tract, inflammation associated with ulcers and irritable bowel disease); inflammation associated with dermatological diseases psoriasis, acne, and other skin inflammation); inflammation associated with the respiratory tract asthma, bronchitis, and allergies); and inflammation in the central nervous system Alzheimer's disease).

Another aspect of the subject invention is methods for treating or preventing pain by administering 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 peripheral pain, menstrual pain, dental pain, and lower back pain.

Another aspect of the subject invention is methods for preventing 15 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 leukotriene synthesis, thereby decreasing neutrophil accumulation at an inflammatory site.

20 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 properties of the subject compounds are known.

Methods for determining acute gastrointestinal safety are disclosed and/or referred to in the following references: Unangst, G.P. Shrum, D.T. Connor, R.D. Dyer, and D.J. Schrier, "Novel 1,2,4-Oxadiazoles and 1,2,4-Thiadiazoles as Dual 5-Lipoxygenase 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 Antiinflammatory Drug N-(3-[3-(piperidinylmethyl)phenoxy] propyl}carbamoylmethylthio]ethyl 1-(p-chlorobenzoyl) 5-Methoxy-2methyl-3indolylacetate", Arzneim.-Forsch./Druq 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, C. Gentry, et al., "Antiinflammatory and Gastrointestinal Effects of Nabumetone or Its Active Metabolite, 6-Methoxy-2-naphthylacetic Acid (6MNA)", Dig. Dis. Sci., Vol. 37 (1992), pp. 1847-1852; and Wong, S.J. Lee, et al., "Antiarthritic Profile of BF-389 A Novel Anti-inflammatory Agent With Low Ulcerogenic Liability", Agents Actions, Vol. 37 (1992), pp. 90-91.

Methods for determining acute gastroprotection are disclosed and/or referred to in the following reference: Playford, D.A. Versey, S.

Haldane, M.R. Alison, and J. Calan, "Dose-dependent Effects of Fentanyl on Indometharin-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 or vehicle at 2 hours and immediately before administration of a gastric damaging dose of indomethacin. The rats are sacrificed 4 hours later by CO 2 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, dermatomucosally (for example, dermally, rectally and the like), and parenterally (for example, by subcutaneous injection, intramuscular Sinjection, 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, intraperitoneal, 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 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.

The following non-limiting examples illustrate the subject invention.

Example A A pharmaceutical composition in tablet form is prepared by conventional methods, such as mixing and direct compaction, formulated as follows: Ingredient Quantity (mq per tablet) 1-(7-tert-butyl-3,3-dimethyl- 200 2,3-dihydrobenzo[b]furan-5-yl)pentan-1-one Microcrystalline Cellulose 100 Sodium Starch Glycollate 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 suffering from osteoarthritis.

Example B A pharmaceutical composition in capsule form is prepared by conventional methods, formulated as follows: Ingredient Quantity (mg per capsule) 1-(7-tert-butyl-3,3-dimethyl- 200 2,3-dihydrobenzo[b]furan-5-yl)- 3-chloro-3-methyl-2 butan-1-one Lactose To fill to volume of capsule The above capsule administered orally once a day substantially reduces the symptoms 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 1-(7-tert-butyl-3,3-dimethyl- 200 mg 2,3-dihydrobenzo(b]furan-5-yl)cyclopropylbutan-1-one EtOH 4 ml Methyl cellulose 0.4 mg Distilled water 76 ml Tween 80 1.6 ml of the above composition administered perorally once a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthritis.

Example D A pharmaceutical composition in liquid form is prepared by conventional methods, formulated as follows: Ingredient Quantity Microcrystalline (micronoized) 200 mg 1-(7-tert-butyl-3,3-dimethyl- S2,3-dihydrobenzo[b}furan-5-yl)ethan-1-one Avicel (microcrystalline cellulose) 50 mg Tween 80 1.6 ml S. 20 Methyl cellulose 0.4 mg Deionized water 80 ml 100 ml of the above composition administered perorally twice a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthritis.

Example E An oral solid pharmaceutical composition is prepared by conventional methods, formulated as follows: Ingredient Quantity by weight) 1-(7-tert-Butyl-3,3-dimethyl- 2,3-dihydrobenzo[b]furan- 5-yl)-4-cyclopropylbutan-1 -one Pluronic F108 Tween 80 Example F An oral solid pharmaceutical composition is prepared by conventional methods, formulated as follows: Ingredient Quantity by weight) 1-(7-tert-Butyl-3,3-dimethyl- 2.3-dihydrobenzo(b]furan- 5-yl)-4-cyclopropylbutan-1 -one Triglycerides and derivatives Cremaphor EL While particular embodiments of the subject invention have been described, it would be obvious to those skilled in the art that various changes arid 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.

The term "comprises" and its grammatical equivalent such as "comprising" when used in the description and claims does not preclude the :addition of one or more other features, integers, steps or components or groups thereof.

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Claims (14)

1. A compound having the structure: Y Y 0 x Z wherein X is sulfur; each Y is independently hydrogen or unsubstituted straight, or branched alkyl or cycloalkyl having from 1 to 3 carbon atoms, or the two Y's are bonded to form a cycloalkyl ring having from 3 to 7 carbon atoms; Z is hydrogen or unsubstituted branched or cyclic alkyl, or unsubstituted or alkanyl-substituted phenyl, Z having from 3 to 10 atoms other than hydrogen; and W is straight, or branched alkyl or cycloalkyl or alkenyl or alkadienyl unsubstituted or substituted, cycloalkenyl, cycloalkadienyl; where no terminal carbon atom of W is part of a double bond, or aryl, W having from n 1 to 15 atoms other than hydrogen, wherein when both Y's are hydrogen, O Z is not hydrogen; wherein when both Y's are methyl and Z is hydrogen, r W is not methyl and when one Y is methyl and the other is hydrogen, W is not 2-(piperidine-1-yl)ethyl.

2. 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 hydrogen, unsubstituted C 4 -C 6 branched alkyl having 2 branches, unsubstituted C 4 -C 6 cycloalkyl, and unsubstituted phenyl.

3. The compound of claim 2 wherein both Y are methyl, and Z is selected from the hydrogen or t-butyl.

4. The compound of claim 3 wherein Z is t-butyl. The compound of claim 2 wherein W is C1-C6 straight or single- branched alkyl, or alkenyl with one double bond between non-terminal carbon atoms, or C3-C6 cycloalkyl or aryl, W is unsubstituted or monosubstituted with a substituent selected from the group consisting of halo, hydroxy, thiol, phenyl, heteroaryl and heterocyclyl; W having from 1 to 7 atoms other than hydrogen.

6. The compound of claim 5 wherein both Y are methyl, and Z is t-butyl.

7. The compound of claim 5 wherein the alkyl of W is substituted with one or more heteroatom selected from the group consisting of oxygen, sulfur, nitrogen or combinations thereof.

8. The compound of claim 2 wherein W is C1-C4 straight or single- branched alkyl, or alkenyl, with one double bond between the carbon atom bonded to the carbonyl carbon atom and an adjacent non-terminal carbon atom, unsubstituted or monosubstituted with a substituent selected from the group consisting of chloro, bromo, and hydroxy; or unsubstituted C3-C6 cycloalkanyl.

9. The compound of claim 8 wherein both Y are methyl, and Z is t-butyl. The compound of claim 2 wherein W is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, i-propyl, cyclopropyl, cyclopentyl, 2-cyclopropylpropyl, 2-chloro-2-methylpropyl, 2-hydroxy-2-methylpropyl, 2- methyl-1-propenyl, 2-thiabutyl, 2-thiapropyl, 2-sulfinylpropyl, and aceylthiomethyl.

11. The compound of claim 10 wherein both Y are methyl and Z is t-butyl. -The compound of claim 11 wherein W is 3-cyclopropylpropyl. m M^)'S 37

13. The compound of any one of claims 5, 8 and 10 wherein both Y are hydrogen.

14. A composition including a compound of any one of claims 1 to 12 and a pharmaceutically-acceptable carrier. A method of treating inflammation or pain, method including administration, to a human or lower animal in need of such treatment, of a safe and effective amount of a compound of any one of claims 1 to 12. S: 16. A method of treating arthritis, method including daily peroral administration, to a human in need of such treatment, of from 1 mg/kg to mg/kg of a compound of any one of claims 1 to 12.

17. A method of treating inflammation or pain, method including administration, to a human or lower animal in need of such treatment, of a safe and effective amount of a compound having the general formula: S. 0 Y v Y W Z i* z wherein X is sulfur; each Y is independently hydrogen or unsubstituted straight, or branched alkyl or cycloalkyl having from 1 to 3 carbon atoms, or the two Y's are bonded to form a cycloalkyl ring having from 3 to 7 carbon atoms; Z is hydrogen or unsubstituted branched or cyclic alkyl, or unsubstituted or alkanyl-substituted phenyl, Z having from 3 to 10 atoms other than hydrogen; and W is straight, or branched alkyl or cycloalkyl, or alkenyl or alkadienyl unsubstituted or substituted, cycloalkenyl, cycloalkadienyl; where no terminal carbon atom of W is part of a double bond or aryl, W having from 1 to 15 atoms other than hydrogen, where when both Y are hydrogen, Z is not hydrogen.

18. Use of a safe and effective amount of a compound of any one of claims 1 to 12 for the manufacture of a medicament to treat inflammation or pain in a human or lower animal in need of such treatment.

19. The compound of claim 1 as hereinbefore described with reference to the examples. DATED this 20 th day of January 2000 THE PROCTER AND GAMBLE COMPANY WATERMARK PATENT AND TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA S •a p. LCG:JGC:VRH P5003AU01.DOC .y O i( zl